S Tsujitani

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 thymidine phosphorylase correlates with angiogenesis and the efficacy of chemotherapy using fluorouracil derivatives in advanced gastric carcinoma

SummaryThe expression of thymidine phosphorylase (TP) and the density of microvessel in advanced gastric carcinoma were examined by immunohistochemistry to evaluate the significance of TP. The expression of TP was negative in 72 cases, positive in 54. The microvessel density correlated with the expression of TP. In total cases, patients with TP-positive tumours survived longer than those with TP-negative tumours. In patients treated with fluorouracil derivatives (FUs), the expression of TP significantly correlated with favourable prognosis and with unfavourable prognosis in those not treated with FUs. The patients with TP-positive tumours, the prognosis of patients treated with FUs was significantly better than that of those not treated with FUs. In patients with TP-positive tumours, treatment with FUs and lymph node metastasis were independent prognostic factors according to the Cox proportional hazards model. Depth of invasion and lymph node metastasis were independent prognostic factors in patients with TP-negative tumours. The determination of the expression of TP might be useful for predicting the efficacy of post-operative chemotherapy using FUs to prevent recurrence in advanced gastric carcinoma patients who undergo curative gastrectomy.

Hypotonic intraperitoneal cisplatin chemotherapy for peritoneal carcinomatosis in mice

The intraperitoneal (i.p.) administration of cisplatin (CDDP) is one of the most effective therapies for cancers that are confined to the abdominal cavity. However, the effect of fluid osmolarity on the therapeutic efficacy of i.p. administration of CDDP has not been well established. In the current study, hypotonic (154 mosmol 1-1), isotonic (308 mosmol 1-1) and hypertonic (616 mosmol 1-1) solutions of CDDP were prepared for an evaluation of their therapeutic efficacy in an experimental system. After i.p. administration, uptake of CDDP in vivo by tumor cells in hypotonic solution was significantly greater than in isotonic or hypertonic solution. The 50% lethal dose (LD50) value of CDDP in hypotonic solution (12.1 mg kg(-1)) was lower than that in isotonic solution (16.9 mg kg(-1)) and than that in hypertonic solution (28.6 mg kg(-1)). However, when a dose equal to one-half of the LD50 was administered in each solution to mice with i.p. tumours, survival of mice given the CDDP in hypotonic solution was significantly prolonged as compared with the survival of the other mice. These results demonstrate that the therapeutic efficacy of i.p. CDDP in mice is augmented when the drug is administered in hypotonic solution.

Administration in a Hypotonic Solution Is Preferable to Dose Escalation in Intraperitoneal Cisplatin Chemotherapy for Peritoneal Carcinomatosis in Rats

An animal model of intraperitoneal (i.p.) cisplatin chemotherapy using hypotonic solutions of sodium chloride has been developed as a treatment for peritoneal carcinomatosis. The concentrations of platinum in the plasma and in the i.p. fluid of Donryu rats were measured after i.p. injection of hypotonic (103 or 154 mosm/l) and isotonic (308 mosm/l) solutions that contained an equal amount of cisplatin. The maximum concentration (Cmax) and the area under the curve of concentration versus time (AUC) of platinum in the plasma increased proportionately with increases in the dose of cisplatin and they were significantly higher in rats given cisplatin in hypotonic solutions than in those given the drug in isotonic solution. The Cmax and AUC of total platinum were similar for the solution of 103 mosm/l with 2.5 mg/kg cisplatin and the isotonic solution with 5.0 mg/kg cisplatin. The Cmax and AUC of free platinum in the plasma did not increase with increases in the dose of cisplatin in isotonic solution but did increase after hypotonic injection. However, the solutions of lower osmolarity gave a decreased AUC of platinum in the i.p. fluid. Hypotonic conditions continued for 30 min at most after i.p. injection of hypotonic solutions. When the same dose of cisplatin was given to rats with tumors derived from AH100B carcinoma cells, the amount of platinum taken by i.p. solid tumors from the solution of 103 mosm/l was about twice that from the isotonic solution and was much the same as that taken up from the isotonic solution with twice the amount of cisplatin. These results indicate that hypotonic i.p. cisplatin chemotherapy might be preferable to escalation of the dose of i.p. cisplatin in the treatment of peritoneal carcinomatosis.

Clinical significance of the detection of thymidine phosphorylase activity in esophageal squamous cell carcinomas

In this study, we obtained fresh samples of tissue (tumors, adjacent normal mucosas, and metastatic lymph nodes) from 64 patients (metastatic lymph nodes were obtained from 16 patients) with esophageal cancer who underwent esophagectomy between 1993 and 1998. The thymidine phosphorylase (dThdPase) levels of tumors as determined by the ELISA method were compared with clinicopathological findings of tumors and were evaluated for their usefulness as a prognostic parameter for these patients. The dThdPase levels of tumors (221 ± 21 U/mg protein) and metastatic lymph nodes (253 ± 51 U/mg protein) were significantly higher than the dThdPase level of normal mucosas (53 ± 7 U/mg protein, p < 0.001). The dThdPase levels of tumors did not correlate with the histopathological grading of tumors, the depth of tumor invasion, and lymph node metastasis. The 3-year survival rate of 32 patients with a high level of dThdPase (42%) was not different from that of 32 patients with a low level of dThdPase (52%, p = 0.267). Moreover, the dThdPase level of tumors was not an independent prognostic factor for patients with esophageal cancer. These findings suggest that the level of dThdPase activity in esophageal cancers may not correlate with tumor progression and may not be a useful prognostic marker for patients with esophageal squamous cell carcinoma.

Number of argyrophilic nucleolar organizer regions is a good indicator of lymph node metastasis in patients with esophageal carcinoma

The number of argyrophilic nucleolar organizer regions (AgNORs) was evaluated as a predictor of lymph node metastasis in 45 patients who had undergone resection of advanced squamous cell carcinoma of the esophagus. The mean AgNOR score of carcinomas was 5.0 ± 1.8, and it was greater than that of normal esophageal epithelium adjacent to a carcinoma (2.3 ± 0.5, P<0.001). The AgNOR score of tumors from 26 patients with lymph node metastasis was 6.1 ± 1.6, and it was greater than that of tumors from 19 patients without lymph node metastasis (3.7 ± 1.0, P<0.001). The AgNOR scores of metastatic lymph nodes (4.9 ± 1.5) from 26 patients with lymph node metastasis were closely related to the number of metastatic lymph nodes of individual patients (r =0.582, P<0.001). The 3-year survival rate in patients with low AgNOR scores (AgNOR score <5, n=22) was 56.2%. By contrast, that in patients with high AgNOR scores (AgNOR score ≥5, n=20) was only 13.1%. There was a statistically significant difference between the two survival curves (P<0.05). These results indicate that the AgNOR score is a good indicator of lymph node metastasis and suggest that it might also be a useful prognostic marker in patients with esophageal cancer.ZusammenfassungDie Anzahl der AgNOR wurde als Indikator für Lymphknotenmetastasen (LKM) bei 45 Patienten mit reseziertem Plattenepithelkarzinom des Ösophagus untersucht. Der mittlere AgNOR-Karzinomscore betrug 5,0 ± 1,8 und war damit höher als bei normalem Ösophagealepithel in der Nachbarschaft des Karzi noms (2,3 ± 0,5, p<0,001). Der AgNOR-Tumorscore betrug bei 26 Patienten mit LKM 6,1 ± 1,6 und war damit höher als bei 19 Patienten ohne LKM (3,7 ± 1,0, p< 0,001). Die AgNOR-Scores der metastatischen Lymphknoten (4,9 ± 1,5) bei 26 Patienten mit LKM wiesen eine enge Korrelation zur Anzahl metastatischer Lymphknoten bei einzelnen Patienten auf (r=0,582, p<0,001). Die Dreijahresüberlebensrate mit niedrigen AgNOR-Scores (AgNOR-Score <5, n=22) betrug 56,2%, hingegen bei Patienten mit hohen AgNOR-Scores (AgNOR-Score ≥ 5, n=20) nur 13,1%. Es gab einen statistischen signifikanten Unterschied zwischen beiden Überlebenskurven (p< 0,05). Nach diesen Resultaten ist der AgNOR-Score ein guter LKM-Indikator und könnte auch gut zur Prognose bei Patienten mit Ösophaguskarzinom verwendet werden.