Nek2 as an effective target for inhibition of tumorigenic growth and peritoneal dissemination of cholangiocarcinoma

We investigated the role of Nek2, a member of the serine/threonine kinase family, Nek, in the tumorigenic growth of cholangiocarcinoma cells. Expression of Nek2 is elevated in cholangiocarcinoma in a tumor-specific manner as compared with that of normal fibroblast cells. Expression of exogenous Nek2 did not perturb the growth of cholangiocarcinoma cells, whereas suppression of the Nek2 expression with siRNA resulted in the inhibition of cell proliferation and induced cell death. In xenograft-nude mouse model, s.c. injection of Nek2 siRNA around the tumor nodules resulted in reduction of tumor size as compared with those of control siRNA injection. In peritoneal dissemination model, Nek2 siRNA-treated mice showed statistically longer survival periods in comparison with those of the control siRNA-treated mice. Taken together, our data indicate a pivotal role of Nek2 in tumorigenic growth of cholangiocarcinoma.     

CD147 overexpression is a prognostic factor and a potential therapeutic target in bladder cancer

CD147, also named extracellular matrix metalloproteinase inducer (EMMPRIN), has been shown to be involved in the progression of malignancy by regulating expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). The goal of this study was to evaluate the role of CD147 in the biology of bladder cancer and to determine its potential as a therapeutic target. CD147 protein expression was detected by immunohistochemistry in 108 bladder cancers using a tissue microarray annotated with patient follow-up. In immunohistochemistry, CD147 protein expression was associated with poor prognosis (P < 0.001), lymph node status (P < 0.001), tumor stage (P = 0.003), histologic grade (P = 0.011). Multivariate analysis showed that CD147 overexpression was an independent prognostic factor (P = 0.019). Infection of T24 bladder cancer cells with an adenovirus that expressed a small interfering RNA (siRNA) against CD147 efficiently inhibited CD147 protein and mRNA expression. This resulted in decreased proliferation, soft agar colony formation, migration, and invasion of T24 cells in vitro. Moreover, downregulation of CD147 reduced secretion of MMP-2 and MMP-9 and expression of VEGF in these cells. Our findings suggest that CD147 overexpression plays an important role in progression of bladder cancer, and CD147 could be a potential target of bladder cancer therapy.     

Co-expression of hepatocyte growth factor and c-Met predicts peritoneal dissemination established by autocrine hepatocyte growth factor/c-Met signaling in gastric cancer

Epithelial-mesenchymal transition (EMT) promotes and facilitates migration and invasion of epithelial tumor cells. EMT is induced by factors such as hepatocyte growth factor (HGF). This study aimed to establish whether the HGF/c-Met pathway is associated with gastric cancer metastasis; especially peritoneal dissemination. HGF and c-Met expression and EMT-related molecules were evaluated using real-time PCR and immunohistochemistry. The role of the HGF/c-Met pathway in EMT and anoikis was determined, and kinase inhibitor SU11274 was tested for its ability to block HGF-induced biological effects. In HGF(-) /c-Met(+) gastric cancer cells, recombinant HGF promoted an EMT phenotype that was characterized by morphology, impaired E-cadherin and induction of vimentin. HGF promoted cell growth, invasiveness and migration and inhibition of anoikis. SU11274 blocked HGF-induced EMT and biological effects in vitro. In HGF(+) /c-Met(+) gastric cancer cells, HGF did not affect the biological outcome of EMT and anoikis, but SU11274 exerted the same inhibitory effects as in HGF(-) /c-Met(+) cells. In vivo, HGF(+) /c-Met(+) gastric cancer cells only established peritoneal dissemination and SU11274 inhibited tumor growth. Clinically, HGF expression was significantly correlated with c-Met expression in gastric cancer. Increased HGF and c-Met had a significant association with poor prognosis and predicted peritoneal dissemination. We demonstrated that the HGF/c-Met pathway induces EMT and inhibition of anoikis in gastric cancer cells. Co-expression of HGF and c-Met has the potential to promote peritoneal dissemination in gastric cancer. Blockade of the autocrine HGF/c-Met pathway could be clinically useful for the treatment of peritoneal dissemination in gastric cancer.     

Lymphatic vessel invasion is an independent prognostic factor for survival in colorectal cancer

To assess whether lymphatic vessel invasion (LVI) is an independent prognostic factor in colorectal cancer, we retrospectively reviewed the records of 462 patients who underwent potentially curative surgery for carcinoma of the colon and rectosigmoid/rectum (rs/rectum) at the New England Deaconess Hospital from 1965-1978. Sixty-one patients were identified as having tumors with lymphatic vessel invasion (LVI+), and they were compared with the remaining group of 401 patients who had tumors without lymphatic vessel invasion (LVI-). The incidence of lymphatic vessel invasion was significantly increased in tumors with blood vessel invasion (24% vs. 5%, p = 0.000001). Patients with LVI+ tumors also had a significantly increased incidence of positive nodes (59% vs. 25%, p = 0.0004), the average number of positive nodes (4.8 vs. 2.2, p = 0.0003), and a lower 5-year survival rate (colon: 57% vs. 84%, p = 0.0001; rs/rectum: 38% vs. 71%, p = 0.004). There was a significant (p less than or equal to 0.05) increase in local (16% vs. 7%), abdominal (33% vs. 9%), and distant (13% vs. 4%) failure as a component of component of failure in patients with LVI+ colon cancer and a significant increase in abdominal (33% vs. 11%) and distant (13% vs. 8%) failure as a component of failure in patients with LVI+ rectosigmoid/rectal cancer. Proportional hazards analysis demonstrated that lymphatic vessel invasion was an independent prognostic factor for survival.     

Skp2 overexpression is a prognostic factor in patients with ovarian adenocarcinoma.

PURPOSE: The purpose of this study was to examine Skp2 expression in epithelial ovarian tumors and to identify the association of Skp2 expression levels with patient survival. EXPERIMENTAL DESIGN: Skp2 protein expression was examined by immunohistochemistry in 134 epithelial ovarian tumors [20 adenomas, 23 low malignant potential (LMP) tumors, and 91 adenocarcinomas]. Results of immunostaining were correlated with clinicopathological variables and overall survival. Skp2 mRNA expression was examined by semiquantitative PCR in 32 ovarian adenocarcinomas and in 3 ovarian cancer cell lines. RESULTS: Skp2 expression was detected in neither ovarian adenomas nor LMP tumors. In contrast, Skp2 expression was detected in 47.3% (43 of 91) of adenocarcinomas. Positive Skp2 expression was detected significantly more often in adenocarcinomas than in LMP tumors (P < 0.0001) or in adenomas (P < 0.0001). A significantly higher detection rate of Skp2 expression was observed in advanced-stage diseases compared with early-stage diseases (P = 0.010). Log-rank testing showed that Skp2 overexpression was significantly correlated with poor patient survival (P = 0.0035). Older age (P = 0.0026), advanced clinical stage (P < 0.0001), and high histological grades of the tumors (P = 0.0018) were also significantly associated with poor prognoses. In multivariate analysis, Skp2 overexpression (P = 0.0069) and clinical stage (P < 0.0001) remained significantly associated with overall survival, whereas age and histological grade lost their significance. Considerable levels of Skp2 mRNA expression were detected in all ovarian adenocarcinomas examined by semiquantitative PCR. CONCLUSIONS: Skp2 expression might play an important role in the development and progression of ovarian adenocarcinomas, and Skp2 overexpression is an independent prognostic marker of ovarian adenocarcinoma patients.     

Significance of vascular endothelial growth factor in growth and peritoneal dissemination of ovarian cancer

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis which drives endothelial cell survival, proliferation, and migration while increasing vascular permeability. Playing an important role in the physiology of normal ovaries, VEGF has also been implicated in the pathogenesis of ovarian cancer. Essentially by promoting tumor angiogenesis and enhancing vascular permeability, VEGF contributes to the development of peritoneal carcinomatosis associated with malignant ascites formation, the characteristic feature of advanced ovarian cancer at diagnosis. In both experimental and clinical studies, VEGF levels have been inversely correlated with survival. Moreover, VEGF inhibition has been shown to inhibit tumor growth and ascites production and to suppress tumor invasion and metastasis. These findings have laid the basis for the clinical evaluation of agents targeting VEGF signaling pathway in patients with ovarian cancer. In this review, we will focus on VEGF involvement in the pathophysiology of ovarian cancer and its contribution to the disease progression and dissemination.     

Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cell line by overexpression of bikunin

Bikunin (bik), a Kunitz-type protease inhibitor, also known as urinary trypsin inhibitor, is proposed as a main participant in the inhibition of tumor cell invasion and metastasis, possibly through the direct inhibition of cell-associated plasmin activity and suppression of urokinase-type plasminogen activator (uPA) mRNA expression. In the present study, we transfected the human ovarian carcinoma cell line HRA, highly invasive cells, with an expression vector harboring a cDNA encoding for human bik. Our study was designed to investigate the effect of bik overexpression and changes in tumor cell phenotype and invasiveness in the stably transfected clones. Bik gene transfection of HRA gave the following results: 1) transfection of HRA with the bik cDNA resulted in 5 variants stably expressing functional bik; 2) bik(+) clones exhibited a significantly reduced uPA mRNA expression as compared to the parental cells; 3) bikunin negatively regulates the ERK1/2 activity; 4) secretion-blocking treatments of bik(+) clones abrogated bik-mediated suppression of ERK1/2 activation and uPA expression; 5) the regulation of invasion seen in the HRA cells is mainly mediated by the uPA-plasmin-MMP-2 system; 6) transfection of HRA with the bik gene significantly reduced invasion, but not proliferation, adhesion, or migration relative to the parental cells; and 7) animals with bik(+) clones induced reduced peritoneal dissemination and long term survival. We conclude that transfection of HRA cells with the bik cDNA constitutively suppresses ERK1/2 activation, which results in inhibition of uPA expression and subsequently reduces dissemination of bik(+) clones.     

CDH1 methylation in preoperative peritoneal washes is an independent prognostic factor for gastric cancer

Background and Objectives

To investigate the clinical value of CDH1 methylation in preoperative peritoneal washes (PPW) from gastric cancer patients.

Methods

CDH1 methylation was detected by real‐time methylation specific‐PCR in tumor tissues and corresponding PPW from 92 gastric cancer patients, gastric mucosa from 40 chronic gastritis patients and 48 normal persons.

Results

CDH1 methylation was found in 75 of 92 (81.5%) gastric cancer tissues, which significantly correlated with size, growth pattern, differentiation, lymphatic invasion, venous invasion, invasion depth, lymph node metastasis, distant metastasis, and TNM stage of tumor (all P < 0.05), but its relationship to age, gender, tumor site, and H. pylori infection was not found (all P > 0.05). The percentage of CDH1 methylation in PPW was 48.9%, of which the Aζ value of ROC curve was 0.8 compared to that in gastric cancer tissues. Kaplan–Meier analysis showed that there was a significant difference in disease‐free survival (DFS) between the patients with or without methylated CDH1 in their PPW (χ² = 109.64, P < 0.000). Cox regression analysis revealed CDH1 methylation in PPW was an independent risk factor for gastric cancer patients, with a remarkable decrease in DFS after postoperative 30 months.

Conclusions

Methylated CDH1 in PPW predicts poor prognosis for gastric cancer patients. J. Surg. Oncol. 2012; 106:765–771. © 2012 Wiley Periodicals, Inc.     

Lymphatic invasion is a prognostic factor for bladder cancer treated with radical cystectomy

Background We aimed to elucidate the significance of pathological prognostic factors in patients with bladder cancer treated with radical cystectomy and pelvic lymphadenectomy focusing on the association between lymphatic invasion and disease recurrence. Methods Ninety-one patients with ladder cancer who had undergone radical cystectomy were examined retrospectively. Clinicopathological findings and clinical outcomes were analyzed. Patients who received palliative cystectomy or neoadjuvant chemotherapy and patients who did not receive lymphadenectomy owing to a poor general condition or far advanced local disease status were excluded. Results Lymphatic invasion and lymph node involvement were present in 45.1% and 23.1% of patients, respectively. Multivariate analyses, using the Cox proportional hazards model, indicated that lymphatic invasion (hazard ratio [HR], 5.30; P = 0.007) and lymph node involvement (HR = 3.05; P = 0.016) were independent prognostic factors for disease-specific survival. Of the 91 patients, 29 (31.9%) had recurrent disease during the follow-up period. The rate of recurrence in patients with lymphatic invasion and without lymph node involvement was 50% (11/22), which was not significantly different from that in patients with both lymphatic invasion and lymph node involvement (73.7%; 14/19; P = 0.121), indicating a high risk of disease recurrence in patients with bladder cancer with lymphatic invasion even in the absence of the lymph node involvement. Conclusion In patients with bladder cancer treated with radical cystectomy, lymphatic invasion is an independent prognostic factor for disease-specific and disease-free survival. Patients with lymphatic invasion have a high risk of disease recurrence after radical cystectomy even in the absence of lymph node involvement.     

Heparin-binding EGF-like growth factor is a promising target for ovarian cancer therapy

Ovarian cancer is the most frequent cause of cancer death among all gynecologic cancers. We demonstrate here that lysophosphatidic acid (LPA)-induced ectodomain shedding of heparin-binding EGF-like growth factor (HB-EGF) is a critical to tumor formation in ovarian cancer. We found that among the epidermal growth factor receptor (EGFR) family of growth factors, HB-EGF gene expression in cancerous tissues and HB-EGF protein levels in patients' ascites fluid were significantly elevated. The human ovarian cancer cell lines SKOV3 and RMG-1 form tumors in nude mice. Tumor formation of these cells was enhanced by exogenous expression of pro-HB-EGF and completely blocked by pro-HB-EGF gene RNA interference or by CRM197, a specific HB-EGF inhibitor. Transfection with mutant forms of HB-EGF indicated that the release of soluble HB-EGF is essential for tumor formation. LPA, which is constitutively produced by ovarian cancer cells, induced HB-EGF ectodomain shedding in SKOV3 and RMG-1 cells, resulting in the transactivation of EGFR and the downstream kinase extracellular signal-regulated kinase/mitogen-activated protein kinase. LPA-induced transactivation was abrogated by HB-EGF gene RNA interference or by CRM197. Introduction of lipid phosphate phosphohydrolase, which hydrolyzes LPA, decreased the constitutive shedding of HB-EGF, EGFR transactivation, and the tumorigenic potential of SKOV3 and RMG-1 cells. These results indicate that HB-EGF is the primary member of the EGFR family of growth factors expressed in ovarian cancer and that LPA-induced ectodomain shedding of this growth factor is a critical step in tumor formation, making HB-EGF a novel therapeutic target for ovarian cancer.     

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

BACKGROUND.

Current prognostic information in ovarian cancer is based on tumor stage, tumor grade, and postoperative tumor size. Reliable molecular prognostic markers are scarce. In this article, the authors describe epigenetic events in a frequently deleted region on chromosome 8p22 that influence the expression of tumor suppressor candidate 3 (TUSC3), a putative tumor suppressor gene in ovarian cancer.

METHODS.

Messenger RNA expression and promoter hypermethylation of TUSC3 were studied in ovarian cancer cell lines and in tumor samples from 2 large, independent ovarian cancer cohorts using polymerase chain reaction‐based methods.

RESULTS.

The results indicated that TUSC3 expression is decreased significantly because of promoter methylation in malignant ovarian tumors compared with benign controls. Almost 33% of ovarian cancer samples had detectable TUSC3 promoter methylation. Furthermore, methylation status of the TUSC3 promoter had a significant and independent influence on progression‐free and overall survival.

CONCLUSIONS.

TUSC3 hypermethylation predicted progression‐free and overall survival in ovarian cancer. The current observations suggested a role for N‐glycosylating events in ovarian cancer pathogenesis in general and identified the epigenetic silencing of TUSC3 as a prognostic factor in this disease. Cancer 2013. © 2012 American Cancer Society.     

Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cells by overexpression of AP-2alpha

A previous report demonstrated that AP-2alpha favors the survival of ovarian cancer patients by clinical findings. However, the functional roles of AP-2alpha in human ovarian cancers have not been determined. To clarify the roles, we overexpressed AP-2alpha in SKOV3 human ovarian cancer cells, which originally possess little AP-2alpha. AP-2alpha overexpression changed cell morphology from spindle to epithelioid type and suppressed cell proliferation and invasion, which would be partially correlated with decreased phosphorylation levels of the erbB2, Akt and ERK pathways, increased E-cadherin and reduced pro-matrix metalloproteinase-2 levels. Moreover, nude mice intraperitoneally injected with AP-2alpha-overexpressing cells survived longer than those with neo-transfected cells. The present data represent the first direct evidence that AP-2alpha plays a tumor suppressive role in ovarian cancer.     

Preoperative combination chemotherapy with TS-1 is effective in a case gastric cancer with peritoneal dissemination

We report a case of peritoneal cancer dissemination with Type 4 gastric cancer, successfully treated with combination chemotherapy with TS-1. The patient was a 59-year-old female, who complained of abdominal distension with pain, weight loss, and poor appetite. She was diagnosed as unresectable Type 4 gastric cancer, T3N2MOHOP1CY1M0, Stage IV with massive ascites (cytology: Class V). After 2 courses of combined chemotherapy with TS-1 and cisplatin (CDDP), primary tumor reduction was confirmed and no cancer cells were detected from a pathological investigation with biopsied specimens by endoscopy. As additional therapy for remained ascites, intraperitoneal administration of paclitaxel and docetaxel was performed, resulting in a remarkable decrease of ascites with cytological disappearance of cancer cells. The patients underwent total gastrectomy with lymph node dissection, pathological diagnosis of primary site and lymph nodes showed grade 2 effect, and no cancer cells were detected in ascites and peritoneum, microscopically. While she died of peritoneal recurrence after the surgery, the case suggested the clinical advantage of controlling the advanced cancer-bearing state by combination chemotherapy with TS-1, instead of surgery.     

LAPTM4B overexpression is an independent prognostic marker in ovarian carcinoma

Lysosome-associated protein transmembrane 4beta (LAPTM4B) is a member of the mammalian 4-tetratransmembrane spanning protein superfamily, which is strongly expressed in some solid malignancies. The present study investigated the correlation of LAPTM4B expression with clinicopathological features and prognosis in ovarian carcinoma. Expression of LAPTM4B was evaluated semiquantitatively by immunohistochemistry in 85 cases of ovarian carcinoma. High LAPTM4B expression was found in 54 (63.5%) of these 85 carcinomas, and was positively correlated with FIGO stage, histological subtype and residual tumor after primary surgery, but not with age and tumor grade. Patients with high LAPTM4B expression had significantly poorer overall survival (OS) and progression-free survival (PFS) (P<0.001 and P<0.001, respectively) compared to patients with low expression of LAPTM4B. On multivariate analysis, LAPTM4B expression was found to be an independent prognostic factor for OS and PFS (P=0.01 and P=0.03, respectively). These results showed that high LAPTM4B expression was associated with progression of ovarian carcinoma and correlated with unfavorable clinical outcome, suggesting that LAPTM4B may be a clinically useful prognostic indicator for ovarian carcinoma.     

Loss of IFN gamma receptor is an independent prognostic factor in ovarian cancer.

PURPOSE: There is evidence that IFN gamma plays an important role in ovarian cancer development. IFN gamma produces numerous antitumor effects and it may be evasion of these effects which allows tumor progression. We postulate that genetic instability in tumor cells may lead to modulation of expression of the IFN gamma receptor, thus leading to altered tumor biology and patient prognosis. This hypothesis would support the theory of immunoediting in ovarian cancer. EXPERIMENTAL DESIGN: Using tissue microarray technology of 339 primary ovarian cancers, the expression of IFN gamma receptor was assessed immunohistochemically. Coupled to a comprehensive database of clinicopathologic variables, its effect on these factors was studied. RESULTS: Tumors expressing high levels of IFN gamma receptor had significantly improved survival (P=0.017) compared with tumors expressing low levels of the receptor; this was also seen with complete receptor loss (P=0.014). Factors shown to predict prognosis independently of each other were the following: age, International Federation of Gynecologists and Obstetricians stage, and the absence of macroscopic disease after surgery. The level of IFN gamma receptor expression and complete receptor loss were independently predictive of prognosis on multivariate analysis. There was no correlation between receptor status and any of the standard clinicopathologic variables. CONCLUSIONS: Loss of IFN gamma receptor independently predicts poor prognosis in ovarian cancer. Loss of receptor expression may be responsible for the limited success in the therapeutic use of IFN gamma in ovarian cancer trials and highlights a subgroup of high expressing IFN gamma receptor tumors which are more likely to be susceptible to such treatments.     

Stage IA non-small cell lung cancer: vessel invasion is a poor prognostic factor and a new target of adjuvant chemotherapy

This study reports the efficacy of adjuvant chemotherapy in stage IA non-small cell lung cancer (NSCLC) with vessel invasion (Vi). We sub-divided 322 patients with surgically resected pathological stage IA NSCLC into two groups according to Vi [non-Vi (n=237) and Vi (n=85)]. Both groups were compared with regard to age, gender, performance status, smoking habits, serum carcinoembryonic antigen level, extent of surgery, tumour size, histopathology, recurrence sites, and survival. The overall 5-year survival rates of non-Vi and Vi groups were 89.6% and 71.8% (P<0.001), respectively. Distant metastasis was observed more frequently in the Vi group (P<0.001, risk ratio: 9.06). Univariate and multivariable analyses identified poor performance status, squamous cell carcinoma, tumour size>or=15 mm and Vi as poor prognostic factors (P<0.05). The overall 5-year survival rate of stage IA Vi group nearly overlapped with that of patients with stage IB NSCLC. Retrospectively, oral uracil-tegafur chemotherapy increased the overall 5-year survival rate of stage IA Vi group by more than 25% (P=0.036). In conclusion, vessel invasion is a poor prognostic factor in patients with stage IA NSCLC. Prognosis of patients with Vi-stage IA NSCLC is similar to that of patients with stage IB NSCLC and is improved significantly by postoperative oral uracil-tegafur chemotherapy. Our preliminary study suggests that stage IA Vi group benefits from adjuvant chemotherapy.     

Quantitative prognostic indicators of peritoneal dissemination of gastric cancer.

There are three classifications that describe the quantitative prognostic indicators of peritoneal dissemination for gastric cancer. The Japanese classification (P1, P2, and P3, Lyon classification, (stage I, II, stage III, and stage IV), and the Peritoneal Cancer Index (PCI). Carcinomatosis with limited extent (P1/ P2) corresponds to the PCI less than 13 and the stage I and II from Lyon classification. Carcinomatosis with large extent (P3) corresponds to PCI of 13 or larger and stage III and IV from Lyon classification. PCI enables one to describe the precise distribution of peritoneal dissemination. All three classifications correlate with prognosis. With regard to the surgical cytoreduction of the primary tumor and the peritoneal dissemination, Sugarbaker proposed the classification of completeness of cytoreduction (CCR). Patients with no macroscopic residual tumor had significantly better prognosis than those with residual disease. CCR is a valuable prognostic indicator after cytoreductive surgery.     

Intraperitoneal chemotherapy with taxanes for ovarian cancer with peritoneal dissemination.

Paclitaxel and docetaxel are currently the two clinically available taxanes. The combination of a taxane and a platinum compound has become the systemic chemotherapy of choice for primary ovarian cancer. Despite the high activity of these drugs in systemic chemotherapy, the majority of patients with advanced ovarian cancer will develop recurrent disease and ultimately decease of this disease. Therefore, more effective systemic chemotherapy regimens or alternative treatment modalities are warranted. Intraperitoneal chemotherapy is such an alternative treatment option. Pharmacokinetic studies on intraperitoneal administration of paclitaxel and docetaxel demonstrated very high locoregional drug concentrations and exposure. Their activity and response seem to be dose-dependent and hence higher efficacy with limited systemic toxicity is to be expected. Intraperitoneal chemotherapy may be combined intraoperatively with hyperthermia, which enhances tissue penetration and cytotoxic activity of many drugs. The data concerning thermal enhancement of taxanes are inconsistent, but at the high locoregional concentrations provided by intraperitoneal drug administration such a thermal enhancement seems to exist. Clinical studies have clearly demonstrated the feasibility and efficacy of intraperitoneal instillation chemotherapy with taxanes in patients with ovarian cancer. Preliminary results of a phase III study demonstrated improved outcome with the addition of intraperitoneal instillation chemotherapy to systemic chemotherapy after optimal primary cytoreductive surgery. Intraoperative hyperthermic intraperitoneal chemotherapy with docetaxel has been performed in a single study, in which promising results were observed. Further clinical investigations with an adequate follow-up period are needed to confirm the promising initial results and to determine the exact efficacy of intraperitoneal chemotherapy with these drugs.