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Supplementary Figure 3 from Inhibition of Cyclooxygenase-2 Suppresses Lymph Node Metastasis via Reduction of Lymphangiogenesis

Supplementary Figure 1 from Inhibition of Cyclooxygenase-2 Suppresses Lymph Node Metastasis via Reduction of Lymphangiogenesis

Supplementary Figure 2 from Inhibition of Cyclooxygenase-2 Suppresses Lymph Node Metastasis via Reduction of Lymphangiogenesis

Supplementary Figure Legends 1-3 from Inhibition of Cyclooxygenase-2 Suppresses Lymph Node Metastasis via Reduction of Lymphangiogenesis

Supplementary Tables from Lysyl Oxidase Is a Tumor Suppressor Gene Inactivated by Methylation and Loss of Heterozygosity in Human Gastric Cancers

Supplementary Table 1 from Inhibition of Cyclooxygenase-2 Suppresses Lymph Node Metastasis via Reduction of Lymphangiogenesis

Cyclooxygenase-2 (COX-2) inhibitor has been reported to suppress tumor progression. However, it is unclear whether this inhibitor can also prevent lymphatic metastasis. To determine the effects of COX-2 inhibitor on lymphatic metastasis, etodolac, a COX-2 inhibitor, was given p.o. to mice bearing orthotopic xenografts or with carcinomatous peritonitis induced with a highly metastatic human diffuse-type gastric carcinoma cell line, OCUM-2MLN. Tumor lymphangiogenesis was significantly decreased in etodolac-treated mice compared with control mice. Consistent with this decrease in lymphangiogenesis, the total weight of metastatic lymph nodes was less in etodolac-treated mice than in control mice. Immunohistochemical analysis revealed that the major source of vascular endothelial growth factor-C (VEGF-C) and VEGF-D was F4/80-positive macrophages in our models. The mRNA levels of VEGF-C in mouse macrophage-like RAW264.7 cells, as well as those in tumor tissues, were suppressed by etodolac. The growth of human dermal lymphatic microvascular endothelial cells was also suppressed by etodolac. Supporting these findings, etodolac also inhibited lymphangiogenesis in a model of chronic aseptic peritonitis, suggesting that COX-2 can enhance lymphangiogenesis in the absence of cancer cells. Our findings suggest that COX-2 inhibitor may be useful for prophylaxis of lymph node metastasis by reducing macrophage-mediated tumor lymphangiogenesis. [Cancer Res 2007;67(21):10181–9]

Lysyl oxidase (LOX) and HRAS-like suppressor (HRASLS) are silenced in human gastric cancers and are reported to have growth-suppressive activities in ras-transformed mouse/rat fibroblasts. Here, we analyzed whether or not LOX and HRASLS are tumor suppressor genes in human gastric cancers. Loss of heterozygosity and promoter methylation of LOX were detected in 33% (9 of 27) and 27% (26 of 96) of gastric cancers, respectively. Biallelic methylation and loss of heterozygosity with promoter methylation were also demonstrated in gastric cancers. Silencing of LOX was also observed in colon, lung, and ovarian cancer cell lines. As for mutations, only one possible somatic mutation was found by analysis of 96 gastric cancer samples and 58 gastric and other cancer cell lines. When LOX was introduced into a gastric cancer cell line, MKN28, in which LOX and HRASLS were silenced, it reduced the number of anchorage-dependent colonies to 57 to 61%, and the number of anchorage-independent colonies to 11 to 23%. Sizes of tumors formed in nude mice were reduced to 19 to 26%. Growth suppression in soft agar assay was also observed in another gastric cancer cell line, KATOIII. On the other hand, neither loss of heterozygosity nor a somatic mutation was detected in HRASLS, and its introduction into MKN28 did not suppress the growth in vitro or in vivo. These data showed that LOX is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in gastric cancers, and possibly also in other cancers.

ObjectiveAn international meeting was organised to develop consensus on (1) the landmarks to define the gastro-oesophageal junction (GOJ), (2) the occurrence and pathophysiological significance of the cardiac gland, (3) the definition of the gastro-oesophageal junctional zone (GOJZ) and (4) the causes of inflammation, metaplasia and neoplasia occurring in the GOJZ.DesignClinical questions relevant to the afore-mentioned major issues were drafted for which expert panels formulated relevant statements and textural explanations.A Delphi method using an anonymous system was employed to develop the consensus, the level of which was predefined as ≥80% of agreement. Two rounds of voting and amendments were completed before the meeting at which clinical questions and consensus were finalised.ResultsTwenty eight clinical questions and statements were finalised after extensive amendments. Critical consensus was achieved: (1) definition for the GOJ, (2) definition of the GOJZ spanning 1 cm proximal and distal to the GOJ as defined by the end of palisade vessels was accepted based on the anatomical distribution of cardiac type gland, (3) chemical and bacterial (Helicobacter pylori) factors as the primary causes of inflammation, metaplasia and neoplasia occurring in the GOJZ, (4) a new definition of Barrett’s oesophagus (BO).ConclusionsThis international consensus on the new definitions of BO, GOJ and the GOJZ will be instrumental in future studies aiming to resolve many issues on this important anatomic area and hopefully will lead to better classification and management of the diseases surrounding the GOJ.

Objectives The Japan Endoscopy Database Project was initiated to develop the world's largest endoscopy data repository. This study describes the first phase of the colonoscopy project in Japan. Methods Data were aggregated offline by integrating information from the endoscopy database software from January 2015 through March 2017. The study population included all patients who underwent colonoscopy at eight centers. Results A total of 31,395 patients who underwent 38,497 colonoscopy procedures were registered. The majority of procedures were performed for screening (n = 14,156), followed by fecal immunochemical test positivity (n = 3960), abdominal symptoms (n = 3864), post-colorectal surgery surveillance (n = 3431), post-endoscopic treatment surveillance (n = 3757), thorough pre-treatment examination (n = 2822), and therapeutic purposes (n = 6507). In the screening group, advanced cancers, early cancers, and adenomas were diagnosed endoscopically in 2.1%, 1.3%, and 28.7% of cases, respectively, while in the fecal immunochemical test-positive group, they were diagnosed in 2.5%, 1.9%, and 41.6% of cases, respectively. The incidence of complications was 0.177% and 0.152% in the screening and fecal immunochemical test-positive groups, respectively. The therapeutic procedures included 1446 cold forceps polypectomy procedures, 4770 cold snare polypectomy procedures, 368 hot biopsies, 2998 hot snare polypectomy procedures, 9775 endoscopic or piecemeal endoscopic mucosal resections, and 1660 endoscopic submucosal dissections. A total of 173 procedure-related complications (0.82%) occurred in 21,017 therapeutic procedures performed in 15,744 patients. Conclusions The first phase of the Japan Endoscopy Database Project established the proportions of the diagnostic and therapeutic colonoscopy procedures, and complication rates in real-world settings.

Background and aim Few studies have reported on a national, population-based endoscopic retrograde cholangiopancreatography (ERCP) database. Hence, in 2015, we established a multicenter ERCP database registry, the Japan Endoscopic Database (JED) Project in preparation for a nationwide endoscopic database. The objective the present study was to evaluate this registry before the establishment of a nationwide endoscopic database. Methods From 1 January 2015 to 31 March 2017, we collected and analyzed the ERCP data of all patients who underwent ERCP in four participating centers in the JED Project based on the JED protocol. Results Four centers carried out 4104 ERCP on 2173 patients. Data entry of ERCP information (age, 100%; gender, 100%; American Society of Anesthesiologists Physical Status Classification System, 74.5%; scope, 92.7%; time to ERCP, 100%; antithrombotic drug information, 55.0%; primary selective common bile duct [CBD] cannulation methods, 73.0%; number of attempts at primary selective CBD cannulation, 67.6%; overall selective CBD cannulation methods, 68.9%; ERCP procedure time, 66.3%; fluoroscopy time, 65.1%; adverse events, 74.9%; serum amylase levels 1 day post-ERCP, 36.5%) was accurately extracted from the four centers. Success rate of CBD cannulation by level of ERCP difficulty was 98.5%, 99.0%, and 96.4% in grades 1, 2, and 3, respectively. Complication rate by overall selective CBD cannulation method was 5.6%, 7.6%, and 10.5% in the contrast-assisted technique, guidewire-assisted technique, and cross-over method, respectively. Conclusion Data from this evaluation of the JED Project, a multicenter ERCP database registry, suggest the feasibility of establishing a nationwide ERCP database and its challenges.

The aim was to investigate the current status of esophageal endoscopy, including the evaluation of smoking and alcohol consumption, in Japan. A total of 47,441 patients who underwent 69,748 sessions of esophageal endoscopy were registered in the Japan Endoscopy Database between January 2015 and March 2017. The study variables were as follows: (1) methods for monitoring the esophagus and the time required for monitoring and (2) the status of smoking and alcohol consumption in patients with esophageal cancer and head and neck cancer. Image-enhanced endoscopy was performed in 10.6%, Lugol chromoendoscopy in 4.1%, and magnifying endoscopy in 3.2%. The mean time required for gastrointestinal endoscopy was 10 min 58 s. The mean examination times in patients with or without monitoring of the head and neck were 10 min 51 s and 11 min 13 s, respectively. In 57.0% of the patients with esophageal cancer, the head and neck were monitored at the time of gastrointestinal endoscopy. The proportion of current smokers (esophageal cancer: 16.8–4.7%; head and neck cancer: 24.3–9.3%) and addicted drinkers (esophageal cancer: 52.3–40.8%; head and neck cancer: 50.2–47.3%) were lower at the second or subsequent endoscopy than at the initial endoscopy. The new strategy for esophageal endoscopy has led to an evolutionary change in Japan. The patients with esophageal cancer and head and neck cancer who underwent a second or subsequent endoscopy had lower incidences of smoking and alcohol consumption, although the incidences remained high.

Aim: To clarify whether antithrombotic drugs affect diagnosis using the immunochemical faecal occult blood test ­(iFOBT) of colorectal neoplasia. Methods: Using the Japan Endoscopy Database from 8 centres between 2015 and 2017, we analyzed data about patients who were iFOBT positive and had received direct oral anticoagulants (DOAC), warfarin, aspirin or thienopyridine. One-to-one matching-analogue propensity score weighted analyses were performed to compare the positive predictive value (PPV) of all neoplasms, invasive and non-invasive colorectal cancers and adenomas between drug users and non-users. All neoplasms included invasive and non-invasive colorectal cancer, and adenomas. Results: We analyzed 197 DOAC users and 196 non-users, 153 warfarin users and 153 non-users, 408 aspirin users and 415 non-users, and 97 thienopyridine users and 97 non-users. No significant differences were observed in the PPV for all neoplasms (56.67 vs. 50.43%), invasive cancer (4.32 vs. 3.53%), non-invasive cancer (15.58 vs. 15.56%) or adenoma (53.13 vs. 48.09%) between the DOAC user and non-user groups. No significant differences were observed in the PPV for all neoplasia, invasive and non-invasive cancer, or adenoma between warfarin, aspirin and thienopyridine use and non-users. Conclusions: DOAC, warfarin, aspirin and thienopyridine use did not decrease the PPVs of the iFOBT used to evaluate all colorectal neoplasia.

Introduction Endoscopic intragastric balloon (IGB) placement has been performed in Japan since 2004. The nationwide surveys were repeatedly carried out to confirm the effectiveness and safety of IGB in Japan. We herein present the accumulated results. Methods Twenty-six Japanese endoscopists personally imported products of the BioEnterics Intragastric Balloon (BIB)/Orbera system after completing the training courses in Japan. Mail surveys were posted to them every 2 years from 2010. This study included the accumulated data of the six surveys, and excluded data from non-Japanese patients and the Orbera365 data. Results Between 2004 and 2019, 399 obese Japanese patients underwent IGB treatment using the BIB/Orbera system. The incidence rates of early removal of IGB within 1 week and complications due to IGB were 4.8% and 6.1%, respectively. The average percent excess weight loss (%EWL) and percent total weight loss (%TWL) at IGB removal were 46.6% and 11.5%, and successful weight loss, defined as %EWL ≥ 25% or %TWL ≥ 10%, was achieved in 65.6% or 54.5% of the patients, respectively. Multivariate analyses revealed that older age and larger saline filling volume were independent predictors of successful weight loss. At 1 year after IGB removal, successful weight loss defined by the %EWL and %TWL was maintained in 44.7% and 34.1% of the patients, respectively. Conclusion IGB therapy using the BIB/Orbera system has been safely and effectively performed in Japan. The successful weight loss may be associated with older age and larger saline filling volume.

The advent of electronic medical records brought image filing systems to many hospitals, as well as electronic endoscopic medical records. However, data integration among multiple different vendors has not yet been accomplished. We start the Japan Endoscopic Database (JED) Project endorsed by Japan Gastroenterological Endoscopy Society (JGES) from January 2015. The purposes of this project are as follows: (i) developing the world's largest endoscopic database generated from daily use of the reporting system; (ii) capturing the actual performance of endoscopic practice in Japan; and (iii) standardizing the terminology and fundamental items for registry of clinical studies. Moreover, the JED project has the potential to automatically collect data about adverse events, competency and evaluation of residents, and actual numbers of procedures on a nationwide scale, certification for the specialty board system, and so on. We believe that this design paper will be helpful not only for future nationwide research but also for international research (UMIN000016093).

Background and Aim The Japan Endoscopy Database (JED) Project was started to develop the world's largest endoscopic database, capture the actual performance of endoscopic practice, and standardize the terminology and fundamental items needed for a clinical and research registry. This paper presents a progress report on the first phase of this project undertaken at eight endoscopic centers in Japan. Methods The list of data items to be collected was drafted by the MSED-J (Minimal Standard Endoscopic Database) subcommittee. These items were aggregated offline by integrating data from two endoscopic filing systems between July 2015 and December 2015. The study population included all patients who underwent esophagogastroduodenoscopy or colonoscopy at all eight centers, patients who underwent enteroscopy at five of the eight centers, and patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) at four of the eight centers. Results Data collected in this phase included 61 070 endoscopic procedures, of which 40 475 were esophagogastroduodenoscopies, 215 were enteroscopies, 19 204 were colonoscopies, and 1176 were ERCPs. Frequencies of complications were 0.68% for esophagogastroduodenoscopy, 0% for enteroscopy, 0.43% for colonoscopy, and 13.34% for ERCP. In addition, we obtained various data including Helicobacter pylori infection status, past history of endoscopy in patients who underwent enteroscopy or colonoscopy, and degree of difficulty of ERCP, although the frequencies of reporting were sometimes low, with some items

Background and Aims: Esophageal adenocarcinoma develops in the setting of gastroesophageal reflux and columnar metaplasia in distal esophagus. Columnar metaplasia arising in gastroesophageal reflux models has developed in rat; however, gastroesophageal reflux models in mice have not been well-characterized. Methods: One hundred thirty-five C57Bl/6J mice aged 8 weeks old were divided into the following operations: esophagogastrojejunostomy (side-to-side) (EGJ), esophageal separation and esophagojejunostomy (end-to-side) (EJ), and EJ and gastrectomy (end-to-side) (EJ/TG). The animals were euthanized after 40 weeks and the histology of the junction was examined. Immunohistochemistry for p53, PDX-1, and CDX-2 was performed. Results: Metaplasia developed in 15/33 (45.5%) of EGJ, 0/38 (0%) of EJ, and 6/39 (15.4%) of EJ/TG (P < .05) and dysplasia developed 7/33 (21.2%) of EGJ, 0% of EJ, and 1/39 (2.6%) of EJ/TG. p53 was positive in all of the dysplastic regions, 12/15 (80%) metaplasias in the EGJ model, and 1/6 (16.7%) metaplasia in the EJ/TG model. CDX-2 was positive in all cases of metaplasias, but decreased in some cases of dysplasia. PDX-1 was positive in 7/8 (88%) cases of dysplasia and in 15/21 (71%) cases of metaplasia (P < .05). Conclusions: The EGJ model, which causes reflux of gastric acid and duodenal content, developed metaplasia and dysplasia most frequently. No metaplasia developed in the EJ model in which gastric juice and duodenal content mixed before reflux. Thus, duodenal contents alone can induce columnar metaplasia and dysplasia; however, the combination of gastric acid with duodenal content reflux can cause metaplasia and dysplasia more efficiently. Keywords: GERD, Esophageal Reflux, Barrettâs Esophagus, Esophageal Adenocarcinoma

Introduction Solitary Peutz-Jeghers-type polyps of the stomach are extremely rare. They are defined as unique polyps that are not associated with Peutz-Jeghers syndrome (PJS). Presentation of Case A 37-year-old woman presented at our hospital with anemia and epigastric discomfort. Esophagogastroduodenoscopy to determine the cause of anemia revealed a 5 × 6-cm pedunculated polypoid tumor at the greater curvature of the upper gastric body. Pathological examination of a biopsy specimen confirmed a Group 1 hyperplastic polyp. Computed tomography revealed neither lymph node swelling nor distant metastasis. A malignant component of the polypoid tumor was difficult to deny because of its size. The patient underwent local resection of the stomach. Her postoperative course was uneventful. A pathological examination of the surgical specimen revealed a Peutz-Jeghers-type, hamartomatous polyp containing an enlarged crypt with hyperplastic foveolar epithelium and smooth muscle proliferating into the lamina propria. No atypical cells were found in the overlying epithelium. Based on these findings, we performed colonoscopy and capsule endoscopy of the intestine. No polyps were found in the intestine or colon. She had no family history of any type of tumor and no mucocutaneous pigmentation. Discussion There were only 10 reports of solitary gastric Peutz-Jeghers polyps published to date. Although most of them did not have atypical cells, one case has proliferative component. A few reports have described relationship with malignant tumor. Conclusion Solitary gastric PJ-type polyps are rare. Careful follow-up should be recommended and further studies are needed to evaluate cancer risk of solitary gastric PJ-type polyps.

Highlights • Non-parasitic hepatic cysts with biliary communication are extremely rare. • Overlooking of the communication site may lead to postoperative bile leakage. • Air leak test was useful for the detection of the small biliary communication., Introduction Symptomatic non-parasitic hepatic cysts with biliary communication are rare and no standard treatment has been established yet. Careful attention should be paid to avoidance of postoperative bile leakage during surgical treatment. Presentation of case We report the case of a 74-year-old man who visited our department complaining of right upper abdominal pain and elevated serum levels of the liver enzymes. Computed tomography revealed hepatic cysts including a large one measuring 16 cm in diameter in Segments IV and VIII. Percutaneous drainage of the cyst revealed bile-staining of the cyst fluid. Endoscopic retrograde cholangiography demonstrated the presence of a cyst–biliary communication. We performed open deroofing of the cyst. During the operation, the biliary fistula was invisible, however, air injection into the bile duct through the stump of the cystic duct caused release of air bubbles from the cyst cavity, which allowed us to detect the small biliary orifice and repair it successfully by suture. Discussion We utilized the intraoperative air leak test, which has previously been reported to be effective for preventing postoperative bile leakage in patients undergoing hepatectomy to detect of a small cyst–biliary communication in a case undergoing non-parasitic hepatic cyst surgery. Conclusion An intraoperative air leak test may be a useful test during surgical treatment of non-parasitic hepatic cysts with biliary communication.

Objective To compare radical surgery with definitive chemoradiation (CRT) for esophageal squamous cell carcinoma using propensity score (PS) matching at our single institution. Materials and methods A total of 386 consecutive, surgically treated and 243 CRT-treated cases between 2001 and 2014 were analyzed. PS was calculated using multivariable analysis (logistic regression) for pairs of variables such as treatment time, age, sex, primary tumor location, clinical stage, and clinical T- and N-stage for patients after excluding clinical T4 and M1 cases. According to PS, 133 surgically-treated and 134 CRT-treated cases were selected randomly by software. Results The patients’ median age was 68 years in the CRT group and 71 years in the surgery group. Clinical stage II-III, T3, N0 (according to the 7th American Joint Committee on Cancer-2009), and upper plus middle thoracic esophageal disease were seen in 68%, 44%, 54%, and 59%, respectively, in the CRT group and 64%, 47%, 55%, and 64%, respectively, in the surgery group. The 3- and 5-year overall survival was 47.1% and 34.0% in the CRT group and 68.3% and 54.4% in the surgery group (p = 0.0019). The 3- and 5-year progression-free survival was 45.3% and 38.8% in the CRT group and 61.1% and 54.4% in the surgery group (p = 0.022). Conclusion CRT may be inferior to surgery in survival, although a selection bias for patients selected for a non-operative approach cannot be excluded, especially since surgery is the standard of care at this institution. A prospective randomized clinical trial will be necessary to draw a definite conclusion.

Background and Aim Type I gastric carcinoids (TIGC) are associated with chronic atrophic gastritis (CAG) with hypergastrinemia and hyperplasia of enterochromaffin-like cells. Several treatment options are currently available for these tumors including total gastrectomy, partial resection, antrectomy, endoscopic resection and endoscopic surveillance. The present study evaluated different treatment approaches and clinical outcomes of patients with TIGC in Japan. Methods Between 1991 and 2011, 82 patients with TIGC were identified at multicenter institutions in Japan. Patient demographics, tumor size, depth of invasion, vessel involvement, treatment approach, Helicobacter pylori infection, serum gastrin level, recurrence-free survival (RFS) and disease-specific survival (DSS) were analyzed. Results Median age of all patients at the time of diagnosis was 56 years (range, 24−79 years). There were 44 males and 38females. Patients underwent endoscopic surveillance (n = 25), endoscopic resection (n = 41) or surgical resection (n = 16). Intramucosal invasion was found in 19 patients, submucosal invasion in 44 patients and muscularis propria invasion in one patient. Tumor diameter was ≤10 mm in 71 patients, 11–20 mm in five patients and ≥21 mm in five patients. None of the patients showed rapidly growing tumors, local recurrence or metastasis. The median (range) follow-up period was 7 (0–20) years. RFS was 97.6% and DSS was 100% in all the patients. Conclusion The prognosis of TIGC patients treated by different modalities in Japan is favorable regardless of the generational change of management for TIGC.

The topical antispasmodic agent l-menthol is useful for inhibiting gastric peristalsis during diagnostic upper gastrointestinal endoscopy. However, it remains unclear whether l-menthol is similarly effective during therapeutic endoscopy, thereby improving treatment outcomes in a clinical setting.A total of 83 patients scheduled to undergo endoscopic treatment at 8 Japanese referral centers were randomly assigned to receive l-menthol or placebo. The degree of gastric peristalsis (peristaltic score: grade 1-5) was assessed by an independent committee. The primary outcome was the proportion of subjects in whom no or mild peristalsis (grade 1 or 2) was maintained throughout endoscopic treatment. Secondary outcomes were the duration of sustained response and the incidence of adverse drug reactions.The proportion of patients with no or mild peristalsis was significantly higher in the l-menthol group (85.4 %, 95 % confidence intervals 70.8-94.4: 35/41 subjects) than in the placebo group (39.0 %, 24.2-55: 16/41; P0.001). The sustained response rates in the l-menthol and the placebo were, respectively, 90.0 and 39.6 % 30 min post-dose, and 79.9 and 35.7 % at the completion of the resection. The sustained response rates were significantly higher in the l-menthol group than in the placebo group (P0.001, log-rank test). The incidence of adverse drug reactions did not differ significantly between the two groups (P = 1.000).During gastric endoscopic submucosal dissection, spraying l-menthol on the gastric mucosa significantly suppressed peristalsis, with minimal adverse drug reactions as compared with placebo. l-menthol solution might be useful for therapeutic endoscopy.

Background The Japanese Gastric Cancer Association (JGCA) started a new nationwide gastric cancer registration in 2008. Methods From 208 participating hospitals, 53 items including surgical procedures, pathological diagnosis, and survival outcomes of 13,626 patients with primary gastric cancer treated in 2002 were collected retrospectively. Data were entered into the JGCA database according to the JGCA classification (13th edition) and UICC TNM classification (5th edition) using an electronic data collecting system. Finally, data of 13,002 patients who underwent laparotomy were analyzed. Results The 5-year follow-up rate was 83.3 %. The direct death rate was 0.48 %. UICC 5-year survival rates (5YEARSs)/JGCA 5YEARSs were 92.2 %/92.3 % for stage IA, 85.3 %/84.7 % for stage IB, 72.1 %/70.0 % for stage II, 52.8 %/46.8 % for stage IIIA, 31.0 %/28.8 % for stage IIIB, and 14.9 %/15.3 % for stage IV, respectively. The proportion of patients more than 80 years old was 7.8 %, and their 5YEARS was 51.6 %. Postoperative outcome of the patients with primary gastric carcinoma in Japan have apparently improved in advanced cases and among the aged population when compared with the archival data. Further efforts to improve the follow-up rate are needed. Conclusions Postoperative outcome of the patients with primary gastric carcinoma in Japan have apparently improved in advanced cases and among the aged population when compared with the archival data. Further efforts to improve the follow-up rate are needed.

The Japanese Gastric Cancer Association (JGCA) started a new nationwide gastric cancer registry in 2008. Approximately 50 data items, including surgical procedures, pathological diagnoses, and survival outcomes, for 12004 patients with primary gastric cancer treated in 2001 were collected retrospectively from 187 participating hospitals. Data were entered into the JGCA database according to the JGCA Classification of gastric carcinoma, 13th edition and the International Union Against Cancer (UICC) TNM Classification of malignant tumors, 5th edition by using an electronic data collecting system. Finally, data of 11261 patients with gastric resection were analyzed. The 5-year follow-up rate was 83.5%. The direct death rate was 0.6%. TNM 5-year survival rates (5YSRs)/JGCA 5YSRs were 91.8/91.9% for stage IA, 84.6/85.1% for stage IB, 70.5/73.1% for stage II, 46.6/51.0% for stage IIIA, 29.9/33.4% for stage IIIB, and 16.6/15.8% for stage IV. The proportion of patients more than 80 years old was 7.0%, and their 5YSR was 48.7%. Compared to the JGCA archived data, though the follow-up rate needs to be improved, these data suggest that the postoperative results of patients with primary gastric carcinoma have improved in those with advanced disease and in the aged population in Japan.

Aim: Peppermint oil solution was found to be effective for reducing gastric spasm during upper gastrointestinal endoscopy. The aim of the present study was to assess whether the gastric peristalsis-suppressing effect is dose-dependently induced by L-menthol, the major constituent of peppermint oil, and to determine the recommended dose of an L-menthol preparation. Methods: In this phase II, multicenter, double-blind, dose–response study, 131 eligible patients were randomly assigned to receive 20 mL of 0.4% L-menthol (n = 32), 0.8% L-menthol (n = 35), 1.6% L-menthol (n = 30), or placebo (n = 34). The primary efficacy measure was the proportion of subjects with no peristalsis in two time periods, 75 to 105 s after treatment and immediately before the completion of endoscopy. Results: The peristalsis-suppressing effect of L-menthol increased dose dependently (5.6%, 32.0%, 47.4% and 52.9% in the 0%, 0.4%, 0.8% and 1.6% groups, respectively: P

The results of a phase III, placebo-controlled study demonstrated that endoscopic direct spraying of L: -menthol onto the gastric mucosa effectively suppressed gastric peristalsis in the study patients. The aim of the study reported here was to determine whether the anti-peristaltic effect of an L: -menthol preparation facilitates endoscopic examinations in a clinical setting.This was a multicenter, open-label, single-arm trial in which the study cohort comprised patients in whom L: -menthol was likely to be used to facilitate endoscopic examination in clinical settings. The primary outcome was the proportion of subjects with no peristalsis (Grade 1) after treatment and at the end of endoscopy (defined as the complete suppression of gastric peristalsis). This variable was assessed according to the level of anti-Helicobacter pylori immunoglobulin G (IgG) antibody, pepsinogen test results, whether sedation was performed, and whether subjects were considered unsuitable for the use of conventional antispasmodics.Of the 119 enrolled subjects, data from 112 were included in the primary efficacy analysis. Gastric peristalsis was completely suppressed in 37.5% of the patients [42/112 patients; 95% confidence interval (CI) 28.5-47.1]. Subgroup analyses revealed that the rate of peristalsis suppression was significantly higher in patients with elevated levels of anti-H. pylori IgG antibody (26/44, 59.1%; 95% CI 43.2-73.7); P 0.001] and positive pepsinogen test results (21/35, 65.6%; 95% CI 46.8-81.4; P 0.001]. There was no significant difference according to sedation (17/52, 32.7%; 95% CI 20.3-47.1; P = 0.434) or whether subjects were considered unsuitable for use of conventional antispasmodic agents (14/28, 50.0%; 95% CI 30.6-69.4; P = 0.12].These findings are comparable to those of the phase III placebo-controlled study and provide further evidence that endoscopic direct spraying of L: -menthol effectively suppresses gastric peristalsis during upper gastrointestinal endoscopy.

GI peristalsis during GI endoscopy commonly requires intravenous or intramuscular injection of antispasmodic agents, which sometimes cause unexpected adverse reactions.Our ultimate goal was to evaluate whether the antiperistaltic effect of L-menthol-based preparations facilitates endoscopic examinations in a clinical setting.Multicenter, randomized, double-blind, placebo-controlled study.Six Japanese referral centers.A total of 87 patients scheduled to undergo upper GI endoscopy were randomly assigned to receive 160 mg of L-menthol (n=45) or placebo (n=42). Both treatments were sprayed endoscopically on the gastric mucosa. The degree of gastric peristalsis was assessed by an independent committee.The proportion of subjects with no peristalsis 90 to 135 seconds after administration and at the end of the endoscopic examination (complete suppression of gastric peristalsis). Other outcomes were the proportion of subjects with no or mild peristalsis (adequate suppression of gastric peristalsis) and the ease of intragastric observation as evaluated by the endoscopist who performed the procedure.Gastric peristalsis was completely suppressed in 35.6% (21.9, 51.2) of the L-menthol group compared with only 7.1% (1.5, 19.5) of the placebo group (P.001). In the L-menthol group, 77.8% (62.9, 88.8) (35/45 subjects) of the subjects had no or mild peristalsis at the completion of endoscopy. Minor peristalsis interfered with intragastric examination in only 1 of these 35 patients (2.9%). The incidence of adverse events did not differ significantly between the groups (P=.512).Small sample size.During upper GI endoscopy, L-menthol sprayed on the gastric mucosa significantly suppresses peristalsis with minimal adverse drug reactions compared with placebo. (NCT00742599.).

Background The main symptom of postoperative ileus (POI) is an intestinal motility disorder in which monocytes/macrophages and neutrophils play crucial roles. Prokinetic 5-hydroxytryptamine 4 receptor (5-HT 4 R) agonists and dopamine receptor antagonists are potential therapeutic agents for directly ameliorating the motility disorder associated with POI. Aim To determine the effects of the 5-HT 4 R agonists mosapride citrate (MOS) and CJ-033466 on intestinal smooth muscle contractility relative to immune reactions after POI. Methods Intestinal manipulation (IM) was applied to the rat distal ileum. Both MOS (0.3 and 1 mg/kg, s.c.) and CJ-033466 (1 mg/kg, s.c.) were administered to the animals before and after IM. At 24 h after IM, isolated intestinal smooth muscle contractile activity in vitro, gastrointestinal transit in vivo, inflammatory mediator expression and leucocyte infiltration were measured. Results After IM, ileal circular muscle contractility in vitro and gastrointestinal transit in vivo were reduced and the number of macrophages and neutrophils increased in the inflamed muscle layer, resulting in the induction of inflammatory mediators such as interleukin 1 β (IL-1β), IL-6, tumour necrosis factor α (TNFα), monocyte chemoattractant protein 1 (MCP-1) and inducible nitric oxide synthase (iNOS). Both MOS and CJ-033466 significantly attenuated not only the intestinal motility dysfunction but also the leucocyte infiltration and inflammatory mediator expression after IM. The autonomic ganglionic blocker hexamethonium (1 mg/kg, i.p.) and the α7-nicotinic acetylcholine receptor (α7nAChR) antagonist methyl lycaconitine citrate (0.087 mg/kg, i.p.) blocked MOS-mediated ameliorative actions. Immunohistochemically, α7nAChR is expressed by monocytes/macrophages but not by neutrophils in the inflamed intestine. Conclusion Stimulating the 5-HT 4 R accelerates acetyl choline (ACh) release from cholinergic myenteric neurons, which subsequently activates α7nAChR on activated monocytes/macrophages to inhibit their inflammatory reactions in the muscle layer. In addition to their gastroprokinetic action, 5-HT 4 R agonists might serve as novel therapeutic agents for POI characterised by anti-inflammatory potency.

The breast cancer susceptibility gene (BRCA2) is localized mainly in the nucleus where it plays an important role in DNA damage repair. Some BRCA2 protein is also present in the centrosome. Here, we demonstrate that BRCA2 interacts with plectin, a cytoskeletal cross-linker protein, and that this interaction controls the position of the centrosome. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin B (CDK1/CycB) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of HeLa cells by adding activated CDK1/CycB kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. Plectin has six homologous ankyrin-like repeat domains (termed PLEC M1-M6). Using a pull-down assay, we found that GST-PLEC M1 and a GST-C-terminal region fusion protein (which comprised PLEC M6, along with an adjacent vimentin site) interacted with BRCA2. Since each PLEC module exhibits high homology to the others, the possibility of all six domains participating in this interaction was indicated. Moreover, when PLEC M1 was overexpressed in HeLa cells, it competed with endogenous plectin and inhibited the BRCA2-plectin interaction. This inhibitory effect resulted in dissociation of the centrosomes from the nucleus and increased the rate of micronuclei formation which may lead to carcinogenesis. In addition, when either BRCA2 or plectin was suppressed by the appropriate siRNA, a similar change in centrosomal positioning was observed. We suggest that the BRCA2-plectin interaction plays an important role in the regulation of centrosome localization and also that displacement of the centrosome may result in genomic instability and cancer development.

International audience; Endothelial cell injury/dysfunction is considered to play a critical role in the pathogenesis of sever sepsis and septic shock. Although it is considered that endothelial cell apoptosis is involved in endothelial injury/dysfunction, physiological involvement remains ambiguous since the induction of apoptosis requires the inhibition of endogenous apoptosis inhibitors. Here we show that caspase-3 activation, a biological indicator of apoptosis, is observed in response to lipopolysaccharide (LPS) stimulation even under the influence of endogenous apoptosis inhibitors, and that activated caspase-3 is rapidly released from human umbilical vein endothelial cells (HUVEC). In the presence of cycloheximide (CHX), an increase in intracellular caspase-3/7 activity in response to LPS was not detected in HUVEC up to 24 hr following stimulation even in the presence of LPS-binding protein (LBP), soluble CD14 and soluble MD-2, whereas the decrease in cell viability and increase in release of the cellular enzyme lactate dehydrogenase (LDH) were observed in a soluble CD14/LBP-dependent manner. On the other hand, even in the absence of CHX, a significant increase in caspase-3/7 activity and a cleaved caspase-3 fragment with a slight increase in LDH release was observed in culture supernatants in response to LPS. This increase in caspase-3/7 activity was observed even when LDH release was undetected. These results indicate that caspase-3 is activated by LPS under physiological conditions and suggest that HUVEC escape from cell death by rapidly releasing activated caspase-3 into extracellular space. Failure of this escape mechanism may result in endothelial injury/dysfunction.

In an attempt to improve survival of patients with locally advanced esophageal cancer, chemoradiotherapy consisting of cisplatin, 5-fluorouracil (5-FU), and irradiation has recently been used. For such patients, concurrent chemoradiotherapy using docetaxel in combination with cisplatin and 5-FU has been introduced and is under evaluation. We herein report an esophageal cancer patient with concomitant distant lymph node metastasis in whom a complete response was achieved by chemoradiation therapy. A 46-year-old man was diagnosed as having stage IV A esophageal cancer with synchronous bulky metastasis in the celiac lymph node, and concurrent chemoradiotherapy was started. Chemotherapy consisting of docetaxel (30 mg/m2 on days 1, 8), cisplatin (60 mg/m2 on day 1), and 5-FU (200 mg/m2/day, continuous infusion on days 1–14) was performed for 2 cycles. At the same time, irradiation therapy (1.8 Gy/day on 1–5 days every week for 6 weeks) was employed for both local and metastatic lesions. Although the patient experienced severe hematological toxicity throughout the course, chemoradiotherapy resulted in complete regression of both local and metastatic disease. Subsequently, he was followed as an outpatient without any maintenance therapy, and he has been free of disease for 38 months after completion of the combination therapy. Thus, concurrent chemoradiotherapy may be effective for esophageal cancer, even with visceral metastasis.

Spasmolytic polypeptide (SP/TFF2)-expressing metaplasia (SPEM) is induced by oxyntic atrophy and is known as a precancerous or paracancerous lesion. We seek to determine whether the gastrin receptor or H(2) histamine receptor influence the development of SPEM. DMP-777 was administered to gastrin receptor and/or H(2) receptor-deficient mice and wild-type mice. Gastric mucosal lineage changes were analyzed. The mucosa from double knockout mice and H(2) receptor knockout mice contained elevated numbers of dual TFF2 and intrinsic factor immunoreactive cells even before DMP-777 treatment. All genotypes of mice showed SPEM after 7-day treatment. In all types of knockout mice, the number of TFF2 immunoreactive cells remained elevated after cessation of treatment. The H(2) receptor and gastrin receptor do not affect emergence of SPEM. However, it is suggested that the absence of H(2) receptor signaling causes a delay in the maturation of chief cells from mucous neck cells.

Gypican-3 (GPC3) has been recognized as an oncofetal protein in hepatic neoplasms and yolk sac tumors. To characterize a distinct subgroup of gastric carcinoma (GC) expressing GPC3 (GPC3-GC), primary and metastatic GC tissues were evaluated by immunohistochemistry with special focus on their related entities: hepatoid, clear-cell, and alpha-fetoprotein-producing GC. GPC3-GC was defined as focal GPC3-GC when 10-49% of neoplastic cells were positive, and as diffuse GPC3-GC when more than 50% of cells were positive. Among 926 GC cases, 101 (11%) were GPC3-GC, of which 45 were diffuse and 56 were focal GPC3-GC. Specific histological patterns, such as the hepatoid and clear-cell patterns, were frequently observed in diffuse GPC3-GC (38 and 49%, respectively) and in focal GPC3-GC (4 and 25%, respectively), whereas these patterns were extremely rare in GPC3-negative GC. Immunoreactive alpha-fetoprotein was only identified in GPC3-GC (38% of diffuse and 14% of focal GPC3-GC). Both diffuse and focal GPC3-GC showed nodal metastasis more frequently (67 and 55%, respectively) than GPC3-negative GC (34%), and the diffuse GPC3-GC had significantly more T2-4 and M1 stage cases. GPC3 immunostaining was present in 57 out of 61 nodal metastases (93%) and in all four liver metastases examined. Importantly, diffuse GPC3 expression was observed in the liver metastasis, even if the primary tumor was focal GPC3-GC. GPC3-GC is a distinctive group of GC, which unifies hepatoid, clear-cell, and alpha-fetoprotein-producing GC. GPC3 is expected to be a target of forthcoming immunotherapy for a patient bearing this specific type of GC.

The presence of frequent methylation of CpG islands (CGIs), designated as the CpG island methylator phenotype in some cancers, is associated with distinct clinicopathological characteristics, including gene amplification, in individual tumor types. Amplification of HER2 in human breast cancers is an important prognostic and therapeutic target, but an association between HER2 amplification and frequent CGI methylation is unknown. To clarify the association, we here quantified methylation levels of promoter CGIs of 11 genes, which are unlikely to confer growth advantage to cells, in 63 human breast cancers. The number of methylated genes in a cancer did not obey a bimodal distribution, and the 63 cancers were classified into those with frequent methylation (n = 16), moderate methylation (n = 26) and no methylation (n = 21). The incidence of HER2 amplification was significantly higher in the cancers with frequent methylation (11 of 16) than in those with no methylation (2 of 21, P = 0.001). Also, the number of methylated genes correlated with the degree of HER2 amplification (r = 0.411, P = 0.002). Correlation analysis with clinicopathological characteristics and methylation of CDKN2A, BRCA1 and CDH1 revealed that frequent methylation had significant correlation with higher nuclear grades (P = 0.001). These showed that frequent methylation had a strong association with HER2 amplification in breast cancers and suggested that frequent methylation can be a determinant of various characteristics in a fraction of human breast cancers.

毛髪胃石により十二指腸閉塞を来したまれな1例を報告する．症例は11歳の女児で，7歳頃から食毛癖があり適応障害・アセトン血性嘔吐症と診断されていた．今回は繰り返す嘔吐と腹痛のため来院した．左上腹部に硬い腫瘤を触知し，白血球，肝胆道系酵素，膵酵素の上昇を認めた．腹部造影CTでは，ガスを含む網目状の巨大な構造物が胃を充満し，十二指腸水平脚にも同様の構造物を認めた．毛髪胃石による十二指腸閉塞と診断し，緊急開腹術にて鋳型状の毛髪胃石と十二指腸水平脚の毛髪結石を一塊にして摘出した．本例は毛髪胃石の一部が尾のように連なり先進部が十二指腸にまで至ったことで，腹痛・嘔吐・腸閉塞症状・胆道系酵素上昇・膵酵素上昇などの症状を呈したと考えられた．診断には食毛癖の把握と特徴的なCT所見が有用であった．

This retrospective study was conducted to compare the treatment results between radical surgery and definitive chemoradiotherapy for resectable squamous cell carcinoma of the esophagus. Between June 2000 and May 2005, 82 consecutive patients were selected for this study in which 33 were treated with chemoradiotherapy and 49 with surgery. The patients in the chemoradiotherapy (CRT) group received 2-4 cycles of 5-fluorouracil (1000 mg/m(2)/day, day 1-4, continuous) combined with cisplatin (75 mg/m(2), day 1, bolus) plus 50.4 Gy of radiation, while those in the surgery group were treated by an esophagectomy with radical node dissection. Eighteen surgical patients received postoperative chemotherapy. The baseline clinical TNM stage was similar between the two groups. With a median follow-up period of 36 months (range: 23-84 months) with 47 survivors (57%), the 3-year overall survival rates (P = 0.22) and disease-free survival rates (P = 0.16) were 48% and 44% in the chemoradiotherapy group versus 65% and 59% in the surgery group, and lacked statistical significance. This non-randomized study on patients with resectable squamous cell carcinoma of the esophagus showed that chemoradiotherapy could result in survival comparable with conventional surgery in spite of selection bias of patients. There is a trend toward improved survival with surgery versus definitive CRT.

Background Endoscopic submucosal dissection is a novel endoluminal technique that enables resection of early stage gastrointestinal malignancies in an en bloc fashion. Aim To assess whether preceding endoscopic submucosal dissection affected the prognoses of patients who underwent additional gastrectomy with lymph node dissection due to suspicion of nodal metastasis from endoscopic submucosal dissection specimens. Patients and methods Thirty-one patients with early gastric cancer who underwent gastrectomy after endoscopic submucosal dissection were retrospectively investigated in terms of their survival and tumour recurrence. Additional gastrectomy was performed when histology of the endoscopic submucosal dissection specimens revealed that the tumours did not meet the criteria for node-negative cancers. Results Twenty-three (74%) and eight (26%) patients had undergone endoscopic submucosal dissection previously due to clinical diagnoses of node-negative cancers and possible node-positive cancers, respectively. Histology of the resected stomachs and lymph nodes revealed residual carcinoma of the stomach in two (6.5%) patients and nodal metastases in four (13%) patients. All patients remain alive without recurrence (median follow-up, 3.4 years; range, 0.6–5.2 years). Conclusions Based on the histology of endoscopic submucosal dissection specimens, preceding endoscopic submucosal dissection itself had no negative influence on a patient's prognosis when additional gastrectomy was performed. It may be permissible to resect some early gastric cancers by endoscopic submucosal dissection as a first step to prevent unnecessary gastrectomy, if technically resectable.

症例は63歳の男性で, 2002年7月にMtUtLt T3-4, N2, cStageIIIの高分化型扁平上皮癌 (以下, SCC) を指摘された. 気管支浸潤も疑われ, 根治的放射線化学療法を施行された. 2002年12月, 腫瘍はCR, リンパ節はPRの評価であった. 2003年9月, 門歯より40～45cmに全周性の粘膜不整像, ルゴール不染があり, 食道癌と診断された. 別照射野にて再度放射線化学療法50Gyを施行されたがNCであり, 2004年に内視鏡的粘膜下層切除術を追加施行された.m1, ly0, v0のSCCであった. さらに, 2004年8月, 下咽頭癌 (SCC, T1 N0 M0) の診断にて下咽頭部分切除術を施行された. 2006年1月, 胃噴門部に径2cmの粘膜下腫瘍様隆起が出現した. 超音波内視鏡下針生検にてSCCと診断され2006年4月噴門側胃切除術を施行した. 病理組織学的検査所見は中分化型SCCであり高度の静脈侵襲を伴い, 最初に診断された食道癌の血行性転移の可能性が示唆された.

近年, 虚血性心疾患に対して行われる冠動脈ステント治療において免疫抑制剤や抗癌剤を表面に塗布し徐放化させる薬剤溶出性ステント (drug-eluting coronary stent; 以下, DES) が多用されている. DESは従来の金属露出型ステントより再狭窄率が低いという重要な長所を持つが, 留置後1か月以降に遅発性血栓症が起こるリスクを有しており, 使用患者はアスピリンの終生投与およびチクロピジンの最低3か月以上の投与が必須とされている. DES留置後に消化器癌が指摘されると, 出血リスクを避けるために周術期に抗血小板薬の休止が必要となるが, ヘパリン点滴持続静脈投与への変更などによる抗凝固療法による代替の安全性に関するエビデンスは乏しい. 我々はDES留置後に胃癌が発見された3症例を経験したため文献的考察を含めて検討し, 指針を考案した.

To detect early esophageal cancer effectively, it is important to select high-risk groups. Because we often see early esophageal cancer after gastrectomy for gastric cancer, we investigated 11 early esophageal cancers treated endoscopically in 7 patients who had undergone gastrectomy for gastric cancer. Their average age was 70.8 ± 5.2 years. Median interval between previous gastrectomy and the diagnosis of esophageal cancer was 10 years. Endoscopic examination revealed mild bile reflux into the remnant stomach and esophagitis, but there was no case of Barrett's esophagus. Histological types were all squamous cell carcinoma. Although it has been reported that cancer development is most frequent in the lower esophagus after gastrectomy, we noticed that the majority of these were located in the middle thoracic esophagus (6/11, 55%), similar to general esophageal cancer. As all cases were detected by a regular checkup, it is important to follow up patients after gastrectomy for gastric cancer.

An endo-cytoscopy system allows acquisition of optical biopsies that are quite similar to conventional histology. To simplify discrimination between normal and malignant tissue in the oesophagus using endo-cytoscopy system, we analysed the nuclear (dark staining) area in the obtained images with the goal of an accurate, automatic diagnosis.Ex vivo endo-cytoscopic observation was performed using endoscopically or surgically resected oesophagus from 10 enrolled patients. Oesophageal tissues were stained using 1% methylene blue, and endo-cytoscopic images were obtained at normal and malignant areas (two areas of each) in each oesophagus. The centre of each image (4x10(-2) mm(2)) was processed by computer, and the area occupied by the total nuclei in each selected field and its ratio to the entire field were calculated.The mean area of the total nuclei was 0.10x10(-2)+/-0.03x10(-2) mm(2) (range 0.05x10(-2) to 0.18x10(-2) mm(2)) in the normal group and 0.40x10(-2)+/-0.06x10(-2) mm(2) (range 0.33x10(-2) to 0.55x10(-2) mm(2)) in the malignant group (P0.001). The mean ratio of total nuclei to the entire selected field was 6.4+/-1.9% (range 3.1-11.3%) in the normal tissues and 25.3+/-3.8% (range 20.5-34.5%) in the malignant samples (P0.001).Endo-cytoscopy system allowed automatic differentiation of normal and malignant tissues in the oesophagus, which could simplify endo-cytoscopic diagnosis. Further study will elucidate whether such analysis is applicable to inflammatory or pre-malignant epithelia in the oesophagus or other gastrointestinal organs.

Transforming growth factor (TGF)-beta plays a pivotal role in regulation of progression of cancer through effects on tumor microenvironment as well as on cancer cells. TGF-beta inhibitors have recently been shown to prevent the growth and metastasis of certain cancers. However, there may be adverse effects caused by TGF-beta signaling inhibition, including the induction of cancers by the repression of TGF-beta-mediated growth inhibition. Here, we present an application of a short-acting, small-molecule TGF-beta type I receptor (TbetaR-I) inhibitor at a low dose in treating several experimental intractable solid tumors, including pancreatic adenocarcinoma and diffuse-type gastric cancer, characterized by hypovascularity and thick fibrosis in tumor microenvironments. Low-dose TbetaR-I inhibitor altered neither TGF-beta signaling in cancer cells nor the amount of fibrotic components. However, it decreased pericyte coverage of the endothelium without reducing endothelial area specifically in tumor neovasculature and promoted accumulation of macromolecules, including anticancer nanocarriers, in the tumors. Compared with the absence of TbetaR-I inhibitor, anticancer nanocarriers exhibited potent growth-inhibitory effects on these cancers in the presence of TbetaR-I inhibitor. The use of TbetaR-I inhibitor combined with nanocarriers may thus be of significant clinical and practical importance in treating intractable solid cancers.