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To assess the clinical indications for, and prognostic impact of surgery after, chemotherapy for type 4 gastric cancer. The subjects of this retrospective study were 67 patients who received chemotherapy for type 4 gastric cancer. The patients were grouped into those with progressive disease (PD group) and those without PD (non-PD group), according to the tumor response to chemotherapy. Distant metastases developed in 58 patients. With regard to tumor response, there were 16 patients in the PD group and 51 patients in the non-PD group. The prognosis of the PD group patients was significantly poorer than that of the non-PD group patients (p

Aberrantly expressed microRNAs (miRNAs) disrupt intracellular RNA networks and contribute to malignant transformation of cancer cells. Utilizing the latest RNA sequencing technology, we newly created the miRNA expression signature of esophageal squamous cell carcinoma (ESCC). A total of 47 miRNAs were downregulated in ESCC tissues, and these miRNAs were candidates for antitumor miRNAs in ESCC cells. Analysis of the signature revealed that several passenger strands of miRNAs were significantly downregulated in ESCC, e.g., miR-28-3p, miR-30a-3p, miR-30c-3p, miR-133a-3p, miR-139-3p, miR-143-5p, and miR-145-3p. Recent studies indicate that some passenger strands of miRNAs closely involved in cancer pathogenesis. In this study, we focused on both strands of pre-miR-143, and investigated their antitumor roles and target oncogenes in ESCC. Ectopic expression of miR-143-5p and miR-143-3p significantly attenuated malignant phenotypes (e.g., proliferation, migration, and invasive abilities) in ESCC cell lines. We revealed that six genes (HN1, HMGA2, NETO2, STMN1, TCF3, and MET) were putative targets of miR-143-5p regulation, and one gene (KRT80) was a putative target of miR-143-3p regulation in ESCC cells. Our ESCC miRNA signature and analysis strategy provided important insights into the molecular pathogenesis of ESCC.

Background Patients with stage IV gastric cancer have a poor prognosis despite the recent development of multidisciplinary treatments that include chemotherapy. However, conversion surgery has emerged as a promising strategy to improve the prognosis in responders with unresectable gastric cancer after chemotherapy. Moreover, nivolumab is currently recommended as a third-line treatment in patients with unresectable advanced gastric cancer. However, there are few reports of conversion surgery after nivolumab in patients with stage IV gastric cancer. Case presentation A 68-year-old woman complaining of nausea was diagnosed with stage I gastric cancer (T2N0M0). Although we planned gastrectomy with lymphadenectomy, multiple liver metastases were detected during the surgery. After staging laparoscopy, we diagnosed this patient as having stage IV unresectable gastric cancer, and we administered chemotherapy and immunotherapy for 39 months (first-line regimen: 6 courses of S-1 plus oxaliplatin; second-line regimen: 6 courses of ramucirumab plus paclitaxel; and third-line regimen: 20 courses of nivolumab). Although the liver metastases completely disappeared after the second-line chemotherapy, lung metastases and a rapid enlargement of the primary tumor were confirmed. Consequently, the patient received nivolumab at a dose of 3 mg/kg intravenously every 2 weeks, then a dose of 240 mg/kg intravenously every 2 weeks from September 2018. After 20 courses of nivolumab, the primary tumor dramatically shrank and the lung metastases disappeared. The patient had a partial primary tumor response to nivolumab. Therefore, the patient underwent laparoscopic distal gastrectomy with D2 lymph node dissection. The macroscopic examination of the resected specimen showed an ulcer scar in the primary tumor site. The pathological examination demonstrated no residual tumors and no lymph node metastases, and the histological response of the primary tumor was categorized as grade 3. The postoperative course was uneventful, and the patient is receiving nivolumab to control potential liver and lung metastases. Conclusions Conversion surgery might help control tumor progression in responders after chemotherapy and immunotherapy.

Objective: Chemotherapy is generally recommended as the first-line standard treatment in patients with liver metastasis from gastric cancer. However, the clinical impact of surgical treatment remains unclear in responders after chemotherapy. The present study aimed to investigate the tumor response and prognosis after chemotherapy and to assess the clinical indication of conversion surgery in responders. Methods: The study retrospectively reviewed the clinical data of 44 patients with liver metastasis from gastric cancer who were treated with chemotherapy between February 2002 and January 2019. These patients were classified into progressive disease (PD) and non-PD groups according to tumor response. Results: Among the 44 patients, 7 and 26 had peritoneal dissemination and ≥5 had metastatic liver nodules. Additionally, 15 and 29 patients had PD and non-PD, respectively. Surgical treatment was significantly correlated with tumor response (p < 0.0321). Prognostic differences between the PD and non-PD groups were significant (p < 0.0001). Moreover, gastrectomy and hepatectomy were significantly correlated with the number of liver metastases (≥5 vs. p = 0.0025 and p = 0.0169, respectively). The 3-year survival rates among patients with non-PD undergoing both gastrectomy and hepatectomy (n = 6), gastrectomy alone (n = 7), and nonsurgical treatments (n = 16) were 100, 66.7, and 0%, respectively (p = 0.0026). Multivariate analysis identified peritoneal dissemination as an independent prognostic factor (p = 0.0225). Conclusion: Our preliminary results suggest that conversion surgery for gastric cancer with liver metastasis might be clinically indicated in chemotherapy responders with

Objective: Although chemotherapy has been clinically recommended as the initial treatment for patients with peritoneal dissemination of gastric cancer, poor prognosis has been noted among the same patients. However, the prognostic significance of conversion surgery after chemotherapy remains unclear. The present study therefore aimed to assess the clinical impact of conversion surgery among patients with peritoneal dissemination of gastric cancer. Methods: A total of 93 patients with peritoneal dissemination of gastric cancer undergoing chemotherapy between February 2002 and October 2019 were retrospectively enrolled and subsequently divided into progressive disease (PD) and non-PD groups based on tumor response to chemotherapy. Results: Among the included patients, 17 developed distant metastases at another site besides peritoneal dissemination. Based on tumor response, 24 and 69 patients were determined to have PD and non-PD, respectively, with the former having significantly poorer prognosis than the latter (p < 0.0001). A total of 19 patients underwent conversion surgery after chemotherapy, with the presence or absence of conversion surgery being significantly correlated with age, first-line chemotherapy regimen, and tumor response (p = 0.0134, p = 0.0337, and p = 0.0024, respectively). Patients in the non-PD group who underwent conversion surgery or chemotherapy alone had 3-year overall survival rates of 55.6 and 6.6%, respectively. Multivariate analysis identified conversion surgery alone as an independent prognostic factor in the non-PD group (p < 0.0001). Conclusion: Our retrospective study demonstrated that conversion surgery for gastric cancer with peritoneal dissemination might improve the prognosis of responders who developed no peritoneal dissemination after chemotherapy.

To elucidate novel aspects of the molecular pathogenesis of colorectal cancer (CRC), we have created a new microRNA (miRNA) expression signature based on RNA-sequencing. Analysis of the signature showed that 84 miRNAs were upregulated, and 70 were downregulated in CRC tissues. Interestingly, our signature indicated that both guide and passenger strands of some miRNAs were significantly dysregulated in CRC tissues. These findings support our earlier data demonstrating the involvement of miRNA passenger strands in cancer pathogenesis. Our study focused on downregulated miR-490-3p and investigated its tumor-suppressive function in CRC cells. We successfully identified a total of 38 putative oncogenic targets regulated by miR-490-3p in CRC cells. Among these targets, the expression of three genes (IRAK1: p = 0.0427, FUT1: p = 0.0468, and GPRIN2: p = 0.0080) significantly predicted 5-year overall survival of CRC patients. Moreover, we analyzed the direct regulation of IRAK1 by miR-490-3p, and its resultant oncogenic function in CRC cells. Thus, we have clarified a part of the molecular pathway of CRC based on the action of tumor-suppressive miR-490-3p. This new miRNA expression signature of CRC will be a useful tool for elucidating new molecular pathogenesis in this disease.

Background/aim To determine the prognostic utility of trastuzumab-based chemotherapy based on human epidermal growth factor receptor 2 (HER2) expression in patients with para-aortic lymph node (PAN) metastasis from gastric cancer. Patients and methods A total of 41 patients with clinical PAN metastasis from gastric cancer who underwent chemotherapy were retrospectively enrolled. Results Eighteen (43.9%) patients had HER2-positive tumors and consequently, received trastuzumab-based chemotherapy. A total of 11 patients underwent surgery. HER2 status was significantly correlated with the number of distant metastatic sites, the presence or absence of trastuzumab-based chemotherapy, and the presence or absence of gastrectomy. HER2-positive patients had significantly better prognosis than HER2-negative patients. Multivariate analysis identified age and trastuzumab-based chemotherapy based on HER2 status as an independent prognostic factor. Conclusion Assessing HER2 expression and subsequent trastuzumab-based chemotherapy can be an effective method for determining the prognosis of patients with PAN metastasis from gastric cancer.

Although the effectiveness of trifluridine/tipiracil(TFTD)with bevacizumab for unresectable colorectal cancer that was refractory to previous standard chemotherapy was reported, its effectiveness as a first-line treatment, especially for elderly frail patients, is unclear. An 85-year-old woman complaining of anorexia was diagnosed with unresectable sigmoid colon cancer with multiple metastases. Her general status was very poor, and her performance status(PS)was 4. We first performed laparoscopic transverse colostomy. As her general status gradually improved, we administered TFTD with bevacizumab as a first-line treatment based on the patient's strong request for chemotherapy. The patient underwent this regimen in the outpatient clinic for 9 months(9 courses). Although the size of the liver metastases increased, lung metastases and abdominal disseminations were under control and her PS became 0. She has been taking mFOLFOX6 with bevacizumab (80%)as a second-line treatment. TFTD with bevacizumab treatment was safe and efficacious as a first-line treatment for a frail elderly patient with unresectable colorectal cancer.

The ubiquitous presence of inhibitory interneurons in the thalamus of primates contrasts with the sparsity of interneurons reported in mice. Here, we identify a larger than expected complexity and distribution of interneurons across the mouse thalamus, where all thalamic interneurons can be traced back to two developmental programmes: one specified in the midbrain and the other in the forebrain. Interneurons migrate to functionally distinct thalamocortical nuclei depending on their origin: the abundant, midbrain-derived class populates the first and higher order sensory thalamus while the rarer, forebrain-generated class is restricted to some higher order associative regions. We also observe that markers for the midbrain-born class are abundantly expressed throughout the thalamus of the New World monkey marmoset. These data therefore reveal that, despite the broad variability in interneuron density across mammalian species, the blueprint of the ontogenetic organisation of thalamic interneurons of larger-brained mammals exists and can be studied in mice.

To investigate the drainage patterns of the inferior mesenteric vein (IMV) and measure the distance from the root of the inferior mesenteric artery (IMA) to the IMV using preoperative three-dimensional computed tomography (3D-CT) angiography in patients undergoing surgery for left-sided colorectal cancer. In this retrospective study, we analyzed data collected prospectively on 167 consecutive patients who underwent laparoscopic left-sided colorectal cancer surgery between July, 2014 and August, 2019. The drainage pattern of the IMV and the distance from the root of the IMA to the IMV were evaluated using 3D-CT angiography. We also assessed intraoperative adverse events and postoperative outcomes. The IMV drained into the superior mesenteric vein (SMV) in 44 patients, into the confluence point of the SMV and splenic vein (SV) in 38 patients, into the SV in 83 patients, and into the middle colic vein in the remaining three patients. The median length from the root of the IMA to the IMV was 22.1 mm (1.3–84.9). IMV injury occurred in only one patient during surgery, but resulted in colonic ischemia. 3D-CT angiography is useful for the preoperative assessment of vascular anatomical variations of the IMV and IMA for safe intraoperative navigation and prevention of complications during laparoscopy-assisted left-sided colorectal surgery.

Our recent studies have implicated some passenger strands of miRNAs in the molecular pathogenesis of human cancers. Analysis of the microRNA (miRNA) expression signature in pancreatic ductal adenocarcinoma (PDAC) has shown that levels of miR-30a-3p, the passenger strand derived from pre-mir-30a, are significantly downregulated in PDAC tissues. This study aimed to identify the oncogenes closely involved in PDAC molecular pathogenesis under the regulation of miR-30a-3p. Ectopic expression assays showed that miR-30a-3p expression inhibited the aggressiveness of the PDAC cells, suggesting that miR-30a-3p acts as a tumor-suppressive miRNA in PDAC cells. We further identified 102 putative targets of miR-30a-3p regulation in PDAC cells by combining in silico analysis with gene expression data. Of these, ten genes (EPS8, HMGA2, ENDOD1, SLC39A10, TGM2, MGLL, SERPINE1, ITGA2, DTL, and UACA) were independent prognostic factors in multivariate analysis of survival of patients with PDAC (p &lt, 0.01). We also investigated the oncogenic function of the integrin ITGA2 in PDAC cell lines. The integrin family comprises cell adhesion molecules expressed as heterodimeric, transmembrane proteins on the surface of various cells. Overexpression of ITGA2/ITGB1 (an ITGA2 binding partner) was detected in the PDAC clinical specimens. The knockdown of ITGA2 expression attenuated the malignant phenotypes of the PDAC cells. Together, results from these microRNA-based approaches can accelerate our understanding of PDAC molecular pathogenesis.

Using a circular stapler to create an anastomosis for esophagogastrostomy after esophagectomy is well accepted; however, it remains uncertain if the greater curvature (GC) or lesser curvature (LC) of the gastric conduit is better for the anastomosis. We conducted this prospective study to compare the integrity of esophagogastrostomy between the esophagus and the GC or LC side of the gastric conduit. The subjects of this study were 70 patients who underwent esophagectomy and were randomized to a “GC” group and an “LC” group (n = 35 each). The primary and secondary end points were anastomotic leakage (AL) and anastomotic stricture (AS), respectively. The overall AL rate was 22.1%, without a significant difference between the groups. Stump leakage developed in eight of nine patients in the GC group, whereas leakage developed at the esophagogastric anastomosis in five of six patients in the LC group. The rate of stump leakage was significantly higher than that of esophagogastric AL in the GC group. The overall AS rate was 4.4%, with a significant difference between the groups (0% in the GC group vs. 9.1% in the LC group). AL rates were comparable in the two groups, but the sites of leakage were significantly different.

A woman in her 50s received a detailed examination for her abdominal pain. CT indicated intestinal wall thickening of the ascending colon, lymphadenopathy, and tumor embolism in the superior mesenteric vein. Colonoscopy revealed type 2 tumor in the hepatic flexure of the colon, and she was diagnosed as having moderately differentiated adenocarcinoma by biopsy specimen. She received 12 courses of FOLFOXIRI plus BV therapy after ileostomy. As the tumor embolism disappeared and the primary lesion shrank after chemotherapy, right hemicolectomy and lymph node dissection were performed. Six months after surgery, she has had no recurrent disease. This case suggests that FOLFOXIRI plus BV therapy could be an effective treatment for right colon cancer with tumor embolism.

Objective: Nivolumab is recommended as a third-line treatment in patients with unresectable advanced or recurrent gastric cancer. Although recent studies have demonstrated the prognostic impact of salvage chemotherapy after immune checkpoint inhibitors in several malignancies, its clinical significance remains unclear in patients with gastric cancer. This study aimed to investigate tumor response to subsequent chemotherapy after nivolumab in patients with advanced gastric cancer and assess the prognostic effect of salvage chemotherapy. Methods: We retrospectively enrolled 31 patients with unresectable advanced or recurrent gastric cancer receiving nivolumab. Results: Twenty-two and nine patients received nivolumab as third-line and fourth- to sixth-line treatments, respectively. The objective response rate (ORR) and disease control rate (DCR) to nivolumab were 20.0% (4/20) and 55.0% (11/20), respectively. Eleven patients received salvage chemotherapy after nivolumab. The ORR and DCR to salvage chemotherapy were 37.5% (3/8) and 75.0% (6/8), respectively. The median progression-free survival and overall survival following salvage chemotherapy were 285 and 360 days, respectively. Conclusion: Our preliminary study indicates that nivolumab exposure may enhance subsequent chemosensitivity in patients with advanced gastric cancer.

Background Rectal gastrointestinal stromal tumor (GIST) is a very rare tumor of gastrointestinal tract. Surgical management of rectal GIST requires special attention for preserving of anal and urinary functions. Transanal minimal invasive surgery (TAMIS) is a well-developed minimally invasive technique for local excision of benign and early malignant rectal tumors; however, the application of TAMIS for rectal GIST is rarely and inadequately reported. We report the novel application of TAMIS for rectal GIST with considerations for anal and urinary functions. Case presentation A 67 years old female, who presented with history of per rectal bleeding, was diagnosed with submucosal GIST of 4.5 cm in diameter at right posterior wall of 7 cm from anal verge. Histology of biopsy showed abundant spindle-shaped cells arranged in bundles that were positive for CD34 and negative for C-Kit, desmin, smooth muscle actin (SMA), and S-100. The tumor was excised by TAMIS successfully. Final histopathology showed pT2 tumor with C-Kit positive and mitosis count 10 per 50 HPF. Postoperative period was uneventful, and she was discharged on adjuvant imatinib mesylate for 3 years. Conclusion TAMIS can be used safely in the management of rectal GIST after appropriate evaluation of tumor size, extent, location, and experience of operating surgeon.

Background Sex-determining region Y-box 9 (SOX9) is an important transcription factor for the development and differentiation of cells and their organization. In the present study, the clinical significance of SOX9 expression in oesophageal squamous cell carcinoma was examined. Materials and methods SOX9 expression in surgical specimens of primary tumours were immunohistochemically investigated in 175 patients with oesophageal squamous cell carcinomas. Results SOX9 was expressed (moderately or strongly) in 62.9% of samples. Expression of SOX9 was significantly positively correlated with depth of invasion, advanced stage, lymphatic and venous invasion, and poor prognosis. Univariate analysis showed that depth of invasion, lymph node metastasis, distant metastasis, stage, lymphatic invasion, venous invasion, and SOX9 expression were prognostic factors. Multivariate analysis indicated that depth of invasion and stage were independent prognostic factors, but SOX9 expression was not. Conclusion SOX9 expression is related to prognosis in patients with oesophageal squamous cell carcinoma, although it is not an independent prognostic factor.

Patients with advanced esophageal squamous cell carcinoma (ESCC) is received chemoradiotherapy or chemotherapy for clinical management. However, it is difficult to predict tumor response and prognosis using blood markers before starting treatments. The purpose of this study was to investigate the pre‐treatment plasma fibrinogen and neutrophil–lymphocyte ratio (NLR) in patients with advanced ESCC treated with chemoradiotherapy or chemotherapy, and to assess the clinical utility of a combined score using these blood markers, named as the F‐NLR (fibrinogen and NLR) score, as a predictor of tumor response and prognosis. A total of 98 advanced ESCC patients, treated with chemoradiotherapy or chemotherapy, were classified into three groups: F‐NLR score of 2, having both hyperfibrinogenemia (>400 mg/dL) and high NLR (>3.0), score of 1, one of these hematological abnormalities, and score of 0, having neither hyperfibrinogenemia nor high NLR. Fibrinogen and NLR were significantly higher in the progressive disease (PD) group than the non‐PD group (P = 0.0419, and P = 0.0001, respectively). A significantly higher F‐NLR score was found in the PD group than the non‐PD group (P = 0.0140). Overall survival was significantly lower in patients with an F‐NLR score of 2 than in those with an F‐NLR score of 0 or 1 (P

Our ongoing analyses identifying dysregulated microRNAs (miRNAs) and their controlled target RNAs have shed light on novel oncogenic pathways in pancreatic ductal adenocarcinoma (PDAC). The PDAC miRNA signature obtained by RNA sequencing showed that both strands of pre-miR-130b (miR-130b-5p, the passenger strand and miR-130b-3p, the guide strand) were significantly downregulated in cancer tissues. Our functional assays revealed that miR-130b-5p significantly blocked the malignant abilities of PDAC cell lines (PANC-1 and SW1990), e.g., cancer cell proliferation, migration, and invasion. A total of 103 genes were identified as possible oncogenic targets by miR-130b-5p regulation in PDAC cells based on genome-wide gene expression analysis and in silico database search. Among the possible targets, high expression of 9 genes (EPS8, ZWINT, SMC4, LDHA, GJB2, ZCCHC24, TOP2A, ANLN, and ADCY3) predicted a significantly poorer prognosis of PDAC patients (5-year overall survival, p

To evaluate the safety and feasibility of laparoscopic complete mesocolic excision via combined medial and cranial approaches with three-dimensional visualization around the gastrocolic trunk and middle colic vessels for transverse colon cancer.We evaluated prospectively collected data of 30 consecutive patients who underwent laparoscopic complete mesocolic excision between January 2010 and December 2015, 6 of whom we excluded, leaving 24 for the analysis. We assessed the completeness of excision, operative data, pathological findings, length of large bowel resected, complications, length of hospital stay, and oncological outcomes.Complete mesocolic excision completeness was graded as the mesocolic and intramesocolic planes in 21 and 3 patients, respectively. Eleven, two, eight, and three patients had T1, T2, T3, and T4a tumors, respectively; none had lymph node metastases. A mean of 18.3 lymph nodes was retrieved, and a mean of 5.4 lymph nodes was retrieved around the origin of the MCV. The mean large bowel length was 21.9 cm, operative time 274 min, intraoperative blood loss 41 mL, and length of hospital stay 15 days. There were no intraoperative and two postoperative complications.Our procedure for laparoscopic complete mesocolic excision via combined medial and cranial approaches is safe and feasible for transverse colon cancer.

Objective: We assessed the clinical applicability of the F-NLR score, which is based on fibrinogen (F) and the neutrophil-lymphocyte ratio (NLR), and the Glasgow Prognostic Score (GPS) to predict the therapeutic effects of chemotherapy or chemoradiotherapy on advanced gastric cancer and the prognoses of patients. Methods: Sixty-eight patients with advanced gastric cancer treated with first-line chemotherapy or chemoradiotherapy were classified into two groups based on tumor response. Furthermore, we categorized patients according to cutoff F-NLR scores of 2 [hyperfibrinogenemia (>400 mg/dl) and high NLR (>3.0)], 1 [one of these hematological abnormalities], and 0 [neither hyperfibrinogenemia nor high NLR]. Results: A total of 27 patients had progressive disease (PD) and 41 did not. The F-NLR scores were significantly higher in the PD than in the non-PD group (p = 0.003). Survival was significantly shorter for patients with high F-NLR scores and GPS (p = 0.0071 and p = 0.0065, respectively). Multivariate analysis selected the F-NLR score as an independent prognostic factor (p = 0.017). Conclusion: A novel grading system based on F-NLR scores, as well as the GPS, appears to have value as a clinical predictor of the therapeutic response of advanced gastric cancer to chemotherapy or chemoradiotherapy and the prognoses of patients.

Background The neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) are representative blood markers of systemic inflammatory responses. However, the clinical significance of the combination of these markers is unclear. This study aimed to investigate the NLR and PLR in patients with advanced gastric cancer treated with chemotherapy and assess the clinical utility of a new blood score combining the NLR and PLR (NLR-PLR score) as a predictor of tumor response and prognosis. Methods We retrospectively analyzed 175 patients with gastric cancer receiving chemotherapy or chemoradiotherapy. These patients were categorized into progressive disease (PD) and non-PD groups according to tumor response. The NLR and PLR before treatment were examined, and the cut-off values were determined. The NLR-PLR score ranged from 0 to 2 as follows: score of 2, high NLR (> 2.461) and high PLR (> 248.4); score of 1, either high NLR or high PLR; score of 0, neither high NLR nor high PLR. Results With regard to tumor response, 64 and 111 patients had PD and non-PD, respectively. The NLR-PLR score was significantly higher in patients with PD than in those with non-PD (p = 0.0009). The prognosis was significantly poorer in patients with a higher NLR-PLR score than in those with a lower NLR-PLR score (p

AIM To examine the depth of tumor invasion and tumor length and assess the clinical impact of the primary tumor score (PTS), based on a combination of tumor invasion and tumor length, in patients with esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS A total of 237 patients with ESCC were classified into three PTS groups based on cut-off values for deeper tumor invasion (pT2-T4) and greater tumor length (≥44 mm). A PTS of 2 indicated the presence of both of these abnormalities, 1 indicated one of these abnormalities, and 0 indicated neither abnormality. RESULTS PTS was significantly positively correlated with depth of tumor invasion, lymph node metastasis, lymphovascular invasion, and stage (all p

Although miR‑145‑5p (the guide strand of the miR‑145 duplex) is established as a tumor suppressive microRNA (miRNA or miR), the functional significance of miR‑145‑3p (the passenger strand of the miR‑145 duplex) in cancer cells and its targets remains obscure. In our continuing analysis of esophageal squamous cell carcinoma (ESCC) pathogenesis, the aim of the present study was to identify important oncogenes and proteins that are controlled by miR‑145‑3p. Overexpression of miR‑145‑3p significantly reduced cancer cell proliferation, migration and invasive abilities, and further increased apoptotic abilities. In ESCC cells, 30 possible oncogenic targets were identified that might be regulated by miR‑145‑3p. Among these targets, dehydrogenase/reductase member 2 (DHRS2) and myosin IB (MYO1B) were focused on to investigate their functional roles in ESCC cells. DHRS2 and MYO1B were directly regulated by miR‑145‑3p in ESCC cells by dual luciferase reporter assays. Aberrantly expressed DHRS2 and MYOIB were detected in ESCC clinical specimens, and their overexpression enhanced cancer cell aggressiveness. Genes regulated by antitumor miR‑145‑3p were closely associated with the molecular pathogenesis of ESCC. The approach based on antitumor miRNAs may contribute to the understanding of ESCC molecular pathogenesis.

Intensive chemotherapy plus molecular targeted agent improve overall survival for patients with unresectable colorectal cancer.We performed laparoscopic surgery following intensive chemotherapy of mFOLFOX6 or FOLFIRI plus molecular targeted agent for 3 patients with unresectable locally advanced colorectal cancer with abscess formation.A 60-year-old man was diagnosed as having unresectable rectal cancer with abscess formation and underwent curative resection after partial response following chemotherapy.A 42-year-old woman was diagnosed as having unresectable sigmoid colon cancer with abscess formation and underwent curative resection after partial response following chemotherapy.A 56-year-old woman was diagnosed as having unresectable sigmoid colon cancer with abscess formation and underwent curative resection after partial response following chemotherapy.They are alive after surgery for 69, 74 and 72 months, respectively.Intensive chemotherapy plus molecular targeted agent for unresectalbe locally advanced colorectal cancer with abscess formation will be one of useful strategies for minimum invasive surgery and effective local control.

As an antagonist of bone morphogenetic proteins (BMPs), 2, 4 and 7, gremlin1 plays a role in regulating organogenesis, tissue differentiation and angiogenesis. However, there is little information regarding gremlin1 in gastrointestinal cancer. We attempted to clarify how gremlin1 expression affects the clinical features and biological properties of gastric cancer. A total of 232 gastric cancer patients who received R0 gastrectomy at Kagoshima University Hospital were enrolled. Gremlin1 expression in gastric cancer was detected by immunohistochemical and western blotting methods. Correlations between clinicopathological parameters and gremlin1 expression were analyzed. Gremlin1 was identified in the cytoplasm and nucleus of all gastric cancer cell lines and some regions of surgical specimens of gastric cancer. One hundred and seventeen of the 232 patients (50.4%) were classified as gremlin1-positive based on gremlin1 expression. Gremlin1 positivity was correlated with shallower tumor depth, smaller tumor size, less nodal involvement and vessel invasion (p

Cysteine/histidine-rich 1 (CYHR1) was first discovered in a yeast two-hybrid screen with murine galectin-3, and no previous reports have described a relationship between the CYHR1 gene and human cancer. The current study evaluated the role and significance of CYHR1 in esophageal cancer. The human esophageal squamous cell carcinoma (ESCC) cell line TE-8 and the CYHR1 knock-down cell line TE-8/small interfering (si)-CYHR1 were used for in vitro and in vivo assays. For clinical study, ESCC tissues (n = 104) were used. Compared with parental cells, TE-8/si-CYHR1 cells had suppressed proliferation and invasion activities. In the in vivo assay, the tumors from TE-8 cells treated with si-CYHR1 had abrogated tumorigenicity. In the clinical study, the expression of CYHR1 mRNA was associated with lymph node metastasis and stage and shown to be an independent prognostic factor. As the findings show, CYHR1 may represent not only a valuable prognostic marker but also a therapeutic target for ESCC patients.

Background: Laparoscopic colectomy has become accepted for resection of colon cancer, and laparoscopic complete mesocolic excision (CME) has proved feasible and safe. We have evaluated the safety, efficacy, and feasibility of laparoscopic CME via reduced port surgery (RPS) in patients with colon cancer. Methods: We prospectively assessed 17 consecutive patients with colon cancer undergoing laparoscopic CME via RPS between February 2012 and January 2014. Video recordings were used to assess the quality of the surgery, including CME completion. We also assessed operative data, complications, pathological findings, visual analog scale (VAS), cosmesis, and the hospital length of stay. Results: All patients underwent en bloc resection of mesocolon with CME completion. The median surgical duration and blood loss were 298 min and 41 ml, respectively. No intraoperative complications occurred in any patient. The median number of lymph nodes retrieved was 20, with lymph node metastasis identified in eight patients. The mean VAS scores for postoperative days 1, 3, and 7 were 3.2, 1.5, and 0, respectively. All patients were satisfied with their cosmesis. The median postoperative hospital stay was 11 days. Conclusions: Laparoscopic CME via RPS for colon cancer is a safe and feasible surgical procedure with cosmetic advantages.

We previously used RNA sequencing to establish the microRNA (miRNA) expression signature of pancreatic ductal adenocarcinoma (PDAC). We found that both strands of pre-miR-148a (miR-148a-5p: the passenger strand and miR-148a-3p: the guide strand) were downregulated in cancer tissues. Ectopic expression of miR-148a-5p and miR-148a-3p significantly inhibited cancer cell migration and invasion, indicating that both strands of pre-miR-148a had tumor-suppressive roles in PDAC cells. In silico database and genome-wide gene expression analyses identified a total of 15 genes that were putative targets regulated by these miRNAs. High expression of miR-148a-5p targets (PHLDA2, LPCAT2 and AP1S3) and miR-148a-3p targets (SMA, ENDOD1 and UHMK1) was associated with poor prognosis of patients with PDAC. Moreover, knockdown of PHLDA2 expression inhibited cancer cell aggressiveness, suggesting PHLDA2 acted as an oncogene in PDAC cells. Involvement of the passenger strand of pre-miR-148a (miR-148-5p) is a new concept in cancer research. Novel approaches that identify tumor-suppressive miRNA regulatory networks in lethal PDAC might provide new prognostic markers and therapeutic targets for this disease.

Immune checkpoint inhibitor therapy has been clinically introduced for several malignancies, and its effectiveness has been confirmed by clinical trials. In particular, programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are widely known as important immune checkpoint molecules associated with the mechanisms of immune escape by malignant tumor cells. In addition, liquid biopsy of blood specimens has the clinical benefit of providing a simple, repeatable sampling tool. Non-invasive liquid biopsy has recently been spotlighted as a promising approach to predicting tumor progression and prognosis. This study assessed the clinical significance of PD-L1 mRNA expression in blood specimens obtained from patients with gastric cancer. Peripheral blood specimens were collected before treatment from 124 patients with gastric cancer. The PD-L1 mRNA expression was evaluated by quantitative RT-PCR. Programmed death-ligand 1 mRNA expression was significantly higher in patients with advanced gastric cancer than in patients with early gastric cancer (P = .002). Moreover, PD-L1 expression correlated significantly with depth of tumor invasion, distant metastasis, and stage (P = .001, P

Background There are two lymphatic flows in lower rectal cancer; one along the inferior mesenteric artery and another towards the internal iliac artery. The benefit of dissection of lateral pelvic (LP) lymph nodes (LPLN) remains controversial. This study aimed to clarify the possibility of detecting the sentinel node (SN) of the LP region (LPSN) and examine metastasis, including micrometastasis, using a radio isotope (RI) method. Methods In total, 62 patients with clinical (c)T1-T4 rectal cancer were enrolled in this study (11, 16 and 35 patients had tumor located in the upper, middle and lower rectal third, respectively). LPSNs were detected using a radio-isotope method in which 99 m technetium-tin colloid was endoscopically injected into the submucosa in patients with cT1, and into the muscularis propria in patients with cT2, cT3 and cT4. All patients underwent curative resection with lymphadenectomy. LPSN metastases were diagnosed by HE staining, immunohistochemical staining using AE1/AE3 as a primary antibody and by RT-PCR using CEA as a marker. Results Of the lower rectal (c)T2–4 tumors, 38.4% had lateral pelvic lymphatic flow that was significantly greater than that of cT1 tumors in the upper and middle thirds of the rectum (p = 0.0074). HE and immunohistochemical staining did not detect LPSN metastases but RT-PCR detected micrometastasis of three SNs. The remaining half of LPSNs were immunohistochemically re-examined; in all three cases, isolated tumor cells were detected. Conclusion The SN concept may be useful for detecting lateral pelvic lymphatic flow and LPSN metastases, including micrometastasis in lower rectal cancer.

While chemoradiation therapy (CRT) is one of the most useful treatments for esophageal squamous cell carcinoma (ESCC), it is important to predict response prior to treatment by using markers because some patients respond well and others do not. Fifty-nine patients with ESCC were treated with neoadjuvant CRT at the Kagoshima University Hospital. The expression of seven types of biomarker candidate proteins in biopsy specimens of untreated primary tumors was evaluated to determine whether it correlated with response and prognosis. The positive expression rates were 47% for p53, 83% for CDC25B, 68% for 14-3-3sigma, 76% for p53R2, 75% for ERCC1, 32% for Gli-1, and 54% for Nrf2. In terms of histological response, tumor grade of the 59 patients was 48.8% for grade 1 as the non-responder, 29.2% for grade 2, and 22.0% for grade 3 as the responder. CRT was significantly effective in p53(−), p53R2(−), ERCC1(−), and Nrf2(−) tumors, while p53(−), p53R2(−), and ERCC1(−) were factors independently correlated with effective histological response. Their combined expression of two or three negative expressions had 100% effective response and was a significant prognostic factor. Our results suggest that two or three negative expressions of p53, p53R2, and ERCC1 in biopsy specimens of primary tumors were associated with a favorable response to CRT for ESCC. Assessment of tumor suppressor and DNA repair protein expressions in biopsy specimens may be useful for the potential utility of CRT therapy for patients with ESCC prior to treatment.

To evaluate the safety and feasibility of laparoscopic complete mesocolic excision (CME) via mesofascial separation for left-sided colon cancer. We evaluated prospectively collected data on 65 consecutive patients with stage I–III left-sided colon cancer, who underwent laparoscopic CME between October 2011 and September 2016. After the exclusion of 5 patients who had T4b or other active tumors, 60 patients were the subjects of this analysis. The completeness of CME, preservation of the hypogastric nerve, operative data, pathological findings, complications, and length of hospital stay were assessed. CME completeness was graded as the mesocolic and intramesocolic plane in 54 and 6 patients, respectively. The hypogastric nerve was preserved in all patients. A total of 17, 12, 28, and 3 patients had T1, T2, T3, and T4a tumors, respectively. The mean number of lymph nodes retrieved was 16.2, and lymph node metastasis was identified in 22 patients. The mean operative time and intraoperative blood loss were 283 min and 38 ml, respectively. One patient had an intraoperative complication and six patients had postoperative complications. The hospital stay was 12 days. Laparoscopic CME via mesofascial separation is a safe and feasible procedure for left-sided colon cancer.

The prognosis of patients with esophageal squamous-cell cancer (ESCC) and multiple lymph-node metastases is quite poor. We examined whether neoadjuvant chemoradiation therapy (CRT) has a beneficial effect in such patients. A total of 50 consecutive patients with T3–4 tumors and without organ metastases were prospectively enrolled. Of those patients, 20, who had four or more nodal metastases, underwent neoadjuvant CRT (CRT group), and the remaining 30 patients, who had three or fewer nodal metastases, underwent surgery alone (surgery group). CRT consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. The groups’ clinical outcomes were compared. Surgery was performed in 48 patients: all enrolled patients except for 2 who had organ metastasis after CRT. In the CRT group, the number of patients with pathological complete response was observed in 8 patients (44 %), mean nodal metastases number was changed from 8.2 to 2.6 and 9 patients had pN0. The 3-year survival rate was 76 % in the CRT group (4 patients relapsed) and 68 % in the surgery group (8 patients relapsed), which is not a statistically significant difference (P = 0.61). Neoadjuvant CRT is beneficial for locally advanced ESCC with four or more lymph-node metastases.

The aim of this study was to assess the role ofThirty patients with advanced ESCC received nCRT followed by surgery, and underwent FDG-PET/CT twice before and after nCRT. We compared the results of FDG-PET/CT with the pathological results and prognosis.Pathological response was found to correlate with the maximum standardised uptake value (SUVThe prediction of pathological response and prognosis using FDG-PET/CT is not as reliable as pathological detection of lymph node metastasis, but could be a useful method contributing to treatment decisions.

AIM To assess the clinical utility of the Glasgow prognostic score (GPS) as a blood predictor of postoperative recurrence in patients with gastric gastrointestinal stromal tumors (GISTs). PATIENTS AND METHODS Twenty-nine patients with gastric GISTs undergoing gastrectomy were retrospectively reviewed. Patients were classified based on GPS criteria as follows: GPS of 2: elevated C-reactive protein (>1.0 mg/dl) and hypoalbuminemia (

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies. Recently developed molecular targeted therapies are not available for patients with ESCC. After curative surgical resection, patients frequently suffer distant metastasis and recurrence. Exploration of novel ESCC metastatic pathways may lead to the development of new treatment protocols for this disease. Accordingly, we have sequentially identified microRNA (miRNA)-mediated metastatic pathways in several cancers. Our past studies of miRNA expression signatures have shown that microRNA-375 (miR-375) is frequently reduced in several types of cancers, including ESCC. In the present study, we aimed to investigate novel miR-375-mediated metastatic pathways in ESCC cells. The expression of miR-375 was downregulated in ESCC tissues, and ectopic expression of this miRNA markedly inhibited cancer cell migration and invasion, suggesting that miR-375 acted as an antimetastatic miRNA in ESCC cells. Our strategies for miRNA target searching demonstrated that matrix metalloproteinase 13 (MMP13) was directly regulated by miR-375 in ESCC cells. Overexpression of MMP13 was observed in ESCC clinical tissues, and the expression of MMP13 promoted cancer cell aggressiveness. Moreover, oncogenic genes, including CENPF, KIF14 and TOP2A, were shown to be regulated downstream of MMP13. Taken together, these findings demonstrated that the antitumor miR-375/oncogenic MMP13 axis had a pivotal role in ESCC aggressiveness. These results provide novel insights into the potential mechanisms of ESCC pathogenesis.

AIM To compare adverse events and post-therapeutic clinical courses between stomach-partitioning gastrojejunostomy with Braun enteroenterostomy (SPGJ-BEE) and endoscopic metallic stent placement (EMSP) in patients with gastric outlet obstruction (GOO) caused by unresectable gastric cancer and assess the clinical utility of SPGJ-BEE. PATIENTS AND METHODS We retrospectively reviewed clinical data of 16 and 9 patients with GOO undergoing SPGJ-BEE and EMSP, respectively. RESULTS Re-obstruction caused by tumor overgrowth was identified in 3 (33.3%) out of 9 patients in the EMSP group. The GOO scoring system (GOOSS) revealed that its score after treatments was significantly higher in the SPGJ-BEE group than in the EMSP group (p

Due to its aggressive nature, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and hard-to-treat malignancies. Recently developed targeted molecular strategies have contributed to remarkable improvements in the treatment of several cancers. However, such therapies have not been applied to PDAC. Therefore, new treatment options are needed for PDAC based on current genomic approaches. Expression of microRNA-375 (miR-375) was significantly reduced in miRNA expression signatures of several types of cancers, including PDAC. The aim of the present study was to investigate the functional roles of miR-375 in PDAC cells and to identify miR-375-regulated molecular networks involved in PDAC aggressiveness. The expression levels of miR-375 were markedly downregulated in PDAC clinical specimens and cell lines (PANC-1 and SW1990). Ectopic expression of miR-375 significantly suppressed cancer cell proliferation, migration and invasion. Our in silico and gene expression analyses and luciferase reporter assay showed that zinc finger protein 36 ring finger protein-like 2 (ZFP36L2) was a direct target of miR-375 in PDAC cells. Silencing ZFP36L2 inhibited cancer cell aggressiveness in PDAC cell lines, and overexpression of ZFP36L2 was confirmed in PDAC clinical specimens. Interestingly, Kaplan-Meier survival curves showed that high expression of ZFP36L2 predicted shorter survival in patients with PDAC. Moreover, we investigated the downstream molecular networks of the miR-375/ZFP36L2 axis in PDAC cells. Elucidation of tumor-suppressive miR-375-mediated PDAC molecular networks may provide new insights into the potential mechanisms of PDAC pathogenesis.

Since antitumor immune reactions between tumors and intratumoral immunocytes have been verified in several human tumors, immunological therapeutic strategies must be considered to obtain the proper efficacy of tumor shrinkage under these conditions. Human leukocyte antigen (HLA) class I expression in cancer cells and degree of infiltration of regulatory T cells (Tregs) in the stroma have been regarded as important markers of antitumor immune reactions in the context of independent immunological mechanisms. In the current study, we investigated HLA class I expression and Treg cells infiltration in gastric cancer and discussed the clinical implications of this combinatory analysis in gastric cancer. A total of 141 gastric cancer patients who received R0 gastrectomy at Kagoshima University Hospital were studied. Immunohistochemically, in 141 gastric cancer patients, HLA class I expression and Treg cell infiltration in cancerous tissue were evaluated using HLA class I (EMR8-5) and forkhead box p3 (FOXP3) monoclonal antibodies. The correlation between clinical factors and tumor-infiltrating Treg cells was analyzed. HLA class I expression was positively associated with depth of tumor invasion (P

Definitive evaluation of surgical specimens obtained after neoadjuvant chemoradiation therapy (CRT) is important for assessing additional treatment or prognosis in patients with esophageal squamous cell carcinoma (ESCC). In this study, we examined the histological prognostic factors for ESCC patients treated with CRT and determined an appropriate strategy for their evaluation. The present study involved 38 consecutive ESCC patients who underwent CRT followed by curative operation. CRT consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. We examined histological variables as follows: CRT effect on primary tumor (T-effect: T-effective/T-ineffective), tumor depth (pT), lymph node metastases (pN: pN0/N1), number of lymph node metastases (number-pN), lymphatic invasion, and venous invasion. Univariate and multivariate analyses were performed to examine the independent prognostic factors. Survivals and mode of recurrence were then evaluated according to the independent prognostic factors. In the univariate analyses, T-effect, pN, number-pN, lymphatic invasion, and venous invasion were found to be prognostic factors with p

Background Recently, neoadjuvant chemoradiation therapy (CRT) has been introduced for treatment of esophageal squamous cell carcinoma (ESCC). This study was performed to investigate the usefulness of endoscopic ultrasonography (EUS) in comparison with EUS findings before and after CRT, and histologic findings. Methods There were 33 patients with potentially resectable ESCC who underwent neoadjuvant CRT. Preoperative EUS and histologic findings were compared. EUS criteria were established on the basis of low and high echoic regions. Resected specimens were examined by hematoxylin-eosin, azan, and cytokeratin immunohistochemical staining. Results Azan and cytokeratin staining clearly delineated fibrous changes and residual tumor. Low echoic regions corresponded to residual tumor and high echoic spots corresponded to fibrosis. All 12 patients classified as grade 1 on EUS diagnosis had histologic grade 1 tumors. Nineteen of 21 cases that presented with high echo were grade 2 or 3. The prognosis according to EUS diagnosis was similar to the histologic effect. Conclusions Preoperative EUS findings reflected the histologic effect after neoadjuvant CRT. EUS is a useful tool to assess the effect for CRT and to predict the prognosis in ESCC patients.

Background Bone morphogenetic proteins (BMPs) are secreted signaling molecules belonging to the transforming growth factor-β (TGF-β) superfamily of growth factors. Recent studies have shown that the influence of the expression of BMP7 was altered in several tumors. The purpose of the current study was to examine the expression of BMP7 in esophageal squamous cell carcinoma and to clarify the clinical impact of BMP7 expression in esophageal squamous cell carcinoma (ESCC). Methods A total of 180 patients with ESCC who underwent surgical resection from 1991 to 2004 were eligible for this study. The expression of BMP7 in esophageal tumor tissues was examined immunohistochemically. Results BMP7 expression was found in the cytoplasm of cancer cells. BMP7 positivity was observed in 61.7% of tumors. The BMP7-positive group had deeper progression, more advanced stages, and greater venous invasion than those without BMP7 expression (p

Background: Bone morphogenetic protein-7 (BMP-7) is a signalling molecule belonging to the transforming growth factor--superfamily. Recent studies have demonstrated the clinical impact of BMP-7 expression in various human cancers. However, there have been few reports detailing this in gastric cancer. Methods: We immunohistochemically investigated the expression of BMP-7 in 233 gastric cancer patients to disclose the clinicopathological features of BMP-7-positive gastric cancer. Results: Immunohistochemically, in human gastric cancer, BMP-7 expression was identified in cellular membranes but also in the cytoplasm of cancer cells. Bone morphogenetic protein-7-positive expression was found in 129 of 233 patients (55%). Bone morphogenetic protein-7 expression was correlated with tumour size, nodal involvement, lymphatic invasion, venous invasion and histology (P

We sought to identify genes associated with the progression and metastasis of esophageal squamous-cell cancer by comparing the expression profiles of normal, primary cancer, and metastatic cancer cells isolated with laser microdissection. Oligo microarray analysis identified several lymph node-specific, metastasis-related genes. STC2 (stanniocalcin 2), which was overexpressed in esophageal cancer cases, was chosen for further characterization. Quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry were used to explore the clinicopathologic significance of STC2 expression status in 70 cases. Additionally, the functional role of STC2 in esophageal cancer was studied by the attenuation of STC2 in an esophageal cancer cell line. Laser microdissection and oligo microarray analysis identified 63 candidate genes. Among them, STC2 showed higher expression in cancer tissue than in corresponding normal tissue (P < 0.001). STC2 expression was significantly correlated with lymph node metastasis, lymphatic invasion, and distant metastasis (P = 0.005, 0.007, and 0.038, respectively). Patients whose tumors had high STC2 expression had a worse 5-year survival rate than patients whose tumors had a low STC2 expression level (P = 0.016). STC2 transfected cells had a significantly higher proliferation rate than control cells (P < 0.001). Additionally, STC2 transfected cells were more invasive in vitro (P < 0.001) than control cells. These findings were validated by means of RNA interference assays. We identified lymph node-specific, metastasis-related genes in esophageal cancer cells. One of these, STC2, may be associated with lymph node metastasis, making it a potential prognostic marker for esophageal cancer patients.

Laser microdissection (LMD) and microarray were used to identify genes associated with colorectal cancer. Stanniocalcin 2 (STC2) expression and clinicopathological significance in 139 clinical colorectal cancer samples were specifically investigated using real-time quantitative reverse transcription-polymerase chain reaction. A number of genes upregulated in colorectal cancer cells compared to normal colorectal epithelial cells were identified including STC2. STC2 gene expression in cancer tissue was higher than in corresponding normal colorectal epithelial tissue in 124 of 139 cases (89.2%, p < 0.01). Tumors with high STC2 expression showed higher frequencies of lymph node metastasis, lymphatic invasion, tumor depth, tumor size and AJCC Stage classification (p < 0.01). Patients with high STC2 expression also showed significantly worse overall survival rates than those with low STC2 expression (p < 0.01). Furthermore, STC2 gene appeared to be associated with colorectal cancer progression and may be a useful prognostic indicator for colorectal cancer.

In perioperative management after hepatectomy, some patients require fresh frozen plasma (FFP) to treat coagulopathy associated with blood loss. However, several studies have suggested a correlation between blood products and pulmonary complications or surgical-site infection (SSI). The subjects were 99 patients who underwent hepatectomy for hepatocellular carcinoma without plasma exchange for postoperative liver failure in the Department of Surgery, Jikei University Hospital, between January 2000 and December 2006. We investigated the association of 16 factors including age; gender; preoperative ICGR15; type of resection; concomitant resection of other digestive organs; duration of operation; blood loss; hepatitis virus status; postoperative minimum platelet count, maximum serum total bilirubin (max T-Bil), minimum serum albumin, or minimum prothrombin time; and the dose of red-blood-cell concentration (RC), FFP, platelet concentration, or albumin given in relation to postoperative pulmonary complications and SSI. In univariate analysis, pulmonary complications were correlated with gender (P = 0.012), max T-Bil (P = 0.043), dose of RC given (P = 0.007), dose of FFP given (P

Urokinase-type plasminogen activator receptor (uPAR) plays a central role in the plasminogen activation cascade and participates in extracellular matrix degradation, cell migration and invasion. We evaluated the expression level of uPAR mRNA and the presence of isolated tumour cells (ITCs) in bone marrow (BM) and peripheral blood (PB) in gastric cancer patients and clarified its clinical significance. We assessed specific uPAR mRNA expression by quantitative real-time reverse transcriptase- polymerase chain reaction (RT–PCR) in BM and PB in 846 gastric cancer patients as well as three epithelial cell markers, carcinoembryonic antigen (CEA), cytokeratin (CK)-19 and CK-7. The uPAR mRNA expression in bone marrow and peripheral blood expressed significantly higher than normal controls (P

Purpose: Recent studies of cancer metastasis have focused on the role of premetastatic gene expression and circulating tumor cells. We did a blind prospective study in gastric cancer to assess the significance of isolated tumor cells (ITC) and to test the hypothesis that vascular endothelial growth factor receptor-1 (VEGFR-1) is expressed within the bone marrow at tumor-specific, premetastatic sites. Experimental Design: Both bone marrow and peripheral blood samples from 810 gastric cancer patients were collected at the Central Hospital, National Cancer Center (Tokyo, Japan). The samples were transferred to Kyushu University Hospital (Beppu, Japan) where they were analyzed by quantitative real-time reverse transcription-PCR for three epithelial cell markers, carcinoembryonic antigen, cytokeratin-19, and cytokeratin-7, as well as VEGFR-1. Results: ITCs were observed in peripheral blood and bone marrow even in early stages of gastric cancer. The frequency of ITC in bone marrow was significantly associated with the stage of disease by ANOVA (P < 0.01). Gastric cancer metastasized when ITCs were observed in the presence of VEGFR-1. In the 380 patients who were ITC negative and showed low VEGFR-1 expression, synchronous (at the time of surgery) and heterochronous (recurrent) metastases were not observed. Conclusions: ITCs circulate even in early stages of disease. Furthermore, elevated expression of VEGFR-1 facilitates the establishment of hematogenous metastases in gastric cancer. This study indicates that the simultaneous presence of ITC and VEGFR-1 expression at premetastatic sites is clinically significant for disease progression.

We previously cloned human G protein gamma 7 (GNG7) and demonstrated that it was downregulated in gastrointestinal cancer. The significance of GNG7 expression in oesophageal cancer is unknown. TaqMan quantitative real-time PCR was performed to determine the clinical significance of GNG7 expression in 55 cases of oesophageal cancer. Furthermore, GNG7-transfected oesophageal cancer cells were analysed in laboratory studies at genomic and epigenetic levels. Twenty-seven patients with low GNG7 expression showed significantly poorer survival than did 28 patients with high expression (P

Ferredoxin reductase (Fdxr) is the mitochondrial cytochrome P-450 NADPH reductase. Fdxr overexpression increases the sensitivity of tumor cells to apoptosis in response to chemotherapy through reactive oxygen species (ROS) production. The aim of the present study was to examine the Fdxr expression in esophageal squamous cell carcinoma (ESCC) and determine if the expression is useful for predicting response to chemoradiation therapy (CRT).Fdxr expression in biopsy specimens from 50 patients before neoadjuvant CRT were immunohistochemically examined. Then, the correlation between Fdxr expression and response to CRT were analyzed.Both clinically and histologically, significant correlations were found between positive Fdxr expression and favorable response to CRT. Furthermore, Fdxr was significantly correlated with postoperative outcomes and was found to be an independent prognostic factor.Fdxr expression was found to be closely related to the effect of CRT and could predict the CRT outcome in patients with ESCC.