Hidetaka A. Ono

Learning curve for laparoscopy-assisted distal gastrectomy with regional lymph node dissection for early gastric cancer.

An assessment of the learning curve of laparoscopy-assisted distal gastrectomy (LADG) might encourage its worldwide spread among inexperienced surgeons. One hundred sixty-seven patients with early gastric cancer were enrolled in this study: 67 underwent conventional open distal gastrectomy and 100 underwent LADG after classification into 5 groups of 20 according to the surgeons level of experience. Patient characteristics and operative findings were compared between groups. Operation time was significantly longer, time to first flatus earlier, and blood loss reduced in the LADG groups compared with the open distal gastrectomy group. Surgeons with experience of 60 cases performed operations of similar times in both groups, and blood loss decreased with experience of 20 cases. There was no operative conversion, the frequency of nonsteroidal anti-inflammatory drugs administered were significantly less, and length of hospital stay were shorter by surgeons with experience of 60 cases. LADG is a technically feasible surgical procedure, depending on the surgeons technical proficiency. Experience of at least 60 cases of LADG seems to result in satisfactory patient outcomes.

Predictive factors for surgical complications of laparoscopy- assisted distal gastrectomy for gastric cancer

BackgroundSome studies have found high incidences of intraoperative and postoperative complications for patients with gastric cancer. To determine the predictive factors for the surgical complications of laparoscopic gastric surgery, surgical outcomes were evaluated.MethodsBetween April 2002 and December 2007, 152 patients with preoperatively diagnosed early gastric cancer who underwent laparoscopy-assisted distal gastrectomy (LADG) were enrolled. Visceral (VFA) and subcutaneous fat areas (SFA) were assessed by Fat Scan software. The predictive factors for surgical complications of LADG were evaluated by univariate and logistic regression analyses.ResultsOf 152 patients, conversion to open surgery due to uncontrollable bleeding was observed in nine male patients, and postoperative complications were detected in seven male and one female patient (four anastomotic leakage, two intraabdominal abscess, one pancreatic fistula, and one lymphorrhea). High body mass index (BMI) and high VFA independently predicted conversion to open surgery and postoperative complications. VFA was significantly higher, operation time was longer, blood loss was greater, and SFA was lower in male than in female patients, whereas no significant difference was observed in BMI between male and female patients.ConclusionsHigh BMI and high VFA can predict technical difficulties during laparoscopic gastric surgery and postoperative complications. Particularly, LADG should be performed cautiously to prevent surgical complications for male patients with high VFA. Predictive impact of VFA should be further determined in a larger set of patients.

Comparison of Surgical Results of D2 Versus D3 Gastrectomy (Para-Aortic Lymph Node Dissection) for Advanced Gastric Carcinoma: A Multi-Institutional Study

Curative gastrectomy is a promising approach for the treatment of gastric cancer; however, the optimal extent of lymph node dissection for advanced cancer remains controversial. The aim of this multi-institutional study was to evaluate the feasibility of D3 gastrectomy (para-aortic lymph node dissection) for advanced gastric cancer. The surgical results of D2 and D3 gastrectomy (para-aortic lymph node dissection) were retrospectively compared. A series of 580 advanced gastric cancer patients were registered between 1992 and 2000. Of these, 430 underwent D2 gastrectomy and 150 underwent D3 gastrectomy. Survival time, prognostic factors, postoperative morbidity/mortality, and pattern of recurrence were compared. There was no significant difference in survival time between D2 and D3 patients. However, the survival times of D3 patients with tumor diameters measuring 50 to 100 mm or with pN1 disease were significantly longer than those of the corresponding D2 patients. Analysis of the survival of patients with tumor diameters measuring 50 to 100 mm revealed that D3 gastrectomy conferred a survival advantage only to patients with pN2 disease. The incidence of lymphatic recurrence was lower in D3 patients with 50- to 100-mm tumors than in the corresponding D2 patients. D3 gastrectomy might be beneficial in patients with advanced pN2 gastric cancer within the group with tumors measuring 50 to 100 mm. A randomized controlled trial of patients with 50- to 100-mm tumors should be performed to test the validity of this preliminary result.BackgroundCurative gastrectomy is a promising approach for the treatment of gastric cancer; however, the optimal extent of lymph node dissection for advanced cancer remains controversial. The aim of this multi-institutional study was to evaluate the feasibility of D3 gastrectomy (para-aortic lymph node dissection) for advanced gastric cancer. The surgical results of D2 and D3 gastrectomy (para-aortic lymph node dissection) were retrospectively compared.MethodsA series of 580 advanced gastric cancer patients were registered between 1992 and 2000. Of these, 430 underwent D2 gastrectomy and 150 underwent D3 gastrectomy. Survival time, prognostic factors, postoperative morbidity/mortality, and pattern of recurrence were compared.ResultsThere was no significant difference in survival time between D2 and D3 patients. However, the survival times of D3 patients with tumor diameters measuring 50 to 100 mm or with pN1 disease were significantly longer than those of the corresponding D2 patients. Analysis of the survival of patients with tumor diameters measuring 50 to 100 mm revealed that D3 gastrectomy conferred a survival advantage only to patients with pN2 disease. The incidence of lymphatic recurrence was lower in D3 patients with 50- to 100-mm tumors than in the corresponding D2 patients.ConclusionsD3 gastrectomy might be beneficial in patients with advanced pN2 gastric cancer within the group with tumors measuring 50 to 100 mm. A randomized controlled trial of patients with 50- to 100-mm tumors should be performed to test the validity of this preliminary result.

Outcomes of mass screening for gastric carcinoma.

BackgroundTherapeutic results of gastric cancer have been improved by early detection of gastric cancer with the mass screening system in Japan. The objective of our study was to assess the efficacy of mass screening for gastric cancer by using a barium meal.MethodsA series of 1050 patients (364 in the screened group and 686 in the nonscreened group) were included in this study from April 1992 to March 2000. Patient characteristics, therapeutic results, and prognostic factors were compared in the two groups.ResultsThe screened patients tended to be younger and male, with tumors in the middle third of the stomach that were of a macroscopically superficial type, with a smaller diameter, and at an earlier stage. They had fewer metastatic lymph nodes and underwent more frequent curative resection. Among the screened patients with curatively resected disease, tumors tended to be of a smaller diameter, and there were fewer metastatic lymph nodes in both early and advanced cases. Disease-specific survival was significantly better in the screened cases among all registered and curatively resected patients. Mass screening achieved significantly better surgical results in early or advanced gastric cancer patients who received curative resection. Multivariate analysis revealed that mass screening was an independent prognostic factor (hazard ratio, .3949; P < .0001), together with depth of invasion, lymph node metastasis, age, and tumor diameter.ConclusionsMass screening by using barium meal examination for gastric cancer detects cancer at an early stage and produces good therapeutic results.

Risk factors for lymph node metastasis in histologically poorly differentiated type early gastric cancer.

BACKGROUND We retrospectively evaluated the predictive factors for lymph node metastasis in poorly differentiated early gastric cancer (poorly differentiated tubular adenocarcinoma, signet-ring cell carcinoma, mucinous adenocarcinoma) in order to examine the possibility of endoscopic resection for poorly differentiated early gastric cancer. METHODS A total of 573 patients with histologically poorly differentiated type early gastric cancer (269 mucosal and 304 submucosal), who had undergone curative gastrectomy, were enrolled in this study. Risk factors for lymph node metastasis were evaluated by univariate and logistic regression analysis. RESULTS Lymph node metastasis was observed in 74 patients (12.9%) (6 with mucosal cancer and 68 with submucosal cancer). By univariate analysis risk factors for lymph node metastasis were lymphovascular invasion (LVI) (presence), depth of invasion (submucosa), and tumor diameter (> 20 mm), ulcer or ulcer scar (presence), and histological type (mucinous adenocarcinoma). By multivariate analysis, risk factors for lymph node metastasis were LVI, depth of invasion, and tumor diameter. In mucosal cancers, the incidence of lymph node metastasis was 0% irrespective of LVI in tumors smaller than 20 mm, and 1.7% in tumors 20 mm or larger without LVI. In submucosal cancers, the incidence of lymph node metastasis was 2.4% in tumors smaller than 20 mm without LVI. CONCLUSIONS A histologically poorly differentiated type mucosal gastric cancer measuring less than 20 mm and without LVI may be a candidate for endoscopic resection. This result should be confirmed in a larger study with many patients.

Clinicopathologic Characteristics and Surgical Outcomes of Mucinous Gastric Carcinoma

BackgroundThe clinicopathologic characteristics of mucinous gastric carcinoma (MGC), an uncommon subtype of gastric carcinoma, were examined by comparing 45 MGC and 1255 non-MGC (NGC) cases.MethodsOf 1300 gastric cancer patients, 1184 (early, n = 568; advanced, n = 616) underwent potentially curative or palliative resection. Age, sex, tumor location, tumor diameter, macroscopic appearance, depth of invasion, lymph node metastasis, lymphatic invasion, and venous invasion were monitored.ResultsIn all registered patients, MGC patients’ characteristics were as follows: advanced-stage disease (P = .0293), macroscopically ill-defined tumors (P = .0051), deeper invasion (P = .0046), and more lymph node involvement (P = .0008). Although there were no significant differences between curatively resected MGC and NGC advanced-cancer patients, in curatively resected early-cancer patients, depth of invasion (P = .0060) and lymphatic invasion (P = .0374) were significantly different. Survival time in all registered patients was shorter for MGC patients (P = .0489). Survival of curatively resected advanced and early gastric cancer patients was not significantly different. Age, macroscopic appearance, tumor diameter, depth of invasion, lymph node metastasis, and curability, but not histological type, were independent prognostic factors in all registered patients. Histological type also did not influence prognosis after curative resection. MGC patients had significantly more metastatic lymph nodes and lymphatic and venous invasion. Survival was significantly different (P = .0450) between all patients with undifferentiated and differentiated MGC, but not in curatively resected patients.ConclusionsMGC patients’ poor prognosis correlates with advanced disease at diagnosis. Therapeutic and follow-up plans after curative resected MGC and NGC should remain the same, possibly with alterations according to the former’s histological subtype.

Promoter-controlled infectivity-enhanced conditionally replicative adenoviral vectors for the treatment of gastric cancer

BackgroundGastric cancer is the fourth most common malignancy worldwide. Adenoviral vectors (Ads) have been applied for gene therapy of various cancers because of their high transduction efficiency. However, the infectivity of gastrointestinal cancer cells is poor due to the limited expression of the Coxsackie-adenovirus receptor (CAR). In addition, few tumor-specific promoters (TSPs) have been characterized for this type of cancer. To overcome these problems, we proposed TSP-driven conditionally replicating adenoviruses (CRAds) with fiber modification for virotherapy of gastric cancer.MethodsWe assessed the expression profile of eight TSPs in gastric cancer cell lines and evaluated promising candidates in the context of CRAd cytocidal effect. Next, infectivity enhancement by fiber modifications was analyzed in the gastric cancer cell lines. Finally, we combined the TSP-driven CRAds of choice with the fiber modifications to augment the killing effect.ResultsOut of the eight TSPs, the midkine (MK) and cyclooxygenase-2 (Cox-2M and Cox-2L) promoters showed high transcriptional activity in gastric cancer cells. When these promoters were used in a CRAd context, Cox-2 CRAds elicited the strongest cytocidal effect. The greatest infectivity enhancement was observed with adenoviral vectors displaying 5/3 chimeric fibers. Likewise, Cox-2 CRAds with 5/3 chimeric fibers showed the strongest cytocidal effect in gastric cancer cell lines. Therefore, Cox-2 CRAds with 5/3 chimeric fiber modification showed good selectivity and infectivity in gastric cancer cells to yield enhanced oncolysis.ConclusionsCox-2 CRAds with 5/3 chimeric fiber modification are promising for virotherapy of gastric cancer.

Significance of long-term follow-up of early gastric cancer.

BackgroundTherapeutic outcomes for most patients with early gastric cancer are favorable. However, mortality among these patients remains a concern. Improvements in therapeutic outcomes are being sought by studying the timing and causes of death. Here, the results of surgery were evaluated to assess the appropriate treatment and follow-up schedule for early gastric cancer.MethodsA total of 1169 patients with early gastric cancer underwent curative gastrectomy between 1992 and 1999. Survival time, prognostic factors, cause of death, and time of death were evaluated retrospectively.ResultsMultivariate analysis of disease-specific survival identified lymph node metastasis as an independent prognostic factor. The anatomical extent of lymph node metastasis and the number of metastatic lymph nodes influenced the rate of recurrence. Multivariate analysis of overall survival identified age as a prognostic factor. A total of 91 patients (7.8%) from the study group died: 56 from comorbid diseases, 21 from gastric cancer, and 14 from other second primary cancers. Death from gastric cancer was frequently observed within 5 years of surgical resection, whereas death from other diseases usually occurred after 5 years. Patients who died as a result of diseases other than gastric cancer tended to be older.ConclusionsAppropriate lymph node dissection is necessary for patients with early gastric cancer, particularly those with risk factors associated with lymph node metastasis. Meticulous follow-up protocols that can detect second primary cancers, together with the development of treatments for comorbid diseases, are required to improve survival.

Noninvasive visualization of adenovirus replication with a fluorescent reporter in the E3 region

To overcome the inefficacy and undesirable side effects of current cancer treatment strategies, conditionally replicative adenoviruses have been developed to exploit the unique mechanism of oncolysis afforded by tumor-specific viral replication. Despite rapid translation into clinical trials and the established safety of oncolytic adenoviruses, the in vivo function of these agents is not well understood due to lack of a noninvasive detection system for adenovirus replication. To address this issue, we propose the expression of a reporter from the adenovirus E3 region as a means to monitor replication. Adenovirus replication reporter vectors were constructed with the enhanced green fluorescent protein (EGFP) gene placed in the deleted E3 region under the control of the adenoviral major late promoter while retaining expression of the adenovirus death protein to conserve the native oncolytic capability of the virus. Strong EGFP fluorescence was detected from these vectors in a replication-dependent manner, which correlated with viral DNA replication. Fluorescence imaging in vivo confirmed the ability to noninvasively detect fluorescent signal during replication, which generally corresponded with the underlying level of viral DNA replication. EGFP representation of viral replication was further confirmed by Western blot comparison with the viral DNA content in the tumors. Imaging reporter expression controlled by the adenoviral major late promoter provides a viable approach to noninvasively monitor adenovirus replication in preclinical studies and has the potential for human application with clinically relevant imaging reporters.

Impact of lymphovascular invasion in patients with stage I gastric cancer.

BACKGROUND Patients with stage I gastric cancer often suffer from tumor recurrence despite a generally favorable operative outcome. It is therefore important to determine the prognostic factors in order to improve such outcomes. METHODS Between April 1985 and March 2000, a total of 1,880 patients with histologically proven stage I gastric cancer were included in this study. Operative outcomes (survival time, prognostic factors, pattern of recurrence) were evaluated in these patients. RESULTS Multivariate analysis in patients with all stage I gastric cancer revealed that depth of invasion, lymph node metastasis, and lymphovascular invasion independently influenced prognosis. Moreover, advanced age was selected as an independent prognostic factor in patients with stage IA, and lymphovascular invasion in patients with stage IB gastric cancer by multivariate analyses. The 5-year survival rates in stage T1N1 patients with moderate to severe lymphovascular invasion, T2N0 with moderate to severe lymphovascular invasion, and II were 95.1%, 83.5%, and 76.9%, respectively. There was a significant difference in survival time between stage T1N1 and II (P = .0189) but not between stage T1N1 and T2N0 or stage T2N0 and II. CONCLUSION T2N0 gastric cancer patients with moderate to severe lymphovascular invasion may be suitable candidates for adjuvant chemotherapy.