Kuniharu Yamamoto

Advanced bile duct carcinoma in a 15-year-old patient with pancreaticobiliary maljunction and congenital biliary cystic disease

We report a case of advanced bile duct carcinoma arising in a 15-year-old female with pancreaticobiliary maljunction and congenital biliary cystic disease. Pancreaticoduodenectomy and partial resection of the liver was performed. Surgical and histopathological findings indicated advanced tubular adenocarcinoma, classified as final stage IVb according to the General rules for surgical and pathological studies on cancer of the biliary tract proposed by the Japanese Society of Biliary Surgery, 5th edition, and stage IV according to the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC), 6th edition. She underwent chemotherapy with gemcitabine HCl after discharge. She died of cachexia 14 months after the surgery. Although it is well known that biliary malignancies arise frequently in patients with pancreaticobiliary maljunction, it is uncommon for advanced bile duct carcinoma to occur in a 15-year-old female. We should pay attention to the possibility of biliary malignancy in patients with pancreaticobiliary maljunction and congenital biliary cystic disease, even when the patients are juveniles.

Phase I trial of neoadjuvant chemoradiation with gemcitabine and surgical resection for cholangiocarcinoma patients (NACRAC study).

BACKGROUND/AIMS The feasibility of neoadjuvant chemoradiation therapy for cholangiocarcinoma, followed by conventional resection, has not been determined yet. Here, a phase I study of neoadjuvant chemoradiation therapy, named NACRAC, was performed to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of gemcitabine when combined with external beam radiation therapy for resectable cholangiocarcinoma. METHODOLOGY From August 2007 to June 2008, 12 patients provided informed consent. Preoperative radiation was administered in 1.8Gy daily fractions up to a total dose of 45Gy. Gemcitabine was administered at day 1 and 8 every three weeks. The initial dose of gemcitabine was started from 400mg/m2. RESULTS One patient was not able to start treatment because of bleeding caused by a duodenal ulcer and cholangitis. At 800mg/m2 of gemcitabine, one patient out of three failed to complete the treatment because of Grade 3 hematological toxicity. In another three cases of 800mg/m2, the second case could not complete the treatment because of cholangitis. Then, 600mg/m2 was determined to be the MTD, and the RD dose decided as 600mg/m2. CONCLUSIONS The RD of gemcitabine in NACRAC study was determined to be 600mg/m2. NACRAC study should proceed to a phase II trial to evaluate the effectiveness.

The preclinical development of regorafenib for the treatment of colorectal cancer

Introduction: The RAS-RAF-MEK-ERK pathway is one of the best characterized kinase cascades. During the exploration of small molecules that inhibit RAF1 kinase, regorafenib (BAY 73-4506) was discovered as a multikinase inhibitor which demonstrated anti-cancer, anti-angiogenic, and apoptotic activities in metastatic colorectal cancer. This was not the first multikinase inhibitor discovered for the disease; indeed, before regorafenib was approved by FDA as a multikinase inhibitor for metastatic colorectal cancer in 2012, sorafenib (BAY 43-9006) had already been developed to be the first in the world as a multikinase inhibitor for malignancy. Indeed, the only difference between the two compounds is fluorine bound to its proximal phenyl ring although the end result is a considerably different profile, both as a kinase inhibitor as well as in its clinical application. Areas covered: In this drug discovery case history, the authors review the design, discovery, and development of both regorafenib and sorafenib from back in the 1990s. Furthermore, the authors highlight the drug’s anti-cancer and anti-angiogenic properties as well as its efficacy, safety pharmacology and toxicology based on FDA documents. Expert opinion: In order to better predict the efficacy of kinase inhibitors and to utilize them more efficiently, our understanding of drug discovery, the approaches for kinase profiling, and technologies needed for their development are paramount. Indeed, the authors believe that the field should better explore the use of predictive biomarkers that might be able to better assess these therapeutics. Pharmaceutical scientists must also consider the cost effectiveness of the targeted agents developed as a number of the drugs developed are very expensive.

An analysis of a second-line S-1 monotherapy for gemcitabine-refractory biliary tract cancer.

BACKGROUND/AIMS Gemcitabine is widely used as a first-line therapy for biliary tract cancer (BTC). However, few studies have been conducted to analyze second- line therapies. METHODOLOGY From 33 patients who had been administered gemcitabine following resection between May 2005 and August 2007, we retrospectively analyzed the safety and efficacy of S-1 in 11 cases who received S-1 as second-line therapy due to recurrence or relapse of the primary disease. RESULTS Among the adverse events (AEs) observed during S-1 administration, the most common was a decrease in the concentration of hemoglobin, followed by thrombocytopenia. No Grade 4 AEs or worse were detected. In addition, the AEs and their respective severity strongly resembled those of gemcitabine used as a first-line therapy. There were 7 cases that could be evaluated according to RECIST criteria, of which 1 was considered in the partial response and 3 as stable disease. The medians of time to progression after S-1 administration and survival after S-1 administration were 5.6 months and 31 months, respectively. CONCLUSIONS S-1 could be taken safely as a second-line therapy without provoking severe AEs. By preventing the cessation of S-1 administration due to its AEs, more continued S-1 administration could lead to a better prognosis for BTC.

The use of natural products in colorectal cancer drug discovery

Introduction: Natural products (NPs) are evolutionarily designed and contain more complex and challenging structures than synthetic compounds. Since the 1980s, the pharmaceutical industry has gradually shifted to a strategy of developing targeted agents by screening libraries of synthetic compounds. However, NPs have recently received renewed focus as a rich repository for drug discovery. Irinotecan was developed as a derivative of camptothecin and was applied in standard regimens for metastatic colorectal cancer (CRC) worldwide. Additionally, polysaccharide K is approved for CRC in Japan and Taiwan in combination with cytotoxic agents. However, after the approval of irinotecan in 1996, no anti-cancer agents derived from NPs have been approved for CRC. Areas covered: This review discusses NPs that are currently under investigation for the treatment of CRC. In addition, other NPs derived as purified ingredients and crude extracts are listed and also discussed. Expert opinion: The use of NPs for the discovery of anti-cancer agents has not been fully investigated. New technologies that are currently applied for synthetic compounds may be utilized for anti-cancer drug discovery including NPs for CRC.

Adenovirus Expressing Mutant p27kip1 Enhanced Apoptosis and Inhibited the Growth of Xenografted Human Breast Cancer

PurposeTo evaluate the anti-tumor effects of a novel adenovirus expressing mutant p27kip1 (Adp27-mt), which consists of a mutation of Thr-187/Pro-188 to Met-187/Ile-188.MethodsUsing the human breast cancer cell lines, MDA-MB-231, ZR-75-1, and MCF-7, we tested Adp27-mt for cell cycle assay, growth inhibition assay, and TdT-mediated dUTP-biotin nick end labeling in a human breast cancer-grafted severe combined immunodeficiency (SCID) mouse model.ResultsThe mutant p27kip1 induced stronger apoptosis in the breast cancer cell lines than adenovirus expressing wild-type p27kip1 (Adp27-wt). Adp27-mt inhibits cell growth significantly; being about 5- and 3.5-fold stronger for IC50 than Adp27-wt in the breast cancer cell lines, MDA-MD-231 and ZR-75-1, respectively. In the human breast cancer-grafted SCID mouse model, Adp27-mt induced tumor regression and antitumor effects significantly better than Adp27-wt. Furthermore, Adp27-mt mainly caused G2/M arrest in the cell cycle progression, whereas Adp27-wt mediated a G1/S arrest 48 h after infection.ConclusionThe mutant p27kip1 protein induced apoptosis, and inhibited cell growth more efficiently with stronger anti-tumor effects than wild-type p27kip1. Thus, the recombinant adenovirus expressing mutant p27kip1 could be useful in gene therapy against breast cancer.

Drug delivery of oral anti-cancer fluoropyrimidine agents

ABSTRACT Introduction: Sixty years since its introduction, 5-FU still forms the core of chemotherapy regimens for many types of malignancies. 5-FU is a time-dependent drug but is rapidly degraded in plasma by dihydropyrimidine dehydrogenase (DPD). Although originally developed in an intravenous form, 5-FU oral prodrugs were developed with the goal of improving efficacy and minimizing toxicity as well as to capitalize on the advantages of oral drug administration. The inactive 5-FU prodrug is gradually converted into the active form in the systemic circulation. UFT, S-1, and capecitabine are oral 5-FU prodrugs currently in clinical use. However, the efficacy of 5-FU can be further improved by its combination with DPD inhibitors and biochemical modulators, such as uracil and leucovorin, in addition to modifying administration schedules. Areas covered: We focused on the drug delivery of oral 5-FU prodrugs, their pharmacokinetics, and the development of DPD inhibitors. Since oral 5-FU prodrugs have been formulated into combination drugs, we also discussed the regulatory approval of combination drugs. Expert opinion: Many regimens that include intravenously administered 5-FU can be replaced by oral 5-FU prodrugs. Patients would benefit from development of combination 5-FU oral prodrug formulations and its associated path through the combination drug regulatory approval process.

Lymph nodes metastasis is a risk factor for bone metastasis from extrahepatic cholangiocarcinoma.

BACKGROUND/AIMS The rate and site of bone metastasis from cholangiocarcinoma as well as the prognosis are unclear. Therefore, we intend to make a comparative review of the background to bone metastasis, examine a high-risk group for bone metastasis and use the data towards the improvement in quality of life. METHODOLOGY We studied 200 cases of cholangiocarcinoma resected in our division from January 2003 to April 2010. RESULTS Bone metastasis was confirmed in four cases (2.0%). The survival period after the diagnosis of bone metastasis ranged from 2.9 months to 21.6 months and the average was 6.7 months. We studied histopathological findings of bone metastasis, lymph node metastasis, lymphatic invasion, blood vessel invasion and perineural invasion (ly, v and pn) and found that all of four bone metastasis cases were positive for lymph node metastasis which was a statistically significant factor affecting bone metastasis. CONCLUSIONS Since the number of cases we studied is small, it is difficult to determine whether lymph node metastasis is a risk factor for bone metastasis; however, we think it is necessary to take the probability of bone metastasis into consideration when we provide medical care to patients positive for lymph node metastasis.

Severe cholestatic liver failure associated with gemcitabine adjuvant monotherapy for pancreatic cancer

We report a case of severe hepatic failure caused by gemcitabine hydrochloride (GEM) monotherapy after pancreaticoduodenectomy for advanced pancreatic cancer. A 73-year-old woman received GEM as an adjuvant chemotherapy. She suffered from progressive edema, fatigue, and jaundice after the third GEM administration. Severe liver dysfunction and elevation of bilirubin was observed. A computed tomography scan and magnetic resonance imaging showed diffuse liver swelling suggesting severe hepatic edema with fat accumulation. Needle biopsy of the liver revealed remarkable cholestasis and fat deposition with mild damage of hepatocytes. Drug-induced liver failure was suspected. GEM-stimulated lymphocyte test was negative, but antinuclear antibody was elevated with a marked inflammatory response. She improved to an almost normal condition by steroid and liver protective therapies within a week. Although the frequency of liver failure induced by GEM monotherapy is very rare, it could be fatal. It is important to distinguish it from other causes of liver dysfunction following pancreaticoduodenectomy. Early detection and appropriate drug therapy can improve the prognosis.

Abstract 5541: Natural products as possible anti-cancer agents for digestive malignancies

Introduction: Natural products are evolutionarily designed and contain more complex and challenging structures than synthetic compounds. Historically, during the 1950s and 1960s anti-cancer agents for digestive malignancies, such as mitomycin and bleomycin, were isolated from actinobacteria; and then anti-cancer agents from plants, which include taxanes and camptothecin, were isolated. Their derivatives were also developed and are in clinical use. Purified ingredients and crude extracts from natural products such as PSK and those of Chinese herbal medicines are also in clinical use. Since the 1980s industries and academia have been focusing on strategies for development of targeted agents by screening a library of synthetic compounds; but recently natural products have been refocused on as a rich repository for drug discovery. Methods: To summarize the information of natural products as novel anti-cancer agents for digestive malignancies as well as their information in clinical trials, we surveyed literatures in the NCBI PudMed database and clinical trials registered in the FDA database, using keywords such as “natural products”, “anti-cancer agents”, and “digestive malignancy” or each of the malignancies (“esophageal cancer”, “stomach cancer”, “colorectal cancer”, “pancreatic cancer”, “biliary cancer” and others). We further classified the products on their chemical structures and their origins depending on types of drug-producing organisms. Results: With the above surveys, over 600 natural products were listed as possible substances as anti-cancer agents of digestive malignancies in preclinical development. Over 75% of the products were from plants. Their main structures consist of flavonoids, lignans, xanthones and others. The products from terrestrial animals and marine organisms were also listed. Curcumin, talaporfin sodium, eicosapentaenoic acid, resveratrol and other products are under clinical trials. Discussion: Despite many efforts, natural products have not been fully investigated for discovery of anti-cancer agents. New technologies having been applied for synthetic compounds, such as those for cultivation of drug-producing organisms, extraction and purification of substances, appreciation of targets, utilization of genomics information, and utilization of bioinformatics and cheminformatics with in silico analysis, can surely be utilized for anti-cancer drug discovery with natural products for digestive malignancies. Citation Format: Koh Miura, Masayuki Satoh, Makoto Kinouchi, Kuniharu Yamamoto, Yasuhiro Hasegawa, Yoichiro Kakugawa, Masaaki Kawai, Kiyoshi Uchimi, Hiroki Aizawa, Hiroto Sakurai, Tsuneaki Fujiya. Natural products as possible anti-cancer agents for digestive malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5541. doi:10.1158/1538-7445.AM2015-5541