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Due to the poor prognosis of pancreatic cancer, novel diagnostic modalities for early diagnosis and new therapeutic strategy are urgently needed. Recently, microRNA-21 (miR-21) was reported to be strongly overexpressed in pancreatic cancer as well as in other solid cancers. We investigated the functional roles of miR-21, which have not been fully elucidated in pancreatic cancer. miR-21 expression was assessed in pancreatic cancer cell lines (14 cancer cell lines, primary cultures of normal pancreatic epithelial cells and fibroblasts, and a human normal pancreatic ductal epithelial cell line) and pancreatic tissue samples (25 cancer tissues and 25 normal tissues) by quantitative real-time reverse transcription-PCR amplification. Moreover, we investigated the proliferation, invasion, and chemoresistance of pancreatic cancer cells transfected with miR-21 precursor or inhibitor. miR-21 was markedly overexpressed in pancreatic cancer cells compared with nonmalignant cells, and miR-21 in cancer tissues was much higher than in nonmalignant tissues. The cancer cells transfected with the miR-21 precursor showed significantly increased proliferation, Matrigel invasion, and chemoresistance for gemcitabine compared with the control cells. In contrast, inhibition of miR-21 decreased proliferation, Matrigel invasion, and chemoresistance for gemcitabine. Moreover, miR-21 positively correlated with the mRNA expression of invasion-related genes, matrix metalloproteinase-2 and -9, and vascular endothelial growth factor. These data suggest that miR-21 expression is increased in pancreatic cancer cells and that miR-21 contributes to the cell proliferation, invasion, and chemoresistance of pancreatic cancer.[Mol Cancer Ther 2009;8(5):1067–74]

Supplementary Table from MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance

Supplementary Figure Legends from MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance

Supplementary Fig. from MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance

The Japanese operative-rating scale for laparoscopic distal gastrectomy (JORS-LDG) was developed through cognitive task analysis together with the Delphi method to measure intraoperative performance during laparoscopic distal gastrectomy. This study aimed to investigate the value of this rating scale as an educational tool and a surgical outcome predictor in laparoscopic distal gastrectomy.The surgical performance of laparoscopic distal gastrectomy was assessed by the first assistant, through self-evaluation in the operating room and by video raters blind to the case. We evaluated inter-rater reliability, internal consistency, and correlations between the JORS-LDG scores and the evaluation methods, patient characteristics, and surgical outcomes.Fifty-four laparoscopic distal gastrectomy procedures performed by 40 surgeons at 16 institutions were evaluated in the operating room and with video recordings using the proposed rating scale. The video inter-rater reliability was 0.8. Participating surgeons were divided into the low, intermediate, and high groups based on their total scores. The number of laparoscopic surgeries and laparoscopic gastrectomy procedures performed differed significantly among the groups according to laparoscopic distal gastrectomy skill levels. The low, intermediate, and high groups also differed in terms of median operating times (311, 266, and 229 min, respectively, P 0.001), intraoperative complication rates (27.8, 11.8, and 0%, respectively, P = 0.01), and postoperative complication rates (22.2, 0, and 0%, respectively, P = 0.002).The JORS-LDG is a reliable and valid measure for laparoscopic distal gastrectomy training and could be useful in predicting surgical outcomes.

To evaluate the status of surgical training in Japan through a national-level needs assessment. A survey was sent to all 909 graduating residents (GRs) and their 611 program directors (PDs) for the year 2016. A working group of surgical educators from around the country was formed under the education committee of the Japan Surgical Society. The survey items were developed by consensus of this working group. The survey investigated the knowledge and problems of the current curriculum, and the status of the current residency training. The response rates were 56.3% of the GRs and 76.8% of the PDs. Among the participants, 47.6% of the GRs and 29.4% of the PDs believed that the residency curriculum did not match the clinical experience. Over 80% of the GRs and PDs agreed on the importance of training outside of the OR, whereas only 13% of the GRs had received such training regularly. Trainees also reported a lower satisfaction rate about the opportunity to train outside of the OR. This national-level needs assessment of surgical training in Japan identified several gaps in the curriculum. These results provide valuable data to assist the ongoing efforts for surgical residency curriculum improvement.

This study sought to assess the disparity between regions and facilities in surgical resident training in Japan via a national level needs-assessment. A survey was sent to all 909 graduating residents of 2016. Residents trained in the six prefectures with a population of 7 million or more were included in the large prefecture (LP) group. Residents trained in the other 41 prefectures were included in the small prefecture (SP) group. Each group was further divided into a university hospital (UH) group and a non-university hospital (NUH) group. The response rate was 56.3% (n = 512). Excluding nine residents who did not report their prefectures and facilities, surveys from 503 residents were analyzed. The UH group received significantly more years of training. In the SP and UH groups, there were significantly fewer residents who had performed 150 procedures or more under general anesthesia in comparison to the LP and NUH groups, respectively. Self-assessed competencies for several procedures were significantly lower in the SP and UH groups. Disparity in surgical resident training was found between regions and facilities in Japan. The surgical residency curriculum in Japan could be improved to address this problem.

There is no definite evidence of the feasibility and safety of laparoscopic distal gastrectomy (LDG) for patients who have undergone incomplete endoscopic resection (ER). We investigated the influence of ER prior to LDG by a propensity score matching analysis. We retrospectively analyzed the outcomes of gastric cancer patients who underwent LDG with or without prior ER from 2000 to 2014. Propensity score matching was performed to compare the two groups of patients. After matching, 47 patients in the ER group and 94 patients in the non-ER group were selected from a total of 365 patients. A residual tumor was observed in 10 of 47 patients (21.3%). The mean number of dissected lymph nodes in the non-ER group (39.4 ± 14.5) was higher than that in the ER group (31.7 ± 13.5) (P = 0.003). However, other perioperative data, such as the operation time and blood loss volume were similar. The complication rate of the ER group (17.0%) and the non-ER group (9.6%) did not differ to a statistically significant extent (P = 0.2). Among these patients, 6 died during the 5-year follow-up period, but no patients showed signs of recurrence. ER prior to surgical resection showed no significant influence on postoperative complications or mortality. LDG can be safely performed to achieve radical resection after incomplete ER.

Specific cell populations leading the local invasion of cancer are called "leading cells". However, the underlying mechanisms are unclear. Here, we identified leading cells in pancreatic cancer and determined how these cells lead and promote cancer cell invasion in the extracellular matrix (ECM). Using three-dimensional matrix remodeling assay, we found that pancreatic stellate cells (PSCs) frequently invaded the collagen matrix with pancreatic cancer cells (PCCs), which invaded behind the invading PSCs. In addition, invading PSCs changed the alignment of collagen fibers, resulting in ECM remodeling and an increase in the parallel fibers along the direction of invading PSCs. Endo180 expression was higher in PSCs than in PCCs, Endo180 knockdown in PSCs attenuated the invasive abilities of PSCs and co-cultured PCCs, and decreased the expression level of phosphorylated myosin light chain 2 (MLC2). In mouse models, Endo180-knockdown PSCs suppressed tumor growth and changes in collagen fiber orientation in co-transplantation with PCCs. Our findings suggest that PSCs lead the local invasion of PCCs by physically remodeling the ECM, possibly via the function of Endo180, which reconstructs the actin cell skeleton by phosphorylation of MLC2.

The aim of this study was to assess the feasibility of prophylactic pancreatojejunostomy after enucleation or limited pancreatic resection regarding the risk of postoperative pancreatic fistula (PF). We retrospectively reviewed the medical records of 32 patients who underwent enucleation or limited pancreatic resection and compared the clinical parameters between patients with ( n = 10) and without ( n = 22) prophylactic pancreatojejunostomy. Prophylactic pancreatojejunostomy was performed in patients with a possible high risk ofPF. No operation-related mortality occurred. Operation time was significantly longer ( P < 0.01) and blood loss significantly greater ( P < 0.01) in patients with pancreatojejunostomy. Overall complications were more frequent ( P = 0.02) and postoperative hospital stay was significantly longer ( P = 0.02) in patients with pancreatojejunostomy. However, other assessed factors including the prevalence of postoperative PF did not differ between groups. In conclusion, prophylactic pancreatojejunostomy is feasible, and its efficacy in preventing PF after enucleation or limited pancreatic resection in high-risk patients will require further study.

Background Circumportal pancreas is a rare congenital pancreatic anomaly. The aim of this study was to clarify the clinical characteristics of patients with circumportal pancreases undergoing pancreatectomy. Methods The medical records of 508 patients who underwent pancreatectomy were retrospectively reviewed. The prevalence of circumportal pancreas and related anatomical variations were assessed. Surgical procedures and postoperative outcomes were compared in patients with and without circumportal pancreas. Results Circumportal pancreas was observed in 9 of the 508 patients (1.7%). In all nine patients, the portal vein was completely encircled by the pancreatic parenchyma above the level of the splenoportal junction, and the main pancreatic duct ran dorsal to the portal vein. The rate of variant hepatic artery did not differ significantly in patients with and without circumportal pancreas. Pancreatic fistula developed more frequently in patients with than without circumportal pancreas (44% vs. 14%, p = 0.03), but other clinical parameters did not differ significantly in these two groups. Conclusions Despite being rare, circumportal pancreas may increase the risk of postoperative pancreatic fistula in patients undergoing pancreatectomy. However, a prospective, large-cohort study is necessary to determine the real incidence of relevant anatomical variations and the definitive clinical significance of this rare anomaly.

Pancreatic cancer is characterized by increased hyperplasia of fibrotic tissue, termed desmoplasia, and lymph node metastasis is an independent prognostic factor in this disease. However, there are no reports focused on desmoplasia in pancreatic cancer lymph node metastases. The present study evaluated a range of factors and investigated their association with poor prognosis in pancreatic cancer cases with lymph node metastasis, including the degree of desmoplasia in lesions. To identify the poor prognostic factors associated with lymph node metastasis, the present study retrospectively reviewed the clinical data of 65 patients with lymph node metastases that underwent surgical pancreatic cancer resection between 2007 and 2012 at a single institution. The investigation focused on the degree of fibrosis in metastatic lesions in 216 lymph nodes, and investigated associations with prognosis or clinicopathological findings. The ratios of the fibrotic area in metastatic lymph node lesions were evaluated and classified into three categories, high (≥70%), moderate (10–70%) and low (

Background An aberrant right subclavian artery (ARSA) with an associated nonrecurrent right inferior laryngeal nerve (NRILN) is a relatively rare anomaly that occurs at a frequency of 0.3 to 2.0% of the general population. NRILN has been mainly documented in the head and neck region; it has been rarely described in patients with esophageal cancer, especially those undergoing thoracoscopic surgery. Video-assisted thoracoscopic surgery for esophageal cancer (VATS-E) is becoming more widespread as a reliable minimally invasive surgical procedure associated with reduced perioperative complications. Case presentation Herein, we report three cases of esophageal cancer with ARSA and NRILN which underwent successful VATS-E. Case 1, a 53-year-old male who had early stage esophageal cancer was performed VATS-E. Upper gastrointestinal (GI) series showed “Bayonet sign” (T1aN0M0, pStageIA in UICC). Case 2, a 75-year-old male who had advanced esophageal cancer was performed neoadjuvant chemotherapy and following VATS-E. This case had right thoracic duct and “Bayonet sign” on upper GI series (T1bN2M0, pStage IIIA in UICC). Case3, a 72-year-old male who had advanced esophageal cancer was performed neoadjuvant chemotherapy and following VATS-E (T3N2M0, pStageIIIB in UICC). All of these three cases were performed VATS-E and discharged without any complication. Conclusion VATS-E in the prone position is a feasible procedure that can reduce the risk of complications with an enlarged and clear view, and knowledge of this type of anomaly is very important for surgeons who perform esophagectomy.

Retrorectal tumors (RT) are uncommon and usually managed by open surgical excision. Laparoscopic excision for RT has been reported in only a small number of papers. We aimed to assess the laparoscopic approach for RT and to discuss the factors that made this procedure difficult. We performed laparoscopic excision using a five-trocar technique for neurogenic RT in three patients. Tumors were successfully excised laparoscopically in two patients. However, the third patient required open conversion because the tumor was strongly adhered to the sacrum and could not be mobilized by dissection, resulting in poor visualization of the dissected site. Laparoscopic excision for RT provides excellent intraoperative visualization and good cosmesis in selected patients, but firm adherence to the sacrum may cause difficulty with this procedure.

Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion. Mice fed a high fat diet had significantly larger primary pancreatic tumors and a significantly higher rate of distant organ metastasis than mice fed a standard diet. In the organotypic fat invasion model, pancreatic cancer cell clusters were smaller and more elongated in shape and showed increased fibrosis. Adipose tissue-derived conditioned medium enhanced pancreatic cancer cell invasiveness and gemcitabine resistance, as well as inducing morphologic changes in cancer cells and increasing the numbers of lipid droplets in their cytoplasm. The concentrations of oleic, palmitoleic, and linoleic acids were higher in adipose tissue-derived conditioned medium than in normal medium, with these fatty acids significantly enhancing the migration of cancer cells. Mature adipocytes were smaller and the concentration of fatty acids in the medium higher when these cells were co-cultured with cancer cells. These findings indicate that lipolytic and fibrotic changes in peripancreatic adipose tissue enhance local invasiveness and metastasis via adipocyte-released fatty acids. Inhibition of fatty acid uptake by cancer cells may be a novel therapy targeting interactions between cancer and stromal cells.

Aims: We reported that pancreatic ductal adenocarcinomas (PDACs) without high-grade pancreatic intraepithelial neoplasia (PanIN) in the vicinity had worse prognoses than PDACs with high-grade PanIN. However, the molecular characteristics of PDACs with and without high-grade PanIN have not been compared. The aim of this study is to clarify the molecular characteristics of PDACs with and without high-grade PanIN. Method and Results: We reviewed all of a consecutive series of 100 patients with PDACs and divided them into 2 groups: the PDACs with PanIN-2 or PanIN-3 in the background (the PanIN-high group, n = 60) and the PDACs without PanIN-2 or PanIN-3 in the background (the PanIN-low group, n = 40). We evaluated the p53, p16, and SMAD4 expressions in the invasive ductal carcinoma (IDC) components by immunohistochemical staining. KRAS mutation was also analyzed in 80 tumors. The PanIN-low group showed significantly more frequent “high p53 expression” and “loss of SMAD4 expression” than the PanIN-high group (p = 0.048 and p = 0.019, respectively). Loss of p16 expression was not significantly different between the groups. The rate of KRAS wild type was significantly higher in the PanIN-low group than the PanIN-high group (p = 0.024). Conclusions: Our results demonstrated that the molecular characteristics in the PDACs with high-grade PanIN were different from those in the PDACs without high-grade PanIN. PDACs without high-grade PanIN may develop via a pathway other than the PanIN-carcinoma sequence.

The interaction between the cancer cells and the peritoneal mesothelial cells (PMCs) plays an important role in the peritoneal dissemination in several types of cancer. However, the role of PMCs in the peritoneal dissemination of pancreatic cancer remains unclear. In the present study, we investigated the interaction between the pancreatic cancer cells (PCCs) and the PMCs in the formation of peritoneal dissemination in vitro and in vivo. The tumor-stromal interaction of PCCs and PMCs significantly enhanced their mobility and invasiveness and enhanced the proliferation and anoikis resistance of PCCs. In a 3D organotypic culture model of peritoneal dissemination, co-culture of PCCs and PMCs significantly increased the cells invading into the collagen gel layer compared with mono-culture of PCCs. PMCs pre-invaded into the collagen gel, remodeled collagen fibers, and increased parallel fiber orientation along the direction of cell invasion. In the tissues of peritoneal dissemination of the KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+;Pdx-1-Cre) transgenic mouse, the monolayer of PMCs was preserved in tumor-free areas, whereas PMCs around the invasive front of peritoneal dissemination proliferated and invaded into the muscle layer. In vivo, intraperitoneal injection of PCCs with PMCs significantly promoted peritoneal dissemination compared with PCCs alone. The present data suggest that the cancer-associated PMCs have important promoting roles in the peritoneal dissemination of PCCs. Therapy targeting cancer-associated PMCs may improve the prognosis of patients with pancreatic cancer.

Purpose To evaluate the self-assessed competency of graduating residents (GRs) in Japan upon completion of their residency and to identify the gap between their competency and the competency expected by their program directors (PDs). Method A list of 31 essential surgical procedures was compiled according to the consensus of surgical educators from around the country. A survey with this list was sent to all 909 GRs and their 611 PDs in 2016. The GRs rated their competency to perform these procedures and the PDs were asked to evaluate the expected competency of their GRs using the Zwisch Scale. Result The response rate was 56.3% for the GRs and 76.8% for the PDs. Fewer than half of the GRs who responded felt confident performing ten (32%) of the surgical procedures evaluated. For most procedures, the GRs' self-reported competency was lower than the expectation reported by their PDs. This gap was more than 10% for 13 of the procedures. Conclusion More than half of the GRs in Japan lacked the confidence in their skill to perform one-third of the surgical procedures selected for evaluation in this study. These findings should be used to update the surgical education curriculum in Japan.

A large-scale multicenter historical cohort study was conducted to investigate the efficacy of laparoscopic gastrectomy (LG) in comparison to open gastrectomy (OG) for locally advanced gastric cancer.LG is now practiced widely, but its applicability for advanced gastric cancer is still controversial. As oncologic outcomes of randomized trials are still pending, there is an urgent need for information that would be relevant to current practice.Through a consensus meeting involving surgeons and biostatisticians, 30 preoperative variables possibly influencing the choice of surgical approach and associated with outcome were identified to enable rigorous estimation of propensity scores. A total of 1948 consecutive patients who underwent gastrectomy for clinical stage II/III gastric adenocarcinoma between 2008 and 2014 were identified, and their clinical data were collected from 8 participating hospitals. After propensity score matching, 610 cases (OG = 305, LG = 305) were finally selected for comparison of long-term outcomes.In the propensity-matched OG and LG populations, the mean observation period was 3.5 and 3.4 years, and the 5-year overall survival was 53.0% and 54.2%, respectively. The hazard ratio (LG/OG) for overall survival was 1.01 (95% confidence interval, 0.80-1.29), and noninferiority of LG was demonstrated statistically as the upper 95% confidence limit was less than the prespecified margin (1.33). The recurrence rate was 30.8% and 29.8% for OG and LG, respectively, and the hazard ratio for recurrence was 0.98 (95% confidence interval, 0.74-1.31). The patterns of recurrence in the 2 groups were similar.This observational study strictly adjusted for confounding factors has provided evidence to suggest that LG is oncologically comparable to OG for locally advanced gastric cancer. The validity of this result will be examined in ongoing randomized trials.

Stroma invasion is an important step in pancreatic cancer progression. However, how pancreatic ductal adenocarcinoma (PDAC) with ductal structure invades the surrounding stroma has not been clear. Here, we elucidated the mechanism of stromal invasion of PDAC, using organoids. From resected PDAC specimens, we established human PDAC organoids, which developed ductal and basement membrane (BM) structures. When the organoids were co-cultured with pancreatic stellate cells (PSCs) in a collagen matrix, organoids lost their BM and ductal structures, and invaded collagen matrix more frequently than did mono-cultured organoids. Interestingly, direct contact by PSCs to PDAC organoids was observed before BM destruction. Matrix metalloproteinase (MMP) 2 or membrane type-1 MMP (MT1MMP) knockdown in PSCs significantly attenuated BM destruction by PSCs, and retained the ductal structures in organoids. Our results imply that direct contact by PSCs induces BM destruction and stromal invasion of PDAC via MMP2 which binds to MT1MMP on PSCs.

Patients with thoracic esophageal cancer are often treated by minimally invasive esophagectomy. However, the long-term survival benefits of minimally invasive esophagectomy remain unclear. Two approaches are available for thoracoscopic surgery: one with the patient in the left lateral decubitus position (LLDP), and the other with the patient in the prone position (PP). We investigated the survival benefit of thoracoscopic esophagectomy according to the tumor stage and patient position during the thoracoscopic procedure. We reviewed the records of 220 consecutive patients with esophageal cancer treated from 1998 to 2012. In total, 146 and 74 patients were treated with thoracoscopic esophagectomy in the LLDP and PP, respectively. No patients were initially proposed to be candidates for esophagectomy by thoracotomy during the study period. Data collection was performed with a focus on survival and recurrent disease. Among all the 220 patients, the overall 5-year survival rates were 83.7%, 74.1%, 45.5%, 78.6%, 44.2%, 29.4% and 24.3% in the patients with pStage IA, IB, IIA, IIB, IIIA, IIIB and IIIC disease, respectively. Despite the greater number of dissected mediastinal lymph nodes in the PP procedure, there were no significant differences in the survival curves between the LLDP and PP procedures. The long-term results of thoracoscopic esophagectomy are comparable and acceptable. The PP procedure was not confirmed to offer a superior survival benefit to the LLDP procedure in this retrospective study.

Live demonstration of endoscopy is one of the most attractive and useful methods for education and is often organized locally in hospitals. However, problems have been apparent in terms of cost, preparation, and potential risks to patients. Our aim was to evaluate a new approach to live endoscopy whereby remote hospitals are connected by the Internet for live endoscopic demonstrations. Live endoscopy was transmitted to the Congress of the Japan Gastroenterological Endoscopic Society by 13 domestic and international hospitals. Patients with upper and lower gastrointestinal diseases and with pancreatobiliary disorders were the subjects of a live demonstration. Questionnaires were distributed to the audience and were sent to the demonstrators. Questions concerned the quality of transmitted images and sound, cost, preparations, programs, preference of style, and adverse events. Of the audience, 91.2% (249/273) answered favorably regarding the transmitted image quality and 93.8% (259/276) regarding the sound quality. All demonstrators answered favorably regarding image quality and 93% (13/14) regarding sound quality. Preparations were completed without any outsourcing at 11 sites (79%) and were evaluated as 'very easy' or 'easy' at all but one site (92.3%). Preparation cost was judged as 'very cheap' or 'cheap' at 12 sites (86%). Live endoscopy connecting multiple international centers was satisfactory in image and sound quality for both audience and demonstrators, with easy and inexpensive preparation. The remote transmission of live endoscopy from demonstrators' own hospitals was preferred to the conventional style of locally organized live endoscopy.

Esophagogastric anastomosis after esophagectomy has been performed with a variety of techniques during the past decade. However, anastomotic leakage and stricture are still important clinical problems after esophagogastric anastomosis, causing burdensome symptoms and poor quality of life. Herein, we describe a novel cervical end-to-side triangulating esophagogastric anastomoasis using linear stapler.A total of 90 patients (85 % male; mean age 63 years) with thoracic esophageal cancer who underwent cervical end-to-side esophagogastric triangular anastomosis using a linear stapler after minimally invasive esophagectomy between November 2006 and April 2013 were retrospectively reviewed.The median operation time was 602 min (range 424-936 min). The volume of blood loss during the entire operative procedure was 127 ml (range 0-700 ml). There were no cases of anastomotic leakage in this study, although four patients (4.4 %) developed dysphagia associated with benign anastomotic stricture formation. All patients with a benign anastomotic stricture underwent balloon dilation, which resulted in improvement in their symptoms.Considering the absence of anastomotic leakage and low rate of anastomotic stricture formation in this study, our modified triangular esophagogastric anastomosis technique appears promising and may contribute to reduced morbidity and mortality rates following esophagectomy.

Background: We previously reported the use of an inverted T-shaped method to obtain a suitable view for hand sewing to close the common entry hole when the linear stapler was fired for esophagojejunostomy after laparoscopic total gastrectomy (LTG). This conventional method involved insertion of the fixed cartridge fork to the Roux limb and the fine movable anvil fork to the esophagus to avoid perforation of the jejunum. However, insertion of the movable anvil fork to the esophagus during this procedure often requires us to strongly push down the main body of the stapler with the fixed cartridge fork to bring the direction of the anvil fork in line with the direction of the long axis of the esophagus while controlling the opening of the movable anvil fork. We therefore modified this complicated inverted T-shaped method using a linear stapler with a movable cartridge fork. This modified method involved insertion of the movable cartridge fork into the Roux limb followed by natural, easy insertion of the fixed anvil fork into the esophagus without controlling the opening of the movable cartridge fork. Methods: We performed LTG in a total of 155 consecutive patients with gastric cancer from November 2007 to December 2015 in Kyushu University Hospital. After LTG, we performed the conventional inverted T-shaped method using a linear stapler with a fixed cartridge fork in 61 patients from November 2007 to July 2011 (fixed cartridge group). From August 2011, we used a linear stapler with a movable cartridge fork and performed the modified inverted T-shaped method in 94 patients (movable cartridge group). We herein compare the short-term outcomes in 94 cases of LTG using the modified method (movable cartridge fork) with those in 61 cases using the conventional method (fixed cartridge fork). Results: We found no significant differences in the perioperative or postoperative events between the movable and fixed cartridge groups. One case of anastomotic leakage occurred in the fixed cartridge group, but no anastomotic leakage occurred in the movable cartridge group. Conclusions: Although there were no remarkable differences in the short-term outcomes between the movable and fixed cartridge groups, we believe that the modified inverted T-shaped method is technically more feasible and reliable than the conventional method and will contribute to the improved safety of LTG.

The benefits and feasibility of laparoscopic surgery for remnant gastric cancer are still unclear. The purpose of this study was to describe the detailed procedure and to evaluate the clinical short-term outcomes of laparoscopic total gastrectomy (LTG) compared with open total gastrectomy (OTG) for remnant gastric cancer (RGC). Of 1,247 consecutive patients who underwent gastrectomy for gastric cancer in our department at Kyushu University Hospital from January 1996 to May 2012, 22 patients who underwent successful curative resection of RGC with precise nodal dissection were enrolled in this study. Twelve patients underwent LTG and the remaining ten patients underwent OTG. We analyzed the clinical short-term outcomes of LTG and compared the results between LTG and OTG groups to evaluate the safety and feasibility of LTG. Twelve patients with RGC successfully underwent LTG without open conversion and morbidity. The mean operation time of LTG, 362.3 ± 68.4 min, was significantly longer than that of OTG (p = 0.0176), but the mean blood loss of LTG, 65.8 ± 62 g, was smaller than that of OTG (p

Background The triangulating stapling technique is one of the reconstruction methods used that provides favorable surgical outcomes in several areas of the digestive tract. However, the results in the cervical esophagogastric anastomosis are not well documented. Methods Using a prospectively maintained comprehensive database, we reviewed the surgical results of 160 consecutive patients who underwent minimally invasive esophagectomy followed by cervical triangulating stapling esophagogastrostomy during 2 periods from May 2002 to May 2012 so as to determine the efficacy of the triangulating stapling technique using 2 different types of stapling devices. Results The rates of anastomotic leakage and stricture in this series were low (1% and 15%, respectively). The rate of anastomotic stricture was significantly reduced when a linear stapler with a cutting knife was used (9%). A logistic regression analysis showed a reduction of anastomotic stricture to be significantly associated with the use of only a linear stapler with a cutting knife. Conclusion Cervical esophagogastric anastomosis by the triangulating stapling technique is safe and feasible. We consider a linear stapling device equipped with a cutting knife to be more suitable for performing the triangulating stapling technique.

Background Although laparoscopic distal gastrectomy has been widely accepted in clinical practice, laparoscopic total gastrectomy (LTG) is not yet familiar because of the difficulty in esophagojejunostomy. The purpose of this study was to evaluate perioperative and short-term outcomes of our procedure of intracorporeal gastrojejunostomy using linear staplers after LTG. Methods Of 98 consecutive patients who underwent LTG for gastric cancer in our department between August 2002 and December 2010, 94 patients underwent esophagojejunostomy with a linear stapling device. After October 2007, we modified the esophagojejunostomy; ie, the most recent 57 patients underwent transection of the esophagus in the ventrodorsal direction and insertion of a linear stapler from the anterior wall of the Roux limb to the posterior wall so as to make an inverted T-shaped anastomosis. We evaluated the results in these 57 patients (recent group) and compared them with the results in the earlier 37 patients (early group). Results The mean operative time in the recent group was 368 to 94.6 min, and the mean estimated blood loss was 57 to 33 g; both were comparable with those in the early group. Neither open conversion nor intraoperative complications were encountered. Two patients experienced anastomotic leakage in the earlier group, but anastomotic leakage did not occur in the recent group. No mortality was encountered. Conclusion We herein report our procedure of intracorporeal gastrojejunostomy using linear staplers after LTG. Our procedure of esophagojejunostomy using linear staplers is safe and feasible and has acceptable morbidity.

Retrorectal tumors (RT) are uncommon and usually managed by open surgical excision. Laparoscopic excision for RT has been reported in only a small number of papers. We aimed to assess the laparoscopic approach for RT and to discuss the factors that made this procedure difficult. We performed laparoscopic excision using a five-trocar technique for neurogenic RT in three patients. Tumors were successfully excised laparoscopically in two patients. However, the third patient required open conversion because the tumor was strongly adhered to the sacrum and could not be mobilized by dissection, resulting in poor visualization of the dissected site. Laparoscopic excision for RT provides excellent intraoperative visualization and good cosmesis in selected patients, but firm adherence to the sacrum may cause difficulty with this procedure.

The clinical importance of intraoperative peritoneal cytology in patients with pancreatic cancer remains incompletely understood.Peritoneal washing samples were collected from 411 consecutive patients with pancreatic ductal adenocarcinoma from 1996 to 2014. Of the 411 patients, 335 underwent macroscopically curative resection and 76 with noncurative factors did not undergo resection. We compared long-term outcomes between patients with positive cytology (cytology+) and those with negative cytology (cytology-) and investigated the importance of clinicopathologic factors.Of 335 patients with curative resection, 300 (89.6%) were cytology- and 35 (10.4%) were cytology+. The median overall survival of cytology+ patients was less than that of cytology- patients (16 vs 31 months, respectively; P .0001). The median overall survival of cytology+ patients with noncurative factors was significantly worse than that of cytology+ patients with curative resection (6.9 vs 16.0 months, respectively; P = .0023). The median disease-free survival of cytology+ patients was less than that of cytology- patients (6.5 vs 16 months, respectively; P .0001). In the multivariate analysis, cytology+ was an independent prognostic factor for overall survival and disease-free survival.Cytology+ without noncurative factors was a predictive factor for a poor prognosis. Therefore, it is important to regard patients with pancreatic cancer characterized by cytology+ as a special group that may warrant more aggressive adjuvant therapy.

There is increasing evidence that microRNAs are differentially expressed in many types of cancers. Despite progress in analyses of microRNAs in several types of cancers, the functional contributions of microRNAs to pancreatic cancer remain unclear.In the present study, the expression levels of specific microRNAs identified by microarray analyses were examined in a panel of 15 pancreatic cancer cell lines. We then investigated the functional roles of these microRNAs in the proliferation and invasion of pancreatic cancer cells.Based on the microarray data, we found frequent and marked overexpression of miR-10a, miR-92, and miR-17-5p in pancreatic cancer cell lines. Microdissection analyses revealed that miR-10a was overexpressed in pancreatic cancer cells isolated from a subset of primary tumors (12 of 20, 60%) compared with precursor lesions and normal ducts (P.01). In vitro experiments revealed that miR-10a inhibitors decreased the invasiveness of pancreatic cancer cells (P.01), but had no effect on their proliferation. Inhibition of HOXA1, a target of miR-10a, promoted the invasiveness of pancreatic cancer cells (P.01).The present data suggest that miR-10a is overexpressed in a subset of pancreatic cancers and is involved in the invasive potential of pancreatic cancer cells partially via suppression of HOXA1.

An advanced granulocyte-colony stimulating factor (G-CSF)-producing tumor is rare, and it exhibits leukocytosis in association with high serum G-CSF levels. A 67-year-old male with a 1-month history of bloody emesis and black stools was revealed to exhibit leukocytosis, anemia and a high serum concentration of G-CSF. During a gastrointestinal endoscopy, an ulcerating tumor was identified in the stomach. Computed tomography and a fluorodeoxyglucose-positron emission tomography scan demonstrated direct invasion of the gastric tumor into the transverse colon, regional lymphadenopathy, lung nodules and diffuse high uptake of FDG in bone marrow. The histological diagnosis was a G-CSF-producing neuroendocrine carcinoma (NEC) (tumor 4b, node 2, metastasis 1, pulmonary, clinical stage IV). Systemic chemotherapy consisting of cisplatin and irinotecan was started. Common terminology criteria of adverse events grade 3 tumor lysis syndrome and gastric penetration appeared. Grade 4 neutropenia lasted for 10 days despite intensive G-CSF administration. Prominent shrinkage of the primary and the metastatic tumors was observed subsequent to 3 cycles of chemotherapy. Total gastrectomy and resection of the transverse colon were subsequently performed. Systemic chemotherapy was effective for a G-CSF-producing advanced gastric NEC with careful monitoring and appropriate supportive care for severe adverse events.

Summary Intraductal papillary mucinous neoplasm of the pancreas is attracting attention as a precursor lesion of the invasive ductal adenocarcinoma, whereas it has been reported that some intraductal papillary mucinous neoplasms do not display progression to malignancy and remain almost unchanged in size and morphology. Recent studies have reported that oncogene-induced senescence has been observed in neoplasms, especially in premalignant lesions, and that it can play an important role in preventing malignant progression. To clarify the presence of senescence in intraductal papillary mucinous neoplasms, we analyzed the expression of several markers of senescence. The intraductal papillary mucinous neoplasms evaluated in this study were classified into 4 groups according to the degree of dysplasia. Senescence-associated β -galactosidase activity and senescence-associated heterochromatin foci formation were investigated in 33 cases of intraductal papillary mucinous neoplasms and 6 normal controls. Immunohistochemical analysis of p16 INK4a and p15 INK4b was performed in 158 cases of intraductal papillary mucinous neoplasms and 10 normal controls. In the normal controls, neither senescence-associated β -galactosidase activity nor senescence-associated heterochromatin foci formation was observed. Most of the normal epithelia were negative for either p16 INK4a or p15 INK4b . For all 4 markers, the percentages of positive cases reached a peak in intraductal papillary mucinous neoplasm with low-grade dysplasia and showed significant decreasing trends in the transition from intraductal papillary mucinous neoplasm with low-grade dysplasia to intraductal papillary mucinous neoplasm with an associated invasive carcinoma. Our results indicate that senescence is induced in the early stage of intraductal papillary mucinous neoplasm and gradually attenuated according to the progression. It is suggested that senescence plays a role in preventing malignant progression of intraductal papillary mucinous neoplasm.

MicroRNAs (miRNAs) have been gaining attention as new, key molecules that contribute to carcinogenesis. In pancreatic cancer, previous profiling analyses of miRNA expression have shown that several miRNAs are differently expressed in normal and cancerous tissues. Several pancreatic cancer-specific miRNAs differed, however, in each analysis.We investigated the miRNA expression profiles of the pancreatic cancer cell lines CAPAN-1 and CFPAC1 and an immortalized human normal pancreatic ductal epithelial cell line (HPDE) using a high-throughput, TaqMan, qRT-PCR array analysis. We also analyzed the expression levels of this miRNA in microdissected (n = 15) and formalin-fixed, paraffin-embedded (FFPE) (n = 115) samples from pancreatic cancers by quantitative RT-PCR. Finally, we investigated the effects of this miRNA on the invasiveness of pancreatic cancer cells.Based on the microarray analysis, miR-372, miR-146a, miR-204, miR-10a, and miR-10b showed particularly large differences (10-fold changes) between both pancreatic cell lines and HPDE cells. Thirteen of the 15 pancreatic cancer cell lines showed 2.1- to 36.4-fold (median, 15.3-fold) greater levels of miR-10b than HPDE cells. Microdissection analysis revealed that miR-10b exhibited greater expression levels in pancreatic cancer cells (n = 5) than in normal pancreatic ductal cells (n = 10) (P.020). Analysis of FFPE samples showed that high miR-10b expression was associated with a lesser overall survival (P = .014). Furthermore, miR-10b correlated with the invasiveness of pancreatic cancer cells (P.01).miR-10b is overexpressed in pancreatic cancer and may be involved in the invasiveness in pancreatic cancer cells, thereby leading to a poor prognosis.

We applied single-incision laparoscopy-assisted surgery for several different types of bowel obstruction in selected patients. Before the operation, a long nasal tube was inserted for intestinal decompression and assessment of a stenotic lesion. A specially-designed instrument for single-incision laparoscopic surgery, the SILS Port, was introduced at the umbilicus or proposed ileostomy site. After intracorporeal procedures, extracorporeal resection and reconstruction of the intestine was performed as needed. Three patients with bowel obstruction due to jejunal carcinoma, colonic stenosis, and adhesion underwent single-incision laparoscopy-assisted surgery. The port site was used for subsequent extracorporeal resection and anastomosis of the jejunum in two patients, and for ileostomy in the remaining patient. All of the procedures were completed safely, and there were no postoperative complications. Single-incision laparoscopy can therefore be applied for selected patients with bowel obstruction. In such cases, the preoperative insertion of a long nasal tube for decompression of intestinal contents and assessment of the stenotic lesion is necessary.

OBJECTIVES Although intestinal-type intraductal papillary mucinous carcinoma (IPMC) is reported to have a better prognosis, few studies have addressed its invasive pattern. The meaning of "minimal invasion" (MI) in IPMC also remains unclear. We investigated the prognosis of intraductal papillary mucinous neoplasm (IPMN) focusing on MI and subtypes. METHODS We evaluated 71 patients with IPMC among a total of 179 patients with resected IPMN. RESULTS Although 2 of 10 MI-IPMC patients had lymph node metastasis, there were no disease-specific deaths among the MI-IPMC patients. Minimally invasive IPMCs were more frequently observed in intestinal-type IPMC (23/33 cases) than in non-intestinal-type IPMCs (16/38 cases; P = 0.019). Among 32 patients with massively invasive IPMC, the prognosis was significantly better for patients with intestinal-type IPMC than for patients with non-intestinal-type IPMC (P = 0.013). When confined to massively invasive IPMC, tubular invasion (P < 0.001) and lymphatic (P = 0.001) or serosal (P = 0.021) invasion were less frequently observed in intestinal-type IPMC than in non-intestinal-type IPMC. CONCLUSIONS Invasive carcinoma derived from intestinal-type IPMN is associated with MI, colloid carcinoma, and less invasive behavior.

Background To improve the prognosis of patients after resection of pancreatic cancer, the most appropriate and efficient treatment should be provided to specific subsets of patients. Our aim was to identify promising microRNAs as markers to predict responses to gemcitabine in patients with resected pancreatic cancer. Methods Two gemcitabine-resistant pancreatic cancer cell lines were established, and global microRNA expression analyses was performed by quantitative reverse transcription–polymerase chain reaction (qRT-PCR). Eleven miRNAs were selected as putative predictive markers and analyzed by means of macrodissected formalin-fixed, paraffin-embedded samples obtained from 90 patients with or without gemcitabine treatment after resection of pancreatic cancer. Results We identified 24 microRNAs whose expression was altered in gemcitabine-resistant cells. qRT-PCR analyses showed that patients with high miR-142-5p and miR-204 expression had significantly longer survival times than those with low miR-142-5p (P = 0.0077) and miR-204 (P = 0.0054) expression in the gemcitabine-treated group. This was not seen in the nontreated group. Multivariate analyses showed that miR-142-5p expression was an independent prognostic marker only in patients treated with gemcitabine (P = 0.034). Conclusions miR-142-5p is a promising predictive marker for gemcitabine response in patients with resected pancreatic cancer.

Intraductal papillary mucinous neoplasm is characterized by cystically dilated main and/or branch pancreatic duct with mucus. According to the degree of atypia, intraductal papillary mucinous neoplasm is classified into 3 groups: adenoma, borderline, and carcinoma. Furthermore, intraductal papillary mucinous neoplasm is considered to progress through an adenoma-carcinoma sequence like colorectal carcinoma. Programmed cell death 4 is a recently identified tumor suppressor that was found to inhibit translation. Programmed cell death 4 has been reported to inhibit tumorigenesis, tumor progression, proliferation, invasion, and metastasis in several human malignancies. We examined 108 cases of intraductal papillary mucinous neoplasm by immunohistochemistry and revealed that programmed cell death 4 expression was recognized in both the nucleus and cytoplasm in intraductal papillary mucinous neoplasm. The positive rate of programmed cell death 4 was 79%, 43%, and 10% in adenoma, borderline, and carcinoma, respectively. The positive rate of programmed cell death 4 decreased from adenoma to carcinoma (P < .0001, both adenoma versus borderline and borderline versus carcinoma), indicating that programmed cell death 4 might inhibit tumor progression in intraductal papillary mucinous neoplasm. Programmed cell death 4 expression had a strong relationship with p21 expression (P < .0001) and an inverse correlation with Ki-67 labeling index (r = -0.6255, P < .0001). Thus, programmed cell death 4 might inhibit the proliferation of intraductal papillary mucinous neoplasm; and its inhibition might partly result from cell cycle arrest caused by the up-regulation of p21. In conclusion, programmed cell death 4 may inhibit tumor progression in intraductal papillary mucinous neoplasm; and the loss of programmed cell death 4 expression is representative of the malignant potential of intraductal papillary mucinous neoplasm including the proliferative activity. Therefore, programmed cell death 4 can be an important biomarker for intraductal papillary mucinous neoplasm.

Rationale Esophageal carcinosarcoma generally comprises 2 histological components: squamous cell carcinoma (SqCC) and sarcoma. Esophageal carcinosarcoma comprising 3 components is extremely rare and no reports have described therapeutic effects for this disease with metastasis. Patient concerns A 76-year-old man with dysphagia presented to a local clinic. Gastrointestinal endoscopy revealed a polypoid tumor in the middle esophagus and he was referred to our hospital. Diagnosis and interventions Thoracoscopic esophagectomy with super-extended (D3) nodal dissection and gastric tube reconstitution was performed, which resulted in carcinosarcoma comprising neuroendocrine carcinoma (NEC), SqCC, and sarcoma. Pathological stage was T1bN1M0 stage IIB according to the TNM Classification of Malignant Tumors-7th edition. The NEC component was observed in lymph node. At 47 days after surgery, lymph nodes, liver, and bone metastasis appeared, and tumor markers such as ProGRP and NSE were elevated. Combination chemotherapy with cisplatin and etoposide (EP) adapted to NEC was performed. Outcomes The patient showed complete response within 4 cycles of chemotherapy. However, the disease recurred 5.5 months after the final course of EP chemotherapy. Lessons A therapeutic strategy based on assessment of which component caused metastasis might be important for metastatic carcinosarcoma comprising 3 components, although more accumulation of data about the efficacy of chemotherapy is necessary. Moreover, elucidation of the mechanisms underlying generation of carcinosarcoma is expected in the future.

To overcome the limited clinical efficacy of conditionally replicative adenoviruses (CRAds), we investigated the effects of combination therapy with gemcitabine (GEM) and the hTERT-promoter-dependent CRAd (hTERT-CRAd), Ad5/3hTERTE1. This combination therapy exhibited enhanced cytotoxic effects on pancreatic cancer both in vitro and in vivo. Furthermore, we revealed that this enhancement effect was due to the multiple bidirectional interactions between hTERT-CRAd and GEM. The GEM-sensitizing effect of E1 expression derived from hTERT-CRAd, and the enhancement effect by GEM on hTERT promoter activity which led to the increase of adenovirus E1 and viral infectivity. This combination therapy may be a promising therapeutic approach for pancreatic cancer.