Development Of Peritoneal Carcinomatosis Research Articles

Treatment of colon cancer using a novel approach comprising cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy and intraoperative radiation therapy.

e15573 Background: Approximately 10% of colon cancer (CCa) develop peritoneal carcinomatosis. Studies have found that the administration of hyperthermic intraoperative chemotherapy (HIPEC) during cytoreductive surgery (CRS) can reduce the risk of recurrence and development of peritoneal carcinomatosis (PC). Additionally, intraoperative radiotherapy (IORT) has been shown to effectively treat and blunt neoplasm growth. However, no reports of the impact of concurrent HIPEC and IORT in CRS on CCa are available. Methods: We retrospectively reviewed the medical records of CCa patients with PC who received HIPEC and IORT during CRS. Demographics, treatment details, PC indexes (PCI), completeness of cytoreduction scores (CCS), and operative complications were recorded. Subsequently, overall survival (OS) was defined as the time period from surgery until death or loss of follow-up, and recurrence-free survival (RFS) was defined as the period from surgery until recurrence or loss of follow-up. Univariate hazard ratios (HR) were used to check for prognostic factors. Results: 17 CCa patients were included in our analysis. Patient characteristics are summarized in Table 1. The pT staging was T0 in 1 (5.9%), T3 in 6 (35.3%), T4a in 4 (23.5%), and T4b in 6 (35.3%). The pN staging was N0 8 (47.1%), N1a in 4 (23.5%), N1b in 2 (11.8%), N1c in 2 (11.8%), and N2b in 1 (5.9%). Finally, the pM staging was M0 in 8 (47.1%), M1a in 4 (23.5%), M1b in 2 (11.8%), and M1c in 3 (16.4%). PCI was ≤6 in 13 (76.5%) patients. The CCS was 0-1 in all, but two, patients. 1 patient had a positive resection margin. 8 (47.1%) received cisplatin with mitomycin C during HIPEC, followed by mitomycin alone (29.4%), reduced doses of cisplatin + mitomycin C (17.6%), and a reduced dose of mitomycin C alone (5.9%). Reduced dosage was due to old age in 3 and renal impairment in 1 patient. There were no intraoperative complications or HIPEC-related adverse effects. Two patients received two doses of IORT. 4 (23.5%) patients had postoperative complications, of which two complications were Clavein-Dindo grade 4a. Recurrence occurred in 8 (47.1%) patients, and 4 (23.5%) patients passed away. The median OS was not reached, and the RFS was 19 months. PCI > 6 (HR: 12.6, 95% CI: 1.6-256.8) and postoperative complication of grade 4 (HR: 8.6, 95% CI: 1-73) were associated with poor OS. Only PCI > 6 was associated with poor RFS (HR: 10.4, 95% CI: 1.7-80.8). Conclusions: Postoperative complications in HIPEC+IORT during CRS are comparable to other accepted treatments for CCa. Large, double-arm studies are needed to compare the effectiveness of this treatment. [Table: see text]

Peritoneal carcinomatosis after partial nephrectomy for renal cell carcinoma: Our experience and literature review

ObjectivePeritoneal carcinomatosis associated with renal cell carcinoma is an infrequent entity, usually associated with large renal masses, and with a very rare presentation after surgery of localized renal tumors. Our objective is to review the literature and analyze the factors involved in the development of peritoneal carcinomatosis after laparoscopic partial nephrectomy in localized tumors. Material and methodsWe present our experience with two cases of peritoneal carcinomatosis after laparoscopic partial nephrectomy. We reviewed the literature and analyzed the factors associated with the development of peritoneal carcinomatosis after laparoscopic partial surgery in renal cell carcinoma. ResultsBetween 2005–2018, 225 patients underwent laparoscopic partial nephrectomy for localized renal neoplasia in our service. Two patients developed peritoneal carcinomatosis during follow-up, at 1.5 and 7 years after surgery. Few cases of postoperative peritoneal carcinomatosis for renal neoplasia have been described in the literature, being more frequently associated with large renal masses, with multiple metastases at diagnosis, with a poor prognosis. The dissemination of tumor cells during surgery, direct tumor extension or metastasis by hematogenous route, are among the factors involved in the development of this condition. ConclusionsPeritoneal carcinomatosis after laparoscopic partial nephrectomy constitutes a very rare event. However, it should be taken into consideration, and, since it is the only factor we can influence, we must maximize precautions during the surgical act, following oncological principles.

Carcinomatosis peritoneal tras nefrectomía parcial laparoscópica en carcinoma de células renales: nuestra experiencia y revisión de la literatura

ObjectivePeritoneal carcinomatosis associated with renal cell carcinoma is an infrequent entity, usually associated with large renal masses, and with a very rare presentation after surgery of localized renal tumors. Our objective is to review the literature and analyze the factors involved in the development of peritoneal carcinomatosis after laparoscopic partial nephrectomy in localized tumors. Material and methodsWe present our experience with two cases of peritoneal carcinomatosis after laparoscopic partial nephrectomy. We reviewed the literature and analyzed the factors associated with the development of peritoneal carcinomatosis after laparoscopic partial surgery in renal cell carcinoma. ResultsBetween 2005-2018, 225 patients underwent laparoscopic partial nephrectomy for localized renal neoplasia in our service. Two patients developed peritoneal carcinomatosis during follow-up, at 1.5 and 7 years after surgery. Few cases of postoperative peritoneal carcinomatosis for renal neoplasia have been described in the literature, being more frequently associated with large renal masses, with multiple metastases at diagnosis, with a poor prognosis. The dissemination of tumor cells during surgery, direct tumor extension or metastasis by hematogenous route, are among the factors involved in the development of this condition. ConclusionsPeritoneal carcinomatosis after laparoscopic partial nephrectomy constitutes a very rare event. However, it should be taken into consideration, and, since it is the only factor we can influence, we must maximize precautions during the surgical act, following oncological principles.

A comparative population-based analysis of peritoneal carcinomatosis in patients undergoing robotic-assisted and open radical cystectomy.

To compare the population-based incidence of peritoneal carcinomatosis following open (ORC) vs. robotic-assisted radical cystectomy (RARC). Using the Surveillance, Epidemiology and End Results Program (SEER)-Medicare linked data, we identified 1,621 patients who underwent radical cystectomy for bladder cancer during 2009 and 2014; 18.1% (n = 294) and 81.9% (n = 1327) underwent RARC and ORC, respectively. We subsequently evaluated the rates of peritoneal carcinomatosis at 6, 12, and 24 months following surgery. Multivariable proportional hazards regression was performed to determine factors associated with development of peritoneal carcinomatosis. Patients who underwent RARC vs. ORC were more likely to be male (p = 0.04); however, age at diagnosis, race, comorbidities, education, and marital status (all p > 0.05) did not differ by surgical approaches. Our findings showed that there were no significant differences in the rates of peritoneal carcinomatosis between ORC and RARC at 6, 12, and 24 months. In adjusted analyses, factors associated with peritoneal carcinomatosis were advanced N stage (N0 versus N2/3: HR 0.30, 95% CI 0.16-0.55, p < 0.01), preoperative hydronephrosis (HR 1.70, 95% CI 1.09-2.65, p = 0.04), higher T stage (T1 versus T4: HR 0.34, 95% CI 0.15-0.79, p < 0.01; T2 versus T4: HR 0.39, 95% CI 0.20-0.76, p < 0.01), and use of neoadjuvant chemotherapy (HR 1.78, 95% CI 1.11-2.84, p < 0.01). However, RARC was not associated with peritoneal carcinomatosis (HR 1.36, 95% CI 0.78-2.35). In this population-based analysis, we found no difference in peritoneal carcinomatosis between robotic or open approaches to radical cystectomy. These data should be reassuring to those utilizing robotic cystectomy.

Dual blockade of MET and VEGFR2 signaling pathways as a potential therapeutic maneuver for peritoneal carcinomatosis in scirrhous gastric cancer

Scirrhous gastric cancer frequently develops into peritoneal carcinomatosis with malignant ascites, leading to an extremely poor prognosis. We had demonstrated that paracrine hepatocyte growth factor (HGF)-induced MET activation promotes peritoneal carcinomatosis with ascites formation. The vascular endothelial growth factor (VEGF) receptor (VEGFR)/VEGF axis facilitates tumor progression and formation of malignant ascites. This study investigated the role of MET and VEGFR2 in the development of peritoneal carcinomatosis with malignant ascites. Cabozantinib is a dual inhibitor of MET and VEGFR2. We examined the effects of cabozantinib on MET- and VEGFR2-mediated progression of peritoneal carcinomatosis in human scirrhous gastric cancer in vitro and in vivo. Cabozantinib inhibited HGF-stimulated proliferation of scirrhous cancer cell lines NUGC4 and GCIY, with a high potential to generate peritoneal carcinomatosis with ascites fluid, as well as the constitutive proliferation of MKN45 cells with MET amplification. Cabozantinib also inhibited the phosphorylation of both MET and VEGFR2 in scirrhous cancer cells and HGF- or VEGF-stimulated HUVECs. It effectively reduced ascitic fluid and prolonged the survival of NUGC4-inoculated nude mice. In clinical specimens, malignant ascites fluid from patients with peritoneal carcinomatosis contained high levels of HGF and VEGF. Our results strongly suggest that MET- and VEGFR2-mediated signaling pathways play pivotal roles in the pathogenesis of peritoneal carcinomatosis in scirrhous gastric cancer. Thus, the dual blockade of MET and VEGFR2 signaling may be a potential therapeutic maneuver for peritoneal carcinomatosis in scirrhous gastric cancer.

Evaluation of the antitumour activity of local intraperitoneal hyperthermia in a model of advanced high-grade ovarian carcinoma in rats

In our study we carried out an exploratory assessment of the antitumor activity of hyperthermic intraperitoneal perfusion (Hipep) with 0.9 % sodium chloride solution and compared it with the effect of a single normothermic intraperitoneal (i.p.) Administration of cisplatin in the maximum tolerated dose (mtd). Thirty-six mature female Wistar rats with transplanted i.p. Syngeneic ovarian carcinoma were randomized into three groups: control group (2 ml of 0.9 % sodium chloride i.p. At room temperature, n=12); cisplatin group (cisplatin 4 mg/kg i.p. At room temperature, n=12); Hipep group (open i.p. Perfusion with 0.9 % sodium chloride solution at a temperature of 40,5–41,5 °c for 45 minutes, n=12). The primary endpoint was the overall survival (os) of the animals in each of the three groups. The total peritoneal cancer index (pci), weight and degree of ascites haemorrhagia were assessed at autopsy. The median os in the control group, Hipep, and cisplatin was 19, 39, and 40 days, respectively (log-rank test р&lt;0.0001). In comparison to the control group, the differences were statistically significant for both cisplatin (HR=0.22; 95 % ci: 0.08–0.62; log-rank test р&lt;0.0001) and Hipep (HR=0.32; 95 % ci 0.13–0.82; log-rank test р=0.0013). There were no differences in os between the cisplatin and Hipep groups (log-rank test р=0.4853). The Hipep procedure was associated with a significant decrease in total pci, a tendency towards a decrease in the ascites weight and a higher severity of haemorrhagia. In terms of os, local hyperthermia, provided by Hipep without a cytostatic drug, was comparable with single normothermic i.p. Administration of cisplatin in mtd and exceeded the effects of the latter in relation to the development of peritoneal carcinomatosis.

Degree of biliary tract violation during treatment of gallbladder adenocarcinoma is independently associated with development of peritoneal carcinomatosis.

Gallbladder cancer (GBC) is often incidentally diagnosed after cholecystectomy. Intra-operative biliary tract violations (BTV) have been recently associated with development of peritoneal disease (PD). The degree of BTV may be associated with PD risk, but has not been previously investigated. We reviewed patients with initially non-metastatic GBC treated at our institution from 2003 to 2018. Patients were grouped based on degree of BTV during their treatment: major (e.g., cholecystotomy with bile spillage, n = 27, 29%), minor (e.g., intra-operative cholangiogram, n = 18, 19%), and no violations (n = 48, 55%). Overall survival (OS) and peritoneal disease-free survival (PDFS) were evaluated with Kaplan-Meier and Cox proportional hazards modeling. Ninety-three patients were identified; the median age was 64 years (range 31-87 years). Seventy-six (82%) were incidentally diagnosed. The median follow-up was 23 months; 20 (22%) patients developed PD. The 3-year PDFS for patients with major, minor, and no BTV was 52%, 83%, and 98%, respectively (major vs. none: p < 0.001; minor vs. none: p < 0.01). BTV was not associated with 5-year OS (HR 1.53, p = 0.16). Increasing degree of BTV is associated with higher risk of peritoneal carcinomatosis in patients with GBC and should be considered during preoperative risk stratification. Reporting biliary tract violations during cholecystectomy is encouraged.

Use of serum and peritoneal CEA and CA19-9 in prediction of peritoneal dissemination and survival of gastric adenocarcinoma patients: are they prognostic factors?

Introduction To evaluate the impact of serum and peritoneal levels of tumour markers on peritoneal carcinomatosis and survival in gastric adenocarcinoma. Materials and methods Patients with gastric adenocarcinoma were evaluated with regard to serum and peritoneal carcinoembryonic antigen (CEA) and CA19-9. Numeric values and groupings based on serum and peritoneal cutoff values were used. Development of peritoneal carcinomatosis, including positive washing cytology, was regarded as main outcome. Gastric cancer outcomes as disease free and overall survival were analysed. Results There were 67 patients with a mean age of 60 ± 11 years. Positive peritoneal washing cytology was significantly associated with serum CA19-9 and high serum CA 19-9 group (P = 0.033 and P = 0.011, respectively). High peritoneal CEA was shown to be significantly associated with peritoneal carcinomatosis (P = 0.032). After a median follow up of 17 months, 48 patients (71.7%) were alive. Patients with peritoneal carcinomatosis showed significant poorer prognosis as shown by overall survival rate of 28.6%. Only serum CEA was significantly associated with lower disease free and overall survival (P = 0.002 and P = 0.001, respectively). Discussion and conclusion Serum CEA is shown to be significantly associated with poor prognosis for gastric cancer patients. Serum level of CA19-9 and high peritoneal CEA levels are significant predictors for positive peritoneal washing cytology and the development of peritoneal carcinomatosis, respectively. Therefore, the possible impact of serum and peritoneal tumor markers especially on the staging and prognosis of gastric cancer remains to be clarified by future studies.

Development of Peritoneal Carcinomatosis in Epithelial Ovarian Cancer: A Review.

Epithelial ovarian cancer (EOC) metastasizes intra-abdominally with often numerous, superficial, small-sized lesions. This so-called peritoneal carcinomatosis is difficult to treat, and peritoneal recurrences are frequently observed, leading to a poor prognosis. Underlying mechanisms of interactions between EOC and peritoneal cells are incompletely understood. This review summarizes and discusses the development of peritoneal carcinomatosis from a cell-biological perspective, focusing on characteristics of EOC and peritoneal cells. We aim to provide insight into how peritoneum facilitates tumor adhesion but limits size of lesions and depth of invasion. The development of peritoneal carcinomatosis is a multistep process that requires adaptations of EOC and peritoneal cells. Mechanisms that enable tumor adhesion and growth involve cadherin restructuring on EOC cells, integrin-mediated adhesion, and mesothelial evasion by mechanical forces driven by integrin-ligand interactions. Clinical trials targeting these mechanisms, however, showed only limited effects. Other factors that inhibit tumor growth and deep invasion are virtually unknown. Future studies are needed to elucidate the exact mechanisms that underlie the development and limited growth of peritoneal carcinomatosis. This review on development of peritoneal carcinomatosis of EOC summarizes the current knowledge and its limitations. Clarification of the stepwise process may inspire future research to investigate new treatment approaches of peritoneal carcinomatosis.

Abstract 4205: Development of peritoneal carcinomatosis by multicellular structures of high-grade serous ovarian cancer

Abstract Poor prognosis in more than 70% of ovarian cancer (OC) patients is tightly associated with: (i) advanced presentation at initial diagnosis with nests of solid tumors widely distributed on the surface of the serous membrane lining peritoneal organs and cavities; and (ii) accumulation of peritoneal malignant effusions (ascites), which carry cells gathered as multicellular structures (MCS). The biology of the solid growths adhered to the peritoneal wall and abdominal organs has been intensively investigated. In contrast, the role of the MCS living in suspension in the peritoneal fluid is less known. Herein, utilizing series of high-grade serous OC (HGSOC) cell lines developed from ascites of the same patients during different stages of disease progression, we provide evidence of an active role of the MCS in the pathobiology of OC. When cultured under adherent conditions, these HGSOC cells, in addition to forming cellular monolayers, develop areas in which the cells grow upwards forming densely-packed multilayers that ultimately detach from the bottom of the plate and live as free-floating MCS. The capacity to form foci and develop MCS increased along the progression of the disease as represented in the PEO1/PEO4/PEO6 series derived from a patient diagnosed with a poorly-differentiated disease, as well as in the PEO14/PEO23 pair, derived from a patient with highly-differentiated OC. When we compared cultures of PEO6 cells vs. PEO23 cells, we observed that both cellular entities gave rise to MCS with two morphological arrangements, one coral-like or irregular, and another more organized and spheroidal. To study whether these MCS are sufficient to generate peritoneal carcinomatosis we injected, into the peritoneal cavity of immunosuppressed female mice, a mixture of MCS obtained from a culture of PEO6 cells. Six-to-seven months after injection, the PEO6-derived MCS were sufficient to recreate discrete solid nodules in the omentum, liver, and lower pelvic cavity, with associated accumulation of abundant bloody peritoneal fluid. The ascites had also a high content of MCS resembling the phenotype of those originally injected. Using inverted confocal microscope we were able to determine that several, yet not all, floating MCS were hollow and contained a well-differentiated lumen. In addition, fluorescence microscopy demonstrated that the cells forming the MCS had replicative capacity and displayed cell-cell interactions mediated by the E-cadherin/beta-catenin complex. Collectively, we provide evidence that HGSOC cell lines: (i) develop MCS in suspension resembling those found in patient's ascites; and (ii) the MCS formed in culture retain the capacity to develop peritoneal carcinomatosis with both adherent (‘solid’) and non-adherent (‘floating’) components of the disease. Citation Format: Alicia A. Goyeneche, Rekha Srinivasan, Juan M. Valdez, Carlos M. Telleria. Development of peritoneal carcinomatosis by multicellular structures of high-grade serous ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4205. doi:10.1158/1538-7445.AM2015-4205

Predictive factors for survival and recurrence rate in patients with node-negative gastric cancer--a European single-centre experience.

Gastric cancer is a common disease with poor prognosis. Lymph node involvement is the strongest prognostic factor regarding survival in curatively (R0) resected patients. The aim of this study was to determine if a subgroup with higher risk for tumour recurrence exists in patients with node-negative gastric cancer. Furthermore, we aimed to identify prognostic factors and recurrence patterns for this subgroup. We collected demographical, clinical, pathohistological and follow-up data from 1,074 patients with gastric cancer in a prospectively maintained database. In 228 cases, R0 resections for node-negative gastric cancer were performed. The median follow-up period was 59 months. Statistical analysis was performed using SPSS 19.0. The 5- , 10- and 15-year overall survival was 83, 75.5 and 73 %, respectively, with a disease-free survival of 78, 73 and 73 %. Tumour recurrence was observed in 18.9 % (43 cases), 14 % of which were diagnosed after more than 5 years. Gender, T-category , lymphangioinvasion, tumour differentiation, serosal infiltration, histological growth pattern, tumour size and classification according to Lauren were significant prognostic factors for overall survival in univariate analysis. Multivariate analysis showed tumour size and female sex to be independent prognostic factors. Non-exophytic tumour growth was a relevant factor for the development of local recurrence. Diffuse type gastric cancers as well as signet ring cells were significantly associated with the development of peritoneal carcinomatosis, and male gender with hematogenous metastases. Multimodal treatment and individual follow-up might be beneficial in patients with higher risk of recurrence after R0 resection of node-negative gastric cancer.

New directions in perioperative management of locally advanced esophagogastric cancer.

Cancers of the esophagus arise as adenocarcinomas and squamous cell carcinomas; these represent distinct diseases, with differing prognosis, yet they are often studied in common trials. With surgery alone, 5 year survival for T2-T3N0 disease is less than 30% to 40%, and declines to less than 25% with nodal involvement. The CROSS randomly assigned patients to surgery alone or to weekly carboplatin/paclitaxel X 5 and 41.4 Gy concurrent radiotherapy, followed by surgery. Seventy-five percent of enrolled patients had adenocarcinoma. Preoperative combined-modality therapy improved R0 resection from 69% to 92% (p &lt; 0.001 and improved median survival from 24 months to 49.4 months (p &lt; 0.003). This regimen reduced both locoregional recurrence (34% to 14%; p &lt; 0.001) and the development of peritoneal carcinomatosis (14% to 4%; p &lt; 0.001). Systemic perioperative therapy may have a greater effect on distant disease, the predominant mode of failure for these patients, and current trials compare preoperative chemoradiation with periooperative systemic therapy. PET scan response during preoperative chemotherapy without radiotherapy correlates with improvements in pathologic response and with improved survival. Nonresponse on early PET scan allows identifıcation of patients for earlier surgery and discontinuation of ineffective preoperative chemotherapy, without survival detriment. There is no predictive benefıt for early PET scan during the course of chemotherapy followed by chemoradiotherapy. The use of early PET scan during induction chemotherapy is being evaluated in CALGB/Alliance trial (NCT01333033). Molecular profıling has identifıed somatic gene mutations and pathways that may be oncogenic in upper gastrointestinal cancers. Potential targets include the epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), HER2, mammalian target of rapamycin (mTOR), fıbroblast growth factor receptor (FGFR), MEK, and others. Targeted therapies with known survival benefit in esophagogastric cancer are currently limited to trastuzumab for HER2 overexpressing cancers, or ramicirumab.

DJ-1 is involved in the peritoneal metastasis of gastric cancer through activation of the Akt signaling pathway

Peritoneal metastasis is a major cause of death in patients with advanced gastric carcinoma. DJ-1 is now considered to play an important role in the metastasis of various malignancies. However, it remains largely unclear whether DJ-1 is involved in the development of peritoneal metastasis by gastric carcinoma. In the present study, we showed that the expression of DJ-1 was significantly upregulated in gastric cancer specimens with peritoneal metastasis compared to those without peritoneal metastasis. Knockdown of DJ-1 expression significantly inhibited invasion and migration, in vitro and the in vivo peritoneal metastatic abilities of SGC7901 gastric cancer cells. Moreover, knockdown of DJ-1 also diminished the expression of matrix metallopeptidase (MMP)-2 and MMP-9. All of these effects were reversed by restoration of DJ-1 expression. Following investigation of the pathway through which DJ-1 regulates cell invasion and migration, DJ-1 was found to cause phosphorylation of Akt in SGC7901 gastric cancer cells. Inhibition of the Akt pathway in SGC7901 cells mimicked the effects of DJ-1 knockdown on cell migration, invasion, MMP-2 and MMP-9 expression, and abolished the effects of DJ-1 in promoting SGC7901 cell invasion and migration. Taken together, the present study revealed that DJ-1 plays an important role in the development of peritoneal carcinomatosis from gastric carcinoma, at least partially through activation of the Akt pathway and consequent upregulation of MMP-2 and MMP-9 expression. Thus, DJ-1 may be a potential therapeutic target for peritoneal carcinomatosis of gastric carcinoma.

Therapeutics target of CXCR4 and its downstream in peritoneal carcinomatosis of gastric cancer

Patients with advanced gastric carcinoma, especially peritoneal dissemination, have a poor prognosis. Various treatments have been used for peritoneal dissemination of gastric cancer, but there is no effective therapy for this condition. At present, similar proprieties of chemokines between trafficking of leukocytes during immune and inflammatory reactions and organ selective migration of cancer cells during metastasis are widely recognized. In particular, chemokine CXCL12 and its receptors CXCR4 are now known to play an important role in cancer progression. Recently, we reported for the first time that CXCR4 and its ligand, CXCL12, were involved in the development of peritoneal carcinomatosis of gastric cancer, and additionally, clarified the molecular mechanisms of the cell signaling pathways by which gastric cancer develops metastatic ability via CXCR4 and mTOR. In this review, we focus on the biological functions of chemokine receptors, particularly CXCR4 expressed on gastric cancer cells, and the therapeutic strategies targeting CXCR4-mediating signaling pathways in peritoneal carcinomatosis.

Embolisation portale préopératoire par Amplatzer® Vascular Plugs (AVP) : 17 patients

The purpose was to determine the efficacy and technical particularities related to the use of Amplatzer® Vascular Plugs (AVP) for preoperative portal vein embolization. Between 2005 and 2009, a total of 48 type I AVP were embolized into the portal venous system of 17 patients (51–83years) prior to extended hepatic resection where the residual liver volume (RLV) was deemed sufficient (RLV < 35–40% in patients with underlying hepatocellular disease, < 25–30% in patients with normal liver). AVP were used alone in seven patients and combined to other embolization agents in 10 patients (coils: n=5, microparticles: n=1, resorbable gel foam: n=4). The procedure was technically successful in 100% of cases with immediate success rate of 94.1% (imcomplete embolization of a segmental branch of segment VIII). The procedure was well tolerated clinically in 94.1% of cases, and in 100% of cases based on laboratory values. The rate of recanalization on follow-up CT at 5weeks (2–22) was 11.7%. The rate of complications, major (left portal vein thrombosis following right portal vein embolization) and minor (one case of portovenous fistula), was 11.7%. The rate of RLV growth was from +13 to +285 cm3 (mean at +122 cm3), or +4.98 to +78.51% (mean at +33.3%) (hepatocellular carcinoma: mean of +30.7%, metastases: mean of +19.7%). The rate of surgical candicacy was 94.1% (two patients were excluded: insufficient growth of RLV, development of peritoneal carcinomatosis). AVP appear to be reliable and effective for the preoperative embolization of the portal vein, with low morbidity and sufficient growth of RLV.

The EGFR Ligands Amphiregulin and Heparin-Binding EGF-like Growth Factor Promote Peritoneal Carcinomatosis in CXCR4-Expressing Gastric Cancer

Peritoneal carcinomatosis, often associated with malignant ascites, is the most frequent cause of death in patients with advanced gastric cancer. We previously showed that the CXCR4/CXCL12 axis is involved in the development of peritoneal carcinomatosis from gastric cancer. Here, we investigated whether epidermal growth factor receptor (EGFR) ligands are also involved in the development of peritoneal carcinomatosis from gastric cancer. The functional involvement of expression of the ErbB family of receptors and/or EGFR ligands was examined in CXCR4-expressing human gastric cancer cells and fibroblasts, clinical samples (primary tumors and ascites), and an animal model. High concentration of the EGFR ligands amphiregulin and heparin-binding EGF-like growth factor (HB-EGF), as well as of CXCL12, were present in malignant ascites. Human gastric cancer cell lines and primary gastric tumors, with high potential to generate peritoneal carcinomatosis, expressed high levels of EGFR and CXCR4 mRNA and protein. Both amphiregulin and HB-EGF enhanced the proliferation, migration, and functional CXCR4 expression in highly CXCR4-expressing gastric cancer NUGC4 cells. Amphiregulin strongly enhanced the proliferation of NUGC4 cells, whereas HB-EGF markedly induced the migration of fibroblasts. Moreover, HB-EGF and CXCL12 together enhanced TNFα-converting enzyme (TACE)-dependent amphiregulin shedding from NUGC4 cells. In an experimental peritoneal carcinomatosis model in mice, cetuximab effectively reduced tumor growth and ascites formation. Our results strongly suggest that the EGFR ligands amphiregulin and HB-EGF play an important role, interacting with the CXCL12/CXCR4 axis, in the development of peritoneal carcinomatosis from gastric cancer, indicating that these two axes may be potential therapeutic targets for peritoneal carcinomatosis of gastric carcinoma.

Role of L1 cell adhesion molecule in gastric carcinoma.

56 Background: L1 cell adhesion molecule (L1) is a 200-220 kDa transmembrane glycoprotein of the immunoglobulin super family initially identified in neural cells. L1 was detected in ovarian cancer in a stage-dependent manner, was found exclusively in the invasion front of colorectal cancer, and has been considered a stem cell marker in glioma. The authors have shown that mRNA expression of L1 was a significant prognostic factor in gastric cancer (Kodera et al. Gastrointestinal Cancer Symposium 2009, abst 37). Its role in gastric cancer was further investigated. Methods: Expression of L1 was observed by immunostaining in 72 surgically resected pT4A-stage gastric cancer specimens. The association of L1 with peritoneal seeding and prognosis was elucidated. mRNA expression of L1-expressing gastric cancer cell line, KATO3, was suppressed using siRNA (KATO3 L1-). Microarray was used to indentify molecules that differ in expression between KATO3 L1- and the parental cell line. Results: L1 was scarcely stained in non-cancerous epithelial cells and intestinal metaplastic cells. L1 was detected mainly in the cell surface membrane of cancer cells in 15 of 72 specimens, more often in the intestinal type cancer. No correlation was found between L1 expression and detection of cancer cells in the peritoneal washes or development of peritoneal carcinomatosis. Nevertheless, the prognosis of L1-positive cancer was significantly inferior (p = 0.024). Prognosis was particularly poor among 6 cases where L1 was expressed in cancer cells at the invasive front (median survival time 149 days). Of 40,000 genes evaluated in the microarray, mRNA expression of 50 genes were amplified by &gt; 4-fold whereas the expression of 20 genes were attenuated to less than 1/4. Of these, expression of DYRK1A that induces apoptosis in conjunction with p53 was markedly suppressed to less than 1/8. Suppression of DYRK1A in the KATO3 L1- in comparison with the parental cell line was confirmed by RT-PCR. Conclusions: L1 affects prognosis of gastric cancer, particularly when it is expressed in cancer cells at the invasion front. Its role in the biology of gastric cancer has began to be elucidated. No significant financial relationships to disclose.

Evaluation of the combined expression of chemokine SDF-1α and its receptor CXCR4 as a marker for prognosis in gastric cancer.

10630 Background: Chemokine SDF-1α and its receptor CXCR4 have been shown to impact cancer progression. Accumulating evidence suggests that CXCR4 and SDF-1α expression is useful for evaluating the risk of gastric cancer progression. CXCR4 expression is associated with lymph node metastasis and development of peritoneal carcinomatosis in patients with gastric cancer, and SDF-1α expression in the primary cancer is reported to be an independent prognostic factor in these patients. Thus, combined analysis of SDF-1α and CXCR4 would have strong prognostic potential as a molecular marker for gastric cancer. Here we investigated for the first time the effects of combined CXCR4 and SDF-1α expression on the prognosis of patients with gastric cancer. Methods: We studied SDF-1α and CXCR4 protein expression in 221 specimens of primary gastric cancer using immunohistochemistry, and analyzed the clinicopathological features and clinical outcomes. Results: Patients were categorized into three groups according to CXCR4 and SDF-1α expression: high CXCR4/high SDF-1α, low CXCR4/low SDF-1α, and high CXCR4/low SDF-1α–low CXCR4/high SDF-1α. No significant differences existed in age, gender, histology, tumor location, lymphovascular invasion, or proportion of tumor size < 5 cm among the three groups. However, high CXCR4/high SDF-1α expression in tumor cells was significantly associated with invasion depth of the tumor (T status; p = 0.001), lymph node involvement (N status; p = 0.029), and higher tumor stage (p = 0.001) compared to tumors with low CXCR4/low SDF-1α expression or high CXCR4/low SDF-1α–low CXCR4/high SDF-1α expression. Furthermore, patients with high CXCR4/high SDF-1α expression had the worst prognosis (5-year survival rate 26.7%; median, 2.2 years; range, 0.8 - 3.6 years), whereas patients who had low CXCR4/low SDF-1α expression showed the most favorable prognosis (5-year survival rate, 57%; median, not reached; log-rank test, p = 0.01). Conclusions: CXCR4 and SDF-1α are useful prognostic factors in gastric cancer, and the combination of high CXCR4 protein expression with high SDF-1α expression suggests a dismal prognosis. No significant financial relationships to disclose.

Phosphoglycerate kinase 1 a promoting enzyme for peritoneal dissemination in gastric cancer

Peritoneal carcinomatosis is a frequent finding in gastric cancer associated with a poor prognosis. The features that enable gastric tumors to disseminate are poorly understood until now. Previously, we showed elevated mRNA levels of phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate-generating enzyme in the glycolytic pathway, the chemokine receptor 4 (CXCR4), the corresponding chemokine ligand 12 (CXCL12) and beta-catenin in specimens from gastric cancer patients with peritoneal carcinomatosis. In this study, the influence of PGK1 on CXCR4 and beta-catenin was assessed as well as the invasiveness of PGK1 overexpressing cancer cells. In this current study, we found that PGK1 regulates the expression of CXCR4 and beta-catenin at the mRNA and protein levels. On the other hand, CXCR4 regulates the expression of PGK1. Plasmid-mediated overexpression of PGK1 dramatically increased the invasiveness of gastric cancer cells. Interestingly, inhibition of CXCR4 in cells overexpressing PGK1 produced only a moderate reduction of invasiveness suggesting that, PGK1 itself has a critical role in tumor invasiveness. Immunohistochemistry in specimens from diffuse gastric cancer patients also revealed an overexpression of PGK1 in patients with development of peritoneal carcinomatosis. Therefore, PGK1 may be a crucial enzyme in peritoneal dissemination. Together these findings suggest that the enhanced expression of PGK1 and its signaling targets CXCR4 and beta-catenin in gastric cancer cells promote peritoneal carcinomatosis. Thus, PGK1 may serve as prognostic marker and/or be a potential therapeutic target to prevent dissemination of gastric carcinoma cells into the peritoneum.

Prevention of Peritoneal Carcinomatosis in Mice by Combining Hyperthermal Intraperitoneal Chemotherapy with the Water Extract from Burr Parsley (Caucalis platycarposL.)

The presence of peritoneal carcinomatosis arising from gastrointestinal and gynecologic tumors is associated with a poor prognosis. Animal models of peritoneal carcinomatosis are important in the evaluation of new treatment modalities. The purpose of this study was to investigate the effect of local chemoimmunotherapy and hyperthermal intraperitoneal chemotherapy (HIPEC) in an animal model of induced peritoneal carcinomatosis in the mouse. For induction of peritoneal carcinomatosis, cells from transplantable mammary carcinoma (MCa) were implanted intraperitoneally in CBA mice. Seven or 3 days before implantation of MCa cells (5 x 10 (3)) the mice were injected with lyophilized water extract from CAUCALIS PLATYCARPOS L. (CPL; 200 mg . kg (-1)) into the abdominal cavity. Immediately after implantation of MCa cells in the abdominal cavity, mice were treated two times with 2 mL of saline that was heated either at 37 degrees C or 43 degrees C (hyperthermal treatment) and cytostatics (doxorubicin 20 mg . kg (-1), cisplatin 10 mg . kg (-1), mitomycin 5 mg . kg (-1), 5-FU 150 mg . kg (-1)). We followed the survival of animals and the side effects appearing with different forms of treatment. CPL increased the life span of mice with peritoneal carcinomatosis without hyperthermal treatment (ILS% = 32.55 %) but showed no effect on the life span of mice with hyperthermal treatment (ILS% = 1.44). Combined treatment with CPL and cytostatics (CIS, DOX, and MIT) significantly affected the development of peritoneal carcinomatosis and increased the survival of mice (ILS% - 37 degrees C = 144.17, 415.46, and 124.13, ILS% - 43 degrees C = 311.42, 200.74, and 138.33, respectively). However, intraperitoneal chemotherapy with 5-FU alone resulted in greater survival time of mice than the treatment with 5-FU + CPL. Results suggest the synergistic effect of hyperthermia, chemotherapy, and immunotherapy. CPL significantly increases the antitumor activity of the hyperthermic chemotherapy and the survival rate of mice with peritoneal carcinomatosis. The stimulative effect of CPL on immunomodulation may be a possible mechanism which protects mice from developing peritoneal carcinomatosis and reduces the side effects of chemotherapy, increasing the life span of mice.