Kiyohiko Shuto

Antitumor effect of 1, 8-cineole against colon cancer

Several essential oils possess pharmacological effects. Among the various constituents of essential oils, 1, 8-cineole has been shown to possess pharmacological effects such as anti-bacterial and anti-inflammatory effects. The effect of 1, 8-cineole on human colorectal cancer cells, however, has not reported previously. In this study, we have investigated the anti-proliferative effect of 1, 8-cineole on human colon cancer cell lines HCT116 and RKO by WST-8 and BrdU assays. The cytotoxicity of 1, 8-cineole was investigated by LDH activity and TUNEL staining. The mechanism of apoptosis by 1, 8-cineole was determined by western blot analyses. In in vivo study, RKO cells were injected into the SCID mice and the effect of 1, 8-cineole was investigated. Specific induction of apoptosis, not necrosis, was observed in human colon cancer cell lines HCT116 and RKO by 1, 8-cineole. The treatment with 1, 8-cineole was associated with inactivation of survivin and Akt and activation of p38. These molecules induced cleaved PARP and caspase-3, finally causing apoptosis. In xenotransplanted SCID mice, the 1, 8-cineole group showed significantly inhibited tumor progression compared to the control group. These results indicated 1, 8-cineole suppressed human colorectal cancer proliferation by inducing apoptosis. Based on these studies 1, 8-cineole would be an effective strategy to treat colorectal cancer.

Enhanced antitumor activity of cerulenin combined with oxaliplatin in human colon cancer cells

Fatty acid synthase is highly expressed in many types of human cancers. Cerulenin, a natural inhibitor of fatty acid synthase, induced apoptosis in the human colon cancer cell lines HCT116 and RKO. Oxaliplatin also induced cell death in these cell lines. Cerulenin treatment was associated with reduced levels of phosphorylated Akt, activation of p38 and induced caspase-3 cleavage and finally caused apoptosis. Oxaliplatin induced activation of the p53-p21 pathway and p38. In combination with cerulenin and oxaliplatin, activation of the p53-p21 pathway and p38 occurred in a smaller concentration and finally induced caspase-3 cleavage in a smaller concentration of cerulenin and oxaliplatin. In xenotransplanted SCID mice, the cerulenin + oxaliplatin group significantly inhibited tumor progression compared to the control, cerulenin and oxaliplatin groups. Based on these studies, inhibiting fatty acid synthase would be an effective strategy to treat unresectable colorectal cancer tumors in combination with oxaliplatin. Fatty acid synthase inhibitor would be one of the best counterparts of oxaliplatin, which reduces the dose and side-effects of oxaliplatin and would make it possible to endure the chemotherapy over a longer period.

A case report of pulmonary tumor thrombotic microangiopathy (PTTM) caused by esophageal squamous cell carcinoma

A 67-year-old male was referred to our hospital after being diagnosed with esophageal squamous cell carcinoma of the middle thoracic esophagus. The clinical stage was T1b(sm)N4M1 cStage IVb, so he was admitted to our hospital for systemic chemotherapy. He had sustained fever and a dry cough. Chest computed tomography showed the presence of irregular shadows, and unidentified respiratory insufficiency had progressed. A transbronchial lung biopsy revealed a pulmonary artery tumor embolus of esophageal squamous cell carcinoma. He developed DIC and died of respiratory failure on the 19th hospital day. The postmortem autopsy detected pulmonary tumor thrombotic microangiopathy accompanied by esophageal squamous cell carcinoma.

Preoperative hepatic CT perfusion as an early predictor for the recurrence of esophageal squamous cell carcinoma: Initial clinical results

Reports suggest that hepatic blood flow may have an association with cancer progression. The aim of the present study was to evaluate whether the hepatic blood flow measured by CT perfusion (CTP) may identify patients at high-risk for postoperative recurrence of esophageal squamous cell carcinoma (ESCC). Prior to surgery, hepatic CTP images were obtained using a 320-row area detector CT. The data were analyzed by a commercially available software based on the dual input maximum slope method, and arterial blood flow (AF, ml/min/100 ml tissue), portal blood flow (PF, ml/min/100 ml tissue) and perfusion index [PI (%) = AF/AF + PF × 100] were measured. These parameters were compared with the pathological stage and outcome of the ESCC patients. Forty-five patients with ESCC were eligible for this study. The median follow-up period was 17 months, and recurrences were observed in 9 patients (20%). The preoperative PI values of the 9 patients with recurrence were significantly higher than those of the 36 patients without recurrence (23.9 vs. 15.9, P=0.0022). Patients were categorized into the following two groups; high PI (>20) and low PI (<20). The recurrence-free survival of the low PI group was significantly better than that of the high PI group (P<0.0001). A multivariate analysis showed that a high PI was an independent risk factor for recurrence (odds ratio, 19.1; P=0.0369). Therefore, the preoperative PI of the liver may be a useful imaging biomarker for predicting the recurrence of patients with esophageal cancer.

Naso-esophageal extraluminal drainage for postoperative anastomotic leak after thoracic esophagectomy for patients with esophageal cancer

Postoperative anastomotic leaks and subsequent mediastinal abscess are serious complications. The purpose of this study was to assess the efficacy of naso-esophageal extraluminal drainage after thoracic esophagectomy with gastric conduit reconstruction using a posterior mediastinal route. About 50 of 365 patients (13.7%) with esophageal cancer and postoperative anastomotic leak after curative esophagectomy was investigated. Beginning in June 2009, naso-esophageal extraluminal drainage by inserting a naso-esophageal aspiration tube into the abscess cavity when percutaneous abscess drainage was introduced which was ineffective or technically impossible. Twenty-five patients underwent naso-esophageal extraluminal drainage concomitantly with enteral nutrition. Twenty-one (84%) patients had major leaks, one (4%) minor leak and three (12%) had endoscopically proven conduit necrosis. None of the naso-esophageal extraluminal drainage cases (100%) required reintervention or reoperation and all experienced complete cure (100%) during hospitalization. Endoscopic balloon dilatation was performed for four patients after discharge because of anastomotic stricture. Patients with leaks were divided into two groups: current group (n = 32), treated after June 2009, and preceding group (n = 18), treated prior to the introduction of naso-esophageal extraluminal drainage. Significantly more patients in the preceding group suffered respiratory failure (28% vs. 61%, p = 0.024), and higher reoperation rate (0% vs. 17%, p = 0.042) and hospital mortality (0% vs. 22%, p = 0.013). In the current group, 31 (97%) patients experienced complete cure during hospitalization. Naso-esophageal extraluminal drainage and concomitant enteral nutritional support are less invasive, and effective and powerful methods to treat even major leakage after esophagectomy. These methods may be an alternative management to improve mortality for patients with esophageal cancer.

Management of complicated diverticulitis of the colon

Diverticular disease of the colon occurs quite frequently in developed countries, and its prevalence has recently increased in Japan. The appearance of diverticulosis increases with age, although mostly remaining asymptomatic. Approximately 20% of cases require treatment. As the Western lifestyle and number of elderly people increase, the need for medical treatment also increases. Computed tomography (CT) is the gold standard for diagnosing diverticulitis. Complicated diverticulitis is classified by the size and range of abscess formation and the severity of the peritonitis. Each case should be classified based on clinical and computed tomography (CT) findings and then treated appropriately. Most patients with uncomplicated diverticulitis (stages 0–Ia) can be treated conservatively. Diverticulitis with a localized abscess (stages Ib–II) is generally resolved with conservative treatment. If the abscess is larger or conservative treatment fails, however, percutaneous drainage or surgery should be considered. Operative treatment is considered standard therapy for severe diverticulitis with perforation and generalized peritonitis (stages III–IV). Colonic diverticulitis treated conservatively frequently recurs. Elective surgery after recovery should be considered carefully and decisions made on a case‐by‐case basis. Because cases of colonic diverticulitis will undoubtedly increase in Japan, it is likely that we will be confronted with increasing numbers of treatment decisions. We therefore need to have a systematic strategy for treating the various stages of colonic diverticulitis appropriately. We herein review the management of complicated diverticulitis.

524PVOICE TRIAL-RESULTS FROM A MULTICENTER PHASE II STUDY OF ASSESSMENT OF CLINICAL EFFICACY AND SAFETY IN CAPECITABINE PLUS INTERMITTENT OXALIPLATIN TOGETHER WITH BEVACIZUMAB AS THE FIRST-LINE THERAPY FOR THE PATIENTS WITH ADVANCED COLORECTAL CANCER

ABSTRACT Aim: The FOLFOX with bevacizumab regimen has been established as a standard first-line therapy for metastatic colorectal cancer (mCRC), and the OPTIMOX1 study suggested that a stop and go strategy for oxaliplatin reduced peripheral sensory neuropathy. We had already evaluated the efficacy of OPTIMOX1 plus bevacizumab in patients (pts) with mCRC (CRAFT study, Tezuka et al, Invest New Drugs 2013). CapeOx is one of the standard treatments for mCRC that has been proven to be as effective as the FOLFOX regimen. Thus we assessed the efficacy and safety of the combination of intermittent CapeOx + Bevacizumab as a first-line therapy in patients with mCRC in this trial. Methods: Eligibility criteria included ECOG PS: 0–1, no peripheral neuropathy ( Results: Between March 2011 and August 2013, 55 pts were enrolled. Baseline characteristics were median age of 67 years (range, 20–83); PS 0/1 (49/6 pts); male/female(33/22 pts), colon/rectum (28/27pts) and metastatic lesion liver/lung/lymph nodes (32/18/21 pts). A total of 47 pts were evaluated as Par Protocol Set population. 38 pts moved from initial CapeOX to maintenance capecitabine. 20 pts moved to CapeOx reintroduction. Median PFS was 12.4 months (95%CI, 7.7–17.1) and Median TTF was 8.3 months (95%CI, 4.5–12.1). Best overall response rate was 50.9%. Median capecitabine courses were 5 cycles (range 1–5). Oxaliplatin reintroduction rate was 52%. The causes of reintroduction failure were disease progression (3 pts), successful liver resection (2 pts), peripheral sensory neuropathy grade 2 (1 pt). Main grade 3/4 toxicities: neutropenia, anemia, peripheral neuropathy, hand-foot syndrome, and hypertension in 1 patient. Conclusions: This study met its primary endpoint PFS. It was longer than the CRAFT study. CapeOx with intermittent oxaliplatin is indicated to reduce incidence of severe neutropenia and peripheral sensory neuropathy. The results suggested that our treatment strategy was well tolerated and effective for first-line therapy in mCRC, and maintenance of duration for 5 cycles was reasonable. Disclosure: All authors have declared no conflicts of interest.