CD4(+) T cells that express the forkhead box P3 (FOXP3) transcription factor function as regulatory T (Treg) cells and hinder effective immune responses against cancer cells. Abundant Treg cell infiltration into tumors is associated with poor clinical outcomes in various types of cancers. However, the role of Treg cells is controversial in colorectal cancers (CRCs), in which FOXP3(+) T cell infiltration indicated better prognosis in some studies. Here we show that CRCs, which are commonly infiltrated by suppression-competent FOXP3(hi) Treg cells, can be classified into two types by the degree of additional infiltration of FOXP3(lo) nonsuppressive T cells. The latter, which are distinguished from FOXP3(+) Treg cells by non-expression of the naive T cell marker CD45RA and instability of FOXP3, secreted inflammatory cytokines. Indeed, CRCs with abundant infiltration of FOXP3(lo) T cells showed significantly better prognosis than those with predominantly FOXP3(hi) Treg cell infiltration. Development of such inflammatory FOXP3(lo) non-Treg cells may depend on secretion of interleukin (IL)-12 and transforming growth factor (TGF)-β by tissues and their presence was correlated with tumor invasion by intestinal bacteria, especially Fusobacterium nucleatum. Thus, functionally distinct subpopulations of tumor-infiltrating FOXP3(+) T cells contribute in opposing ways to determining CRC prognosis. Depletion of FOXP3(hi) Treg cells from tumor tissues, which would augment antitumor immunity, could thus be used as an effective treatment strategy for CRCs and other cancers, whereas strategies that locally increase the population of FOXP3(lo) non-Treg cells could be used to suppress or prevent tumor formation.

We developed a new endoscopic thyroid surgery by the axillo-bilateral-breast approach (ABBA) method, which is different from the previously described breast approach (BA) in that the port sites are modified to obtain a better view and to prevent the interference of surgical instruments. This modification also improves cosmetic results by eliminating the parasternal incision, which results in hypertrophic scar in a significant number of cases treated with BA. Twelve patients with benign thyroid tumors successfully underwent endoscopic thyroid surgery by ABBA, and their clinical outcomes were compared with those of four patients treated with BA. The mean operation time was significantly shorter in the ABBA group than in the BA group (188 minutes vs. 270 minutes; P < 0.01). Furthermore, the mean blood loss in the ABBA group (53 mL) was half of that in the BA group (108 mL). Neither conversion to open surgery nor significant intraoperative complications were experienced. The operative scars by ABBA became inconspicuous in a few weeks. These results seem to indicate that ABBA is a better method than BA and can be a feasible option, particularly for young patients who opt for the better cosmetic outcome.

Purpose: To determine the relationship between resistance to chemotherapy and microRNA (miRNA) expression in esophageal cancer, we focused on miRNAs known to be associated with maintenance of stem cell function.Experimental Design: Using 98 formalin-fixed, paraffin-embedded samples obtained from patients with esophageal cancer who had received preoperative chemotherapy followed by surgery, we measured expression levels of several miRNAs that are considered to be involved in the regulation of stem cell function (e.g., let-7a, let-7g, miR-21, miR-134, miR-145, miR-155, miR-200c, miR-203, and miR-296) by real-time reverse transcriptase PCR. Then, we examined the relationship between miRNA expression and prognosis or response to chemotherapy. To investigate the mechanism of miRNA-induced chemoresistance, in vitro assays were carried out using esophageal cancer cells.Results: Analyses of the 9 miRNAs expression showed that overexpression of miR-200c (P ¼ 0.037), underexpression of miR-145 (P ¼ 0.023), and overexpression of miR-21 (P ¼ 0.048) correlated significantly with shortened overall duration of survival. In particular, miR-200c expression correlated significantly with response to chemotherapy (P ¼ 0.009 for clinical response; P ¼ 0.007 for pathologic response). In vitro assay showed significantly increased miR-200c expression in cisplatin-resistant cells compared with their parent cells ($1.7-fold). In anti-miR-200c-transfected cells, chemosensitivity to cisplatin and apoptosis after exposure to cisplatin was found to increase as compared with the negative control. Western blotting showed that knockdown of miR-200c expression was associated with increased expression of PPP2R1B, a subunit of protein phosphatase 2A, which resulted in reduced expression of phospho-Akt.Conclusions: Results of this study emphasized the involvement of miR-200c in resistance to chemotherapy among esophageal cancers and that this effect was mediated through the Akt pathway. Clin Cancer Res; 17(9); 3029-38. Ó2011 AACR.

PSVT is a more frequent complication of laparoscopic splenectomy than previously reported but can be treated safely following early detection by CT with contrast.

Abstract. Autophagy is a bulk protein and organelle degradation process essential for cell maintenance and viability. Microtubule-associated protein 1 light chain 3 (LC3), the mammalian homologue of yeast Atg8, is involved in autophagosome formation during autophagy. The aim of this study was to investigate LC3 expression in gastrointestinal cancers to elucidate the role of autophagy in human cancer development. We evaluated LC3 expression by immunohistochemistry in 163 gastrointestinal cancers including 106 esophageal, 38 gastric and 19 colorectal cancers. Seventy precancerous intraepithelial neoplasias were found in esophageal cancer specimens. LC3 expression was compared with Ki-67 staining and expression of carbonic anhydrase (CA) IX, a hypoxic marker. LC3 was expressed in the cytoplasm of cancer cells, but not in noncancerous epithelial cells. A high expression of LC3 was observed in 53% of esophageal, 58% of gastric and 63% of colorectal cancers. LC3 immunoreactive score gradually increased during early esophageal carcinogenesis in low-and high-grade intraepithelial neoplasia and T1 carcinoma, while it did not change in later cancer progression (T2-T4 carcinomas). In early esophageal carcinogenesis, LC3 expression correlated with Ki-67 labeling index (p=0.0001), but showed no significant association with CAIX expression. In esophageal cancers, LC3 expression did not correlate with various clinicopathological factors, including survival. LC3 is upregulated in various gastrointestinal cancers and partly associated with Ki-67 index. Our results suggest that LC3 expression is advantageous to cancer development especially in earlyphase carcinogenesis.

The biological significance of micro (mi)RNAs has traditionally been evaluated according to their RNA expression levels based on the assumption that miRNAs recognize and regulate their targets in an unvarying fashion. Here we show that a fraction of mature miRNAs including miR-17-5p, -21-5p, and -200c-3p and let-7a-5p harbor methyl marks that potentially alter their stability and target recognition. Importantly, methylation of these miRNAs was significantly increased in cancer tissues as compared to paired normal tissues. Furthermore, miR-17-5p methylation level in serum samples distinguished early pancreatic cancer patients from healthy controls with extremely high sensitivity and specificity. These findings provide a basis for diagnostic strategies for early-stage cancer and add a dimension to our understanding of miRNA biology.

Purpose: Cisplatin-based chemotherapy is widely used for esophageal cancer, sometimes in combination with surgery/radiotherapy, but poor response to chemotherapy is not uncommon. The aim of this study was to examine whether miRNA expression is useful to predict the response to chemotherapy in patients with esophageal cancer.Experimental Design: Using pretreatment biopsy samples from 98 patients with esophageal cancer who received preoperative chemotherapy, we measured the expression level of several miRNAs whose expression was altered in cisplatin-resistant esophageal cancer cell lines compared with those parent cell lines and examined the relationship between the miRNA expression and response to chemotherapy. In vitro assays were conducted to clarify the mechanism of miRNA-induced changes in chemosensitivity.Results: The expression levels of 15 miRNAs were altered in cisplatin-resistant cells. Of these, low expression of let-7b and let-7c in before-treatment biopsies from 74 patients of the training set correlated significantly with poor response to chemotherapy, both clinically and histopathologically. Low expression of let-7c also correlated with poor prognosis (P ¼ 0.032). The relationship between let-7b and let-7c expression and response to chemotherapy was confirmed in the other 24 patients of the validation set. In in vitro assay, transfection of let-7c restored sensitivity to cisplatin and increased rate of apoptosis after exposure to cisplatin. Let-7c directly repressed cisplatin-activated interleukin (IL)-6/STAT3 prosurvival pathway.Conclusions: Let-7 expression in esophageal cancer can be potentially used to predict the response to cisplatin-based chemotherapy. Let-7 modulates the chemosensitivity to cisplatin through the regulation of IL-6/STAT3 pathway in esophageal cancer.

Background Robotic gastrectomy (RG) for gastric cancer (GC) has been increasingly performed for a decade; however, evidence for its use as a standard treatment has not yet been established. The present study aimed to determine the safety, feasibility, and effectiveness of RG for GC. Methods This multi-institutional, single-arm prospective study, which included 330 patients from 15 institutions, was designed to compare morbidity rate of RG with that of a historical control (conventional laparoscopic gastrectomy, LG). This trial was approved for Advanced Medical Technology ("Senshiniryo") B. The included patients were operable patients with cStage I/II GC. The primary endpoint was morbidity (Clavien-Dindo Grade ≥ IIIa). The specific hypothesis was that RG could reduce the morbidity rate to less than half of that with LG (6.4%). A sample size of 330 was considered sufficient (one-sided alpha 0.05, power 80%). Results Among the 330 study patients, the protocol treatment was suspended in 4 patients. Thus, 326 patients fully enrolled and completed the study. The median patient age and BMI were 66 years and 22.4 kg/m 2 , respectively. Distal gastrectomy was performed in 253 (77.6%) patients. The median operative time and estimated blood loss were 313 min and 20 mL, respectively. No 30-day mortality was seen, and morbidity showed a significant reduction to 2.45% with RG (p = 0.0018). Conclusions RG for cStage I/II GC is safe and feasible. It may be effective in reducing morbidity with LG.