Development of novel treatment with a bioabsorbable esophageal patch for benign esophageal stricture.

Using a large animal model, we examined whether circumferential stricture after esophageal endoscopic submucosal dissection (ESD) can be treated by grafting a bioabsorbable esophageal patch. Circumferential ESD was performed on the thoracic esophagus in pigs (n = 6) to create a stricture, for which one of the following interventions was performed: (1) the stricture site was longitudinally incised, and an artificial esophageal wall (AEW) was grafted after placing a bioabsorbable stent (AEW patch group, n = 3); (2) endoscopic balloon dilation (EBD) was performed every other week after stricture development (EBD group, n = 3). In both groups, esophageal fluoroscopy was performed 8 weeks after the interventions, and the esophagus was excised for histological examination of the patched site. In the AEW patch group, esophageal fluoroscopy revealed favorable passage through the patched site. Histologically, the mucosal epithelium and lamina propria had regenerated as in the normal area. In the EBD group, the circumferential stricture site showed marked thickening, and there were hypertrophic scars associated with epithelial defects on the luminal surface. Histologically, defects of the mucosal epithelium and full-thickness proliferation of connective tissue were observed. AEW patch grafting was suggested to be a potentially novel treatment strategy for post-ESD esophageal circumferential stricture.

Factors associated with the presence of multiple Lugol-voiding lesions in patients with esophageal squamous-cell carcinoma.

Multicentric squamous dysplasia of the esophagus is characterized by multiple Lugol-voiding lesions (LVLs) on Lugol chromoendoscopy. Multiple LVLs are associated with a very high risk of multiple cancers arising in the esophagus as well as the head and neck. To gain insight into the pathogenesis of multiple LVLs of the esophageal mucosa, we studied risk factors for the development of such lesions in 76 patients who had a current or previous diagnosis of esophageal squamous cell carcinoma. All patients underwent Lugol chromoendoscopy of the esophageal mucosa. The history of tobacco and alcohol use was documented. Polymorphisms of the aldehyde dehydrogenase type 2 (ALDH2) gene were identified by polymerase chain reaction using sequence-specific primers. Clinical factors related to multiple LVLs were analyzed. All patients with multiple LVLs were drinkers. On univariate analysis, male sex (odds ratio [OR] 15, 95% confidence interval [CI] 1.84-122.45: P = 0.011), presence of the ALDH2-2 allele (OR 4.5, 95% CI 1.55-13.24: P = 0.006), and smoking index ≥1000 (OR 2.6, 95% CI 1.02-6.6: P = 0.045) were associated with multiple LVLs. On multivariate analysis, male sex (OR 10.02, 95% CI 1.13-88.44: P = 0.038) and presence of the ALDH2-2 allele (OR 4.56, 95% CI 1.4-14.82: P = 0.012) were associated with multiple LVLs. Among drinkers, a daily alcohol intake of ≥100 g pure ethanol with the ALDH2-2 allele (OR 17.5, 95% CI 1.97-155.59: P = 0.01) and a daily alcohol intake of <100 g pure ethanol with the ALDH2-2 allele (OR 8.85, 95% CI 1.68-46.69: P = 0.01) more strongly correlated with multiple LVLs than did a daily alcohol intake of <100 g pure ethanol without the ALDH2-2 allele, whereas a daily alcohol intake of ≥100 g pure ethanol without the ALDH2-2 allele (OR 4.0, 95% CI 0.54-29.81: P = 0.18) did not. In conclusion, male sex and the ALDH2-2 allele are associated with an increased risk for multiple LVLs of the esophageal mucosa in patients with esophageal squamous cell carcinoma. Among drinkers with the ALDH2-2 allele, the risk of multiple LVLs increased in parallel to the daily alcohol intake.

Potential utility of HOP homeobox gene promoter methylation as a marker of tumor aggressiveness in gastric cancer.

HOP homeobox (HOPX) is an unusual homeobox gene encoding three spliced transcript variants, among which the only HOPX-beta promoter harbors CpG islands. The characteristics of its promoter methylation was analyzed using bisulfite sequencing and quantitative-methylation-specific polymerase chain reaction (Q-MSP), and the effects of HOPX expression were also examined. HOPX-beta expression was silenced in all gastric cancer cell lines tested; its expression could be restored by treatment with demethylating agent. On Q-MSP, HOPX-beta hypermethylation (cut-off value of 3.55) was found in 84% (67 out of 80) of primary tumor tissues and 10% (8 out of 80) of the corresponding normal tissues and could discriminate normal from tumor tissues (P<0.0001). The prognosis of the advanced cases with HOPX-beta hypermethylation was as poor as those with stage IV disease when cut-off value was set at 11.28. This finding was validated in an independent cohort of 90 advanced gastric cancers. The HOPX-beta hypermethylation was also an independent prognostic factor (P=0.029) on multivariate analysis. Exogenous HOPX expression significantly inhibited cell proliferation, colony formation and invasion as well as enhanced apoptosis. Taken together, HOPX-beta promoter methylation is a frequent and cancer-specific event in gastric cancer. Quantitative assessment of HOPX-beta methylation has great clinical potential as a marker of tumor aggressiveness.

Diffuse type advanced gastric cancer showing dismal prognosis is characterized by deeper invasion and emerging peritoneal cancer cell: the latest comparative study to intestinal advanced gastric cancer.

BACKGROUND/AIMS: Diffuse type advanced gastric cancer (D-AGC) is highly malignant disorder with dismal prognosis, however the causative attribution explaining such malignancy remains fully unexplained as compared to intestinal type AGC (I-AGC). METHODOLOGY: We examined the archive of 232 AGC with cytology test (CY) but no distant metastasis, who underwent gastrectomy in Kitasato University Hospital in order to reveal the prognostic significance of D-AGC in a multivariate approach. RESULTS: D-AGC occupied 68% (157/232) among AGC, and showed poorer prognosis than I-AGC (p = 0.024). Multivariate prognostic analysis revealed that independent prognostic factors for AGC are CY (p < 0.0001), pN (p = 0.0068), pT (p = 0.015), and age (p = 0.012), and that histology was eliminated, suggesting that histology itself does not represent high malignancy within the identical stage. D-AGC was significantly associated with younger age (p = 0.018), female preponderance (p = 0.006), advanced pT (p = 0.0002), advanced pN (p = 0.016), and positive CY factors (p = 0.032), among which negative prognostic factors were pT, pN, and CY factors. Multivariate logistic regression analysis elucidated that both pT (serosal exposure, p = 0.013) and CY (p = 0.034) factors were finally remnant independent predictors for D-AGC among the 3 univariate negative prognostic factors, but that pN was not. Intriguingly, age could be an independent prognostic factor only in D-AGC. CONCLUSION: Our research revealed for the first time that more dismal prognosis of D-AGC than I-AGC could be explained by propensity of deeper invasion and emerging peritoneal cancer cell, and histology itself did not have a prognostic value, hence indicating that present staging system works properly even in D-AGC as well as I-AGC. We must identify its molecular mechanism of both invasion and emerging peritoneal disease of D-AGC in order to improve the prognosis.

Laparoscopy-assisted distal gastrectomy for early gastric cancer: experience with 111 consecutive patients.

BACKGROUND: Laparoscopy-assisted distal gastrectomy (LADG) is gaining wider acceptance for the treatment of early gastric cancer. However, firm evidence supporting its safety and usefulness is scant, and no study has compared the outcomes of various procedures for LADG. We examined the surgical outcomes of LADG performed using different methods for lymph node dissection. METHODS: Between September 1998 and January 2005, we performed LADG in 111 patients with early gastric cancer. In the 55 patients treated initially, group 2 lymph node dissection was performed through a small, 7-cm-long incision (minilaparotomy). In 43 of these patients, hand-assisted laparoscopic surgery (HALS) was done. In the 56 patients treated more recently, lymph node dissection was performed laparoscopically. In 31 of these patients, the celiac branches of the vagus nerve were preserved. Clinical outcomes of these procedures were compared. RESULTS: In the first 55 patients, HALS significantly shortened the operation time (277 vs 243 min, p < 0.05). In the latter 56 patients, LADG with preservation of the celiac branches of the vagus nerve was associated with a longer operation time (283 vs 228 min, p < 0.01) and higher blood loss (150 vs 92 g, p < 0.05) than with LADG without celiac branch preservation. There were no differences among the various operative procedures in postoperative course, including the length of the postoperative hospital stay or the rate of complications. CONCLUSIONS: LADG is a safe and technically feasible procedure for the treatment of early gastric cancer. Laparoscopic lymph node dissection provided a good visual field and was easier to perform and required less time when the celiac branches of the vagus nerve were not preserved, with no negative effect on outcome.

Factors associated with pN3 stage tumors according to the TNM classification in advanced gastric cancer.

BACKGROUND/AIMS: The aim of the present study was to analyze factors associated with pN3-stage tumors, as classified according to the TNM Classification of Malignant Tumors, in patients who undergo curative resection for advanced gastric cancer. METHODOLOGY: A total of 391 patients with advanced gastric cancer (247 males and 144 females; average age, 59.2 years) were enrolled in the present study. The numbers of dissected regional lymph nodes and positive nodes were assessed, and node stage was determined according to TNM. Patient survival and factors associated with pN3-stage tumors were then analyzed. RESULTS: The 5-year survival rate was 82.9% for the 132 N0 patients, 66.4% for the 154 N1 patients, 41.1% for the 64 N2 patients and 21.1% for the 41 N3 patients. A significant difference was found between some of the curves (N0 and N1, p = 0.0012; N1 and N2, p = 0.0007; N2 and N3, p = 0.0055). In logistic regression analysis, independent factors associated with advanced gastric cancers with a pN3-stage tumor were tumor diameter (> 6 cm vs. < or = 6 cm, p = 0.0037), number of dissected nodes (> 30 vs. < or = 30, p = 0.0143), depth of invasion (T3 or T4 vs. T2, p = 0.0028) and microscopic type (undifferentiated vs. differentiated, p = 0.0147). CONCLUSIONS: The results of the present study suggest that tumor diameter (> 6 cm), depth of invasion (T3 or T4) and microscopic type (undifferentiated type) are the most reliable indicators of pN3-stage tumors in patients who undergo curative resection for advanced gastric cancer.

A new staging system based on tumor volume in gastric cancer.

BACKGROUND: Development of a more appropriate staging system for gastric cancer may prove useful in clinical practice. MATERIALS AND METHODS: A total of 171 patients with solitary carcinoma of the stomach (112 males and 59 females; age range, 20 to 84 years; mean, 57.7 years) who underwent curative surgery were examined. The volume of each tumor was measured from serial tumor tissue sections using a computer software program. The utility of a new staging system based on tumor volume was assessed with respect to patient survival in comparison with other clinicopathological factors and conventional staging. RESULTS: Significant differences in survival time were found for depth of invasion (T1 vs T2 or T3; p=0.008), nodal status (n0 vs n1 or n2; p=0.032), tumor volume (< or = 2,000 mm vs >2,000 mm3; p<0.001) and stage (stage I vs stage II, III or IV; p =0. 003). However, multivariate analysis only identified tumor volume as a significant prognostic factor in the present study (p <0.001; relative risk 10.351). CONCLUSION: The above findings suggest that a new staging system based on tumor volume may have advantages over the conventional staging system in the assessment of gastric cancer.

Limited effectiveness of extended lymph-node dissection for node-negative patients with proximal gastric cancer.

BACKGROUND: The optimal surgical treatment with respect to the extent of lymph-node dissection for node-negative patients with gastric cancer remains to be established. MATERIALS AND METHODS: A total of 101 node-negative patients with proximal gastric cancer (62 males and 39 females; age range 33 to 79 years; mean 58.0 years), who had undergone curative total gastrectomy, were retrospectively evaluated to determine whether any correlation existed between survival and the extent of lymph-node dissection (D1, limited; D2, extended lymph-node dissection). RESULTS: The 10-year survival rates of patients with T1 (n = 59), T2 (n = 31) or T3 tumors (n = 11) were 100%, 90.0% and 46.7%, respectively. Significant differences in survival were found between patients with T1 and T2 tumors (p = 0.018), T2 and T3 tumors (p = 0.003), and T1 and T3 tumors (p < 0.0001). Despite the fact that only 9 patients with a T1 tumor underwent a D2 lymph-node dissection, all other patients had an excellent prognosis. On the other hand, the 10-year survival rates of patients with T2 or T3 tumors who underwent a D1 or D2 lymph-node dissection were 83.3% and 76.8%, respectively, representing no significant difference between the two procedures for advanced stage cases (p = 0.590). Multivariate analysis showed that depth of invasion was the only statistically significant prognostic factor (p < 0.0001; relative risk, 19.018). CONCLUSIONS: Conventional radical prophylactic D2 lymph-node dissection does not improve the survival of node-negative patients with proximal gastric cancer when compared to limited D1 dissection.

Recent results in the surgical treatment of gastric cancer according to the Japanese and TNM classification.

BACKGROUND: Recent outcomes based on surgical long-term follow-up of patients with gastric cancer using current staging systems have not been fully evaluated. MATERIALS AND METHODS: A total of 1357 patients with primary gastric carcinoma (911 males and 446 females, ranging in age from 20 to 87 years; average 59.1 years) who had undergone gastric resection between 1986 and 1996 were examined with respect to their clinicopathological features, surgical procedures and patient survival according to Japanese and UICC-TNM classifications. RESULTS: The 5-year survival rate was 95.3% for stage Ia, 85.5% for stage Ib, 73.8% for stage II, 45.7% for stage IIIa, 20.9% for stage IIIb, 17.3% for stage IVa and 5.8% for stage IVb (8.8% for IVa and IVb) on the Japanese classification. By way of contrast, the 5-year survival rate was 95.6% for stage Ia, 85.0% for stage Ib, 72.1% for stage II, 49.3% for stage IIIa, 30.2% for stage IIIb and 12.0% for stage IV on the TNM classification. CONCLUSION: Although minor problems are associated with both the Japanese and TNM classification systems, both appear to be clinically significant and appropriate independent predictors of prognosis. The findings of the present study provide important information for comparing results among different institutes and for introducing new clinical trials for gastric cancer at the beginning of the new century.

[Combined laparoscopic-endoscopic procedure in stomach carcinoma]. / Kombiniertes laparoskopisch-endoskopisches Vorgehen beim Magencarcinom.

The purpose of this review is to outline the laparoscopic-endoscopic procedures that we perform for early gastric cancer. These procedures were applied to 29 patients. Preoperative work-up included gastric endoscopy, barium X-ray examination, endoscopic ultrasonography, and histological examination, and surgery was performed in patients diagnosed as having mucosal gastric cancer for which endoscopic mucosal resection (EMR) was difficult. Laparoscopic wedge resection of the stomach using the lesion-lifting method, by which a wedge resection is made while pulling up the full-thickness gastric wall, was carried out in the 16 patients with lesions of the anterior wall, lesser curvature, and greater curvature of the stomach. On pathological examination of resected specimens, the surgical margin and lymphatic or venous invasion were negative in all these patients. The histological depth of the lesions was m (mucosal cancer) in 15 patients and sm1 (slight cancer infiltration into the submucosal layer) in one. This one patient later underwent gastrectomy but no lymph node metastases were found. Oral nutrition was resumed for a mean (+/- SD) of 2.9 +/- 0.8 days after operation, and the duration of hospitalization after operation was 12.3 +/- 3.4 days. The 13 patients with lesions of the posterior wall of the stomach and near the cardia or the pylorus received laparoscopic intragastric mucosal resection. Laparotomy was required in 1 of these patients due to intraoperative hemorrhage. The surgical margins were negative in all 12 patients in whom laparoscopic intragastric mucosal resection was successful. Lymphatic or venous invasion was positive in 2, both of whom had sm1 cancer lesions of both of these patients were located in the cardiac region, total gastrectomy was avoided, and careful observation is continued. Oral nutrition was resumed 4.0 +/- 1.6 days after operation, and the duration of hospitalization after operation was 12.0 +/- 3.5 days. In addition, no postoperative complication was noted after either procedure, and all patients have been recurrence free for a follow-up period of 460 months. Selected properly, these laparoscopic endoscopic procedures are considered to be curative and minimally invasive treatments for early gastric cancer.

Preoperative evaluation to predict technical difficulties of laparoscopic cholecystectomy on the basis of histological inflammation findings on resected gallbladder.

BACKGROUND: No papers have heretofore documented histological studies of cases involving the inflammation of resected gallbladder or examined surgical difficulties on the basis of pathological findings. METHODS: On the basis of the histological inflammation findings on the resected gallbladders of 437 patients who underwent laparoscopic cholecystectomy (LC), the factors affecting the technical difficulty of the operation were examined through preoperative clinical findings (13 items), diagnostic imaging (22 items), and blood test findings (6 items), using multivariate analysis. RESULTS: In accordance with the four-stage classification of inflammation findings for the resected gallbladder, the inflammation findings on the resected gallbladder indicated a higher correlation with the time required for gallbladder dissection (30.2 +/- 16.3 minutes) than with the operation time (77.6 +/- 32.7 minutes). Thus, the technical difficulty of the operation was judged according to the time required for gallbladder dissection. For the preoperative findings on 418 patients who underwent successful LC, the most influential factors on the time required for gallbladder dissection were the presence of abnormal findings on computed tomography, the degree of fever, obesity index, nonvisualized gallbladder cholangiography, and cystic duct length. According to the multiple regression equation of these five factors, the gallbladder dissection for the 19 patients who underwent conversion to open cholecystectomy (OC) due to extreme inflammation was calculated to require 61.9 +/- 12.3 minutes, and the patients who showed a gallbladder dissection time longer than 49.6 minutes were judged to have high technical difficulty predicted from the preoperative evaluation. In the preoperative evaluation, sensitivity was 79.6%, specificity was 97.6%, accuracy was 95.0%, positive predictive value was 85.0%, and negative predictive value was 96.6%. Next, each finding was scored on the basis of a multiple regression equation of five factors, and the technical difficulty of the operation was quantified using these scores. The score of the patients who underwent conversion to OC was 8.0 +/- 2.0, and the patients who showed a score higher than 6 were judged to have high technical difficulty. Almost the same results as in the aforementioned preoperative evaluation were obtained using these scores. CONCLUSION: The judgment using the scores was satisfactory in terms of the simplicity of evaluating the technical difficulties associated with each patient and the ease of obtaining information for each factor. The quantification of technical difficulty using the scores is useful for preoperative prediction of which patients will have difficulties in gallbladder dissection and the conversion to OC in LC. Our results suggest that the consideration of technical difficulties is important for conducting safe operations with avoiding intraoperative complications.

Tumor volumetry: proposal of a new concept to predict lymph node metastasis in early gastric cancer.

BACKGROUND: The present study was conducted to evaluate the significance of tumor volumetry in early gastric cancer for predicting lymph node metastasis. MATERIALS AND METHODS: [corrected] Computer-generated three-dimensional images of tumors from 147 patients with early gastric cancer, who underwent curative gastrectomy with lymphadenectomy, were reconstructed from continuous tissue sections and the volume (mm3) of each tumor was measured by the surface rendering method. Logarithmic tumor volume and conventional pathological factors were then studied with respect to the prevalence of metastasis to regional lymph nodes. RESULTS: The results of univariate analysis showed that lymph node metastasis was associated with a larger tumor diameter, larger logarithmic tumor volume, a higher rate of blood and lymphatic vessel invasion and a higher incidence of submucosal invasion. However, the results of logistic regression analysis showed that only two factors, logarithmic tumor volume and blood vessel invasion, were independent variables that correlated with lymph node metastasis. Moreover, logarithmic tumor volume was the most important variable correlated with lymph node metastasis in early gastric cancer (p = 0.004, odds ratio: 23.831). CONCLUSIONS: Based on the present results, tumor volumetry appears to represent a novel method of predicting the likelihood of lymph node metastasis in early gastric cancer.

Surgical outcome of node-positive early gastric cancer with particular reference to nodal status.

BACKGROUND: The risk of recurrence according to nodal status in patients with node-positive early gastric cancer (EGC) remains unclear and no appropriate treatment approaches have yet been established for such patients. MATERIALS AND METHODS: The surgical outcome of gastrectomy in combination with lymphadenectomy was examined in a total of 100 patients (54 males and 46 females, ranging in age from 25 to 84 years; average 56.6 years) with EGC and metastasis to lymph nodes. The outcome was assessed with particular reference to the extent of lymph node metastasis. RESULTS: The 5 and 10-year overall survival rates were 93.5 and 89.8%, respectively. Significant differences in survival were detected when anatomical distribution of lymph node metastasis (p < 0.0001), number of positive nodes (p = 0.0004) and tumor size (p = 0.0085) were examined. In particular, in 73 patients for whom the metastasis was limited to a perigastric node, prognosis was excellent and no recurrence was observed during the follow-up period. On the other hand, 27 patients with metastasis to a lymph node beyond the perigastric region were defined as comprising a high risk group for recurrence among node-positive EGC patients due to their poor prognosis (10-year survival rate, 58.5%). CONCLUSION: The results of the present study have suggested that radical gastrectomy combined with lymphadenectomy is essential to achieve complete remission in patients with lymph node metastasis restricted to perigastric nodes. For patients with a high risk of recurrence in EGC, whose condition is complicated by lymph node metastasis beyond the perigastric region, care should be taken to prevent recurrence by conducting long-term follow-up even after radical surgery. In order to improve survival, an appropriate protocol for post-operative adjuvant therapy may be needed for patients such as those with advanced gastric cancer.

Intragastric pH in postlaparotomy patients--effects of cimetidine.

Intragastric pH was continuously monitored in 21 patients who underwent colorectal surgery. Monitoring was started before surgery, and was continued for two days after surgery. Intragastric pH tended to increase during surgery, compared with measurements obtained before and after surgery, but was not affected by the duration of anesthesia or of the surgical procedure, or surgical position. After surgery, patients were divided into two groups: the cimetidine group (10 patients) received intravenous cimetidine 200 mg 4 times a day, while the control group (11 patients) received no treatment. Postoperative intragastric pH was higher than 3.0 throughout the study in the cimetidine group, but was approximately 1.3 in the control group. Upper gastrointestinal bleeding occurred in 2 patients in the control group, with intragastric pH falling abruptly during the bleeding episode. To prevent post-operative upper gastrointestinal bleeding, in addition to the administration of H2-blockers or antacids, appropriate treatments in response to changes in intragastric pH are necessary. Continuous monitoring of intragastric pH in surgical patients is considered to be of clinical importance.

Poly(ADP ribose) polymerase-defective mutant cell clone of mouse L1210 cells.

By a sequential mutation and selection utilizing N-methyl-N'-nitro-N-nitrosoguanidine as a mutagen, we succeeded in separating a poly(ADP ribose) polymerase-defective mutant clone (Cl-3527) from a mouse L1210 cell clone (Cl-3). The enzyme activity per cell in Cl-3527 cells was only 8% of that in wild type L1210 (CCL 219) cells. Immunoblot analysis of the enzyme protein in crude extracts of the mutant and wild type cells revealed that the enzyme defect was manifested as the loss of a 113-kDa wild type enzyme band in Cl-3527. Further analysis of partially purified enzyme from Cl-3527 by immunoblotting revealed that the molecular size of the enzyme in Cl-3527 was 108 kDa and that the amount of the mutant enzyme protein was markedly decreased in Cl-3527. The mutant enzyme was much more heat-labile than the wild type enzyme but the Km for NAD+, requirements for Mg2+ and nicked DNA, and the inhibition by 3-aminobenzamide, a potent inhibitor of the enzyme, however, were not so different from those of wild type enzyme. The mutant cells showed prolonged doubling time, increased temperature-sensitivity, increased percentage of active enzyme on a treatment of cells at high temperature, and increased expression of plasma membrane NADase, compared to wild type cells. Introduction of wild type ADPR pol gene into Cl-3527 cells partially restored the ADPR pol activity and the heat-resistance.