Hidenobu Kawamura

Significance of Ductal Margin Status in Patients Undergoing Surgical Resection for Extrahepatic Cholangiocarcinoma

ObjectivesThe objective of this study was to determine whether carcinoma in situ at the bile duct margin is prognostically different from residual invasive carcinoma in patients with extrahepatic cholangiocarcinoma.Summary Background DataAlthough there are many reports that the ductal margin status at bile duct resection stumps is a prognostic indicator in patients with extrahepatic cholangiocarcinoma, some patients who undergo resection with microscopic tumor involvement of the bile duct margin survive longer than expected.MethodsA retrospective clinicopathological analysis of 128 patients who had undergone surgical resection for extrahepatic cholangiocarcinoma was conducted. The status of the bile duct resection margin was classifiedas negative in 105 patients (82.0%), positive for carcinoma in situ in 12 patients (9.4%), and positive for invasive carcinoma in 11 patients (8.6%).ResultsDuctal margin status was an independent prognostic indicator by both univariate (p = 0.0022) and multivariate (p = 0.0105) analyses, along with lymph node metastasis. There was no significant difference between patients with a negative ductal margin and those with a positive ductal margin with carcinoma in situ (p = 0.5247). The 5-year survival rate of patients with a positive ductal margin with carcinoma in situ (22.2%) was significantly better (p = 0.0241) than with invasive carcinoma (0%). There was a significant relationship between local recurrence and ductal margin status (p = 0.0401).ConclusionsAmong patients undergoing surgical resection for extrahepatic cholangiocarcinoma, invasive carcinoma at the ductal resection margins appears to have a significant relation to local recurrence and also a significant negative impact on survival, whereas residual carcinoma in situ does not. Discrimination whether carcinoma in situ or invasive carcinoma is present is important in clinical setting in which the resection margin at the ductal stump is positive.

The usefulness of the ATP assay with serum-free culture for chemosensitivity testing of gastrointestinal cancer

In order to predict a patients response to a drug prior to chemotherapy for gastrointestinal cancer, we developed an adenosine triphosphate (ATP) assay with serum-free culture (SF-ATPA) which enables fibroblast overgrowth to be suppressed. A total of 244 gastrointestinal cancer tissue samples were obtained from surgical resection. After enzymatic digestion, cells (2 x 10(4)/well) were cultured for 72 h with continuous exposure to drugs (single or combined use), and cell viability was evaluated by measuring the intracellular ATP level. 208 of 244 samples (85%) were considered to be evaluable in terms of drug response. There were no differences in the evaluability rates among the tumour types. A drug was judged as active using the criterion of < or = 50% reduction of the intracellular ATP level in a single-agent treated group compared with the level of the control. Similarly, in the combined drug treated group, drugs were considered as active using two different criteria (< or = 30% reduction of the intracellular ATP level for two drugs and < or = 20% for three drugs). Each tumour type had its own spectrum for chemosensitivity. Of 25 patients evaluated for assay-clinical correlations, 16 were examined by both single-agent and combined drug administration and the predictive accuracy of the assay was higher for the combined drug than for the single agent (88% versus 69%, respectively). In 25 patients, the true positive rate was 64% and the true negative rate was 100%, yielding an overall predictive accuracy of 84%. These results suggest that SF-ATPA may be useful for predicting drug response in patients with gastrointestinal cancer.

Angiotensin II and epidermal growth factor receptor cross-talk mediated by a disintegrin and metalloprotease accelerates tumor cell proliferation of hepatocellular carcinoma cell lines.

Aim:  The cross‐talk pathway between angiotensin II (AngII) and the epidermal growth factor receptor (EGFR) mediated by epidermal growth factor (EGF)‐like ligands cleaved by a disintegrin and metalloprotease (ADAM) has been elucidated in several cell types. Even though the liver is a representative angiotensinogen‐producing organ, such cross‐talk has never been elucidated in hepatocellular carcinomas (HCCs). We investigated whether AngII exerted a mitogenic effect on HCC cell lines through the AngII–EGFR cross‐talk pathway.

Aberrant maspin expression in gallbladder epithelium is associated with intestinal metaplasia in patients with cholelithiasis

Objective: Aberrant expression of maspin protein related to DNA hypomethylation in the promoter region is frequently observed in gallbladder carcinomas, whereas the non-tumorous gallbladder epithelium is maspin negative. We investigated maspin expression in non-tumorous gallbladder epithelium in patients with cholelithiasis. Methods: An immunohistochemical study of maspin expression was performed in 69 patients with cholelithiasis and 30 patients with gastric cancer without cholelithiasis. Results: Immunoreactivity for maspin was observed in focal and patchy regions of the gallbladder epithelium. Positive immunoreactivity for maspin was significantly associated with the presence of intestinal metaplasia in patients with cholelithiasis (p<0.05). Conclusion: The high incidence of aberrant maspin expression in both intestinal metaplasia and carcinoma of the gallbladder supports the assumption that intestinal metaplasia of the gallbladder may predispose to gallbladder carcinoma.

Drug-sensitivity testing in patients with human oesophageal squamous cell carcinoma

To evaluate the response to chemotherapeutic agents against human oesophageal cancer, 19 samples were tested by the human tumour clonogenic assay (HTCA), 21 samples by subrenal capsule assay (SRCA) and 33 samples by SRCA with immunosuppressant (IS-SRCA). The evaluability rate of was 21% for HTCA, 95% for SRCA and 91% for IS-SRCA. No active agent was detected by HTCA, however, 29% of the drugs tested by SRCA and 22% by IS-SRCA were considered to be active. Histological analysis revealed substantial inflammatory infiltrates and poor tumour cell preservation with SRCA; however, infiltrates were minimal and there was a high degree of tumour cell preservation with IS-SRCA. The response rates of IS-SRCA were comparable with those of prior clinical tests for each drug. These results suggested that IS-SRCA is the most useful drug sensitivity test for human oesophageal cancer.