An effective training system for endoscopic submucosal dissection of gastric neoplasm.

BACKGROUND AND STUDY AIMS: A standard training system for endoscopic submucosal dissection (ESD) remains to be established. In this study, we evaluated the validity of our training program for gastric ESD. PATIENTS AND METHODS: Four trainees performed gastric ESD for a total of 117 lesions in 107 patients (27 to 30 consecutive lesions per trainee) at a tertiary referral center during 2 years in the training program. Trainees, who already had the fundamental skills and knowledge needed for ESD, each assisted at 40 gastric ESD procedures, then in 20 cases applied post-ESD coagulation (PEC) to gastric mucosal defects; they then began to perform ESD, starting with gastric antral lesions. Treatment outcomes, including mean procedure time, and rates of en bloc resection, en bloc plus R0 resections, complications, and self-completion, were evaluated, for the initial 15 and subsequent 12 to 15 cases. RESULTS: Overall rates of en bloc resection and en bloc plus R0 resection were as high as 100 % and 96.6 %, respectively. Regarding complications, seven cases of delayed hemorrhage (6.0 %) and three cases of perforation (2.6 %) occurred; all complications were solved endoscopically. The most frequent reason for operator change was lack of submucosal dissection skill. The self-completion rate was more than 80 % even in the early period, and did not increase for later cases. CONCLUSIONS: Our training system enabled novice operators to perform gastric ESD without a decline in clinical outcomes. Key features of this training are prior intensive learning and actual ESD during the learning period under expert supervision.

Long-term outcomes of endoscopic submucosal dissection for colorectal epithelial neoplasms.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) provides a high en bloc resection rate with less invasiveness than surgical resection for large or scarring gastrointestinal neoplasms. However, detailed outcomes in colorectal ESD are still lacking. The aim of our study was to elucidate short- and long-term outcomes of colorectal ESD. PATIENTS AND METHODS: 310 consecutive colorectal epithelial neoplasms (146 adenomas, 164 carcinomas), in 290 patients, which fulfilled our indication criteria and were treated with ESD between July 2000 and December 2008 were studied. ESD was done by three skilled endoscopists. As short-term outcomes, rates of en bloc resection, en bloc plus R0 resection, and major complications were analyzed. As long-term outcomes, disease-free and overall survival were assessed in 224 patients. RESULTS: Rates of en bloc resection and en bloc plus R0 resection were 90.3 % and 74.5 %, respectively. Eight patients underwent additional colectomy due to histopathologically proven possible node-positive cancer. Intraoperative perforations occurred with 14 lesions (4.5 %), which were treated successfully only by endoscopic clipping. Emergent surgery was needed for one case of postoperative perforation. Blood transfusion due to intraoperative massive bleeding was required in 1 case (0.3 %). Postoperative bleeding occurred with four lesions (1.3 %), and was endoscopically managed without blood transfusion. Local recurrence was detected in 4 lesions (4/202 patients, 2.0 %); resection had been piecemeal in all 4. During a median follow-up of 38.7 months (range 12.8 - 104.2), the 3- and 5-year overall/disease-specific survivals were 97.1/100 % and 95.3/100 %, respectively. CONCLUSIONS: Colorectal ESD showed favorable long-term outcomes. It may largely replace colectomy for node-negative colorectal epithelial neoplasia.

Predictors of postoperative stricture after esophageal endoscopic submucosal dissection for superficial squamous cell neoplasms.

BACKGROUND AND STUDY AIMS: Although endoscopic submucosal dissection (ESD) is becoming accepted as an established treatment for superficial esophageal squamous cell neoplasms, the risks for developing postoperative stricture have not been elucidated. PATIENTS AND METHODS: This was a retrospective study at a single institution. From January 2002 to October 2008, 65 patients with high-grade intraepithelial neoplasms (HGINs) or m2 carcinomas treated by ESD were enrolled. Predictors of postoperative stricture were investigated by comparing results from 11 patients who developed strictures with those from 54 patients who did not. RESULTS: Significant differences between the two groups were observed in longitudinal diameter (45.0 +/- 15.9 mm vs. 31.5 +/- 13.6 mm) and circumferential diameter (37.2 +/- 8.6 mm vs. 26.8 +/- 9.7 mm) of the resected specimens, and the proportion of extension to the whole circumference of the lumen (< 1 / 2/ > 1 / 2/ > 3 / 4 : 2 / 4 / 5 vs. 40 / 13 / 1), histologic depth (HGIN/m2 : 2 / 9 vs. 41 / 13), and procedure time (85.6 +/- 42.8 minutes vs. 53.3 +/- 30.1 minutes). Multivariate analysis revealed that circumferential extension of > 3 / 4 (odds ration [OR]: 44.2; 95 % confidence interval [CI]: 4.4 - 443.6) and histologic depth to m2 (OR: 14.2; 95 %CI: 2.7 - 74.2) are reliable risk factors. Subanalysis for each category by combinations of these risk factors revealed that patients with lesions in > 3 / 4 of the circumferential area were associated with a high rate of postoperative stricture. By contrast, patients with HGIN lesions in < 3 / 4 extension have no probability of postoperative strictures. Additionally, subanalysis of patients with m2 lesions in < 3 / 4 circumferential extension revealed that circumferential diameter can be a reliable predictor for postoperative stricture. CONCLUSIONS: Circumferential extension and histologic depth are the reliable risk factors for postoperative strictures. In combination with circumferential diameter, we can perform effective and appropriate preventive balloon dilatations after esophageal ESD.

Technical feasibility of endoscopic submucosal dissection for early gastric cancer in patients taking anti-coagulants or anti-platelet agents.

BACKGROUND: Endoscopic submucosal dissection is a novel technique that is expected to be a curative treatment for early gastric cancers. Anti-coagulants and anti-platelet agents are widely used, especially in elderly patients, to prevent thromboembolic disease. However, the feasibility of endoscopic submucosal dissection for such patients has not been investigated. AIMS: To determine the feasibility of endoscopic submucosal dissection for patients using anti-coagulant and anti-platelet agents via retrospective investigation of clinical outcomes. METHODS: Of 408 patients with 444 early gastric cancers consecutively treated by endoscopic submucosal dissection from January 2000 to December 2007 in our hospital, 47 patients with 56 early gastric cancers were receiving anti-coagulants or anti-platelet agents. All patients were classified into groups for high and low risk of thromboembolism. In 44 low-risk patients, these agents were stopped for 1 week before and after treatment. Only three high-risk patients underwent intravenous heparin replacement during the cessation period. RESULTS: Comparison with other patients showed no significant differences in complete en-bloc resection (96.4%) or perforation (1.8%). Postoperative bleeding requiring endoscopic treatment occurred for six early gastric cancers (10.7%) in the anti-coagulant and anti-platelet group; this frequency was slightly higher than that observed for other patients (5.2%). The healing of endoscopic submucosal dissection ulcers was not delayed by anti-coagulant and anti-platelet treatment (91% in the scarring stage) when checked at the 8th week after endoscopic submucosal dissection. CONCLUSION: The clinical outcomes of endoscopic submucosal dissection for early gastric cancers in patients receiving anti-coagulants or anti-platelet agents indicated that endoscopic submucosal dissection for low-risk patients could be a reliable technique with equivalent efficacy and risk in comparison with that for other early gastric cancer patients.

Successful nonsurgical management of perforation complicating endoscopic submucosal dissection of gastrointestinal epithelial neoplasms.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is a novel technique used for the treatment of gastrointestinal neoplasia. One of its major limitations, however, is the complication of perforation. PATIENTS AND METHODS: We included in our study all the cases of perforation that occurred during ESD procedures for gastrointestinal epithelial neoplasia between February 2000 and February 2005. Clinical outcomes after perforation were investigated. RESULTS: Perforation was experienced at 27 lesions in 27 patients (four in the esophagus, fourteen in the stomach, seven in the colon, and two in the rectum). Fibrosis under the lesions was confirmed histologically in seven patients (26 %). Immediate closure using endoclips was performed in all patients except for three asymptomatic patients in whom a stomach perforation was first noticed when free air was noticed on a radiograph the morning after the ESD procedure. Air accumulation was detected radiographically in 21 patients (78 %). The mean duration of antibiotic treatment was 6.7 days and the patients were fasted for a mean period of 5.3 days. The mean maximum body temperature was 37.3 degrees C, the mean white blood cell count was 9733/mm3, and the mean C-reactive protein level was 5.0 mg/dl. All the patients were discharged well from the ward after a mean time of 12.1 days after ESD, and no recurrence caused by tumor spread from the perforation occurred in any patient after a median follow-up period of 36 months (range 9 - 52 months). CONCLUSION: Successful nonsurgical management after ESD complicated by perforation is a highly feasible option if intensive conservative treatments are used following immediate endoscopic closure of the perforation.

Correlation of serum pepsinogens and gross appearances combined with histology in early gastric cancer.

The correlation between serum pepsinogen (PG) levels and the gross types was investigated in 128 consecutive patients with early gastric cancer. Although there was no significant difference in age, gender, cancer location, or cancer depth among gross appearances, the distribution of histological type was significantly different between polypoid and depressed cancers: all polypoid cancers except one were intestinal type, whereas nearly a third of depressed cancers were diffuse type. All the patients in whom Helicobacter pylori status was investigated had Helicobacterpylori infection. Combination of gross appearances and histology (polypoid cancer with intestinal type, depressed cancer with intestinal type and depressed cancer with diffuse type) showed a clear difference in distribution of serum PG levels and a ratio between levels of PG I and PG II (I/II ratio). In polypoid cancer with intestinal type, a PG I level and a I/II ratio were significantly lower than those of the others. In depressed cancer with diffuse type, PG I and PG II levels were significantly higher. These findings revealed that backgrounds such as intragastric acidity and extent of gastric atrophy might differ among early gastric cancers with different morphology and histology.

Endoscopic submucosal dissection for rectal epithelial neoplasia.

BACKGROUND AND STUDY AIMS: The technique of endoscopic submucosal dissection (ESD) has recently been developed for en-bloc resection of gastric tumors. For oncological reasons and in order to improve the patients' quality of life, it may be desirable to use the same technique for rectal neoplasia. PATIENTS AND METHODS: Thirty-five consecutive patients with rectal neoplasia who had a preoperative diagnosis of large intraepithelial neoplasias with submucosal fibrosis or located on the rectal folds were enrolled. ESD was carried out with the same technique previously described for the stomach, with some modifications. The efficacy, complications, and follow-up results of the treatment were assessed. RESULTS: The rates of en-bloc resection and en-bloc plus R0 resection were 88.6 % (31 of 35) and 62.9 % (22 of 35), respectively. Hemoglobin levels did not drop by more than 2 g/dl in any of the patients after ESD. None of the patients had to receive blood transfusions or undergo emergency colonoscopy due to bleeding during ESD or hematochezia after ESD. Perforation during ESD occurred in two patients (5.7 %), who were managed with conservative medical treatment after endoscopic closure of the perforation. Excluding three patients in whom additional surgery was carried out, all but one of 32 patients were free of recurrence during a mean follow-up period of 36 months (range 12 - 60 months). The exception was a patient in whom a multiple-piece resection was required; the recurrent (residual) tumor, found 2 months after ESD, was a small adenoma that was again treated endoscopically. CONCLUSIONS: ESD is applicable in the rectum with promising results, but the technique is still at a developmental stage and patients should be informed of the potential risks.

SWI/SNF complex is essential for NRSF-mediated suppression of neuronal genes in human nonsmall cell lung carcinoma cell lines.

Mammalian chromatin remodeling factor, SWI/SNF complex contains a single molecule of either Brm or BRG1 as the ATPase catalytic subunit. Here, we show that the SWI/SNF complex forms a larger complex with neuron-restrictive silencer factor (NRSF) and its corepressors, mSin3A and CoREST, in human nonsmall cell lung carcinoma cell lines. We also demonstrate that the strong transcriptional suppression of such neuron-specific genes as synaptophysin and SCG10 by NRSF in these non-neural cells requires the functional SWI/SNF complex; these neuronal genes were elevated in cell lines deficient in both Brm and BRG1, whereas retrovirus vectors expressing siRNAs targeting integral components of SWI/SNF complex (Brm/BRG1 or Ini1) induced expression of these neuronal genes in SWI/SNF-competent cell lines. In cell lines deficient in both Brm and BRG1, exogenous Brm or BRG1 suppressed expression of these neuronal genes in an ATP-dependent manner and induced efficient and specific deacetylation of histone H4 around the NRSF binding site present in the synaptophysin gene by a large complex containing the recruited functional SWI/SNF complex. Patients with Brm/BRG1-deficient lung carcinoma have been reported to carry poor prognosis; derepression of NRSF-regulated genes including these neuron-specific genes could contribute to enhance tumorigenicity and also would provide selective markers for Brm/BRG1-deficient tumors.

Kinetics of v-src-induced epithelial-mesenchymal transition in developing glandular stomach.

The oncogene function in primary epithelial cells is largely unclear. Recombination organ cultures in combination with the stable and transient gene transfer techniques by retrovirus and electroporation, respectively, enable us to transfer oncogenes specifically into primary epithelial cells of the developing avian glandular stomach (proventriculus). In this system, the epithelium and mesenchyme are mutually dependent on each other for their growth and differentiation. We report here that either stable or transient expression of v-src in the epithelium causes budding and migration of epithelial cells into mesenchyme. In response to the transient expression of v-Src or a constitutive active mutant of MEK, we observed immediate downregulation of the Sonic hedgehog gene and subsequent elimination of E-cadherine expression in migrating cells, suggesting the involvement of MAP kinase signaling pathway in these processes. v-src-expressing cells that were retained in the epithelium underwent apoptosis (anoikis) and detached from the culture. Continuous expression of v-src by, for example, Rous sarcoma virus (RSV) was required for the epithelial cells to acquire the ability to express type I collagen and fibronectin genes (mesenchymal markers), and finally to establish the epithelial-mesenchymal transition. These observations would partly explain why RSV does not apparently cause carcinoma formation, but induces sarcomas exclusively.

Identification of SWI.SNF complex subunit BAF60a as a determinant of the transactivation potential of Fos/Jun dimers.

Fos family proteins form stable heterodimers with Jun family proteins, and each heterodimer shows distinctive transactivating potential for regulating cellular growth, differentiation, and development via AP-1 binding sites. However, the molecular mechanism underlying dimer specificity and the molecules that facilitate transactivation remain undefined. Here, we show that BAF60a, a subunit of the SWI.SNF chromatin remodeling complex, is a determinant of the transactivation potential of Fos/Jun dimers. BAF60a binds to a specific subset of Fos/Jun heterodimers using two different interfaces for c-Fos and c-Jun, respectively. Only when the functional SWI.SNF complex is present, can c-Fos/c-Jun (high affinity to BAF60a) but not Fra-2/JunD (no affinity to BAF60a) induce the endogenous AP-1-regulated genes such as collagenase and c-met. These results indicate that a specific subset of Fos/Jun dimers recruits SWI.SNF complex via BAF60a to initiate transcription.

Frequent expression of mucin core protein MUC1 in non-neoplastic gallbladder mucosa from patients with pancreaticobiliary maljunction.

BACKGROUND: Gallbladder carcinoma is known to develop frequently in patients with pancreaticobiliary maljunction, though the causal relationship remains speculative. METHODS: Histopathologic changes, expression of mucin core protein MUC1 and MUC2, and cell proliferative activities in the gallbladder mucosa from 27 patients with panceaticobiliary maljunction and 21 control gallbladders were examined. Three cases of pancreaticobiliary maljunction were associated with gallbladder carcinoma. RESULTS: The lining epithelia of the non-neoplastic gallbladder mucosa of pancreaticobiliary maljunction showed frequently papillary hyperplasia and higher proliferative activities, when compared to the control. In 3 cases with carcinoma, MUC1 was expressed on the luminal border and in the cytoplasm of carcinoma cells, particularly in de-differentiated and invasive areas. MUC1 was variably expressed on the luminal surface of the lining epithelia of non-neoplastic gallbladder mucosa in babies, children, youths and adults with pancreaticobiliary maljunction. However, such expression was focally seen in 2 of the 21 control cases (p<0.01). MUC2 was scattered in the hyperplastic and carcinomatous epithelial cells appearing as goblet cells in pancreaticobiliary maljunction and control groups. CONCLUSIONS: This study suggests that persistent MUC1 expression and increased cell proliferative activities of non-neoplastic gallbladder epithelium of the patients with pancreaticobiliary maljunction after birth reflect an altered phenotype of epithelial cells and these abnormalities may be related to carcinogenesis in such patients.

Ectopic Breast Caner: Two Case Reports and Review of the Japanese Literature.

Two cases of carcinoma involving ectopic breast tissue are reported, along with a review of the Japanese literature. A total of 65 cases of ectopic breast cancer have been reported; 59 of which occurred in the axilla. Total mastectomy with axillary dissection was performed in 29 cases, and tumor excision with or without nodal dissection was done in 30 cases. Outcome was known in 33 cases, and 5 cases had recurred at the time of this writing. Although the prognosis of ectopic breast cancer was difficult to establish with the limited follow-up data, all the 5 cases in our series with recurrence had axillary lymph node metastases at the time of surgery. Therefore, the complete excision of ectopic breast tissue with nodal dissection, and subsequent chemoendocrine therapy, especially in node-positive patients, is recommended as the treatment of choice.

Characteristics of Epstein-Barr virus-associated gastric carcinoma with lymphoid stroma in Japan.

BACKGROUND: Gastric carcinoma with lymphoid stroma (GCLS), known to have a more favorable prognosis than ordinary gastric carcinoma, has been suggested to be closely associated with the Epstein-Barr virus (EBV). However, there are many clinicopathologic problems that remain unsolved. METHODS: In 21 patients, 26 GCLS lesions and 4 non-GCLS intramucosal adenocarcinomas that developed synchronously or metachronously with GCLS were examined for EBV involvement by in situ hybridization (ISH) and were analyzed clinicopathologically. In addition, nine patients who had advanced gastric carcinoma with massive liver metastases, who showed good response to chemotherapy and had prolonged survival, were examined for the presence or absence of EBV-associated GCLS. RESULTS: On ISH with EBV-encoded small RNAs, diffuse hybridization signals were noted in 22 (84.6%) of 26 GCLS. Hybridization signals were also noted in all four non-GCLS adenocarcinomas accompanying GCLS. As a result, hybridization signals were noted in nine of ten cancerous lesions in four cases of synchronous multiple cancers and in all five cancerous lesions in two cases of metachronous multiple cancers. Long term survivors with liver metastases included two patients with EBV-associated GCLS. CONCLUSION: Approximately 84.6% of GCLS were related to EBV. EBV-associated GCLS constitutes one-half of the EBV-infected stomach cancers in our institution. The complete response and long term survival after conventional chemotherapy of two patients with Stage IV GCLS suggests that this form of gastric carcinoma may be especially sensitive to this treatment. The identification of EBV-associated synchronous multicentric cancers of both GCLS and non-GCLS type suggests that EBV infection may be an early event in the induction process of these tumors.

Alpha-fetoprotein-producing gastric carcinoma with enteroblastic differentiation.

BACKGROUND: Alpha-fetoprotein (AFP) is a useful tumor marker for hepatoma and yolk sac tumor. Recently, elevations of serum AFP were reported in patients with other malignancies, especially gastric cancers. Two distinct tumor morphologies, hepatoid and clear cell, have been correlated with AFP production. METHODS: Two patients with AFP-producing gastric carcinoma were evaluated with immunohistochemical, ultrastructural, and biochemical studies. RESULTS: In Patient 1, the primary and metastatic carcinomas consisted homogeneously of tubulopapillary carcinoma with clear cytoplasm. In Patient 2, the cancer was composed of three different areas: tubulopapillary carcinoma with clear cytoplasm, tumor cartilage, and so-called hepatoid carcinoma. The morphologic characteristics of tubulopapillary carcinoma with clear cytoplasm were similar to those of the developing gut epithelium at the stage of 2-4 months' gestation. The elution patterns of the serum AFP on lectin-affinity sepharose column study also suggested a correlation with fetal gut differentiation. CONCLUSIONS: AFP-producing clear cell gastric carcinomas are differentiated into fetal intestine. One patient also had hepatocytic and cartilaginous differentiation, indicative of a blastomatous characteristic of the tumor. These tumors arose in association with intestinal metaplasia.

Morphological study of cholesterol hepatolithiasis. Report of three cases.

Three cases of pure cholesterol intrahepatic stones are compared morphologically to those of calcium bilirubinate stones. Cholesterol stones were found in the intrahepatic bile duct of the left lateral lobe in two cases and in both the left lateral and the right posterior lobe in one. Although the chronic inflammatory reaction and fibrous thickening of bile duct wall were similar in both types of hepatolithiasis, the proliferation of intrahepatic periductal glands and the production of mucin were rather mild, compared to that is the liner containing calcium bilirubinate stones. Multiple intramural cholesterol calculi and cholesterin granulomas (cholesterin crystals surrounded by foreign-body giant cells) were found within the cystically dilated small bile duct branches and/or conduits of periductal glands. The calculi and granulomas were characteristic for cholesterol hepatolithiasis. These findings suggest that the formation of the cholesterol stones differs from that of calcium bilirubinate stones; the perturbation of factors influencing cholesterol nucleation in the hepatic bile may be related to the changed microenvironment of the intrahepatic bile ducts, which is followed by the formation of cholesterol stones.

Desmoplastic fibroma of the temporal bone.

A desmoplastic fibroma is a rare entity in the temporal bone. An 86-year-old woman was seen for evaluation of ear discharge and stenosis of the ear canal with a mass involving the post-auricular region. The tumor was found to be a desmoplastic fibroma. The clinical picture, pathology, diagnosis and prognosis of the tumor are discussed.

[A case of Borrmann type 4 gastric carcinoma which disappeared by intraaortic infusion chemotherapy with ADM and MMC].

A 64-year-old woman with Borrmann type 4 gastric cancer was treated by intraaortic (celiac artery) one-shot infusion chemotherapy with adriamycin (ADM) and mitomycin C (MMC). One month after the first administration of 30 mg ADM and 20 mg MMC, the second administration of 50 mg ADM and 20 mg MMC was done. The third administration of 50 mg ADM and 20 mg MMC was performed one month after the second administration. Clinical symptoms of back pain, lumbago and anorexia had almost disappeared soon after the third administration. Although the findings of the X-ray examination of stomach, gastroscopy and celiac angiography showed marked improvement, total gastrectomy with lymphadenectomy was performed 2 months after the third administration because residual cancer cell nests were highly suspect. Histological examination of the resected stomach and lymphnodes revealed no cancer cells. The patient has been in good health without any recurrent signs for 16 months after operation.

Solid, infiltrating variety of papillary cystic neoplasm of the pancreas.

Four tumors with histologic, histochemical, and ultrastructural characteristics of papillary cystic neoplasm of the pancreas but lacking the capsule commonly observed in papillary cystic neoplasm and infiltrating interiorly into the pancreatic parenchyma were seen in two men and two women who were 39 to 51 years old. These tumors contrasted with typical encapsulated papillary cystic neoplasms that show extrapancreatic growth and that are detected as a palpable abdominal mass in young women. These four tumors, although unpalpable, were all detected by nodular images of calcification in abdominal plain radiography. The tumors had a mean diameter of 3.1 cm (range, 1.7 to 4.5 cm), were confined within the pancreatic parenchyma, and showed central fibrosis accompanied by dystrophic changes such as calcification and ossification. A small necrotic cyst contiguous to the fibrous focus also was observed in the tumor in three patients. Tumor cells similar to those of a papillary cystic neoplasm had infiltrated among the pancreatic parenchyma in solid and pseudopapillary patterns, and pleomorphic atypism was observed in some parts of the tumor in three patients. These tumors were tentatively designated solid, infiltrating variety of papillary cystic neoplasms to differentiate them from ordinary encapsulated papillary cystic neoplasms. Although no signs of recurrence have been noticed after surgical treatment in these patients, the infiltrating growth pattern and the presence of pleomorphic atypism suggest higher malignancy than the ordinary papillary cystic neoplasm. The contrasting growth pattern and possible malignancy may warrant establishment of these tumors as a papillary cystic neoplasm subclass.