Intralesional steroid injection to prevent stricture after endoscopic submucosal dissection for esophageal cancer: a controlled prospective study.

BACKGROUND AND STUDY AIMS: The frequency of stricture after endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma with a mucosal defect involving more than three-quarters of the circumference is 70% - 90%. Stricture decreases quality of life and requires multiple endoscopic balloon dilation (EBD) sessions. We investigated the efficacy and safety of a single session of intralesional steroid injections to prevent post-ESD stricture. PATIENTS AND METHODS: We conducted a prospective study on 30 patients with esophageal squamous cell carcinoma treated by ESD, who had a more than three-quarter but less than whole circumferential defect. A single session of intralesional steroid injections was undertaken immediately after ESD. Esophagogastroduodenoscopy was performed whenever patients reported dysphagia and 2 months after ESD in patients without dysphagia. Results were compared with a historical control group of 29 patients who underwent ESD without intralesional steroid injection. The primary endpoint was the post-ESD stricture rate. Secondary endpoints were the number of EBD sessions and the complication rate. RESULTS: Compared with the historical control group, the study group had a significantly lower stricture rate (10%, 3/30 patients vs. 66%, 19/29 patients; P < 0.0001) and a lower number of EBD sessions (median 0, range 0 - 2 vs. median 2, range 0 - 15; P < 0.0001). The study group had a complication rate of 7 % (2 /30 patients), comprising a submucosal tear in one patient and bleeding in another, which were not a direct result of EBD. CONCLUSIONS: A single session of intralesional steroid injections showed promising results for the prevention of stricture after ESD for esophageal cancer.

Clinical features and outcomes of delayed perforation after endoscopic submucosal dissection for early gastric cancer.

Perforation is a major complication of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). However, there have been no reports on delayed perforation after ESD for EGC. We aimed to elucidate the incidence and outcomes of delayed perforation after ESD. Clinical courses in 1159 consecutive patients with 1329 EGCs who underwent ESD were investigated. Delayed perforation occurred in six patients (0.45 %). All these patients had complete en bloc resection without intraoperative perforation during ESD. Five of six perforations were located in the upper third of the stomach, while one lesion was found in the middle third. Symptoms of peritoneal irritation with rebound tenderness presented within 24 h after ESD in all cases. One patient did not require surgery because the symptoms were localized, and recovered with conservative antibiotic therapy by nasogastric tube placement. The remaining five patients required emergency surgery. There was no mortality in this case series.

Endoscopic submucosal dissection for early gastric cancer performed by supervised residents: assessment of feasibility and learning curve.

BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) is feasible as a treatment for early gastric cancer (EGC) when it is performed by an experienced endoscopist. We investigated whether it was feasible for novice endoscopists to perform ESD for EGC, and how difficult it was to learn the procedure. METHODS: This case series study was performed in a cancer referral center. Three resident endoscopists, who had already learned basic procedures, performed ESD under supervision for 30 consecutive lesions, and their procedures were analyzed. The procedure was divided for assessment into (i) mucosal incision and (ii) submucosal dissection by completion of the circumferential mucosal cut. An insulated-tip knife was used for mucosal incision and submucosal dissection. A total of 90 mucosal EGCs (< or = 2 cm) without ulcers or scars in 87 patients were included. Outcomes were: rates of complete resection, complications, and self-completion; operation time; learning curve; and reasons for change of supervisor as an indicator of difficulty. RESULTS: Among the 90 procedures, there was a good overall complete resection rate of 93 %, with an acceptable complication rate of 4.4 %; the complications were delayed hemorrhage in two patients, and perforations in another two patients that were repaired successfully by endoscopic clipping. The self-completion rate and operation time were significantly worse for submucosal dissection than for mucosal incision. Two of the three operators showed a flat learning curve for submucosal dissection. Difficulty with the procedure was related mainly to uncontrollable hemorrhage. CONCLUSIONS: With appropriate supervision, gastric ESD by residents is feasible, with equivalent complete resection rates and acceptable complication rates compared with those of experienced endoscopists, although there was difficulty in achieving sufficient self-completion rates in submucosal dissection. Better control of bleeding during submucosal dissection may be a key to improving the procedure.

A new method of diagnosing gastric intestinal metaplasia: narrow-band imaging with magnifying endoscopy.

BACKGROUND AND STUDY AIMS: With endoscopy, there is a high rate of interobserver variability in the identification of gastric intestinal metaplasia, and the endoscopic findings correlate poorly with the histological findings. Previous studies by our group investigating the use of a narrow-band imaging system with magnifying endoscopy (NBI-ME) in the gastric mucosa suggested that the appearance of a light blue crest (LBC) on the epithelial surface may be a distinctive endoscopic finding associated with the presence of intestinal metaplasia. The aim of the present study was to clarify the value of NBI-ME for diagnosing gastric intestinal metaplasia. PATIENTS AND METHODS: The LBC was defined as a fine, blue-white line on the crests of the epithelial surface/gyri. To investigate the histology underlying the appearance of LBC, 44 biopsy specimens were obtained from regions containing LBC and 44 from non-LBC mucosa in 34 patients with atrophic gastritis. Three endoscopists then carried out NBI-ME in 107 consecutive patients to validate the diagnostic accuracy of the novel endoscopic technique. The degree of correlation between the LBC grading and the histological parameters of intestinal metaplasia was then assessed. RESULTS: The LBC grading correlated with cells that were positive for CD10 ( P = 0.0001) and Alcian blue ( P = 0.036). The appearance of LBC correlated with histological evidence of intestinal metaplasia with a sensitivity of 89 % (95 % CI, 83 - 96 %), a specificity of 93 % (95 % CI, 88 - 97 %), a positive predictive value of 91 % (95 % CI, 85 - 96 %), a negative predictive value of 92 % (95 % CI, 87 - 97 %), and an accuracy of 91 % (95 % CI, 88 - 95 %). CONCLUSIONS: In narrow-band imaging with magnifying endoscopy, observation of a light blue crest on the epithelial surface in the gastric mucosa is a highly accurate sign of the presence of histological intestinal metaplasia.

RhoC is essential for TGF-beta1-induced invasive capacity of rat ascites hepatoma cells.

Transforming growth factor-beta1 (TGF-beta1) is a multifunctional growth factor that plays a role in cell proliferation, differentiation, extracellular matrix production, apoptosis, and cell motility. We show here that TGF-beta1 increased the invasiveness of MM1 cells, which are a highly invasive clone of rat ascites hepatoma cells. Both mRNA and protein levels of RhoC but not RhoA in TGF-beta1-treated MM1 cells increased. In parallel with this increase in expression, RhoC activity was induced by TGF-beta1 treatment. When RhoC was overexpressed in MM1 cells, the invasive capacity increased. The RhoC-overexpressing cells formed more nodules than did mock cells when injected into rat peritoneum. Furthermore, when RhoC expression was reduced by transfection with shRNA/RhoC, the invasiveness of MM1 cells decreased with concomitant suppression of RhoC expression. Thus, the induced expression of RhoC by TGF-beta1 in MM1 cells plays a critical role in TGF-beta1-induced cell migration.

Helicobacter pylori-induced atrophic gastritis progressing to gastric cancer exhibits sonic hedgehog loss and aberrant CDX2 expression.

BACKGROUND: The loss of sonic hedgehog is an early change that occurs in the mucosa prior to neoplastic transformation and correlates with the type of intestinal metaplasia. Aberrant expression of CDX has also been shown to correlate with the development of intestinal metaplasia. AIM: To examine CDX2 expression in the non-cancerous mucosa of patients with gastric cancer and compared it to CDX2 expression in controls with intestinal metaplasia. METHODS: Sixty patients who had undergone endoscopic mucosal resection for early gastric cancer and 60 gender- and age-matched controls were studied. Two specimens each were obtained from the greater and lesser curves of the corpus and from the greater curve of the antrum. Expression of CDX2 and sonic hedgehog were evaluated by immunostaining. RESULTS: Gastric cancer was associated with a higher frequency of incomplete intestinal metaplasia (OR = 8.3; 95%CI, 3.7-18.9, P < 0.001). CDX2 negatively correlated with sonic hedgehog expression, however, multivariate analysis revealed that CDX2 correlated with the intestinal metaplasia scores. Sonic hedgehog indices were lower and CDX2 staining in the corpus lesser curve was higher in the cancer group than in the controls. Sonic hedgehog indices in the corpus decreased and CDX2 indices in both areas increased in patients in the ascending order of those without intestinal metaplasia, those with complete intestinal metaplasia and those with incomplete intestinal metaplasia (P < 0.001). CONCLUSIONS: Loss of sonic hedgehog expression and aberrant expression of CDX2 correlates with the type of intestinal metaplasia and may play a role in carcinogenesis.

Suppression of PI3K/mTOR pathway rescues LLC cells from cell death induced by hypoxia.

Cancer cells in solid tumors are challenged by various microenvironmental stresses, including hypoxia, and cancer cells in hypoxic regions are resistant to current cancer therapies. To investigate the mechanism of resistance to hypoxia in cancer cells, we examined mouse Lewis lung carcinoma (LLC) cells, which died due to necrosis at high density under hypoxic but not under normoxic conditions. Levels of mammalian target of rapamycin (mTOR), a central regulator of cellular energy, are reported to be suppressed in hypoxia. We found that phosphorylation of two molecules downstream to it, ribosomal p70 S6 kinase (S6K) and ribosomal protein S6, was markedly suppressed by hypoxia. Overexpression of the active form of S6K increased the sensitivity of LLC cells to hypoxia. On the other hand, inhibition of PI3K or mTOR dramatically reduced hypoxia-induced cell death under hypoxic conditions. Under hypoxic conditions, blockade of the PI3K or mTOR pathway increased levels of intracellular ATP and delayed decreases in pH and glucose level in culture medium, without affecting the cell cycle.

Outcome of 51 nonmalignant nodules in the liver: usefulness of aspiration cytology for diagnosis of dysplastic nodules.

Pathologic diagnostic criteria for intrahepatic nonmalignant nodules using needle biopsy are controversial. To evaluate the cytodiagnostic criteria for dysplastic nodules using aspiration biopsy, a follow-up study of nonmalignant nodules was performed. Fifty-one intrahepatic nodules diagnosed histologically and cytologically as nonmalignant using an aspiration biopsy in 39 patients were followed up without treatment. The outcomes of the nodules were investigated using the Kaplan-Meier method and Cox's multivariate analysis. The cumulative rates of development to HCC at the 2nd year were 0%, 18%, and 53% in the non-dysplastic nodules, the low-grade dysplastic nodules, and the high-grade dysplastic nodules, respectively; and significant differences were seen among them (P= 0.0001). Multivariate analysis showed that cytologic grade was a significant risk factor for development to HCC (P=0.020). In conclusion, aspiration cytology was useful for diagnosis of the dysplastic nodules to predict risks of development to HCC.

Hypoacidity combined with high gastric juice nitrite induced by Helicobacter pylori infection is associated with gastric cancer.

BACKGROUND: In patients with Helicobacter pylori infection, the concentration of nitrite in gastric juice is elevated. The degree of elevation correlates with that of inflammation and H. pylori density. AIM: The aim of this study was to examine hypoacidity and high nitrite levels related to H. pylori infection in patients with gastric cancer. METHODS: We studied 88 patients with more than one history of endoscopic mucosal resection (EMR) for early gastric cancer and 88 age-matched controls. Concentration of nitrite in gastric juice was measured by Griess reaction, and serum pepsinogen levels were measured by RIA. RESULTS: Multiple malignant lesions were found in 20 of the 88 patients. Serum gastrin, gastric juice pH and nitrite levels in patients with gastric cancer were significantly higher and pepsinogen I and pepsinogen I/II significantly lower than in control subjects. Pepsinogen I level and I/II ratio were lower and gastric juice pH was higher in the protruded-type group than in the depressed-type group. Pepsinogen I and pepsinogen I/II were lower and gastric juice pH was higher in multiple than in single cases. CONCLUSIONS: Hypoacidity combined with high gastric juice nitrite induced by H. pylori infection is associated with the intestinal type of gastric cancer, especially protruded lesions.

Endoscopic resection with a two-channel videoendoscope for gastric carcinoid tumors.

BACKGROUND/AIMS: Endoscopic resection has been used to treat hypergastrinemia-associated early carcinoid tumors of the stomach. However, indications for endoscopic treatment of these tumors have not been established. Moreover, endoscopic resection of these tumors is often difficult with conventional polypectomy, because these tumors are often located in the submucosal layer. To completely remove these tumors, we used a two-channel videoendoscope with which both grasping forceps and a polypectomy snare could be used simultaneously. METHODOLOGY: At Osaka Medical Center for Cancer and Cardiovascular Diseases, eight carcinoid tumors in six patients were removed with a two-channel videoendoscope. Reports of early carcinoid tumor in Japanese literature were reviewed to analyze the relationship between lymph node metastasis and the size and depth of involvement of these tumors. RESULTS: Six carcinoid tumors were completely removed "en bloc", but two tumors were incompletely removed. In these two patients, submucosal tumor invasion was observed on the excision line. To completely remove these tumors, the oral side, but not the top, of the tumor should be strongly grasped and pulled toward the center of the lumen as far as possible by the grasping forceps, which had been passed through the snare loop. Endoscopic follow-up studies showed no local recurrence in any patients with and without complete tumor resection during the average observation period of 30 months. A review of histological reports in Japanese literature showed that lymph node metastasis did not occur when the tumors were less than 10 mm in diameter, and could be completely removed by an endoscope. CONCLUSIONS: Endoscopic resection with a two-channel videoendoscope is a useful and safe method for resection of small carcinoid tumors of the stomach.

Pre-medication with pronase reduces artefacts during endoscopic ultrasonography.

BACKGROUND: Gastric mucus usually induces artefacts during endoscopic ultrasonography. AIM: To investigate the effectiveness of pre-medication with the proteolytic enzyme, pronase, before endoscopic ultrasonography. METHODS: Out-patients scheduled for endoscopic ultrasonography were randomly assigned to oral pre-medication with the anti-foam agent, dimethylpolysiloxane, alone (treatment A; n = 29), with dimethylpolysiloxane plus sodium bicarbonate (treatment B; n = 29) or with dimethylpolysiloxane, sodium bicarbonate and pronase (treatment C; n = 29). All drinks were given about 10 min before the start of the procedure. After insertion of the endoscope, endoscopists recorded visibility scores before the procedure, imaging scores at endoscopic ultrasonography and the numbers of high-echo spots in the gastric cavity and on the gastric wall surface after the procedure. RESULTS: Pre-medication with pronase (treatment C) significantly reduced (both at P < 0.05) the visibility score (score 4, 46%) in comparison with that obtained for pre-medication without pronase (10% for both treatments A and B). Treatment with pronase significantly reduced (both at P < 0.05) the endoscopic ultrasonography score in the gastric cavity (score 4, 34%) in comparison with that found for treatments A (7%) and B (0%). It also significantly reduced (P < 0.05) the endoscopic ultrasonography score on the gastric wall surface (score 4, 14%) in comparison with that observed for treatment A (3%). The numbers of high-echo spots in the gastric cavity and on the gastric wall surface were significantly less (both at P < 0.001) for pre-medication with pronase (treatment C) than for pre-medication with treatments A and B. There were no complications associated with the solutions. CONCLUSIONS: Pre-treatment with pronase reduced the artefacts during endoscopic ultrasonography.

[Anomalous systemic arterial supply to the basal segment of the left lung; report of a case].

A 35-year-old female was admitted to our hospital for hysteromyoma. Chest X-ray showed a mass shadow in the left lung field. A thorough examination revealed anomalous systemic arterial supply to the basal segment of the left lung with 2 abnormal arteries. Because the patient had no symptoms, no operation was performed. After 9 months however, the patient had bloody phlegm and chest pain and received an operation. Thus, we propose that the operation for the pulmonary sequestration is to be performed when such a diagnosis is made.

Induction by bombesin of peritoneal metastasis of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

BACKGROUND: We investigated the effect of the gastrointestinal regulatory peptide, bombesin, on the development of peritoneal metastasis from gastric cancers induced in rats by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and on Rho activity in the gastric cancers. METHODS: Rats were allocated to three groups. All groups received MNNG (100 micrograms/ml) solution for 25 weeks from the start of the experiment. Group 1 (controls) received olive oil injections from the start of MNNG treatment; group 2 animals received alternate-day s.c. injections of bombesin (40 micrograms/kg body weight) in olive oil from the start of the experiment until the end of the experiment at week 52; and group 3 received the s.c. bombesin injection on alternate days from week 26 until week 52. The effect of bombesin on Rho activity in gastric cancer was examined by Western blotting. RESULTS: Bombesin given from the start of the experiment (group 2) and after the MNNG treatment (group 3) both significantly increased the incidence of gastric cancer metastasis, compared with controls, at week 52: The incidence of metastasis was significantly higher in group 2 than in group 3. Bombesin from the start of the experiment (group 2) significantly increased the incidence of tumors with deeper invasion or more infiltrative growth pattern, or lymphatic vessel tumor invasion, while bombesin after MNNG treatment (group 3) significantly increased the incidence of lymphatic vessel invasion. Bombesin also increased the activity of Rho protein in the tumors. CONCLUSION: Bombesin significantly increased the incidence of peritoneal metastasis from gastric cancers through the activation of Rho protein.

[The significance of neoadjuvant intra-arterial chemotherapy for locally advanced breast cancer by different methods].

For neoadjuvant intra-arterial (IA) chemotherapy in locally advanced breast cancer patients, Seldinger's methods were found to be convenient and had the same effect and outcome as conventional methods. The prognosis of the patients in whom IA chemotherapy was locally effective and had fewer than n 1 lymph node metastases was comparatively favorable. However, several patients who underwent IA chemotherapy later experienced local recurrence, and the cause of these patient's death was distant metastases in almost all cases. We recommend neoadjuvant IA and systemic chemotherapy, and systemic adjuvant chemotherapy.

[A case of locally advanced breast cancer successfully treated with wide resection and reconstruction of chest wall with A-O metallic plates].

A 63-year-old female with locally advanced breast cancer was treated with preoperative chemotherapy using docetaxel. The therapeutic regimen was comprised of four cycles at 3-week intervals. One cycle consisted of 80 mg of docetaxel which was administered on day 1. A remarkable response was confirmed. The side effects such as leukopenia, general fatigue and alopecia were moderate and had no influence on the patient's QOL. After preoperative chemotherapy, a full thickness chest wall resection was performed. Chest wall defect was reconstructed with orthopedic A-O metallic plates, Marlex mesh and rectus abdominis myocutaneous flap. These metal plates were very useful because it was easy to bend and twist them manually to fit the defect at the time of operation. Moreover, the curved metal plates preserved the cone form of the chest cage. The postoperative course was favourable without frail chest or wound infection.

Reduced expression of focal adhesion kinase in liver metastases compared with matched primary human colorectal adenocarcinomas.

The focal adhesion kinase (FAK) is implicated in integrin-mediated signal transduction pathways used in cell adhesion, cell motility, apoptosis, and anchorage-independent growth. Because cancer invasion and metastasis are thought to be associated with alterations in cellular adhesive and motile properties, we studied the expression of four focal adhesion proteins including FAK in matched samples of human normal colorectal mucosa (N), primary colorectal adenocarcinomas (T) and liver metastases (M) from 10 patients by Western blot analysis. This gave us the advantage of directly comparing levels of focal adhesion protein expression within the same genetic background. Average FAK expression level was significantly higher in T than in N and it was significantly lower in M than in T. Average paxillin expression level was also significantly higher in T than in N, but it was not significantly different between T and M. Similar results were obtained by immunohistochemical analyses of FAK and paxillin expression. Average vinculin and talin expression levels showed no significant differences among these three samples (N, T, and M). These data demonstrate that the FAK expression level increases in primary tumors compared with normal mucosa and decreases in liver metastases to the level of normal mucosa in the majority of human colorectal adenocarcinomas. Up- and down-regulation of FAK protein expression observed in this study may have a profound effect on the signal transduction.

Transfer of bcl-xs plasmid is effective in preventing and inhibiting rat hepatocellular carcinoma induced by N-nitrosomorpholine.

To examine the effect of the bcl-xs gene on the sequence from hepatic precancerous lesions, foci and neoplastic nodules, to hepatocellular carcinomas, Sprague-Dawley rats were given water containing 175 mg/l N-nitrosomorpholine (NNM) for 8 weeks. At weeks 1, 4 and 7, the left lobe of the rat liver was exposed and injected with the bcl-xs plasmid (pCR3.1-rat bcl-xs cDNA) or pCR3.1 encapsulated in cationic empty liposomes each at a dose of 80 microg plasmid/kg body weight. One minute later, low-field-strength, long-duration electric pulses were applied to the left lobe using a pincette electrode with circular poles 1 cm in diameter. The in vivo electroporation procedure significantly increased the transfer of the reporter gene chloramphenicol acetyl transferase (CAT) plasmid via empty liposomes. Thus, CAT mRNA was expressed not only at the sites of electrode contact but at sites 0.5-1.0 cm away from the electrode, and expression also increased with increasing doses of plasmid, meaning that in vivo electroporation enabled the expression of plasmid DNA throughout an extensive area of the rat liver. By week 11, the neoplastic nodules were significantly fewer and smaller in the bcl-xs group than in the pCR3.1 group at the two sites, one with and the other without electrode contact. No hepatocellular carcinomas were found in the rats that had received the bcl-xs plasmid, whereas these tumors were observed in 30% of the rats given pCR3.1. Moreover, overexpression of the bcl-xs protein was detected, and apoptotic activity was significantly increased in the neoplastic nodules, foci and hepatocytes adjacent to the hepatic lesions. These results indicate that the bcl-xs plasmid inhibits the occurrence and growth of rat hepatocellular carcinoma and may thus be effective for the prevention and treatment of human liver tumors.

Inhibition by d-limonene of experimental hepatocarcinogenesis in Sprague-Dawley rats does not involve p21(ras) plasma membrane association.

The effects of d-limonene on hepatocarcinogenesis induced by N-nitrosomorpholine (NNM) and on membrane-associated p21(ras) and labeling and apoptotic indices of the liver were investigated in male Sprague-Dawley rats. Rats were given drinking water containing NNM for 8 weeks, and from the beginning of experimental week 9, they received chow pellets containing 1% or 2% limonene. The preneoplastic and neoplastic liver lesions (cellular alteration foci, neoplastic nodules and hepatocellular carcinomas), and hepatic foci staining positive for glutathione-S-transferase, placental type (GST-P) were examined microscopically and histochemically. At week 16, quantitative histologic analysis showed that oral administration of 1% or 2% limonene resulted in significant reductions in the number and mean area of GST-P-positive hepatic foci and the number of cellular alteration foci, neoplastic nodules and hepatocellular carcinomas. Limonene, at both doses, also caused significant decreases in the labeling indices and significant increases in the apoptotic indices of cellular alteration foci, neoplastic nodules, hepatocellular carcinomas and adjacent liver. However, limonene, at both doses, had no significant influence on the production of membrane-associated p21(ras) in the visible liver white nodules. These findings indicate that limonene inhibits hepatocarcinogenesis and suggest that this effect may be clearly related to its effect in inhibiting cell proliferation and in enhancing apoptosis, but not through ras oncoprotein plasma membrane association.