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Background Nanoliposomal irinotecan (nal-IRI) was recently authorized in Japan for unresectable pancreatic cancer after disease progression following chemotherapy. Physicians now consider certain aspects of nal-IRI safety profile as slightly different from conventional irinotecan. This report aims to explore additional aspects of the nal-IRI safety in Japanese phase 2 study. Methods We analyzed the incidence, time to first onset, and time to resolution for adverse events that require special attention and other selected toxicities in the nal-IRI combination group (n = 46). Results Leukopenia/neutropenia (76.1%/71.7%), diarrhea (58.7%) and hepatic dysfunction (41.3%) were the most commonly reported treatment-emergent adverse events, with a median time to onset of 21.0 days (range: 8, 97), 9.0 days (1, 61) and 22.0 days (2, 325), respectively, and a median time to resolution of 8.0 days (95% confidence intervals: 8, 9), 4.0 days (4, 8) and 40.0 days (9, –), respectively. Eight patients experienced Grade ≥ 3 diarrhea and their symptoms were well controlled by dose modification except one patient who had drug withdrawal. The median time to resolution for Grade ≥ 3 and Grade ≤ 2 diarrhea was 17.5 days (95% confidence intervals: 1, 31) and 4 days (3, 7), respectively. Anorexia occurred in 28/46 patients (60.9%) with a median time to onset of 4.0 days (range: 2, 132) and a median time to resolution of 12.0 days (95% confidence intervals: 6, 26). Conclusions We explored safety profile of nal-IRI combination regimen recognized as effective and tolerable treatment for Japanese unresectable pancreatic cancer patients. Although the treatment-emergent adverse events occurred were controllable, patients with prolonged toxicities should be closely managed.

Systemic chemotherapy plays important role in pancreatic cancer not only for palliative treatment of unresectable disease, but also for neoadjuvant and adjuvant treatment of resectable disease. Most clinical trials of systemic chemotherapy have been conducted in non-elderly patients, and the results cannot always be extrapolated to elderly patients because of the uniqueness of this population. The number of elderly patients with pancreatic cancer has increased in an aging society; therefore, there is an urgent need to develop specific treatments for elderly patients with pancreatic cancer. Gemcitabine or S-1 monotherapy is generally considered appropriate even for vulnerable elderly patients. FOLFIRINOX is considered inapplicable based on its safety profile. Gemcitabine plus nab-paclitaxel and nanoliposomal irinotecan with fluorouracil plus folinic acid can be administered to elderly patients, because the phase III trials have shown the efficacy and safety for patients including those who were 75 years or older. However, the feasibility of these therapies for elderly patients is still under debate since the number of elderly populations was relatively small in these studies. To determine the indication for these regimens in the elderly, the background of each patient should be considered. Geriatric assessment such as the Geriatric 8 and the Geriatric Nutritional Risk Index can identify vulnerabilities and are therefore recommended in daily clinical practice as well as in clinical studies of elderly patients. It is expected that geriatric assessment will elucidate the eligibility criteria for those regimens in elderly individuals. Randomized clinical trials are ongoing to establish a standard treatment in the vulnerable elderly with advanced pancreatic cancer, who cannot tolerate the same regimen as in the non-elderly patients.

Neuroendocrine neoplasms (NENs) constitute a heterogeneous group of tumors. In this review, we summarize the results of various clinical trials that have been conducted to investigate the efficacy and safety of various therapeutic options for NENs. Based on the encouraging results obtained from these trials, various therapeutic options have been established for the treatment of NENs, including somatostatin analogs (SSAs), molecularly targeted drugs and cytotoxic agents. In addition, peptide receptor radionucleotide therapy has recently been evaluated for the treatment of various NENs. We also discuss the approach for selecting the appropriate drugs and sequence of treatment with the various drug classes, as recommended by different treatment guidelines. Finally, we discuss the scope for future research in this field, especially into the merits of combination therapy with molecularly targeted drugs plus SSAs, along with ongoing studies.

Objective To evaluate prospectively the efficacy and safety of sorafenib, which has been the first-line treatment for advanced hepatocellular carcinoma (HCC), in Japanese HCC patients (pts) with not only Child-Pugh (C-P) A class but also C-P B class. Methods Sorafenib was administered orally at the dose of 400 mg twice daily for pts with HCC and liver function of C-P score of 5-8. Administration was continued until the detection of disease progression or appearance of unacceptable toxicity. The primary endpoint was time to progression (TTP), and toxicity and the secondary endpoints included objective response, overall survival (OS). Results Forty C-P A pts and 12 C-P B pts were enrolled. The median TTP in the C-P A pts and C-P B pts was 3.3 months and 3.2 months, respectively. Among the pts with C-P A, complete response, partial response, and stable disease were achieved for 2.5%, 7.5% and 47.5%. Among the pts with C-P B, there were no treatment responses, 66.7% of pts had stable disease. The median OS in the C-P A pts and C-P B pts was 13.4 months and 7.4 months, respectively. With regard to toxicities, fewer C-P A pts experienced Grade 3/4 toxicities than C-P B pts (77.5% vs. 91.6%). There were no treatment-related deaths in either group of patients. Conclusions This study shows sorafenib has similar effectiveness in the recent post-approval studies and is well-tolerated in Japanese pts with HCC and Child Pugh A class. Sorafenib should be used with great care for Child Pugh class B pts.

No standard adjuvant treatment has been established for patients with curatively resected biliary tract cancer. S-1 has been reported to show promising efficacy with mild toxicity profiles in patients with advanced biliary tract cancer, and adjuvant S-1 therapy has been demonstrated to provide survival benefit in patients with resected gastric cancer and pancreatic cancer. The aim of this open-label, multicenter, randomized Phase III trial is to confirm that adjuvant chemotherapy with S-1 would prolong overall survival in patients with resected biliary tract cancer. This study was activated in September 2013. A total of 350 patients planned to be enrolled from 36 Japanese institutions over a period of 4 years. At July 2017, the protocol was revised to increase power from 70% to 80%. Therefore, the planned total sample size is 440. The primary endpoint is overall survival. This trial is registered with the UMIN Clinical Trials Registry as UMIN000011688.

Chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC). On the basis of the results of two pivotal Phase III placebo-controlled studies, sorafenib is currently acknowledged worldwide as the standard therapeutic agent for advanced HCC. Following the introduction of sorafenib for the treatment of HCC, Phase III trials of numerous other agents as first-line or second-line chemotherapy have been conducted to determine if any of these agents might offer superior survival benefit to sorafenib. In 2016, a clear survival benefit of regorafenib over placebo was demonstrated in HCC patients showing disease progression after sorafenib treatment. A year later, in 2017, lenvatinib has been shown to be non-inferior to sorafenib, in terms of the overall survival, in chemo-naïve patients with advanced HCC. More recently, promising outcomes have also been reported with new agents, such as nivolumab and cabozantinib. At present, various novel combination regimens including these agents are currently under development. Hepatic arterial infusion chemotherapy (HAIC) is frequently adopted for the treatment of locally advanced HCC in Japan, based on reports of high response rates and favorable long-term outcomes. Although some randomized controlled trials of HAIC plus sorafenib vs. sorafenib alone as first-line therapy have been conducted in patients with advanced HCC, no firm evidence of the superiority of one over the other has been established yet. In the future, demonstration of the survival advantage of HAIC and the recognition of HAIC as one of the standard treatments for patients with advanced HCC are expected.

Erlotinib plus gemcitabine has an acceptable safety and efficacy profile in pancreatic cancer. Interstitial lung disease remains a concern; patients should be assessed for risk factors prior to and during treatment., Objective Erlotinib plus gemcitabine is approved in Japan for the treatment of metastatic pancreatic cancer. The POLARIS surveillance study investigated safety (focusing on interstitial lung disease [ILD]) and efficacy of erlotinib plus gemcitabine in Japanese pancreatic cancer patients. Methods Patients receiving erlotinib plus gemcitabine for pancreatic cancer in Japan between July 2011 and August 2012 were enrolled. ILD-like events were independently confirmed by a review committee. Overall survival (OS) and progression-free survival (PFS) were assessed, and risk factors for ILD occurrence were analyzed by multivariate Cox regression analysis. Results Safety data were available for 843 patients and efficacy data for 841. Adverse drug reactions were reported in 83.5% of patients, no new safety signals were identified. ILD events were confirmed by the review committee in 52 patients (6.2%), with two fatal cases (0.2%). Median time from initial erlotinib treatment to ILD events was 70.5 days. Of the 52 patients with ILD events, 86.5% improved or fully recovered from ILD (median time 24 days). Multivariate analysis identified previous or concurrent lung disease (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.0–4.5; P = 0.0365) and ≥3 organs with metastases (HR, 4.2; 95% CI, 2.2–8.2; P < 0.0001) as potential ILD risk factors. Accumulated OS rate at 28 weeks was 68.2%, and median PFS was 92 days (95% CI, 86–101). Conclusions Erlotinib plus gemcitabine has an acceptable safety and efficacy profile in pancreatic cancer; however, patients should be assessed for previous/concurrent lung disease and metastatic burden, before and during treatment.

Background The aim of this study was to investigate the dose-limiting toxicities (DLTs) and determine the recommended doses in the Phase I part of the study, and to evaluate the efficacy and toxicity in the Phase II part, of continuous hepatic intra-arterial infusion therapy with 5-fluorouracil, mitoxantrone and cisplatin (FMP therapy) in patients with advanced hepatocellular carcinoma (HCC). Methods Forty-five patients with advanced HCC were enrolled. The therapy consisted of continuous intra-arterial infusion of 5-fluorouracil from Day 1 through Day 5, and intra-arterial administration of mitoxantrone and cisplatin on Day 1 [5-fluorouracil/mitoxantrone/cisplatin (mg/m2): Level 1; 400/4/60, Level 2; 400/6/60, Level 3; 500/6/60]. Results In the Phase I part of the study, one of the six patients at Level 1 developed DLTs, including Grade 3 pulmonary embolism, while none of the patients at either Level 2 or Level 3 exhibited any DLTs. In the Phase II part, at Level 3, 36 patients were enrolled. Nine patients (25%) showed partial response, representing a response rate of 25% (95% confidence interval: 12-42%). The overall median survival time, 1-year survival rate and median progression-free survival time were 11.3 months, 46.9% and 7.0 months, respectively. The main Grade 3 or 4 hematological and non-hematological toxicities were leukopenia (36%), neutropenia (39%), thrombocytopenia (19%), and elevated serum aspartate aminotransferase (22%), elevated serum alanine aminotransferase (14%) and occlusion of hepatic artery (22%), respectively. Conclusion Hepatic intra-arterial infusion therapy of FMP could not demonstrate a favorable tumor response and overall survival in patients with advanced HCC.

Lessons Learned Axitinib exhibited marginal activity against gemcitabine-refractory unselected biliary tract cancer. Pretreated soluble vascular endothelial growth factor receptor-2 may be a useful biomarker for axitinib treatment outcome. Ascites should be carefully monitored in patients receiving anti–vascular endothelial growth factor receptor therapy including axitinib in advanced biliary tract cancer. Background There are no clear options for second-line treatment in patients with gemcitabine (GEM)-refractory biliary tract cancer (BTC). We conducted a multicenter, single-arm, phase II trial to confirm the efficacy and safety of axitinib, a potent selective inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3, in patients with GEM-refractory BTC. Methods Patients refractory or intolerant to GEM-based chemotherapy were enrolled. Axitinib was administered orally at an initial dose of 5 mg twice daily. The primary endpoint was progression-free survival (PFS), and the threshold and expected values were set at 2 and 3 months, respectively. The target sample size was 32 patients. Results Nineteen patients were enrolled. The trial was interrupted for a total of 13 months for the evaluation of adverse events. Thirteen patients were previously treated with ≥2 regimens. The median PFS was 2.8 months (95% confidence interval [CI]: 2.1–4.1). The median overall survival was 5.8 months (95% CI: 3.3–9.7). The response rate was 5.3% (95% CI: 0.0–15.3). Grade 3 ascites occurred in two patients. Baseline soluble VEGFR-2 levels were significantly associated with PFS. Conclusion Axitinib exhibited marginal activity against GEM-refractory BTC. Ascites should be carefully monitored in axitinib-treated patients with advanced BTC.

Objective Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1–3. This analysis compared efficacy and safety of axitinib plus gemcitabine in patients with advanced pancreatic cancer from Japan, North America and the European Union, enrolled in a randomized Phase III study. Methods Patients (n = 632), stratified by disease extent, were randomly assigned (1:1) to receive axitinib/gemcitabine or placebo/gemcitabine. Axitinib was administered at a starting dose of 5 mg orally twice daily and gemcitabine at 1000 mg/m2 once weekly for 3 weeks in 4 week cycles. Primary endpoint was overall survival. Results Among Japanese patients, median overall survival was not estimable (95% confidence interval, 7.4 months—not estimable) with axitinib/gemcitabine (n = 58) and 9.9 months (95% confidence interval, 7.4–10.5) with placebo/gemcitabine (n = 56) (hazard ratio 1.093 [95% confidence interval, 0.525–2.274]). Median survival follow-up (range) was 5.1 months (0.02–12.3) with axitinib/gemcitabine vs. 5.4 months (1.8–10.5) with placebo/gemcitabine. Similarly, no difference was detected in overall survival between axitinib/gemcitabine and placebo/gemcitabine in patients from North America or the European Union. Common adverse events with axitinib/gemcitabine in Japanese patients were fatigue, anorexia, dysphonia, nausea and decreased platelet count. Axitinib safety profile was generally similar in patients from the three regions, although there were differences in incidence of some adverse events. An exploratory analysis did not show any correlation between axitinib/gemcitabine-related hypertension and overall survival. Conclusions Axitinib/gemcitabine, while tolerated, did not provide survival benefit over gemcitabine alone in patients with advanced pancreatic cancer from Japan or other regions.

Objective The aim was to determine the recommended dose of combined chemotherapy with mitoxantrone and uracil/tegafur (Phase I part) and to clarify its efficacy and safety in patients with advanced hepatocellular carcinoma at the recommended dose (Phase II part). Methods Patients eligible had histologically confirmed, chemo-naive advanced hepatocellular carcinoma and were amenable to established forms of treatment. The therapy consisted of mitoxantrone administered intravenously at one of three dosages (6, 8 and 10 mg/m(2)/day) on day 1 and uracil/tegafur administered orally at 300 mg/m(2) from day 1 through day 21. The treatment was repeated every 4 weeks until evidence of tumor progression or unacceptable toxicity. Results A total of 25 patients were enrolled. In the Phase I part, dose-limiting toxicities occurred in all three patients, given mitoxantrone at the dosage of 10 mg/m(2)/day, and the recommended mitoxantrone dosage was determined to be 8 mg/m(2)/day. Among 19 patients administered the drug at the recommended dosage, 1 patient (5.3%) showed partial response, 8 patients (42.1%) showed stable disease and 10 patients (52.6%) showed progressive disease. The median survival and median progression-free survival were 8.4 and 2.5 months, respectively. The most common toxicities were Grade 3-4 leukopenia (63.2%) and neutropenia (68.4%). Conclusions Mitoxantrone at 8 mg/m(2) combined with uracil/tegafur at 300 mg/m(2)/day was determined to be the recommended regimen. Although this regimen was generally well tolerated, it appeared to have little activity against advanced hepatocellular carcinoma. These findings do not support the use of this combination regimen in practice.

Objective: Chemoradiotherapy with 5-fluorouracil has been accepted as a standard care for locally advanced pancreatic cancer; however, it has not been shown to be superior to chemotherapy alone in the gemcitabine era. The present multicentre phase II study was conducted to evaluate the efficacy and safety of Gem monotherapy against locally advanced pancreatic cancer in comparison with the historical data of chemoradiotherapy with 5-fluorouracil. Methods: Eligibility criteria included patients with histologically proven locally advanced pancreatic cancer, all lesions encompassed by a square of 15 cm on one side, no prior treatment, good performance status and adequate organ function. Gemcitabine was given intravenously at a dose of 1000 mg/m 2 over 30 min on days 1, 8 and 15, repeated every 4 weeks. The primary endpoint was %1-year survival. Expected and threshold %1-year survival were 40 and 25%, respectively. Results: Between January 2006 and February 2007, 50 locally advanced pancreatic cancer patients were registered. The major grade 3‐4 adverse events were neutropaenia (62%), thrombocytopaenia (18%), fatigue (12%) and infection-biliary tree (12%). Haematological toxicity was mostly transient and there was no episode of infection with grade 3‐4 neutropaenia. Up to the final follow-up in February 2009, the median overall survival was 15.0 months with a %1-year survival of 64.0%. Conclusions: Gemcitabine monotherapy demonstrated far better survival than historical data for chemoradiotherapy with 5-fluorouracil with mild toxicities. Gemcitabine could be consider as a standard treatment for locally advanced pancreatic cancer. Trial Registration: This trial was registered in UMIN-CTR (http://www.umin.ac.jp/ctr/index-j. htm), identification number (C000000308).

Background: This study examined the effect of five systemic chemotherapy regimens on survival in patients with unresectable biliary tract cancer (BTC) as compared with the best supportive care (BSC). Methods: This study retrospectively reviewed data from 413 consecutive patients with BTC who were seen at any of nine central hospitals in Japan between April 2000 and March 2003. Patients were eligible if they had intra- or extrahepatic cholangiocarcinoma or gallbladder cancer with no prior chemotherapy. Hazard ratios of treatment regimens were estimated using the Cox proportional hazard model and the propensity score method. Results: Three-hundred and four patients were enrolled: 125 (41.1%) received BSC and 179 (58.9%) took chemotherapy. Of those who received chemotherapy, 58 (19.1%) took gemcitabine (GEM), 45 (14.5%) took a cisplatin (CDDP)-based regimen, 30 (9.9%) took a 5-fluorouracil (5-FU)-based regimen, 27 (8.9%) took 5-FU þ doxorubicin þ mitomycin (FAM) and 20 (6.6%) took S-1. The response rate was 8.4% (n ¼ 15). The CDDP-based regimen was associated with a high frequency of toxicity symptoms. The adjusted hazard ratio for GEM in the Cox regression was 0.53 (95% CI 0.34‐0.82) and the hazard ratio for the CDDP-based regimen was 0.49 (95% CI 0.36‐0.99). Conclusion: Chemotherapy with GEM may benefit patients with BTC.

Background: Despite the high complete necrosis rate of radiofrequency ablation (RFA), tumor recurrence, either local tumor recurrence or new tumor formation, remains a significant problem. Purpose of this study is to evaluate the pattern and risk factors for intrahepatic recurrence after percutaneous RFA for hepatocellular carcinoma (HCC). Methods: We studied 40 patients with 48 HCCs (� 3.5 cm) who were treated with percutaneous RFA. The mean follow-up period was 24.1+15.7 months. We evaluated the cumulative disease-free survival of overall intrahepatic recurrence, local tumor progression (LTP) and intrahepatic distant recurrence (IDR). Thirty host, tumoral and therapeutic risk factors were reviewed for significant tie-in correlation with recurrence: age; gender; whether RFA was the initial treatment for HCC or not; severity of liver disease; cause of liver cirrhosis; contact of tumor to major hepatic vessels and liver capsule; degree of approximation of tumor to the liver hilum; ablation time; degree of benign pre-ablational enhancement; sufficient safety margin; tumor multinodularity; tumor histological differentiation; tumor segmental location; maximum tumor diameter; degree of tumor pre-ablational enhancement at arterial phase CT, MRI or CT-angiography; and laboratory markers pre- and post-ablation (AFP, PIVKA II, TP, AST, ALT, ALP and TB). Results: The incidence of overall recurrence, LTP and IDR was 65, 23 and 52.5%, respectively. The cumulative disease-free survival rates were 54.6, 74.8 and 78.3% at 1 year, 27.3, 71.9 and 46.3% at 2 years and 20, 71.9 and 29.4 at 3 years, respectively. Univariate and multivariate analysis showed that the significant risk factors for LTP were: tumor size � 2.3 cm, insufficient safety margin, multinodular tumor, tumors located at segments 8 and 5, and patient’s age . 65 years (P , 0.05). No significant risk factor relationship for IDR could be detected. Conclusion: Our results would have clinical implications for advance warning and appropriate management of patients scheduled for RFA. Patients at risk of LTP should be closely monitored in the first year. Furthermore, regular long-term surveillance is essential for early detection and eradication of IDR.

BACKGROUND: Recent advances in cancer chemotherapy have increased not only the survival rate but also the treatment cost, although there has been little interest in cost analyses in Japan. METHOD: The actual cost of pancreatic cancer treatment was surveyed especially with respect to the difference after April 2001, which was the date that gemcitabine was introduced in Japan. RESULTS: A total of 113 patients were admitted consecutively from April 2000 to March 2002. Among the 113 patients, the total treatment cost over a lifetime was calculated in 54. In those 54 patients, the median treatment cost and survival time were $43,865 and 26.2 months for resectable disease (n = 14), $30,676 and 10.0 months for locally advanced disease (n = 21), and $29,255 and 4.8 months for metastatic disease (n = 19), respectively. Of the 54, 26 patients were admitted before April 2001 (Group A) and the remaining 28 were admitted thereafter (Group B). There were significantly more patients who received gemcitabine chemotherapy in Group B (19 of the 28) than in Group A (none of the 26). The median treatment cost and survival times were $35,744 and 7.4 months in Group A, and $35,226 and 8.8 months in Group B, respectively, whereas the total cost of anticancer agents was significantly higher in Group B than in Group A. CONCLUSION: Although cost of gemcitabine is about 18-fold higher than 5-fluorouracil in Japan, the total costs after gemcitabine introduction did not tend to become higher in our hospital, probably because of simplification in examinations and shorter hospitalization.

Background Uracil-tegafur (UFT) has been reported to have broad antitumor activity in a variety of malignancies. However, its activity in biliary tract carcinoma has not been fully evaluated. The aim of this study was to evaluate the antitumor activity and toxicity of UFT in chemotherapy-naive patients with advanced biliary tract carcinoma. Methods Nineteen patients with advanced biliary tract carcinoma that was histologically confirmed as adenocarcinoma were enrolled in this phase II trial of UFT. A dose of 360 mg/m(2)/day of UFT was administered orally if there was no evidence of tumor progression or there was unacceptable toxicity. Results Of the 19 patients evaluable for response, one patient (5%) achieved a partial response with a duration of 2.0 months. Six patients (32%) showed no change and the remaining 12 (63%) had progressive disease. The median survival, 6-month survival rate and 1-year survival rate for all patients were 8.8 months, 52.6 and 21.1%, respectively. The chemotherapy was well tolerated, because grades 3 or 4 toxicity were not observed. Conclusion UFT appears to have little activity as a single agent in treating patients with advanced biliary tract carcinoma. These findings do not support its use in practice, and further trials with this regimen in patients with biliary tract carcinoma are not recommended.

There is no standard treatment for patients with extrahepatic spread from hepatocellular carcinoma. The aim of this retrospective study was to identify candidates for aggressive intervention or new drug trial among such patients.Retrospective exploration was performed to extract a patient cohort step by step using univariate and multivariate analyses.There were 201 subjects from the past 12 years. The 1-, 3- and 5-year survival rates were 31.0, 9.2 and 4.5%, respectively. The upper limit of the 95% confidence interval of median survival time did not reach 3 months in patients with a performance status of 2 or worse, or with Child-Pugh grades B or C. After excluding those, univariate and multivariate analyses were performed in the remaining 124 subjects. Three independent prognostic factors--brain metastasis, number of metastatic tumors and primary tumor status--were identified. The final cohort was set at 121 after excluding three with brain metastasis. Among these 121, there were 11 with a solitary metastatic tumor and T1/2 primary tumor. In this subgroup, 10 underwent complete removal of the metastatic tumor, and the median survival time exceeded 5 years.Candidates for anti-cancer treatment should meet the following requirements: a performance status of 0 or 1, a Child-Pugh grade A and no brain metastasis. Among these, challenging locoregional intervention was acceptable only for patients with solitary metastatic tumor and T1/2 primary tumor.

Background: Hepatic arterial infusion of zinostatin stimalamer and lipiodol emulsion shows a moderate activity against hepatocellular carcinoma. However, the anti-tumor activity of zinostatin stimalamer alone is uncertain. Methods: The primary endpoint was to evaluate the frequency of dose-limiting toxicity and determine the maximum-tolerated dose of zinostatin stimalamer when used by intra-arterial infusion. The candidates for this study were patients with hepatocellular carcinoma no longer amenable to established forms of treatment. Hepatic arterial infusion chemotherapy was performed by selectively introducing a catheter into the hepatic artery with zinostatin stimalamer alone. Treatment was repeated at 4–8-week intervals until disease progression or the appearance of unacceptable toxicity. The starting dose of zinostatin stimalamer was 3 mg/m 2 , and doses were increased in 1 mg/m 2 increments in successive cohorts. At least three patients were treated at each dose level and three additional patients were treated in the presence of dose-limiting toxicity. Results: Twelve patients were entered into this trial. Dose-limiting toxicity was observed in one of six patients at 3 mg/m 2 , and in two of six patients at 4 mg/m 2 . The maximum-tolerated dose was judged to be 3 mg/m 2 with liver dysfunction and serum creatinine increase as the doselimiting toxicity. There was one early death suggested to be related to the protocol treatment. None of the 12 patients achieved an objective tumor response. Conclusion: Hepatic arterial infusion with a zinostatin stimalamer of 3 mg/m 2 may be tolerated, but not active, in patients with far advanced hepatocellular carcinoma.

A randomized Phase II selection design trial comparing gemcitabine plus S-1 combination therapy with S-1 monotherapy for chemo-naïve unresectable or recurrent biliary tract cancer patients was started in Japan. The aim of this trial is to evaluate the efficacy and safety of the two regimens and to determine which is more promising as a test arm regimen to be compared with the current standard regimen, gemcitabine plus cisplatin, in a subsequent Phase III trial. Patients with unresectable or recurrent biliary tract cancer are randomized to either gemcitabine plus S-1 combination therapy arm or S-1 monotherapy arm. A total of 100 patients will be accrued for this study from 18 institutions over 1 year. The primary endpoint is the proportion of 1-year overall survival, and the secondary endpoints are progression-free survival, response rate and adverse events.

Small hepatic nodular lesions are frequently detected by ultrasonography in patients with liver cirrhosis during follow-up. However, hepatocellular carcinomas (HCCs) and non-HCC nodules are difficult to differentiate by ultrasonography because they have a similar appearance. We used color Doppler ultrasonography (CDU) to examine 29 HCCs and 26 non-HCC nodules less than 2 cm in diameter to determine whether CDU can be used to differentiate small hepatic nodules. There were no significant differences between the examined HCCs and non-HCC nodules with regard to ultrasonographic appearance, i.e., hypoechoicity or hyperechoicity. Blood flow signals were detected in a significantly higher percentage of HCCs (13 of 29, 44.8%) than in non-HCC nodules (2 of 26, 7.7%; P

We report a case of leiomyosarcoma originating from the second portion of the duodenum and associated with von Recklinghausen's disease. A 62-year-old man was admitted to our hospital complaining of abdominal pain and melena. A 5 cm tumor in the descending part of the duodenum was detected by hypotonic duodenography, CT, ultrasonography and endoscopy. Angiography revealed the tumor to be supplied by the mesenteric artery of the transverse colon. A segmental resection of the distal part of the duodenum was performed, preserving the head of the pancreas. Histologically, the tumor was a leiomyosarcoma, and the surgical margin was free of tumor cells. This surgery is safer than pancreatoduodenectomy, and is appropriate for treating non-epithelial tumors in the distal part of the duodenum in the absence of invasion of the head of the pancreas and regional lymph node metastasis. When carrying out the procedure, it is essential to ligate the branch of the pancreaticoduodenal vessels as close as possible to the duodenal side in order to preserve the blood supply to the pancreatic head.