A randomised phase II trial of capecitabine plus cisplatin versus S-1 plus cisplatin as a first-line treatment for advanced gastric cancer: Capecitabine plus cisplatin ascertainment versus S-1 plus cisplatin randomised PII trial (XParTS II).

BACKGROUND: Capecitabine plus cisplatin (XP) is a standard global regimen, while S-1 plus cisplatin (SP) is a Japanese standard for first-line treatment of advanced gastric cancer (AGC). We conducted a phase II trial comparing XP with SP for patients with AGC to confirm whether these regimens can be used as controls in a phase III study and to explore whether histological subtypes favour XP or SP. PATIENTS AND METHODS: Eligible patients were randomised to receive either S-1 40 mg/m2 for 21 days plus cisplatin 60 mg/m2 (q5w) or capecitabine 1000 mg/m2 for 14 days plus cisplatin 80 mg/m2 (q3w). The primary end-point was progression-free survival (PFS). The secondary end-points were overall survival (OS), overall response rate (ORR) and safety. RESULTS: In 110 eligible patients, 24-week PFS was higher in both groups (SP 50.9%, XP 43.5%) than the protocol-specified threshold of 40%. The median PFS for SP versus XP was 5.6 and 5.1 months (hazard ratio [HR], 1.126; p = 0.5626); OS was 13.5 and 12.6 months (HR, 0.942; p = 0.7769) and the ORR was 42.4% and 69.4% (p = 0.0237), respectively. The most common grade ≥3 adverse events with SP/XP were anaemia (16%/20%), neutropenia (9%/18%) and anorexia (18%/13%). Subgroup analysis by histological classification showed no statistical difference between treatments. CONCLUSIONS: XP and SP are comparable and can be recommended as control arms in a phase III study for AGC. Histological subtypes were not sensitive markers for the selection of XP or SP. CLINICAL TRIAL REGISTRATION: NCT00140624.

Open-label, randomized, comparative, phase III study on effects of reducing steroid use in combination with Palonosetron.

The purpose of this study is to compare the efficacy of a single administration of dexamethasone (DEX) on day 1 against DEX administration on days 1-3 in combination with palonosetron (PALO), a second-generation 5-HT3 receptor antagonist, for chemotherapy-induced nausea and vomiting (CINV) in non-anthracycline and cyclophosphamide (AC) moderately-emetogenic chemotherapy (MEC). This phase III trial was conducted with a multi-center, randomized, open-label, non-inferiority design. Patients who received non-AC MEC as an initial chemotherapy were randomly assigned to either a group administered PALO (0.75 mg, i.v.) and DEX (9.9 mg, i.v.) prior to chemotherapy (study treatment group), or a group administered additional DEX (8 mg, i.v. or p.o.) on days 2-3 (control group). The primary endpoint was complete response (CR) rate. The CR rate difference was estimated by logistic regression with allocation factors as covariates. The non-inferiority margin was set at -15% (study treatment group - control group). From April 2011 to March 2013, 305 patients who received non-AC MEC were randomly allocated to one of two study groups. Overall, the CR rate was 66.2% in the study treatment group (N = 151) and 63.6% in the control group (N = 154). PALO plus DEX day 1 was non-inferior to PALO plus DEX days 1-3 (difference, 2.5%; 95% confidence interval [CI]: -7.8%-12.8%; P-value for non-inferiority test = 0.0004). There were no differences between the two groups in terms of complete control rate (64.9 vs 61.7%) and total control rate (49.7% vs 47.4%). Anti-emetic DEX administration on days 2-3 may be eliminated when used in combination with PALO in patients receiving non-AC MEC.

Current status of hepatocellular carcinoma treatment in Japan: practical use of sorafenib (Nexavar®).

The efficacy of sorafenib in hepatocellular carcinoma (HCC) has been demonstrated in two pivotal clinical trials: the European SHARP trial and a second trial that recruited patients in the Asia-Pacific region. Sorafenib was approved for the treatment of advanced HCC in Japan based on the results of these studies. This article presents experiences with sorafenib in patients with HCC at three institutions in Japan, representing the viewpoints of a liver surgeon and a hepatologist at university hospitals, and a hepatologist at a community hospital. The three physicians discuss representative cases and current clinical practice at their institutions, and their recommendations for the use of sorafenib in the wider clinical setting. Overall, the experiences at these institutions show that sorafenib is most effective when administered for a long time, and the management of adverse events (AEs) [including dose-reduction and modification] is critical to achieving high levels of adherence to treatment. A team-focussed treatment strategy that includes patient counselling and follow-up can contribute to managing AEs to ensure successful continuation of sorafenib therapy. In addition, a proposed definition of unresponsiveness to transarterial chemoembolization and the implications of treatment lag on the outcomes of sorafenib therapy, as well as measures for the prevention and treatment of hand-foot skin reaction are discussed.

[Clinical efficacy of adalimumab for a postoperative marginal ulcer in gastrointestinal Behçet disease].

A 63-year-old woman with Behçet disease presented with epigastric pain due to refractory gastric ulcers. Examinations indicated that these ulcers were caused by gastrointestinal Behçet disease. Steroid therapy proved ineffective, so we gave 5mg/kg of infliximab. However, since the patient responded poorly to the treatment the infliximab was discontinued and a total gastrectomy was performed. After surgery, a marginal ulcer developed and infliximab was again administered. Although this brought about improvement in the conditions of the marginal ulcer, infusion-related hypersensitivities in the patient caused polyarthralgia. We therefore discontinued the infliximab treatment and began 40 mg of adalimumab every other week. After 3 months of the new treatment, the patient's marginal ulcer completely healed and her epigastric pain disappeared. This case suggests that adalimumab may be as useful as infliximab for treating refractory gastrointestinal Behçet disease.

[Osteoclast-like giant cell tumor (OGCT) of the liver: report of a case].

A 57-year-old man presented with jaundice. Abdominal computed tomography showed a 10-cm left hepatic lobe heterogeneous solid mass with low attenuated areas in the mass, multiple liver metastases and lung metastasis. Serology for hepatitis B and C were negative. Serum alpha-fetoprotein, CEA and CA19-9 were normal. The patient died a few weeks later of progressive liver failure and an autopsy was performed. Histologically, the tumor consisted of sarcomatoid mononuclear cells and osteoclast-like giant cells. The liver tissue surrounding the tumor showed no cirrhotic pattern. The osteoclast-like giant cells were uniformly and strongly immunoreactive with CD68. The mononuclear cells demonstrated expression of vimentin but were negative for CAM5.2. The MIB-1 index was 20% for the mononuclear cells. In conclusion, the histopathological diagnosis revealed an osteoclast-like giant cell tumor of the liver.

Anti-tumor activity of ESX1 on cancer cells harboring oncogenic K-ras mutation.

Human ESX1 is a 65-kilodalton (kDa) paired-like homeoprotein that is proteolytically processed into N-terminal 45-kDa and C-terminal 20-kDa fragments. The N-terminal ESX1 fragment, which contains the homeodomain, localizes to the nucleus and represses mRNA transcription from the K-ras gene. When we inoculated human colorectal carcinoma HCT116 constitutive expressing N-terminal region of ESX1 (N-ESX1) into nude mice, transfectant cells uniformly showed decreased tumor-forming activity compared with that of the parental cells. Furthermore, pretreatment of HCT116 carcinoma cells with a fusion protein consisting of N-ESX1 and the protein-transduction domain derived from the human immunodeficiency virus type-1 TAT protein gave rise to a dramatic reduction in the tumorigenicity of HCT116 cells in nude mice. Our results provide first in vivo evidence for the molecular targeting therapeutic application of the K-ras repressor ESX1, especially TAT-mediated transduction of N-ESX1, in the treatment of human cancers having oncogenic K-ras mutations.

Paired-like homeoprotein ESXR1 acts as a sequence-specific transcriptional repressor of the human K-ras gene.

Gain-of-function mutation of the K-ras gene is one of the most common genetic changes in human tumors. In tumors carrying K-ras mutation, the presence of oncogenic K-Ras is necessary for maintenance of the transformed phenotype. ESXR1 is a human paired-like homeodomain-containing protein expressed primarily in the testis. In cells, the 65-kDa full-length ESXR1 protein is proteolytically processed into an N-terminal 45-kDa fragment containing the homeodomain, which localizes exclusively within the nucleus, and a C-terminal 20-kDa fragment consisting of a proline-rich repeat region, which is located in the cytoplasm. In this work, we demonstrated that the N-terminal ESXR1 fragment specifically recognizes the TAATNNNATTA P3 consensus sequence for the paired-like homeodomain and functions as a sequence-specific transcriptional repressor. We also showed that the N-terminal ESXR1 fragment binds to the TAATGTTATTA sequence present within the first intron of the human K-ras gene and inhibits its expression at both mRNA and protein levels. Ectopic expression of the N-terminal ESXR1 fragment in human carcinoma cells that carry mutated K-ras reduces the level of K-Ras and thereby inhibits the tumor cell proliferation. Identification of ESXR1 as a transcriptional repressor of K-ras has an important implication for the development of cancer therapy that inhibits oncogenic K-Ras expression.