S-1 monotherapy as first-line treatment in patients with advanced biliary tract cancer: a multicenter phase II study.

A pilot phase II study showed S-1 monotherapy to be safe and active against biliary tract cancer (BTC). We, therefore, conducted a multicenter phase II study to evaluate the antitumor effect and safety of S-1 in previously untreated patients with advanced BTC. Eligible patients had pathologically proven, unresectable adenocarcinoma with no prior chemotherapy or radiotherapy. Patients received S-1 orally at 80 mg/m2 total daily dose divided b.i.d. for 28 days followed by 14 days of rest. Of the 41 enrolled patients, 40 were assessable. The primary tumor sites were as follows: gallbladder (n = 20), extrahepatic bile duct (n = 15), and the ampulla of Vater (n = 5). One patient (2.5%) achieved a complete response, 13 patients (32.5%) had partial responses, 17 patients (42.5%) had no change, 7 patients (17.5%) had progressive disease, and 2 patients (5.0%) were not evaluable. The overall objective response rate was 35.0%. The median overall survival (median OS) was 9.4 months, and the median time to progression was 3.7 months. Grade 3 or 4 toxicities included fatigue (7.5%), anorexia (7.5%) and T-Bil elevation (7.5%). Significant antitumor activity combined with a mild toxicity profile was observed. This monotherapy warrants further evaluation in a randomized study.

Anti-HBs-positive liver failure due to hepatitis B virus reactivation induced by rituximab.

A 59-year-old man developed acute hepatitis with reactivated hepatitis B virus (HBV) following administration of rituximab (anti-CD20 monoclonal antibody). The patient was diagnosed with malignant lymphoma in 1998, and virus marker testing indicated HBV surface antigen (HBsAg)-negative and anti-HBs antibody (anti-HBs)-positive results when chemotherapy including rituximab was started. Levels of aminotransferases were elevated, and HBsAg results turned positive. Despite therapy for late-onset hepatic failure, the patient died. Rituximab appears likely to have induced HBV reactivation in this case. Anti-viral agents should be administered for both HBsAg-positive and anti-HBs-positive patients who are scheduled to receive rituximab.

An in situ carcinoma of the pancreas forming 2 invasive ductal carcinomas.

A 62-year-old man underwent distal pancreatectomy for invasive pancreatic carcinoma. Histopathologically, the main lesion that obstructed the main pancreatic duct and measured 2.0 cm in diameter was a moderately differentiated adenocarcinoma with marked neural invasion. The main pancreatic duct immediately distal to the tumor was lined with carcinoma in situ, and gradual transition from carcinoma in situ to mild atypia was observed. An accessory tumor measuring 0.8 cm in diameter was located in the pancreatic tail. The adjacent pancreatic contained carcinoma in situ and flat dysplastic cells without papillary growth. We concluded that the structure of the cells lining the ducts and the comparatively flat formation and gradual transition indicated that 2 lesions, each invading the pancreatic parenchyma, arose from the intraductal tumor (carcinoma in situ or precancerous lesion).

Small hepatocellular carcinoma associated with Wilson's disease.

We report a 66-year-old male patient with hepatocellular carcinoma (HCC) associated with Wilson's disease. The patient presented with unresolving abnormal liver function test, decreased serum ceruloplasmin levels and increased 24-hour urine copper excretion. Liver biopsy specimen revealed the presence of increased levels of copper and features suggestive of Wilson's disease. Abdominal imaging showed the existence of a small HCC. Three years after chemoembolization and microwave coagulation therapy for HCC, he died of hepatic failure, which apparently resulted from chemoembolization. Patients with Wilson's disease should be screened for HCC. We should elude therapies such as chemoembolization in these patients.

Unusual metastasis of hepatocellular carcinoma to the esophagus.

This report describes a case of metastatic hepatocellular carcinoma (HCC) presenting as a polypoid mass in the lower esophagus. The patient was a 63-year-old man with HCC. An endoscopic examination revealed a pedunculated polypoid mass, about 3 cm in diameter, at the lower part of the esophagus. The biopsy specimen obtained from the tumor revealed that the mass consisted of a pseudoglandular arrangement of tumor cells, and the tumor was diagnosed as metastatic HCC. There were no symptoms due to esophageal tumor. He died of progressive hepatic failure. Cases of premortem-diagnosed esophageal metastasis from HCC are extremely rare.

A phase I study of doxifluridine combined with weekly paclitaxel for metastatic gastric cancer.

PURPOSE: Based on the synergistic effect in preclinical studies, a phase I clinical trial for the combination of paclitaxel and doxifluridine (an intermetabolite of capecitabine) was performed to determine the recommended dose for the treatment of patients with metastatic gastric cancer. METHODS: The dose of paclitaxel was increased from 60 mg/m2 at level 1 to 90 mg/m2 at level 5. It was administered as a 1-h infusion on days 1 and 8. The dose of doxifluridine was fixed at 600 mg/m2 per day up to level 3, and escalated to 800 mg/m2 per day at levels 4 and 5. It was administered orally for 2 weeks. The treatment was repeated every 3 weeks. RESULTS: A total of 28 patients were enrolled. No dose-limiting toxicity (DLT) was observed at levels 1 and 2 (paclitaxel 70 mg/m2). A DLT of grade 4 neutropenia lasting for more than 4 days was observed in one patient at level 3 (paclitaxel 80 mg/m2). In addition, the first five of six patients in this group experienced grade 3 neutropenia during the first treatment cycle. A further six patients were added in order to confirm the safety of this dosage level, and no more DLTs except for grade 3 nausea in one patient were observed in the second cohort. No DLT was seen in three patients at level 4 (paclitaxel 80 mg/m2). DLTs (grade 3 neuropathy in one patient and a treatment delay of the second cycle for more than 1 week due to grade 3 neutropenia in another) were observed in two out of six patients at level 5 (paclitaxel 90 mg/m2), and this dose level was determined as the maximum tolerated dose. The tumor response rate was 42% (95% confidence interval 20-67%) in 19 patients with measurable lesions. CONCLUSIONS: The recommended dose was determined as 80 mg/m2 of paclitaxel (days 1 and 8) and 800 mg/m2) of doxifluridine (days 1-14) every 3 weeks. The results of this phase I study are encouraging and a phase II trial is thus warranted.

Gastritis cystica polyposa concomitant with gastric inflammatory fibroid polyp occurring in an unoperated stomach.

The endoscopic examination of a 61-year-old male patient revealed a protruding lesion in the greater curvature of the lower third area of the stomach. The lesion, 17 mm in size, was resected completely with endoscopic submucosal dissection using an insulated-tip diathermic knife (IT-ESD). Histological examination of the protruding lesion revealed proliferation of fibroblasts and infiltration of inflammatory cells in the mucosa and submucosa, and it was diagnosed as an inflammatory fibroid polyp (IFP). Gastritis cystica polyposa (GCP) was presented adjacent to the IFP. This may be the first report of GCP concomitant with gastric IFP occurring in an unoperated stomach.

[Clinical study of irinotecan therapy in patients with fluoropyrimidine-resistant advanced colorectal cancer].

The clinical efficacy and safety of irinotecan (CPT-11) therapy were studied retrospectively in patients with fluoropyrimidine-resistant advanced colorectal cancer. The subjects were 44 patients who were treated with CPT-11 alone or with a combination of CPT-11 and mitomycin C (MMC) at our institute from April 1999 to March 2003. CPT-11 (120-150 mg/m2) alone or CPT-11 with MMC (5 mg/m2) was administered every 2 weeks. The objective overall response rate was 11% (95% confidence interval, 3.8-25%). In 38 patients who were treated until October 2002, the median survival time was 12 months. Two-year survival rate was 13%. Grade 3 anorexia or diarrhea occurred in 6 patients (14%) and 5 patients (11%), respectively. There was no treatment-related death or early death within 30 days from the last administration of CPT-11 (+MMC). This retrospective study demonstrated the reproducible activity and safety of CPT-11 for the treatment of fluoropyrimidine-resistant advanced colorectal cancer in clinical practice.

[Clinical study of gemcitabine therapy for recurrent or metastatic pancreatic cancer].

The clinical efficacy and safety of gemcitabine (GEM) monotherapy were studied retrospectively in the patients with recurrent or metastatic pancreatic cancer. The subjects were 30 patients who were treated with GEM at our center between May 2001 and August 2003. The objective overall response rate was 11% (3/28; 95% confidence interval, 2.3-28%). The disease control rate (CR+PR+SD) was 54%. Grade 3 or 4 neutropenia was most frequently seen in 46%. Non-hematological toxicities were mild. The median survival time was 4.8 months. One-year survival rate was 15%. This study showed the reproducible activity and safety of GEM in practice.

Granular cell tumor occurring in the sigmoid colon treated by endoscopic mucosal resection using a transparent cap (EMR-C).

A case of granular cell tumor occurring in the sigmoid colon is reported. The patient, a 56-year-old man, visited our hospital for further evaluation of occult blood in his stool. Endoscopic examination revealed a yellowish, hemispheric submucosal tumor (SMT) with redness, about 6 mm in diameter, in the sigmoid colon. Endoscopic mucosal resection using a transparent cap (EMR-C) was performed, and histological examination revealed that the tumor consisted of a nested growth of large tumor cells with ample granular cytoplasm and small round nuclei. The tumor cells expressed S-100 protein and were stained with neuron-specific enolase (NSE) and periodic acid-Schiff, but were negative for desmin, vimentin, and cytokeratin. The resected tumor was diagnosed as a granular cell tumor. This may be the first report of a colorectal granular cell tumor successfully treated with EMR-C.

[Clinical study of TS-1 therapy for inoperable and recurrent gastric cancer].

The clinical efficacy and safety of TS-1 therapy were studied retrospectively in patients with inoperable and recurrent gastric cancer. The subjects were 45 patients who were treated with TS-1 for more than 4 weeks at our center between May 1999 and July 2002. The objective overall response rate was 32% (14/44; 95% confidence interval, CI, 19-48). The response rate in the chemo-naive patients was 44% (11/25; 95% CI, 24-65), and that in the patients with previous chemotherapy was 16% (3/19; 95% CI, 3.4-40). Although doses or durations of TS-1 administration were reduced in 22 patients (reduction group) due to adverse effects or poor performance status, they achieved a fairly high response rate of 38% (8/21). For primary lesions, the response rate was 30% (8/27). The prevalence of adverse reactions with a grade of 3 or 4 was 36%. However, the prevalence of each grade 3 or 4 adverse effect was relatively low, at 13% for neutropenia, and around 5% for anorexia, nausea, vomiting, and diarrhea. The median administration period was 10 weeks (4-47 weeks) in all patients and 11 weeks (6-47 weeks) in the reduction group. The relative dose intensity was 0.89 in all patients and 0.81 in the reduction group. In patients who were treated until August 2001, the median survival time (MST) was 13 months with 1-year and 2-year survival rates of 53% and 14%, respectively. These results were similar to those reported in the phase II study for the new drug approval. This study demonstrated the reproducible activity and safety of TS-1 in practice.

Spontaneous closure of intrahepatic portovenous shunt in a noncirrhotic patient with recurrent encephalopathy.

A 70-year-old man was admitted to our hospital with recurrent encephalopathy. Liver function tests, abdominal computerized tomography, ultrasonography, angiography, and laparoscopy revealed an intrahepatic portovenous shunt in a noncirrhotic liver. During follow-up, the intrahepatic portovenous shunt closed spontaneously. Subsequent liver function tests were markedly improved, with resolution of the patient's previously disturbed consciousness. In the elderly, intrahepatic portovenous shunt that can be managed with conservative therapy may spontaneously close, suggesting that management options should include watchful waiting.

Gastric cancer concomitant with inflammatory fibroid polyp treated with endoscopic mucosal resection using an insulation-tip diathermic knife.

The endoscopic examination of a 66-year-old male patient revealed a protruding lesion close to a reddish IIc area in the antrum of the stomach. The protruding lesion and reddish area were resected completely with endoscopic mucosal resection using an insulation-tip diathermic knife (IT-EMR). Histological examination of the protruding lesion revealed proliferation of fibroblasts and infiltration of inflammatory cells, and it was diagnosed as an inflammatory fibroid polyp (IFP). Adenocarcinoma in the IIc area was present adjacent to the IFP. This may be the first report of gastric cancer concomitant with gastric IFP treated by endoscopic mucosal resection.

Specially designed needle-guide for intercostal puncture of hepatocellular carcinoma seen on computed tomography and not visualized on ultrasonography.

Ultrasound (US)-guided ethanol injection therapy is becoming popular as a therapeutic tool for treating hepatocellular carcinoma (HCC); however, there are some HCCs seen on computed tomography (CT) and not visualized on US. The aim of this study was to learn whether ethanol could be injected into such tumors correctly using a specially designed needle-guide for intercostal puncture on US. We developed a new needle-guide attachment for US. In vitro experiments were done with gelatin gel and porcine liver to evaluate the accuracy of the puncture depth. We calculated the difference between the distance from the surface to the needle tip and the set depth as errors. Fifteen patients with HCC in which CT revealed a tumor but US did not were subjected to US-guided ethanol injection using this needle-guide, and the entry of ethanol into tumors was confirmed by subsequent enhanced CT. The errors were within 1.0 mm in the in vitro experiments using gelatin gel and porcine liver. In all HCC patients, ethanol was injected accurately. This new needle-guide may be useful for needle insertion to HCCs seen on CT and not visualized on US.

Acute-onset autoimmune hepatitis treated with living donor-liver transplantation.

A 50-year-old woman was diagnosed with acute-onset autoimmune hepatitis. She did not respond to steroid therapy including pulse therapy, and was subsequently treated with living donor-liver transplantation 36 days after the beginning of steroid therapy. Except for a period of transient mild acute rejection, her liver function tests remained within a normal range for 2.5 years after the operation. The courses of autoimmune hepatitis patients treated with living-donor liver transplantation have not been previously documented to our knowledge. Living donor-liver transplantation is thought to be one of the therapy options for severe autoimmune hepatitis.

Diagnosis of drug-induced liver injury in Japanese patients by criteria of Consensus Meetings in Europe.

Eighty-five Japanese patients with drug-induced liver injury were assessed by criteria of Consensus Meetings in Europe on causality assessment of drug-induced liver injury. Histopathological investigation was performed for all patients to confirm the diagnosis. We divided these patients into two groups by the date of disease onset. Cases before 1989 were defined as past cases, and those after 1990 as recent cases, because the clinical-pathological characteristics of drug-induced liver injury have changed due to the ability to diagnose hepatitis C virus infection since 1990. Fifty-seven patients with drug-induced liver injury were enrolled as past cases, and 28 as recent cases. For past cases, the results of assessment by the criteria of Consensus Meetings in Europe were as follows: 'very likely': 14 patients (25%), 'likely': 23 patients (40%), 'possible': 15 patients (26%), 'dubious': five patients (9%), and 'unlikely': none (0%). For recent cases, the results were as follows: 'very likely': six patients (22%), 'likely': 14 patients (42%), 'possible': six patients (22%), 'dubious': two patients (7%), and 'unlikely': none (0%). There were no differences between the past and recent cases in distribution of assessment. More than 90% of patients were assessed as 'possible' or more, and the remaining seven patients were assessed as 'dubious'. No patients were assessed as 'unlikely'. Five of seven patients assessed as 'dubious' had long-term cholestasis, and two had alcohol consumption. These results indicated that the criteria of Consensus Meetings in Europe were useful for diagnosing drug-induced liver injury in Japanese patients.

Combination therapy with interferon alpha and beta to chronic hepatitis C.

To increase the sustained response (SR) rate in chronic hepatitis C (CHC), we tried a combination therapy with interferon (IFN) alpha and beta. Fifty patients were grouped into 4 groups: group 1H (n=9), HCV serotype 1 and high HCV-RNA titer (over 6 log copies/ml); group 1L (n=11), HCV serotype 1 and low HCV-RNA titer (less than 6 log copies/ml); group 2H (n=23), HCV serotype 2 and high HCV-RNA titer; group 2L (n=7), HCV serotype 2 and low HCV-RNA titer. They were given a total dose of 768 MIU which included natural IFN beta (6 MIU) once daily for 28 consecutive days and then natural IFNalpha (10 MIU) three times a week for 20 weeks. Forty-nine patients with CHC receiving IFN alpha at total dose of 480 MIU served as single therapy group. In combination group, SR rate was achieved in 62%, 44% in 1H, 45% in 1L, 70% in 2H, and 86% in 2L, respectively. In single group, SR rate was achieved in 45, 14, 58, 60, and 82%, respectively. There was no significant difference for SR rate between combination group and single group. However, in patients with HCV-RNA titer between 6-7 log copies/ml of 1H group, SR rate in combination group (67%, 4/6) was significantly higher than that of single group (18%, 3/17) (p<0.05). These data suggest the usefulness of combination therapy with IFN alpha and beta in CHC with serotype 1 having moderately high HCV-RNA titer.

Influencing factors for recurrence of hepatocellular carcinoma treated with radiofrequency ablation.

Radiofrequency ablation (RFA), a new local therapy, has recently been developed for hepatocellular carcinoma (HCC). In this study, we have checked for the factors influencing the recurrence of HCC following RFA. We gave special emphasis to complete coagulation. The study population was comprised of 47 patients (80 tumors) with HCC with tumor size of <3 cm in maximal diameter. The patients were observed for a period of 2-3 years (average 865 days). The local recurrence rate was 19% at the end of 1 year, and 21% by the end of 2 years. The patients with local recurrence received significantly fewer RFA sessions (P<0.05) compared to patients with no recurrence. The frequencies of complete coagulation were significantly less (P<0.05) in patients with local recurrence than patients without local recurrence. The distant recurrence rate was 38% at 1 year, and 60% at 2 years. Patients with distant recurrence had significantly increased number of tumors (2.0+/-1.4) (P<0.05) compared to patients without distant recurrence (1.2+/-0.4). In conclusion, obtaining complete coagulation is an important factor to prevent local recurrence and the number of tumors predicted the distant recurrence in patients with HCC undergoing RFA.

Clinical characteristics of autoimmune hepatitis with histological features of acute hepatitis.

The number of patients with autoimmune hepatitis with histological features of acute hepatitis (AIH-AH) has been increasing recently. Here, the clinical features of patients with AIH-AH have been compared with those of patients with AIH with histological findings of chronic hepatitis (AIH-CH) and liver cirrhosis (AIH-LC). The levels of total serum bilirubin (P<0.05) and serum transaminases (P<0.05) were significantly higher in patients with AIH-AH than in patients with AIH-CH and AIH-LC. However, the serum levels of gamma-globulin (P<0.05) and immunoglobulin G (P<0.05) were significantly lower in AIH-AH than in patients with AIH-CH and AIH-LC. The aggregate score according to the criteria of the International Autoimmune Hepatitis Group in 1999 was also significantly lower in AIH-AH patients than in patients with AIH-CH and AIH-LC (P<0.05). Eleven patients with AIH-AH were treated with corticosteroids, however, the clinical response was insignificant in three patients. In summary, it is difficult to diagnose of patients with AIH-AH using the criteria of the International AIH scoring system. We wish that this scoring system would be modified in the near future.