Nobuaki Kaibara

Intraperitoneal thermochemotherapy for prevention of peritoneal recurrence of gastric cancer. Final results of a randomized controlled study

Background. Continuous hyperthermic peritoneal perfusion (CHPP) with a solution that contained 10 μg/ml mitomycin C was devised initially as a method for intraperitoneal thermochemotherapy. The authors conducted a randomized clinical trial to evaluate the efficacy of CHPP as a prophylactic treatment for prevention of peritoneal recurrence of gastric cancer with serosal invasion.

Less invasive surgery for early gastric cancer based on the low probability of lymph node metastasis

BACKGROUND Less invasive treatment is the current trend in many surgical fields. Most patients with early gastric cancer do not have lymph node metastasis. Thus extensive resection of the stomach and extended lymph node dissection do not appear to be necessary. METHODS In a retrospective study, 890 consecutive patients with early gastric cancer who had undergone standard gastrectomy were assessed for depth of invasion, gross appearance, and maximum diameter of the tumor to examine the possibility of limiting the extent of lymph node dissection. A variety of limited gastrectomies have been developed and now include endoscopic mucosal resection, wedge resection, segmental gastrectomy, limited proximal gastrectomy, and distal hemigastrectomy. RESULTS A retrospective study revealed that extensive lymph node dissection did not improve the survival of patients with early gastric cancer. Endoscopic mucosal resection was suitable for cancers of the depressed type of less than 1 cm in diameter and the elevated type of less than 2 cm in diameter. Wedge, segmental, or limited proximal gastrectomy was suitable for the elevated type of 2 to 3 cm in diameter. The elevated type of more than 3 cm in diameter and the depressed type of 1 to 3 cm in diameter sometimes involved metastasis to group 1 nodes. The depressed type of more than 3 cm in diameter sometimes involved metastasis to group 2 nodes. Thus such cases should be treated by gastrectomy with dissection of potentially metastatic lymph nodes. CONCLUSIONS Limitation of the extent of gastrectomy and lymph node dissection may be possible, depending on the gross appearance and size of the tumor.

Relationship between the expression of vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue

It has been reported that decreased numbers of dendritic cells (DCs) are correlated with poor prognosis in some types of malignancy, such as gastric cancer. However, factors that determine the density of DCs have not been characterized. It was recently reported that vascular endothelial growth factor (VEGF) inhibits the functional maturation of DCs from CD34+ precursors. In this study, we analysed the relationship between the expression of VEGF and the density of DCs in gastric carcinoma tissues by immunohistochemical staining. The extent of infiltration by DCs was graded from marked to slight on the basis of the mean densities of DCs. The prognosis of patients with marked infiltration was significantly better than that of patients with slight infiltration among patients who had undergone curative resection. Multivariate analysis showed that infiltration by DCs was an independent prognostic indicator. Furthermore, there was an inverse correlation between the density of DCs and the expression of VEGF Our results suggest that expression of VEGF might be associated with tumour progression and poor prognosis not only because VEGF stimulates angiogenesis, but also because it allows tumours to escape from attack by the immune system in patients with gastric carcinoma.

The expression of transforming growth factor-β1 is significantly correlated with the expression of vascular endothelial growth factor and poor prognosis of patients with advanced gastric carcinoma

Transforming growth factors β (TGFs β) are involved in a variety of important cellular functions, including cell growth and differentiation, adhesion, migration, extracellular matrix formation, and immune function. Moreover, it has been reported that TGFs β are correlated with angiogenesis. However, the role of TGF‐β as an angiogenic factor in gastric carcinoma is still unclear.

Prognostic significance of intraperitoneal free cancer cells in gastric cancer patients

SummaryWe performed intraoperative peritoneal cytology in 171 gastric cancer patients undergoing curative surgery. Intraperitoneal free cancer cells were demonstrated in almost all patients in whom the area of serosal cancer invasion exceeded 15–20 cm2. In patients with both serosal cancer invasion and free cancer cells the 5-year survival rat was 13% as compared with 85% for patients who had neither, and 40% for patients who had serosal invasion but no free peritoneal cancer cells. Peritoneal metastasis was the most frequently observed recurrence pattern. There-fore, in gastric cancer patients with marked serosal invasion, intraoperative IP administration of cytocidal anticancer drugs should be considered.

Expression of survivin messenger RNA correlates with poor prognosis in patients with hepatocellular carcinoma.

Suppression of apoptosis is important for carcinogenesis and tumor growth. Recent studies revealed that survivin not only inhibited apoptosis but also accelerated cancer cell proliferative activity. To investigate the prognostic role of expression of the antiapoptosis gene, survivin, in hepatocellular carcinoma (HCC), the authors analyzed the correlation between the expression pattern of survivin messenger RNA (mRNA) and clinicopathologic findings of patients. Tissues were obtained by surgical resection of livers from 51 patients with HCC and 6 patients without HCC. Expression of survivin mRNA was evaluated using reverse transcription-polymerase chain reaction in 51 tumors, 51 adjacent histologically noncancerous livers, and 6 normal livers. Survivin protein expression was evaluated using Western blotting, and apoptotic cancer cells were detected by immunostaining with polyclonal rabbit anti-single-stranded DNA. Survivin mRNA expression was detected in 21 of 51 (41%) tumors, 2 of 51 (4%) noncancerous livers, and none of the 6 normal livers. Survivin mRNA expression did not correlate with tumor size or stage of HCC. Percentage of apoptotic cancer cells of 30 survivin mRNA-negative tumors (5.2 ± 3.4%) was significantly higher than that of 21 survivin mRNA-positive tumors (2.2 ± 2.3%, P = 0.0019). The disease-free 5-year survival rate of 21 patients positive for survivin mRNA (19%) was significantly poorer than that of 30 patients negative for survivin mRNA (39%, P = 0.0148). Survivin mRNA was detected in 57% (17/30) patients with HCC recurrence but in only 19% (4/21) of patients without recurrence (P = 0.0072). These results indicated that survivin mRNA expression could be used as an independent prognostic factor for patients with HCC after hepatectomy.

Expression of vascular endothelial growth factor correlates with hematogenous recurrence in gastric carcinoma

BACKGROUND It has recently been reported that the microvessel density in a tumor correlates with hematogenous metastasis in gastric carcinoma. The aim of this study was to evaluate the relationship between the expression of vascular endothelial growth factor (VEGF), which was thought to be a potent angiogenesis-promoting factor, and hematogenous recurrence in advanced gastric carcinoma. METHODS The expression of VEGF and the density of the microvessels were examined by immunohistochemistry in patients with advanced gastric carcinoma with serosal invasion who had undergone curative resection. RESULTS The prognosis of patients with a VEGF-negative tumor was significantly better than that of patients with a VEGF-positive tumor. Multivariate analysis by Cox proportional hazards model showed that the expression of VEGF was an independent prognostic indicator. The expression of VEGF provided a significant estimate of relative risk for the development of hematogenous recurrence by multivariate logistic regression analysis. The microvessel count in VEGF-positive tumors was significantly higher than that in VEGF-negative tumors. CONCLUSIONS VEGF is associated with hematogenous recurrence. Assessment of the expression of VEGF may therefore prove valuable in identifying patients with gastric carcinoma at high risk for recurrence who would benefit from adjuvant therapy.

Synchronous and metachronous malignancies of the colon and rectum in Japan with special reference to a coexisting early cancer

The authors reviewed the medical records of 1005 patients with multiple colorectal cancers (763 synchronous and 242 metachronous) to study the number and site of the tumors, their preoperative detectability, and the results of treatment. Concurrent advanced cancers were found in 35.1%, concurrent advanced and early cancers in 59.0%, and concurrent early cancers in 5.9% of patients with synchronous malignancy. In 60.1% of these patients, the existence of multiple lesions was diagnosed preoperatively; coexisting early cancers were often overlooked. In patients with metachronous malignancy, early cancers were less frequent than in patients with synchronous malignancy. The cumulative 5‐year survival rate in curatively operated patients was 70.4% for synchronous malignancy and 66.5% for metachronous malignancy, similar to that for colon cancer in general.

Apoptosis occurs more frequently in metastatic foci than in primary lesions of human colorectal carcinomas: analysis by terminal-deoxynucleotidyl-transferase-mediated dUTP-biotin nick end labeling.

We examined the occurrence of apoptotic cell death in 15 advanced colorectal carcinomas with lymph‐node and/or liver metastases by terminal‐deoxynucleotidyl‐transferase (TdT)‐mediated dUTP‐biotin nick end labeling (TUNEL). TUNEL‐positive cells were used to quantify the apoptotic index (AI: percentage of TUNEL‐positive cells in carcinomatous cells). Similarly, Ki‐67‐positive cells were used to quantify Ki‐67 labeling (Kl: percentage of Ki‐67‐positive cells in carcinomatous cells) as a proliferative index. The mean AIs of primary colorectal carcinomas, lymph‐node and liver metastases were 3.5%, 5.6% and 6.2% respectively. There was a significant group difference between primary carcinomas and lymph‐node or liver metastases. The mean Kls of primary colorectal carcinomas, lymph‐node and liver metastases were 51.8%, 60.1% and 61.7% respectively. There was a significant group difference between primary carcinomas and lymph‐node or liver metastases. In addition, there was a close positive relationship between the AI and MI per specimen. There was no apparent correlation between AI or MI and the expression of nuclear p53 of cancer cells. These results suggested that cell proliferation and loss (apoptosis) were more frequent in metastatic foci than in primary lesions, and that apoptosis might reflect not only cell loss but also the proliferative activity of human colorectal carcinomas.

Expression of survivin mRNA and protein in gastric cancer cell line (MKN-45) during cisplatin treatment

Survivin is a member of the inhibitor of apoptosis protein (IAP) family. Survivin has been reported to be expressed in many cancers, but not in differentiated normal tissue. Recent studies revealed that survivin correlated with the chemo-resitance of cancer cells. In the present study, the changes in expression levels of survivin messenger RNA (mRNA) and survivin protein in a gastric cancer cell line (MKN-45) during cisplatin (CDDP) treatment were analyzed and compared with the occurrence of apoptotic cell death. Cell growth was inhibited even with a low dose CDDP (0.1 or 1 μg/ml) 1 hr treatment. However, the percentage of apoptotic cells did not change after 48 hr incubation with low dose CDDP. Only with high dose CDDP (10 μg/ml), did the percentage of apoptotic cells explosively increase between 12 and 24 hr treatment. Relative expression levels of survivin mRNA and survivin protein increased after CDDP treatment. The cell expression rates of survivin mRNA after 48 hr treatment with 0.1 and 1 μg/ml of CDDP were 2 to 6 fold higher than that of the survivin mRNA of untreated cells. Also, the relative cell expression level of survivin protein after 24 hr treatment with 0.1 or 1 μg/ml of CDDP was 3 to 6.5 fold higher than that of the survivin protein of untreated cells. These results indicate that survivin expression may correlate with the chemo-resistance of malignant cells.