Detailed analyses of the data from more than 100,000 patients show the recent trends of the outcomes of gastric cancer treatment in Japan and provide baseline information for use by medical communities around world.
PURPOSE S-1 is a standard postoperative adjuvant chemotherapy for patients with stage II or III gastric cancer in Asia. Neoadjuvant or perioperative strategies dominate in Western countries, and docetaxel has recently shown significant survival benefits when combined with other standard regimens in advanced cancer and perioperative settings. PATIENTS AND METHODS This randomized phase III study was designed to prove the superiority of postoperative S-1 plus docetaxel over S-1 alone for R0 resection of pathologic stage III gastric cancer. The sample size of 1,100 patients was necessary to detect a 7% increase in 3-year relapse-free survival as the primary end point (hazard ratio, 0.78; 2-sided α = .05; β = .2). RESULTS The second interim analysis was conducted when the number of events reached 216 among 915 enrolled patients (median follow-up, 12.5 months). Analysis demonstrated the superiority of S-1 plus docetaxel (66%) to S-1 (50%) for 3-year relapse-free survival (hazard ratio, 0.632; 99.99% CI, 0.400 to 0.998; stratified log-rank test, P < .001), and enrollment was terminated as recommended by the independent data and safety monitoring committee. Incidences of grade 3 or greater adverse events, particularly neutropenia and leukopenia, were higher in the S-1 plus docetaxel group, but all events were manageable. CONCLUSION Addition of docetaxel to S-1 is effective with few safety concerns in patients with stage III gastric cancer. The present findings may also be applicable in countries in which perioperative adjuvant chemotherapy or chemoradiation is not standard.
Tumor associated macrophages (TAMs) are the most abundant cancer stromal cells educated by tumor microenvironment to acquire trophic functions facilitating angiogenesis, matrix breakdown and cancer cell motility. Tumor associated macrophages have anti-inflammatory properties or "alternatively" activated (M2) phenotype expressing CD204 and ⁄ or CD163. To know the role of TAMs in the growth and progression of esophageal squamous cell carcinomas (ESCCs), we calculated intratumoral CD204, CD163 or CD68 expressing macrophage count (M/C) and CD34-positive microvessel density (MVD) by immunohistochemistry in 70 cases of surgically resected ESCCs and compared them with the clinicopathological factors and prognosis of patients. M/C had positive linear association with MVD. High CD204 + M/C were significantly correlated with more malignant phenotypes including depth of tumor invasion, lymph and blood vessel invasion, lymph node metastasis as well as clinical stages. On the other hand, CD163+ M/C did not associate with these clinicopathological factors with the exception of depth of tumor invasion and blood vessel invasion. Patients with high CD204 + M/C ESCCs showed poor disease-free survival (P = 0.021). Conditioned media of five ESCC cell lines (TE-8, -9, -10, -11 and -15) induced mRNA as well as protein expression of CD204 but not of CD163 with upregulation of vascular endothelial growth factor-A mRNA in TPA treated human acute monocytic leukemia cell line THP-1. These results overall indicate that CD204 is a useful marker for TAMs contributing to the angiogenesis, progression and prognosis of ESCCs whose specific tumor microenvironment may educate macrophages to be CD204
ObjectiveEarly detection and early treatment are of vital importance to the successful treatment of various cancers. The development of a novel screening method that is as economical and non-invasive as the faecal occult blood test (FOBT) for early detection of colorectal cancer (CRC) is needed. A study was undertaken using canine scent detection to determine whether odour material can become an effective tool in CRC screening.DesignExhaled breath and watery stool samples were obtained from patients with CRC and from healthy controls prior to colonoscopy. Each test group consisted of one sample from a patient with CRC and four control samples from volunteers without cancer. These five samples were randomly and separately placed into five boxes. A Labrador retriever specially trained in scent detection of cancer and a handler cooperated in the tests. The dog first smelled a standard breath sample from a patient with CRC, then smelled each sample station and sat down in front of the station in which a cancer scent was detected.Results33 and 37 groups of breath and watery stool samples, respectively, were tested. Among patients with CRC and controls, the sensitivity of canine scent detection of breath samples compared with conventional diagnosis by colonoscopy was 0.91 and the specificity was 0.99. The sensitivity of canine scent detection of stool samples was 0.97 and the specificity was 0.99. The accuracy of canine scent detection was high even for early cancer. Canine scent detection was not confounded by current smoking, benign colorectal disease or inflammatory disease.ConclusionsThis study shows that a specific cancer scent does indeed exist and that cancer-specific chemical compounds may be circulating throughout the body. These odour materials may become effective tools in CRC screening. In the future, studies designed to identify cancer-specific volatile organic compounds will be important for the development of new methods for early detection of CRC.
The clinicopathological characteristics of gastric cancer determine the type of recurrence, although the clinical outcome is the same for each type of tumour and is not related to the number of sites of recurrence.
Akt (protein kinase B) is a serine/threonine kinase which is a central regulator of widely divergent cellular processes including proliferation, differentiation, migration, survival and metabolism. Akt is activated by a variety of stimuli, through growth factor receptors, in phosphatidylinositol 3-kinase (PI3K)-dependent manner. Akt is also negatively regulated by the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN). A disruption of normal Akt/PKB/PTEN signaling frequently occurs in many human cancers, which plays an important role in cancer development, progression and therapeutic resistance. Numerous studies have revealed the blockage of Akt signaling to result in apoptosis and growth inhibition of tumor cells. Therefore, this signaling pathway, including both upstream and downstream of Akt, has recently attracted considerable attention as a new target for effective cancer therapeutic strategies. In fact, many inhibitors of Akt pathway have been identified and clinical studies of some agents are ongoing. In this review, we describe Akt signaling pathway components and its cellular functions as well as the alterations in human cancers and the therapeutic approaches for targeting the Akt pathway in cancer.
Akt/PKB is a serine/threonine kinase that plays an important role in survival when cells are exposed to different apoptotic stimuli. Aberrant activation of Akt/PKB in breast carcinoma is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway currently attracts considerable attention as a new target for effective therapeutic strategies. We therefore investigated the relationship between activation of Akt and clinicopathologic variables including hormone receptor and HER2/neu status. Breast cancer tissues obtained from 252 patients were utilized for this study. We evaluated Akt activation by immunohistochemical assessment of the expression of phosphorylated Akt (pAkt) at Ser-473. Eighty-four cases (33.3%) were diagnosed as positive for pAkt expression. pAkt was significantly associated with HER2/neu overexpression (p < 0.0001). There was an inverse correlation between pAkt and PR expression (p 5 0.0321); however, there was no association between pAkt and ER expression. Survival analysis showed that pAkt positivity was associated with poor disease-free survival in cases with postoperative hormone therapy; however, there was no association in cases without hormone therapy. Our results indicate that Akt activation induced poor prognosis in patients who received adjuvant hormone therapy. This finding suggests that inhibition of the Akt signaling pathway may increase the efficacy of hormone therapy and improve the prognosis of patients who receive adjuvant hormone therapy. ' 2005 Wiley-Liss, Inc.
Growth factor receptor-mediated signal transduction has been implicated in conferring resistance to conventional chemotherapy on cancer cells. We describe a pathway that involves AKT/PI3K to mediate chemoresistance in gastric cancer patients. Primary gastric carcinoma tissues and corresponding normal mucosa were obtained from 76 gastric cancer patients who underwent surgery in the Department of Surgery II in Kyushu University Hospital from the years 1996-2000. AKT activation was investigated by immunostaining with a phosphorylation-specific antibody, and LOH (loss of heterozygosity) of PTEN was studied in the same samples. AKT was phosphorylated in 22 cases (28.9%) of gastric cancer cases. AKT and phosphorylated AKT were not correlated with any clinicopathological factor. We found that the gastric cancer patients who had higher AKT phosphorylation (activated AKT) seemed to have LOH of PTEN (p 5 0.0008). When the chemotherapeutic sensibilities of these patients were studied in an MTT assay, it was found that the activated AKT was associated with increased resistance to multiple chemotherapeutic agents (5-fluorouracil, adriamycin, mitomycin C and cis-platinum). The results of our study indicate that AKT activation and LOH of PTEN plays an important role in conferring a broad-spectrum chemoresistance in gastric cancer patients. It also indicates that AKT may therefore be a novel molecular target for therapies or chemosensitivity tests that improve the outcomes of gastric cancer patients. ' 2005 Wiley-Liss, Inc.
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