Kensuke Otani

Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis

BACKGROUND A phase II study to evaluate the efficacy and tolerability of weekly i.v. and i.p. paclitaxel (PTX) combined with S-1 was carried out in gastric cancer patients with peritoneal metastasis. PATIENTS AND METHODS Gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered i.v. at 50 mg/m(2) and i.p. at 20 mg/m(2) on days 1 and 8. S-1 was administered at 80 mg/m(2)/day for 14 consecutive days, followed by 7 days rest. The primary end point was the 1-year overall survival (OS) rate. Secondary end points were the response rate, efficacy against malignant ascites and safety. RESULTS Forty patients were enrolled, including 21 with primary tumors with peritoneal dissemination, 13 with peritoneal recurrence and six with positive peritoneal cytology only. The median number of courses was 7 (range 1-23). The 1-year OS rate was 78% (95% confidence interval 65% to 90%). The overall response rate was 56% in 18 patients with target lesions. Malignant ascites disappeared or decreased in 13 of 21 (62%) patients. The frequent grade 3/4 toxic effects included neutropenia (38%), leukopenia (18%) and anemia (10%). CONCLUSION Combination chemotherapy of i.v. and i.p. PTX with S-1 is well tolerated and active in gastric cancer patients with peritoneal metastasis.

Phase I Pharmacokinetic Study of Weekly Intravenous and Intraperitoneal Paclitaxel Combined with S-1 for Advanced Gastric Cancer

Objectives: A dose-escalation study of weekly intraperitoneal paclitaxel (PTX) combined with S-1 and intravenous PTX was performed to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in gastric cancer patients. Patients and Methods: Nine gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered intravenously on days 1 and 8 at a fixed dose of 50 mg/m2, and intraperitoneally with an initial dose of 20 mg/m2, stepped up to 30 or 40 mg/m2. S-1 was administered at a fixed dose of 80 mg/m2/day for 14 consecutive days, followed by 7 days of rest. A pharmacokinetic study of PTX was also performed. Results: The MTD was determined to be 30 mg/m2, as 2 of 3 patients developed dose-limiting toxicities, grade 3 febrile neutropenia and diarrhea. Therefore, the RD was determined to be 20 mg/m2. The intraperitoneal and serum PTX concentration remained effective for over 72 and 48 h, respectively. Conclusions: Combined chemotherapy of S-1 plus weekly intravenous and intraperitoneal PTX was shown to be a safe regimen that should be further explored in clinical trials.

Adiponectin suppresses tumorigenesis in ApcMin/+ mice

Recent reports have shown that adiponectin has a suppressive effect on various types of malignancy. In order to clarify the role of adiponectin in colorectal carcinogenesis, we examined the effect of exogenous administration of adiponectin on intestinal polyp formation in C57BL/6J-Apc(Min)(/+) mice, which possess a point mutation in the Apc gene. And we found that adiponectin treatment significantly decreased the number of adenomatous polyps, especially polyps larger than 2mm in diameter, in the small intestine. Two major receptors for adiponectin, AdipoR1 and AdipoR2, were expressed in adenomatous polyps, and their expression levels were not altered by adiponectin injection. In conclusion, adiponectin suppresses the growth of intestinal adenomas in the Apc(Min)(/+) mice. Increasing the adiponectin level may be a new strategy for the prevention of colorectal cancer at an early step of carcinogenesis.

Level of arterial ligation in sigmoid colon and rectal cancer surgery.

BackgroundCurative resection of sigmoid colon and rectal cancer includes “high tie” of the inferior mesenteric artery (IMA). However, IMA ligation compromises blood flow to the anastomosis, which may increase the leakage rate, and it is unclear whether this confers a survival advantage. Accordingly, the IMA may be ligated at a point just below the origin of the left colic artery (LCA) “low tie” combined with lymph node dissection (LND) around the origin of the IMA (low tie with LND). However, no study has investigated the detailed prognostic results between “high tie” and “low tie with LND.” The aim of this study was to assess the utility of “low tie with LND” on survival in patients with sigmoid colon or rectal cancer.MethodsA total of 189 sigmoid colon or rectal cancer patients who underwent curative operation from 1997 to 2007 were enrolled in this study. The patient’s medical records were reviewed to obtain clinicopathological information. Overall survival (OS) and relapse-free survival (RFS) rates were calculated using the Kaplan-Meier method, with differences assessed using log-rank test.ResultsForty-two and 147 patients were ligated at the origin of the IMA (high tie) and just below the origin of the LCA combined with LND around the origin of the IMA (low tie with LND), respectively. No significant differences were observed in the complication rate and OS and RFS rates in the two groups. Further, no significant difference was observed in the OS and RFS rates in the lymph node-positive cases in the two groups.Conclusions“Low tie with LND” is anatomically less invasive and is not inferior to “high tie” with prognostic point of view.

Adiposity and Gastrointestinal Malignancy

Recent epidemiologic studies have shown a positive association between obesity and certain cancers. Our retrospective studies show that hypertriglyceridemia is an independent risk factor for the development of colonic adenoma and nodal metastasis in early gastric and esophageal cancer in men. High-fat condition may be favorable for the growth of malignant cells. Serum level of adiponectin is reduced in patients with advanced gastric cancer, which may be associated with the positive link between adiposity and cancer. In early gastric cancer, patients with undifferentiated type have lower fat volume than those with differentiated type. Adiposity appears to be closely related with various aspects in pathophysiology of gastrointestinal malignancy.

Intra-peritoneal administration of paclitaxel with non-animal stabilized hyaluronic acid as a vehicle--a new strategy against peritoneal dissemination of gastric cancer.

BACKGROUND AND AIM Intra-peritoneal administration (i.p.) of Taxanes has recently been reported to be effective for the treatment of peritoneal dissemination, presumably because extremely high concentration of the drug is achievable onto the disseminated nodules as compared to intra-venous administration. Here, we aimed to investigate the ability of non-animal stabilized hyaluronic acid (NASHA) to retain the anti-cancer drugs in the peritoneal cavity, and, consequently, improve the efficacy of i.p. administration of paclitaxel. METHODS Mice were inoculated i.p. with MKN45P gastric cancer cells. The mice received i.p. administrations of paclitaxel, without or with NASHA, once a week for 3 consecutive weeks, and the intra-peritoneal nodules were counted after 4 weeks. The ability of NASHA to retain the i.p. administered liquid and paclitaxel in abdominal cavity was also investigated. Finally, the concentration of paclitaxel in metastatic nodule was measured with HPLC. RESULTS In the group receiving paclitaxel with NASHA, the number of disseminated nodules were significantly smaller than in those receiving paclitaxel without NASHA. The fluid volumes and concentration of paclitaxel recovered from the abdominal cavity as well as the concentrations of paclitaxel in metastatic nodule were significantly increased by the addition of NASHA. CONCLUSION Our results indicate that NASHA improves the exposure time of i.p. administrated paclitaxel to disseminated nodules by retaining the drug in the abdominal cavity. Since the material is used in cosmetic surgery with few adverse effects, NASHA can be clinically used as the vehicle for the i.p. administration of anti-cancer agents for advanced gastric cancer with peritoneal dissemination.

Weekly intravenous and intraperitoneal paclitaxel combined with S-1 for malignant ascites due to advanced gastric cancer.

Malignant ascites caused by gastric cancer are chemotherapy resistant and carry a poor prognosis. The efficacy of a regimen including intraperitoneal paclitaxel (PTX) was evaluated in 33 gastric cancer patients with ascetic fluid in the peritoneal cavity diagnosed with computed tomography (CT) scanning. Synchronous administration of intravenous (50 mg/m2) and intraperitoneal (20 mg/m2) PTX was performed via a subcutaneously placed intraperitoneal catheter on days 1 and 8, and S-1 was administered twice daily at 80 mg/m2/day for 14 consecutive days from day 1 to day 14, followed by 7 days of rest. The ascitic fluid volume was calculated with NIH Image J software using continuous CT images. After 2–4 treatment cycles, 23 (70%) patients showed reductions in their ascitic volumes of >50%. Ascites disappeared completely in 8 patients and were markedly reduced (to <3% of the original volume) in 4 of the 9 patients (44%) who initially had massive (>2,500 ml) ascites. Median overall survival was significantly better in patients with ascitic reduction. Weekly intravenous and intraperitoneal PTX combined with S-1 was highly effective in gastric cancer with malignant ascites. The change in ascitic fluid volumes determined by CT image measurements is a useful predictor of outcome in these patients.

LINE-1 hypomethylation status of circulating cell-free DNA in plasma as a biomarker for colorectal cancer

Colorectal cancer (CRC) is a serious public health problem and non-invasive biomarkers improving diagnosis or therapy are strongly required. Circulating cell-free DNA (cfDNA) has been a promising target for this purpose. In this study, we evaluated the potential of long interspersed nuclear element-1 (LINE-1) hypomethylation as a blood biomarker for CRC. LINE-1 hypomethylation level in plasma cfDNA in 114 CRC patients was retrospectively examined by absolute quantitative analysis of methylated alleles real-time PCR, and was expressed using LINE-1 hypomethylation index (LHI) [unmethylated copy number/ (methylated copy number + unmethylated copy number)]. Greater LHI values indicated enhanced hypomethylation. In our clinicopathological analysis, CRC patients with large tumors (≥6.0 cm), advanced N stage (≥2), and distant metastasis (M1) had statistically significantly higher cfDNA LHI than other CRC patients, suggesting cfDNA LHI as a disease progression biomarker for CRC. Furthermore, early stage I/II (n = 57) as well as advanced stage III/IV (n =57) CRC patients had significantly higher cfDNA LHI than healthy donors (n=53) [stage I/II: median 0.369 (95% confidence interval, 0.360–0.380) vs. 0.332 (0.325–0.339), P < 0.0001; stage III/IV: 0.372 (0.365–0.388) vs. 0.332 (0.325–0.339), P < 0.0001]. The receiver operating characteristic analysis showed that cfDNA LHI had the detection capacity of CRC with area under the curve(AUC) of 0.79 and 0.83 in stage I/II and stage III/IV CRC patients, respectively. The present study demonstrated for the first time the potential of plasma cfDNA LHI as a novel biomarker for CRC, particularly for early stage detection.

Hereditary gastrointestinal cancer

Gastrointestinal (GI) cancer, including gastric and colorectal cancer, is a major cause of death worldwide. A substantial proportion of patients with GI cancer have a familial history, and several causative genes have been identified. Gene carriers with these hereditary GI syndromes often harbor several kinds of cancer at an early age, and genetic testing and specific surveillance may save their lives through early detection. Gastroenterologists and GI surgeons should be familiar with these syndromes, even though they are not always associated with a high penetrance of GI cancer. In this review, we provide an overview and discuss the diagnosis, genetic testing, and management of four major hereditary GI cancers: familial adenomatous polyposis, Lynch syndrome, hereditary diffuse gastric cancer, and Li–Fraumeni syndrome.

Ultrafast optical excitation of coherent magnons in antiferromagnetic NiO

Antiferromagnets are rapidly gaining importance as crucial ingredients in many applications. They are abundant in nature and they are robust against externally applied fields. Rather usefully, their spin resonances often lie within the THz regime, which makes them ideal candidates for optical studies. In this paper, the authors present a thorough experimental and theoretical exploration of the optical spin excitation in antiferromagnetic NiO. Based on a phenomenological theory, they derive expressions for the optically induced magnetization via the inverse Faraday effect and the inverse Cotton-Mouton effect. Light polarization is conserved by pumping and probing along the optical axis of the material, facilitating the comparison between theory and experiment. Those agree amazingly well, making possible the identification of the driving mechanism behind the ultrafast magnon excitations. Moreover, the authors succeed in obtaining information about the otherwise elusive spin-domain distribution in NiO and in showing that the energy transfer into the magnon mode is about three orders of magnitude more efficient via the inverse Cotton-Mouton effect than via the inverse Faraday effect.