Molecular Biomarker Study in a Randomised Phase III Trial of Irinotecan Plus S-1 versus S-1 for Advanced Gastric Cancer (GC0301/TOP-002).

AIMS: Gastric cancer is a common and heterogeneous disease; however, global standard and biomarkers for selecting chemotherapy regimens have not been established. This study was designed retrospectively to identify molecular biomarkers for irinotecan plus S-1 (IRI-S) and S-1 therapy from subset analyses in GC0301/TOP-002, a randomised phase III trial for advanced gastric cancer. MATERIALS AND METHODS: Paraffin-embedded primary tumour specimens were collected from 126 of 326 randomised patients in GC0301/TOP-002. The mRNA was measured for thymidylate synthase, dihydropyrimidine dehydrogenase, topoisomerase I, excision repair cross-complementing gene 1 (ERCC1) and thymidine phosphorylase; categorised into low and high to analyse their association with efficacy end points. RESULTS: There was no significant difference in each mRNA between S-1 and IRI-S groups, whereas there were differences among some clinical characteristics. Multivariate analyses for overall survival showed that mRNA levels were not correlated with prognosis. By comparison, between IRI-S and S-1 arms, low thymidylate synthase, low ERCC1 and high thymidine phosphorylase were associated with better prognosis for IRI-S versus S-1 (hazard ratio = 0.653, 0.702 and 0.709, respectively; P < 0.15 for each interaction). CONCLUSION: Low thymidylate synthase, low ERCC1 and high thymidine phosphorylase are candidates for predictive biomarkers for first-line treatment in advanced gastric cancer by IRI-S. Further study is warranted to confirm these results in other clinical trials and cohort studies.

Randomized controlled trial of adjuvant uracil-tegafur versus surgery alone for serosa-negative, locally advanced gastric cancer.

BACKGROUND: This prospective randomized study compared the survival of patients with tumour node metastasis (TNM) stage T2 N1-2 gastric cancer treated by gastrectomy alone or gastrectomy followed by uracil-tegafur. METHODS: Patients were randomly assigned to surgery alone or to surgery and postoperative uracil-tegafur 360 mg per m(2) per day orally for 16 months. The primary endpoint was overall survival. Relapse-free survival and site of recurrence were secondary endpoints. RESULTS: Of 190 registered patients, 95 were randomized to each group; two patients with early cancer were subsequently excluded from the chemotherapy group. The trial was terminated before the target number of patients was reached because accrual was slower than expected. Drug-related adverse effects were mild, with no treatment-related deaths. At a median follow-up of 6.2 years, overall and relapse-free survival rates were significantly higher in the chemotherapy group (hazard ratio for overall survival 0.48, P = 0.017; hazard ratio for relapse-free survival 0.44, P = 0.005), confirming the survival benefit shown in an interim analysis performed 2 years earlier. CONCLUSION: Interim and final analyses revealed a significant survival benefit for postoperative adjuvant chemotherapy with uracil-tegafur in patients with serosa-negative, node-positive gastric cancer. REGISTRATION NUMBER: NCT00152243 (http://www.clinicaltrials.gov).

Hepatectomy using an ultrasonically activated scalpel for hepatocellular carcinoma.

BACKGROUND: The first retrospective studies were performed to compare the efficacy of the ultrasonic cavitational aspirator (aspirator group) and the ultrasonically activated scalpel (scalpel group) for hepatic resection in patients with hepatocellular carcinoma. PATIENTS AND METHODS: The aspirator group consisted of 8 patients (6 with liver cirrhosis and 2 with chronic hepatitis in the nontumorous liver), and the scalpel group of 7 patients (6 with liver cirrhosis and 1 with chronic hepatitis). All patients underwent limited hepatic resection, and the intermittent Pringle maneuver was applied during hepatic transection. RESULTS: There were no significant differences in preoperative hepatic function, type of hepatectomy, tumor size and maximum cross-sectional area of the resected specimen between the 2 groups. The amount of intraoperative blood loss was significantly less in the scalpel group than in the aspirator group (684 versus 1,859 ml, p < 0.05). The operation time was significanly shorter in the scalpel group than in the aspirator group (176 versus 262 min, p < 0.05). There were no significant differences in postoperative liver function and morbidity between the 2 groups. CONCLUSIONS: The ultrasonically activated scalpel is effective in reducing blood loss and in shortening the time of operation, and can be employed during limited resection of the liver with cirrhosis or chronic hepatitis.

Mitotic index is the best predictive factor for survival of patients with resected hepatocellular carcinoma.

BACKGROUND: In patients with hepatocellular carcinoma (HCC), tumor recurrence is not infrequent after resection. It is presumed that characteristics of the tumor such as cellular malignancy might influence the prognosis of the patients in association with tumor stage and radicality of the procedure. METHODS: Univariate and multivariate analyses were used to retrospectively determine the clinicopathologic factors potentially related to survival in 40 patients who underwent hepatectomy for HCC. RESULTS: In univariate analysis, tumor stage I or II, mitotic index of 4 or less/10 random high-power fields, solitary tumor, and curative resection were significantly correlated with better survival. In multivariate analysis, the mitotic index and surgical curability were independently significant variables influencing survival of patients, and the mitotic index was the best predictive factor. A highly significant correlation was found between the mitotic index and Ki-67 labeling index. Compared to tumors with a mitotic index of 4 or less, those with a mitotic index of 5 or more had a higher association with multiple tumors and advanced tumor stage, which preclude curative resection. CONCLUSION: Analysis of the mitotic index is quite simple, and the mitotic index could be a useful factor for predicting the long-term survival of patients with HCC following hepatic resection.

Prediction of recurrence and extratumor spread of hepatocellular carcinoma following resection.

BACKGROUND AND OBJECTIVES: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing hepatectomy depends mostly on tumor recurrence. Portal vein invasion (Vp) and intrahepatic metastasis (IM) might strongly reflect the invasiveness of HCC, but the number of patients in the present series in whom either of these factors were detected was small. In this study, we defined Vp and IM as the extratumor spread, and we focused on the relationship between recurrence in patients after hepatectomy and the extratumor spread and the mitotic activities of cancer cells, in the hope that careful monitoring of recurrence might be possible by simply analyzing histology of the resected specimens. METHODS: Univariate and multivariate analyses were used to determine the factors potentially related to recurrence in 50 patients who underwent hepatectomy for HCC. RESULTS: The cumulative recurrence rate at 5 years was 81.0%. In univariate analysis, absence of the extratumor spread, mitotic index of four or less, and curative resection were significantly correlated with low incidence of recurrence. In multivariate analysis, the extratumor spread was the only significant variable influencing recurrence. The mitotic index in HCCs with the extratumor spread was significantly higher than the mitotic index in HCCs without the extratumor spread. CONCLUSIONS: As a predictive factor for recurrence after resection of HCC, the extratumor spread that reflects the malignant potential of cancer cells was found to be more accurate than is any single invasiveness parameter such as Vp or IM.

Diagnostic capability and rational resectional surgery for early gallbladder cancer.

Gallbladder carcinoma limited to the mucosa (pT1a) or muscularis proper (pT1b) with no lymph node metastasis (stage I) is defined as early carcinoma of the gallbladder. Eleven patients with early carcinoma of the gallbladder, treated by either simple or extended cholecystectomy (cholecystectomy plus wedge resection of the gallbladder bed of the liver and lymphadenectomy), were reviewed to determine the diagnostic capability and to clarify the rational resectional procedure for this stage of the disease. A definitive pre-operative diagnosis was made in only 2 patients with pT1b tumors. Most of the remaining 9 patients were diagnosed incidentally after cholecystectomy for polyps or stones. Among 7 patients with pT1a tumors, 5 underwent simple cholecystectomy and 2 underwent extended cholecystectomy. All 7 patients survived with a recurrence-free condition for 5 years or more following the operation. Two patients with pT1b tumors, however, died of a local recurrence or bile duct carcinoma following simple cholecystectomy. Two patients with pT1b tumors who were correctly diagnosed before the operation and underwent extended cholecystectomy survived without recurrence. It is concluded that patients with pT1a tumors can be successfully treated by simple cholecystectomy, while patients with pT1b tumors require extended cholecystectomy.

Therapeutic significance of palliative operations for gastric cancer for survival and quality of life.

BACKGROUND AND OBJECTIVES: There have been few reports on the objective assessment of quality of life (QOL) in patients with gastric cancer following palliative operations. The benefit of a palliative operation for survival and QOL of patients with gastric cancer is not clear. METHODS: Survival and hospital-free survival (HFS), which is considered to be one objective indicator of QOL, were studied in 95 patients undergoing palliative operations for gastric cancer. Univariate and multivariate analyses were used to determine the clinicopathologic factors potentially related to survival of patients. RESULTS: In univariate analysis, palliative gastrectomy and absence of peritoneal dissemination were significantly correlated with better survival. The significance of palliative gastrectomy for survival was, therefore, evaluated for various degrees of peritoneal dissemination: P0 no dissemination; P1, metastasis to the adjacent peritoneum; P2, a few scattered metastases to the distant peritoneum; and P3, numerous metastases. Survival and achievement of HFS for 3 months or longer were higher following palliative gastrectomy than gastrojejunostomy. Among gastrectomies, however, total gastrectomy performed in patients with P2 or P3 showed a poorer outcome for survival and HFS than total gastrectomy performed with P0 or P1 and distal gastrectomy. CONCLUSIONS: As a palliative measure, gastrojejunostomy and total gastrectomy performed with P2 or P3 peritoneal dissemination had no beneficial effect on the prolongation of survival or improvement of QOL of patients with gastric cancer.

Palliative operation for cancer of the head of the pancreas: significance of pancreaticoduodenectomy and intraoperative radiation therapy for survival and quality of life.

The benefits of a palliative operation and intraoperative radiation therapy (IORT) for survival and quality of life (QOL) of patients with cancer of the head of the pancreas are not clear. Survival and hospital-free survival (HFS), which are considered to be objective indicators of QOL, were studied in 13 patients who underwent palliative pancreaticoduodenectomy (PD) and 32 patients who underwent surgical bypass. Although there was no significant difference in the survival of patients who underwent PD or bypass (median survivals of 9 months and 7 months, respectively), HFS for 3 months or longer was achieved in 84.6% of the patients who underwent PD, which was significantly higher than that of the 53.1% in patients who underwent surgical bypass (p < 0.05). Among TNM stage III patients, a significant difference in survival was observed between surgical bypass associated with IORT and bypass alone (p < 0.05); the median survival time of the IORT group was 10 months, whereas that of the control group was 5 months. In addition, HFS of 3 months or longer was achieved in 83.3% of patients who underwent bypass with IORT but in only 25.0% of the patients who underwent surgery alone (p < 0.01). The addition of IORT to palliative PD neither prolonged survival nor improved HFS. These results show the beneficial effect of palliative PD on QOL, and the efficacy of IORT for survival and QOL was proved in cases with stage III pancreatic cancer who underwent surgical bypass. For patients subjected to palliative PD, however, IORT is not thought to be beneficial for either survival or QOL.

Histologic features and clinical significance of venous invasion in colorectal carcinoma with hepatic metastasis.

BACKGROUND: In colorectal carcinoma, venous invasion has been related to patient survival. Liver metastasis develops more frequently when venous invasion is present. However, the histologic features and clinical significance of venous invasion are not well understood. METHODS: A histologic study of venous invasion in colorectal carcinoma was performed on 19 patients with synchronous hepatic metastasis (Group A), 16 patients with metacaronous hepatic metastasis (Group B), and 26 patients with Dukes Stage C tumors who survived for 5 years without recurrence (Group C). The histologic features of venous invasion were classified into three types: tumor cells that were distant from the vein walls were categorized as floating type, those filling the lumen of a vein as filling type, and those surrounded by a vein obliterated with inflammatory reaction as occlusive type. RESULTS: Venous invasion was present in 89.5% of Group A patients and 75% of Group B patients, which was significantly higher than the 15.4% observed in Group C patients (P < 0.001). A slight to extensive degree of venous invasion was found in Groups A and B, but no extensive venous invasion was found in Group C. All patients in Groups A and B (except one patient) had floating, filling, or a combination of floating and filling types of venous invasion, whereas all patients in Group C had the occlusive type of venous invasion. A majority of the patients in all three groups showed invasion of extramural veins. CONCLUSIONS: There is a close relationship between venous invasion and the development of liver metastasis in patients with colorectal carcinoma. Patients with no sign of metastasis had a lower incidence and lower extent of venous invasion, and inflammatory damage to the vein walls around the intravenous tumor appeared to reduce the likelihood of distant metastasis.

[Changes in hepatic and renal tissue blood flows in cirrhotic rat in hemorrhagic shock].

The purpose of present study is to elucidate the influence of hypotension on hepatic and renal tissue circulations in cirrhosis. The changes of hepatic and renal tissue blood flows (TBF) were studied in hemorrhagic shock using cirrhotic rats. The hepatic and renal energy charges (EC) were measured in normal and cirrhotic rats. Hepatic TBFs of the cirrhotic rats decreased to 74% of the normal, portal pressure increased to 140%, but renal TBF was not changed significantly. In hemorrhagic shock induced by blood exsanguination, hepatic and renal TBFs of normal rats were restored to the preshock levels by transfusion of shed blood, but those of cirrhotic rats were not restored. Furthermore, the hepatic and renal ECs of normal-shocked rats were not different from those of control rats, but the ECs of cirrhotic-shocked rats were decreased significantly. These findings suggest that hypotension under cirrhosis disturbs hepatic and renal tissue circulations and energy metabolisms also in a period of after-shock phase.

Effects of superselective arterial embolization and chemoembolization on energy charge and total blood flow of the rat liver.

The superselective transcatheter arterial embolization (TAE) and chemoembolization (TAC) of the periphery of the left and median lobes of the rat liver were performed using 1.5 mg of gelatin sponge dissolved in saline solution and mitomycin (MMC) at a dose of 1.6 mg/kg b.wt. The energy charge (EC) of the embolized and chemoembolized lobes decreased after the embolization but was restored 3 h later. The total hepatic blood flow (THBF) was reduced to about one half and required 1 week to be restored to the preembolization levels in both groups. Microscopic centrilobular necrosis and vacuolization were found. The addition of MMC did not produce marked untoward effects. Thus, the normal liver is able to restore its energy pool despite a reduction in the THBF after superselective arterial embolization, and this recovery is not altered even by the use of a high dose of MMC.