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Preliminary results of prophylactic HIPEC in patients with locally advanced gastric cancer
S40 through the haematic torrent or through the peritoneal cavity fluids. An important component of treatment failure is cancer dissemination within the peritoneal cavity and nodal metastasis. Intraperitoneal chemotherapy (IPC) gave a fundamental contribute in treating advanced GC. The purpose of the study is to investigate the effects of IPC in patients with advanced GC A meta-analysis of randomized trials was performed. Twenty prospective randomized trials have been included for a total of 2145 patients. 1152 into surgery þ IPC arm and 993 into control arm. 1, 2 and 3-years mortality rate were favorable to the surgery plus IPC arm (OR ¼ 0.31, 0.27, 0.29 respectively). 2 and 3 year mortality in patients with loco-regional nodal metastasis were favorable to the surgery plus IPC arm (OR¼ 0.28, 0.16 respectively). 1 and 2-year mortality rate in patients with serosal infiltration was favorable to the surgery plus IPC arm (OR ¼ 0.33, 0.27 respectively). The overall recurrence rate was favorable to the surgery plus IPC arm (OR ¼ 0.46). The peritoneal recurrence rate was favorable to the surgery plus IPC arm (OR ¼ 0.47). There were no statistically significant differences in lymph-nodal recurrence rate. The rate of haematogenous metastasis was favorable to the surgery plus IPC arm (OR ¼ 0.63). 2 and 3 year mortality rates in patients with nodal invasion are improved by the use of IPC. Loco-regional nodal invasion in patients affected by advanced GC is not a contraindication to IPC. 1, 2 and 3 year survival is incremented by IPC. No differences have been found at 5 years in survival rate. A positive effect of IPC has been found on distant metastasis. http://dx.doi.org/10.1016/j.ejso.2013.07.021
01 e Epigenetic modulation of adhesion and proliferation pathways by methionine deficiency attenuates potential for dissemination of gastric cancer L. Graziosi*, E. Marino, E. Cavazzoni, A. Donini University of Perugia, Perugia, Italy * Corresponding author. Graziosi L. University of Perugia, Perugia, Italy. E-mail address: [email protected] (L. Graziosi). Methionine deficiency is a feature unique to cancer cells, exhibited as inability to grow in a methionine depleted environment supplemented with homocysteine, the immediate precursor of methionine. Our aim is to investigate the effect of methionine deficiency in gastric cancer cells in vitro and in vivo. We have performed the experiments using human gastric cancer cell lines, moderate (MKN74) and poorly differentiated (MKN45 and KatoIII) cell lines. For in vivo experiments, model of peritoneal carcinomatosis (10 days) and xenograft model (for 65 days), the cells were injected intraperitoneally and subcutaneously, respectively, in NOD-SCID mice. For in vitro experiments we used a medium, with 10% of dialyzed bovine serum and compared the methionine-free but homocysteine-containing (Met-Hcyþ) medium with methionine-containing but Hcy-depleting (MetþHcy-) medium. In xenograft models, using MNK45 and MNK74 cells we evaluated, after randomization on day 20, 2 cycles of methionine deficient diet (from day 20 to 27 and from day 34 to 41) reduced the tumour growth drastically (50 % versus control diet; p<0.05) as observed until day 70. In the model of peritoneal carcinomatosis, after MNK45 cell injection, the mice received a cycle of methionine deficient diet for 10 days and we counted in control group 273.68 peritoneal nodules compared to 6.70.8 in methionine deprived group (p<0.05). The intraperitoneal injection of MNK74 cells precultured for 3 days in vitro with Met-Hcyþ medium abrogate the ability of tumour cells to induce peritoneal dissemination (p<0.05 versus MetþHcy- medium precultured group). In vitro the methionine deficiency for 3 days induced an inhibition of proliferation (70-80%) cellular apoptosis, an alteration of cell cycle distribution, an inhibition of cellular adhesion (30%) and migration (10%) compared
ABSTRACTS MetþHcy- medium group (p<0.05). Finally we observed, in vitro, that the methionine deficiency (3 days) abrogated and reduced (50%) the promoter methylation of E-Cadherin and secreted frizzled-related protein 2 two genes involved in the gastric cancer cell adhesion and proliferation, respectively Our experimental data suggest that a deficient methionine diet might affect neoplastic tumour growth by regulation of cell cycle, inducing apoptosis and decreasing cellular adhesion and migration. http://dx.doi.org/10.1016/j.ejso.2013.07.022
01 e Preliminary results of prophylactic HIPEC in patients with locally advanced gastric cancer L. Graziosi, E. Mingrone*, L.P. Evoli, V. Ciaccio, A. Donini University of Perugia, Perugia, Italy * Corresponding author. Mingrone E. University of Perugia, Perugia, Italy. E-mail address: [email protected] (E. Mingrone). The prognosis of locally advanced Gastric Cancer following surgical therapy alone is poor. Peritoneum represents a preferential site of dissemination in such neoplasm. Hyperthermic intraperitoneal chemotherapy (HIPEC) has been used in association with cytoreductive surgery (CRS) in the treatment of GC peritoneal carcinomatosis (PC). Aim of our preliminary experience is reporting our data on prophylactic HIPEC (P-HIPEC) in patients with GC at high risk of developing PC. Eleven patients underwent P-HIPEC at our General and Emergency Surgery Department. All the patients were affected by high risk GC: serosa invasive tumours (T4), conventional cytology-positive or quantitative PCR detection of CEA mRNA on peritoneal lavage. Seven subtotal and four total gastrectomies with D2 or D2þ were performed. All the anastomoses were made before HIPEC. The procedure was carried out for 60 minutes with Mitomycin C and Cisplatin in all patients. Post-operative monitoring in Intensive Care Unit at least for 24-48 hours. Gastric resection was guided on tumour location while the choice of performing a D2 or D2 þ lymphadenectomy was up to pre-operative imaging and intra-operative nodal status. No intra-operative complications were recorded. Median operation time was 398 minutes. In our series we recorded 20 adverse events. Only one patient with duodenal stump dehiscence and intra-abdominal sepsis (G4-G5) underwent re- operation and died for severe hemorrhagic pancreatitis. Per-operative mortality was 9%. Median hospital stay was 14 days. Median follow-up was 15.9 months. Median survival was 29.6 months and median DFS was 20 months. Peritoneal dissemination appears to be a strong determinant in defining GC patient prognosis. At present day there are not studies evaluating the role of P-HIPEC in patients at high risk of developing PC. The rationale of P-HIPEC is based on the concept that positive peritoneal lavage is considered an M1 (stage IV) similarly to macroscopic PC by the 7th TNM classification. We can conclude, although preliminary experience, that prophylactic HIPEC in locally advanced gastric cancer is feasible, increasing median survival compared to surgery alone. For sure this procedure need to be performed in the highly specialized centres strongly respecting the eligibility criteria. http://dx.doi.org/10.1016/j.ejso.2013.07.023
01 e The CCR5 antagonist maraviroc reduces the potential for gastric cancer dissemination in rodent models L. Graziosi*, P. Ricci, S. Fiorucci, A. Donini Universiy of Perugia, Perugia, Italy * Corresponding author. Graziosi L. University of Perugia, Perugia, Italy. E-mail address: [email protected] (L. Graziosi).
01 e Epigenetic modulation of adhesion and proliferation pathways by methionine deficiency attenuates potential for dissemination of gastric cancer L. Graziosi*, E. Marino, E. Cavazzoni, A. Donini University of Perugia, Perugia, Italy * Corresponding author. Graziosi L. University of Perugia, Perugia, Italy. E-mail address: [email protected] (L. Graziosi). Methionine deficiency is a feature unique to cancer cells, exhibited as inability to grow in a methionine depleted environment supplemented with homocysteine, the immediate precursor of methionine. Our aim is to investigate the effect of methionine deficiency in gastric cancer cells in vitro and in vivo. We have performed the experiments using human gastric cancer cell lines, moderate (MKN74) and poorly differentiated (MKN45 and KatoIII) cell lines. For in vivo experiments, model of peritoneal carcinomatosis (10 days) and xenograft model (for 65 days), the cells were injected intraperitoneally and subcutaneously, respectively, in NOD-SCID mice. For in vitro experiments we used a medium, with 10% of dialyzed bovine serum and compared the methionine-free but homocysteine-containing (Met-Hcyþ) medium with methionine-containing but Hcy-depleting (MetþHcy-) medium. In xenograft models, using MNK45 and MNK74 cells we evaluated, after randomization on day 20, 2 cycles of methionine deficient diet (from day 20 to 27 and from day 34 to 41) reduced the tumour growth drastically (50 % versus control diet; p<0.05) as observed until day 70. In the model of peritoneal carcinomatosis, after MNK45 cell injection, the mice received a cycle of methionine deficient diet for 10 days and we counted in control group 273.68 peritoneal nodules compared to 6.70.8 in methionine deprived group (p<0.05). The intraperitoneal injection of MNK74 cells precultured for 3 days in vitro with Met-Hcyþ medium abrogate the ability of tumour cells to induce peritoneal dissemination (p<0.05 versus MetþHcy- medium precultured group). In vitro the methionine deficiency for 3 days induced an inhibition of proliferation (70-80%) cellular apoptosis, an alteration of cell cycle distribution, an inhibition of cellular adhesion (30%) and migration (10%) compared
ABSTRACTS MetþHcy- medium group (p<0.05). Finally we observed, in vitro, that the methionine deficiency (3 days) abrogated and reduced (50%) the promoter methylation of E-Cadherin and secreted frizzled-related protein 2 two genes involved in the gastric cancer cell adhesion and proliferation, respectively Our experimental data suggest that a deficient methionine diet might affect neoplastic tumour growth by regulation of cell cycle, inducing apoptosis and decreasing cellular adhesion and migration. http://dx.doi.org/10.1016/j.ejso.2013.07.022
01 e Preliminary results of prophylactic HIPEC in patients with locally advanced gastric cancer L. Graziosi, E. Mingrone*, L.P. Evoli, V. Ciaccio, A. Donini University of Perugia, Perugia, Italy * Corresponding author. Mingrone E. University of Perugia, Perugia, Italy. E-mail address: [email protected] (E. Mingrone). The prognosis of locally advanced Gastric Cancer following surgical therapy alone is poor. Peritoneum represents a preferential site of dissemination in such neoplasm. Hyperthermic intraperitoneal chemotherapy (HIPEC) has been used in association with cytoreductive surgery (CRS) in the treatment of GC peritoneal carcinomatosis (PC). Aim of our preliminary experience is reporting our data on prophylactic HIPEC (P-HIPEC) in patients with GC at high risk of developing PC. Eleven patients underwent P-HIPEC at our General and Emergency Surgery Department. All the patients were affected by high risk GC: serosa invasive tumours (T4), conventional cytology-positive or quantitative PCR detection of CEA mRNA on peritoneal lavage. Seven subtotal and four total gastrectomies with D2 or D2þ were performed. All the anastomoses were made before HIPEC. The procedure was carried out for 60 minutes with Mitomycin C and Cisplatin in all patients. Post-operative monitoring in Intensive Care Unit at least for 24-48 hours. Gastric resection was guided on tumour location while the choice of performing a D2 or D2 þ lymphadenectomy was up to pre-operative imaging and intra-operative nodal status. No intra-operative complications were recorded. Median operation time was 398 minutes. In our series we recorded 20 adverse events. Only one patient with duodenal stump dehiscence and intra-abdominal sepsis (G4-G5) underwent re- operation and died for severe hemorrhagic pancreatitis. Per-operative mortality was 9%. Median hospital stay was 14 days. Median follow-up was 15.9 months. Median survival was 29.6 months and median DFS was 20 months. Peritoneal dissemination appears to be a strong determinant in defining GC patient prognosis. At present day there are not studies evaluating the role of P-HIPEC in patients at high risk of developing PC. The rationale of P-HIPEC is based on the concept that positive peritoneal lavage is considered an M1 (stage IV) similarly to macroscopic PC by the 7th TNM classification. We can conclude, although preliminary experience, that prophylactic HIPEC in locally advanced gastric cancer is feasible, increasing median survival compared to surgery alone. For sure this procedure need to be performed in the highly specialized centres strongly respecting the eligibility criteria. http://dx.doi.org/10.1016/j.ejso.2013.07.023
01 e The CCR5 antagonist maraviroc reduces the potential for gastric cancer dissemination in rodent models L. Graziosi*, P. Ricci, S. Fiorucci, A. Donini Universiy of Perugia, Perugia, Italy * Corresponding author. Graziosi L. University of Perugia, Perugia, Italy. E-mail address: [email protected] (L. Graziosi).