Peritoneal Metastatic Nodules Research Articles

The accuracy of whole-body 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the detection of ovarian cancer relapse in patients with rising cancer antigen 125 (CA-125) levels

Background18F-fluorodeoxyglucose (FDG) PET/CT is a noninvasive imaging tool that has been used successfully for the diagnosis, staging, restaging, therapy monitoring, and prognostic prediction of ovarian cancer. For ovarian cancer surveillance, rising CA-125 levels raise the suspicion of recurrence despite its reported low specificity; being elevated in other benign and inflammatory conditions, and thus, confirmation is required. This work aimed to evaluate the role of 18F-FDG PET/CT in suspected ovarian cancer recurrence in patients presenting with elevated CA-125 levels.ResultsFifty female patients with suspected ovarian cancer recurrence owing to elevated CA-125 levels were included in this study. Recurrence was confirmed in 46/50 cases whether by histopathological confirmation or by serial follow-up imaging and clinical follow-up. Positive PET/CT findings were reported in 45/50 cases with 2 false-negative cases and 1 false-positive case. PET/CT examination was found to be superior to contrast-enhanced CT in the detection of peritoneal metastatic nodules and metastatic lymph nodes. According to this study, the estimated sensitivity, specificity, and overall diagnostic accuracy of PET/CT in the detection of recurrent ovarian cancer were 95.6%, 75%, and 94%, respectively.ConclusionsIn ovarian cancer surveillance, 18F-FDG PET/CT was found to be a sensitive and accurate noninvasive imaging tool that can be used in the detection of recurrent ovarian cancer in patients with elevated CA-125 levels, thus interfering with the management plan. The advantage of whole-body imaging in PET/CT allows for the detection and precise localization of recurrent or metastatic foci in abdominal and extra-abdominal sites as well.

HSF-1/miR-145-5p transcriptional axis enhances hyperthermic intraperitoneal chemotherapy efficacy on peritoneal ovarian carcinosis

Hyperthermic intraperitoneal administration of chemotherapy (HIPEC) increases local drug concentrations and reduces systemic side effects associated with prolonged adjuvant intraperitoneal exposure in patients affected by either peritoneal malignancies or metastatic diseases originating from gastric, colon, kidney, and ovarian primary tumors. Mechanistically, the anticancer effects of HIPEC have been poorly explored. Herein we documented that HIPEC treatment promoted miR-145-5p expression paired with a significant downregulation of its oncogenic target genes c-MYC, EGFR, OCT4, and MUC1 in a pilot cohort of patients with ovarian peritoneal metastatic lesions. RNA sequencing analyses of ovarian peritoneal metastatic nodules from HIPEC treated patients unveils HSF-1 as a transcriptional regulator factor of miR-145-5p expression. Notably, either depletion of HSF-1 expression or chemical inhibition of its transcriptional activity impaired miR-145-5p tumor suppressor activity and the response to cisplatin in ovarian cancer cell lines incubated at 42 °C. In aggregate, our findings highlight a novel transcriptional network involving HSF-1, miR145-5p, MYC, EGFR, MUC1, and OCT4 whose proper activity contributes to HIPEC anticancer efficacy in the treatment of ovarian metastatic peritoneal lesions.

Neoadjuvant intraperitoneal chemotherapy for advanced stage gastric cancer (Review).

Gastric cancer remains one of the most lethal malignancies especially when diagnosed in advanced stages of the disease; most often patients diagnosed later during the progression of their disease will present a certain degree of peritoneal contamination such as positive peritoneal cytology or peritoneal metastatic nodules. In such cases most often they then progress to peritoneal carcinomatosis and succumb to the disease within one year. In order to increase the lifespan in such cases multiple therapeutic strategies have been proposed such as radical surgery and intraperitoneal heated chemotherapy or direct intraperitoneal chemotherapy followed by radical surgery. To date, the benefits of intraperitoneal heated chemotherapy at the time of resection have been widely investigated; however the method is still associated with increased rates of perioperative complications. Therefore, attention was focused on investigating the benefits of such procedures as neoadjuvant therapies followed by radical surgery. The aim of the present review was to examine the most efficient therapeutic strategies in advanced-stage gastric cancer such as neoadjuvant laparoscopic heated intraperitoneal chemotherapy, perioperative heated intraperitoneal chemotherapy and neoadjuvant systemic and peritoneal chemotherapy.

Correlation between CT and operative findings in pancreatic cancers and role of pre-operative CA19-9 values in predicting metastatic disease

Background: Pancreatic cancers carry a poor prognosis with 20-30% of cases found resectable on MDCT (Multi-detector CT). 60-91% of these lesions are actually found resectable during surgery. CA 19-9 is an extensively studied tumour marker in pancreatic cancers and its abnormally high value may point towards metastatic disease.Methods: A study was conducted in a tertiary care centre in which all patients of pancreatic cancers found resectable on imaging were subjected to surgery after staging laparoscopy to find metastatic disease missed on MDCT, the findings were noted and correlated with the radiological findings. Also, pre-operative CA 19-9 levels were analysed to predict metastatic disease in patients with high CA 19-9 values.Results: The study included 34 patients of pancreatic cancers deemed resectable on imaging. Out of these, four (11.7%) patients were found to be unresectable on staging laparoscopy in the form of subcentimetric liver/peritoneal metastasis. It was also found that preoperative CA 19-9 levels were higher in patients found to be metastatic. By using ROC curve, it was found that pre-operative values of CA 19-9 had 100% sensitivity and 80% specificity at the cut off level >106.75 U/ml.Conclusions: MDCT fails to identify some unresectable diseases because of presence of distant metastasis in the form of liver and peritoneal metastatic nodules and malignant ascites. Staging laparoscopy prior to laparotomy is a useful procedure which prevents unwanted laparotomy in some cases of metastatic pancreatic cancer not identified on imaging. Abnormally high values of CA 19-9 may point towards metastatic disease.

Strategies of chemotherapy for peritoneal metastasis of gastrointestinal cancer

Peritoneal metastasis of gastrointestinal cancer is an independent factor that seriously affects the prognosis of patients. The "seed-soil" theory is considered to be the main theory to explain peritoneal metastasis. Because of the small size of peritoneal metastatic nodules at the initial stage, early diagnosis is particularly difficult, therefore, the risk assessment of peritoneal metastasis is very important. Recently, the diagnosis methods have gradually developed from clinicopathological factors to cytology and molecular level. In addition, the integrated assessment of multiple groups including radiomics further enriches the accurate diagnosis of peritoneal metastasis. Peritoneal metastasis is a big challenge in the treatment of gastrointestinal cancer which may also lead to refractory malignant ascites, intestinal obstruction, cachexia and other related complications. At present, the treatment is based on systemic chemotherapy. The combination of surgery, intraperitoneal chemotherapy and HIPEC is an effective treatment for peritoneal metastasis of gastrointestinal cancer. How to enrich peritoneal metastasis patients with potential benefits, how to determine the timing of conversion surgery, how to further optimize the existing treatment plan, especially how to formulate treatment plan for patients after conversion surgery, call for improved study design and prospective randomized controlled trials. The goal of continuous efforts is to effectively prolong the survival of gastrointestinal cancer trials patients with peritoneal metastasis.

1. Modeling ovarian cancer for dendritic cells‐derived exosomes treatment

Ovarian cancer (OC) is the fifth leading cause of death from cancer among women in the United States and high‐grade serous carcinoma (HGSC) is the most common subtype. Patients often present metastatic disease with ascites buildup, which further complicates the treatment landscape. Although immunotherapy is a promising cancer treatment method, it fails to have an impact on HGSC patients due to the immunosuppressive and heterogeneous micro‐environment and impaired lymphatic drainage created by cancer cells within the peritoneal cavity. We are interested in boosting the anti‐tumor immunity by employing exosomes derived from dendritic cells (DC)‐based vaccines (Dex) for their capacity of overcoming the transport barriers, bypassing the immunosuppressive environment, prompting T cell infiltration in target organs, and activating them. Dex were collected and characterized in terms of yield, size distribution, and their biomolecular features as compared to parental cells, proving the expression of MHC‐II and co‐stimulatory markers (CD80 and CD86). When DC were pulsed with tumor antigen lysates from an ovalbumin‐overexpressing cancer cell line (ID8‐OVA), Dex presented OVA on their surface and activated the proliferation of OVA‐specific T cells (OT‐I). Intra‐peritoneal injection of Dex into a metastatic OC mouse model revealed a preferential accumulation within the peritoneal metastatic nodules, in tumors and in the liver. Preliminary data suggest Dex as a potential complement to the standard of care treatments for metastatic OC. We are currently testing their ability to induce an anti‐tumor immune response and increase survival when coupled with standard chemotherapeutics, with the potential of being effective in several metastatic diseases with peritoneal invasion.

1-calcium phosphate-uracil inhibits intraperitoneal metastasis by suppressing FAK in epithelial ovarian cancer

ABSTRACT The high mortality of epithelial ovarian cancer (EOC) is primarily due to vast intraperitoneal dissemination. 1-calcium phosphate-uracil (1-CP-U) has previously shown the function of inhibiting migration and invasion in multiple tumor cell lines. In this study, we further assessed the possible role of 1-CP-U in suppressing the peritoneal metastasis of EOC cells. First, we demonstrated that 1-CP-U had an inhibitory effect on EOC cells in cell-matrix adhesion, migration and invasion assay in vitro. Within the in vivo model, animals were intraperitoneally inoculated with SKOV3-Luc cells and then 1-CP-U intraperitoneal (i.p.) injection was performed every 5 d for a total of 3 wk. At the 7th d, omenta from each group were analyzed with luciferase activity and bioluminescence imaging assay, which showed a significant reduction of luciferase activity in the omenta from 1-CP-U group. In addition, the rest mice continued treatment and consistent detection of bioluminescence imaging. The data indicated that intraperitoneal metastatic nodules were less-developed in 1-CP-U group. Peritoneal metastatic tumor nodules were detected for immunofluorescent staining, which showed a reduction in FAK and p-FAK staining with 1-CP-U treatment group. Meanwhile, expressions of FAK and its downstream signaling were detected by western blot in tumor tissues and EOC cell lines, which showed significant decreases in the 1-CP-U treatment group. In conclusion, 1-CP-U had a profound inhibitory effect on adhesion, invasion and metastasis of EOC in vitro and suppressed intraperitoneal dissemination and cancer growth in vivo assay, which was associated with inhibition on the FAK pathway.

Intraperitoneal Administration of Plasma-Activated Medium: Proposal of a Novel Treatment Option for Peritoneal Metastasis From Gastric Cancer.

The administration of fluid irradiated with non-equilibrium atmospheric pressure plasma (NEAPP) has attracted much interest as a novel therapeutic method for cancer. The authors previously reported on the efficacy of plasma-activated medium (PAM) for treating cancer cell lines through the induction of apoptosis. In this study, the therapeutic effect of PAM was evaluated in vivo using a peritoneal metastasis mouse model. Two gastric cancer cell lines were used in proliferation assays performed to optimize the production of PAM by changing the distance between the plasma source and the medium surface and by altering the volume of irradiated medium. Wound-healing and adhesion assays were conducted to determine the effect of PAM therapy on cell migration and adhesion capacity in vitro. Finally, a mouse model established by the intraperitoneal injection of enhanced green fluorescent protein-tagged gastric cancer cells was used to explore the efficacy of PAM administered intraperitoneally in inhibiting peritoneal metastasis formation. Shorter distances between the plasma source and the medium surface and smaller volumes of treated medium increased the anti-tumor effect of PAM. The PAM treatment attenuated gastric cancer cell migration and adhesion in vitro. The intraperitoneal administration of PAM decreased the formation of peritoneal metastatic nodules by 60% in the mouse model, and no adverse events were observed. Plasma-activated liquids may represent a novel therapeutic method for the treatment of peritoneal metastases in gastric cancer.

A Bottleneck in Understanding Metastatic Cancer Stem Cell of Peritoneal Seeding from Gastric Cancer: A Null Result in Brief.

The capture of peritoneal metastatic cancer stem cell of human gastric cancer (pMCSC-hGC) is important to further understand the mechanism of peritoneal metastasis in gastric cancer patients. Previously, cancer stem cells (CSCs) of gastric and rectal cancers were captured and identified. However, the bottleneck of capturing pMCSC-hGC may be the scarce surgical specimen and limited volume of peritoneal metastatic lesions from gastric cancer. Only 5.2% of patients were diagnosed of unpredictive peritoneal seeding intraoperatively, while none cell sphere were successfully formed through the identical culture approach based on peritoneal metastatic nodules. The attempt to enrich and capture pMCSC of transplanted gastric cancer (pMCSC-tGC) in immunodeficiency mice model through intraperitoneal injection of CSC-hGC may be a considerable and feasible alteration.

Ovarian Carcinosarcoma and Its Association with Mature Cystic Teratoma and Primary Tubal Carcinoma.

Introduction. Carcinosarcoma is an uncommon form of ovarian cancers, classified as being part of the group of mixed epithelial and mesenchymal tumors. The occurrence of carcinosarcoma in association with a mature cystic teratoma and synchronous tubal carcinoma is very rare. Case Report. A 69-year-old woman presented with a pelvic mass. An abdominal computerized tomographic scan detected a 15 cm right pelvic mass which was suggestive of malignant transformation of a dermoid cyst. Intraoperative, bilateral ovarian masses (left 10 cm and right 12 cm) with diffuse peritoneal metastatic nodules were identified. Histologically, the left ovarian mass was composed of 2 components including carcinosarcoma and mature cystic teratoma, whereas the right ovarian mass represented a mature cystic teratoma with serosal surface involvement of high-grade serous adenocarcinoma. The left fallopian tube was macroscopically unremarkable but contained a 5.0 mm focus of high-grade serous adenocarcinoma in the distal part, with adjacent serous tubal intraepithelial carcinoma. Conclusion. As the fallopian tube has recently been proposed to be an origin for a majority of pelvic or ovarian high-grade serous adenocarcinomas, tubal carcinoma may be the origin for ovarian carcinosarcomas through an epithelial-mesenchymal transition. The coexistence of ovarian carcinosarcoma and teratoma in the present case should represent a collision tumor.

ZnPPIX inhibits peritoneal metastasis of gastric cancer via its antiangiogenic activity

Our previous study suggests that heme oxygenase-1 (HO-1) may play an important role in the metastasis of gastric cancer. Zinc protoporphyrin IX (ZnPPIX) is a special HO-1 inhibitor that inhibits the angiogenesis of pancreatic and lung cancer. In this study, we employed ZnPPIX to investigate the role of HO-1 in peritoneal metastasis of gastric cancer (PMGC) and explored the potential mechanism. We established animal model of PMGC by orthotopic implantation into nude mice of human gastric cancer cell line GC9811-P with high peritoneal metastasis potential. The mice were injected intraperitoneally with saline, CTX or ZnPPIX. Tumor microvessel density (MVD) in peritoneal metastatic nodules was determined by immunohistochemistry, and vascular endothelial growth factor (VEGF) level was determined by ELISA. We found that the number, volume, weight of peritoneal metastatic nodules and volume of seroperitoneum in ZnPPIX (4mg/kg) group decreased remarkably compared with control group. MVD value and VEGF level of peritoneal metastatic tumor in ZnPPIX (4mg/kg) group also decreased significantly, while the survival rate and survival time of the mice were higher than control group. ZnPPIX dose-dependently suppressed VEGF and GC9811-P induced angiogenesis. Furthermore, ZnPPIX suppressed VEGF induced reactive oxygen species production and ERK phosphorylation in human umbilical vein endothelial cells. In conclusion, our results suggest that HO-1 plays an important role in PMGC and ZnPPIX is an effective antitumor and antiangiogenic agent for PMGC.

Breakthrough therapy for peritoneal carcinomatosis of gastric cancer: Intraperitoneal chemotherapy with taxanes.

The effect of chemotherapy on peritoneal carcinomatosis (PC) of gastric cancer remains unclear. Recently, the intraperitoneal (IP) administration of taxanes [e.g., paclitaxel (PTX) and docetaxel (DOC)] during the perioperative period has shown promising results. Herein, we summarized the rationale and methodology for using IP chemotherapy with taxanes and reviewed the clinical results. IP administered taxanes remain in the IP space at an extremely high concentration for 48-72 h. The drug directly infiltrates peritoneal metastatic nodules from the surface and then produces antitumor effects, making it ideal for IP chemotherapy. There are two types of perioperative IP chemotherapy with taxanes: neoadjuvant intraperitoneal and systemic chemotherapy and sequential perioperative intraperitoneal chemotherapy (SPIC). In SPIC, patients receive neoadjuvant IP chemotherapy and the same regimen of IP chemotherapy after cytoreductive surgery (CRS) until disease progression. Usually, a taxane dissolved in 500-1000 mL of saline at ordinary temperature is administered through an IP access port on an outpatient basis. According to phase I studies, the recommended doses (RD) are as follows: IP DOC, 45-60 mg/m(2); IP PTX [without intravenous (IV) PTX], 80 mg/m(2); and IP PTX (with IV PTX), 20 mg/m(2). Phase II studies have reported a median survival time of 14.4-24.6 mo with a 1-year overall survival of 67%-78%. A phase III study comparing S-1 in combination with IP and IV PTX to S-1 with IV cisplatin started in 2011. The prognosis of patients who underwent CRS was better than that of those who did not; however, this was partly due to selection bias. Although several phase II studies have shown promising results, a randomized controlled study is needed to validate the effectiveness of IP chemotherapy with taxanes for PC of gastric cancer.

Research on the efficacy of Celastrus Orbiculatus in suppressing TGF-β1-induced epithelial-mesenchymal transition by inhibiting HSP27 and TNF-α-induced NF-κ B/Snail signaling pathway in human gastric adenocarcinoma.

BackgroundCelastrus orbiculatus has been used as a folk medicine in China for the treatment of many diseases. In the laboratory, the ethyl acetate extract of Celastrus orbiculatus (COE) displays a wide range of anticancer functions. However, the inhibition of the metastasis mechanism of COE in gastric cancer cells has not been investigated so far.MethodsThe present study was undertaken to determine if the anti-metastasis effect of COE was involved in inhibiting of epithelial–mesenchymal transition (EMT) of human gastric adenocarcinoma SGC-7901 cells. In vitro, a well-established experimental EMT model involving transforming growth factor β1 (TGF-β1) was applied. Viability, invasion and migration, protein and mRNA expression of tumor cells were analyzed by MTT assay, transwell assay, western blot and real-time PCR, respectively. The molecular targets of COE in SGC-7901 cells were investigated by two-dimensional gel electrophoresis (2-DE) and MALDI-TOF-TOF mass spectrometer. Overexpression of heat shock protein 27 (HSP27) was performed by transfected with the recombinant retroviral expression plasmid. In vivo, the anti-metastasis mechanisms of COE in the peritoneal gastric cancer xenograft model was explored and the effect was tested.ResultsThe non-cytostatic concentrations of COE effectively inhibited TGF-β1 induced EMT process in SGC-7901 cells, which is characterized by prevented morphological changes, increased E-cadherin expression and decreased Vimentin, N-cadherin expression. Moreover, COE inhibited invasion and migration induced by TGF-β1. Using a comparative proteomics approach, four proteins were identified as differently expressed, with HSP27 protein being one of the most significantly down-regulated proteins induced by COE. Moreover, the activation of nuclear factor κB (NF-κB)/Snail signaling pathway induced by tumor necrosis factor-α (TNF-α) was also attenuated under the pretreatment of COE. Interestingly, overexpression of HSP27 significantly decreases the inhibitory effect of COE on EMT and the NF-κB/Snail pathway. Furthermore, COE significantly reduced the number of peritoneal metastatic nodules in the peritoneal gastric cancer xenograft model.ConclusionsTaken together, these results suggest that COE inhibits the EMT by suppressing the expression of HSP27, correlating with inhibition of NF-κB/Snail signal pathways in SGC-7901 cells. Based on these results, COE may be considered a novel anti-cancer agent for the treatment of metastasis in gastric cancer.

Brain-derived neurotrophic factor (BDNF)-induced tropomyosin-related kinase B (Trk B) signaling is a potential therapeutic target for peritoneal carcinomatosis arising from colorectal cancer.

Tropomyosin-related receptor kinase B (TrkB) signaling, stimulated by brain-derived neurotrophic factor (BDNF) ligand, promotes tumor progression, and is related to the poor prognosis of various malignancies. We sought to examine the clinical relevance of BDNF/TrkB expression in colorectal cancer (CRC) tissues, its prognostic value for CRC patients, and its therapeutic potential in vitro and in vivo. Two hundred and twenty-three CRC patient specimens were used to determine both BDNF and TrkB mRNA levels. The expression of these proteins in their primary and metastatic tumors was investigated by immunohistochemistry. CRC cell lines and recombinant BDNF and K252a (a selective pharmacological pan-Trk inhibitor) were used for in vitro cell viability, migration, invasion, anoikis resistance and in vivo peritoneal metastasis assays. Tissue BDNF mRNA was associated with liver and peritoneal metastasis. Tissue TrkB mRNA was also associated with lymph node metastasis. The co-expression of BDNF and TrkB was associated with liver and peritoneal metastasis. Patients with higher BDNF, TrkB, and co-expression of BDNF and TrkB had a significantly poor prognosis. BDNF increased tumor cell viability, migration, invasion and inhibited anoikis in the TrkB-expressing CRC cell lines. These effects were suppressed by K252a. In mice injected with DLD1 co-expressing BDNF and TrkB, and subsequently treated with K252a, peritoneal metastatic nodules was found to be reduced, as compared with control mice. BDNF/TrkB signaling may thus be a potential target for treating peritoneal carcinomatosis arising from colorectal cancer.

In vivo optical pathology of paclitaxel efficacy on the peritoneal metastatic xenograft model of gastric cancer using two-photon laser scanning microscopy

We previously visualized in vivo responses to chemotherapy in a colorectal liver metastatic xenograft model using in vivo real-time and time-series intravital two-photon laser scanning microscopy (TPLSM). In this study, we established the method for evaluating the response of peritoneal xenografts to chemotherapy of metastatic gastric cancer using intravital TPLSM. Red fluorescent protein-expressing gastric cancer cells (NUGC4) were inoculated into the peritoneal cavity of green fluorescent protein nude mice. Laparotomy revealed that 2 weeks after inoculation, macroscopic peritoneal metastatic nodules were formed. The first intravital TPLSM session revealed that they were composed of red tumor cell clusters and green surrounding stroma. Paclitaxel was administered intraperitoneally after the first TPLSM three times a week for 7 days in the treatment group. At the second laparotomy, there were significantly fewer and smaller nodules in the treated mice than in the controls. The second intravital TPLSM session showed tumor cell fragmentation, swelling, and nuclear condensation in the metastatic nodules--a response to chemotherapy. There were multinuclear tumor cells in the paclitaxel-treated living mice. Our method may become a powerful tool for evaluating the efficacy of novel anti-gastric cancer drugs in a preclinical murine model with minimum interindividual variation.

Ovarian carcinosarcoma associated with mature cystic teratoma and tubal carcinoma - a case report

Carcinosarcoma is a rare type of ovarian cancer of epithelial cell origin. The occurrence of carcinosarcoma associated with mature cystic teratoma is very rare. The recent information regarding histogenesis of pelvic or ovarian epithelial cancers suggests a tubal origin in most of these tumors. However, the presence of synchronous tubal neoplastic lesions and ovarian carcinosarcoma is extremely rare. We report a coexistence of ovarian carcinosarcoma and mature cystic teratoma with a synchronous tubal carcinoma. A 69-year-old woman presented with a pelvic mass. Intraoperatively, bilateral ovarian masses with peritoneal metastatic nodules were observed. Histologically, mature cystic teratoma was identified in both ovaries. The left ovary showed another component of carcinosarcoma. The left fallopian was macroscopically unremarkable but contained a microscopic area of high-grade serous adenocarcinoma in the distal part, with adjacent serous tubal intraepithelial carcinoma. While ovarian teratoma and carcinosarcoma may represent incidental coexisting lesions, the association between the ovarian carcinosarcoma and tubal carcinoma remains to be elucidated.

Knockdown of Slit2 promotes growth and motility in gastric cancer cells via activation of AKT/β-catenin

We previously showed that Slit2 was highly expressed in gastric cancer tissues that exhibit less advanced clinicopathological features, suggesting a tumor suppressor role for Slit2. In the present study, we investigated the effects of Slit2 knockdown on gastric cancer cells. Slit2-specific shRNAs were used to generate Slit2-knockdown SGC-7901 gastric cancer cells. Cell proliferation assay, Annexin V/PI double staining and cell cycle analysis were used to investigate the role of Slit2 knockdown in cell growth. Wound-healing and in vitro migration/invasion assays were performed. Subcutaneous tumor formation and peritoneal spreading in nude mice were employed to examine the in vivo effects of Slit2 knockdown. Cell signaling changes induced by Slit2 knockdown were analyzed by immunoblotting. Slit2 knockdown increased gastric cancer cell growth in monolayer and soft agar/Matrigel 3D culture. Slit2 knockdown inhibited apoptosis but did not alter cell cycle progression. Slit2-knockdown cells formed larger tumors and produced more peritoneal metastatic nodules in nude mice. Slit2 knockdown increased AKT phosphorylation, activated anti-apoptotic signaling, suppressed GSK3β activity and induced β-catenin activation. Blocking the effects of PI3K/AKT using pharmacological inhibitors abolished the ability of Slit2 knockdown to induce apoptosis resistance and cell migration/invasion. These results indicate that Slit2 knockdown promotes gastric cancer growth and metastasis through activation of the AKT/β‑catenin-mediated signaling pathway.

Abstract 4344: Intraperitoneal administration of docetaxel loaded in thermo-responsive conjugated linoleic acid-incorporated poloxamer hydrogel for the suppression of peritoneal dissemination of gastric cancer.

Abstract Thermo-responsive hydrogel consisting of conjugated linoleic acid-coupled Pluronic F127 (Plu-CLA) is an optimized drug delivery system with anti-cancer activity for controlled release of the hydrophobic drug, docetaxel. In this study, we evaluated the effect of Plu-CLA as a potential new intraperitoneal docetaxel delivery system for peritoneal dissemination of gastric cancer. We have established a peritoneal metastasis models using BALB/c mice by injection with TMK-1 human gastric cancer cells. Mice were injected intraperitoneally with docetaxel alone and docetaxel loaded Plu-CLA at 1 week after TMK1 cells were injected. Tumor progression and response to therapy were monitored by micro-positron emission tomography. The total number of peritoneal tumors and ascites volume were also measured. Compared to docetaxel alone, the combination of docetaxel and Plu-CLA significantly and synergistically reduced cell survival. The combination of docetaxel and Plu-CLA showed excellent anti-tumor activity inducing stronger apoptosis than docetaxel alone. The combination of docetaxel and Plu-CLA also significantly reduced number of peritoneal metastatic nodules and increased the survival in the peritoneal gastric cancer xenograft model. Our results showed that intraperitoneal administration of docetaxel combined with Plu-CLA synergistically inhibited peritoneal metastasis and prolonged the survival in peritoneal gastric cancer model. Therefore, Plu-CLA could be a potential intraperitoneal carrier for hydrophobic docetaxel for the effective treatment of peritoneal metastatic gastric cancer. Citation Format: Woo Kyun Bae, Lothar Hennighausen, Ji Hee Lee, Dae Eun Kim, Jun Eul Hwang, Hyun Jeong Shim, Sang Hee Cho, In-Kyu Park, Ik-Joo Chung. Intraperitoneal administration of docetaxel loaded in thermo-responsive conjugated linoleic acid-incorporated poloxamer hydrogel for the suppression of peritoneal dissemination of gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4344. doi:10.1158/1538-7445.AM2013-4344

Adjuvant Chemotherapy with S-1 Followed by Docetaxel for Gastric Cancer and CY1P0 Peritoneal Metastasis after Relatively Curative Surgery

The aim of this study was to assess the feasibility and safety of adjuvant chemotherapy with S-1 followed by docetaxel. Twenty-eight patients with advanced gastric cancer underwent gastrectomy without preoperative chemotherapy. These patients were divided into 3 groups on the basis of cytologic results of peritoneal lavage (CY) and the presence of local peritoneal metastatic nodules (P): CY1-P0, CY0-P1, and CY1-P1. Oral S-1 (80 mg/m(2)/day) was administered for 3 consecutive weeks, followed by intravenous docetaxel (35 mg/m(2)) on days 29 and 43 (1 cycle). This cycle was repeated every 8 weeks. The primary endpoint was the ability to complete 6 cycles of S-1 followed by docetaxel. The secondary endpoints were safety, progression-free survival, mean survival time (MST), and overall survival (OS). The subjects were 18 men and 10 women (39 to 78 years old, median age, 64 years). The extent of peritoneal metastasis was CY1-P0 in 8 patients, CY0-P1 in 14 patients, and CY1-P1 in 6 patients. Both hematologic and nonhematologic toxicities were generally mild. The completion rate of the planned 6 cycles of the protocol was 71.4% (20 of 28 patients). Median progression-free survival was 22.9 months, and the 2-year survival rate was 78.6%. The overall MST was 34.3 months, and the MST by group was 34.5 for CY1-P0, 34.3 for CY0-P1, and 19.3 months for CY1-P1. The OS in the CY1-P0 and CY0-P1 groups was significantly longer than that in the CY1-P1 group (P<0.05). Adjuvant chemotherapy with S-1 followed by docetaxel is safe and well tolerated and has the potential to improve OS in patients with a status of CY1P0 following relatively curative resection.

Docetaxel-loaded thermoresponsive conjugated linoleic acid-incorporated poloxamer hydrogel for the suppression of peritoneal metastasis of gastric cancer

We evaluated the potential of a thermoresponsive hydrogel consisting of conjugated linoleic acid-coupled Pluronic F-127 (Plu-CLA) as a controlled release, intraperitoneal delivery system for docetaxel with the aim of treating peritoneal dissemination of gastric cancer. Previously, we established a peritoneal metastasis model that involves the injection of BALB/c mice with TMK1 human gastric cancer cells. One week after the TMK1 cells were injected, the mice were injected intraperitoneally with docetaxel alone or docetaxel-loaded Plu-CLA. Tumor progression and response to therapy were monitored by micro-positron emission tomography. The total number of peritoneal tumors and the ascites volume were also measured. Compared with docetaxel alone, the combination of docetaxel and Plu-CLA (docetaxel–Plu-CLA) significantly and synergistically reduced tumor cell survival. Docetaxel–Plu-CLA showed excellent anti-tumor activity, inducing apoptosis more potently than docetaxel alone. Docetaxel–Plu-CLA also significantly reduced the number of peritoneal metastatic nodules and increased survival in the peritoneal gastric cancer xenograft model. Our results show that intraperitoneal administration of docetaxel–Plu-CLA synergistically inhibits peritoneal metastasis and prolongs survival in a peritoneal gastric cancer model. Therefore, Plu-CLA is a potential intraperitoneal-route carrier for hydrophobic docetaxel for the effective treatment of peritoneal metastatic gastric cancer.