Hiroshi Yabusaki

Role of staging laparoscopy with peritoneal lavage cytology in the treatment of locally advanced gastric cancer

BackgroundMore accurate preoperative staging is necessary to determine the treatment strategy for locally advanced gastric cancer. Laparoscopy has been suggested as an appropriate staging modality. The aim of this study was to clarify the role of staging laparoscopy in patients with locally advanced gastric cancer.MethodsOne hundred patients with primary gastric adenocarcinoma underwent laparoscopy with peritoneal lavage cytology. The disease stages determined were compared with those obtained by conventional methods.ResultsThe disease stages were corrected after laparoscopy for 47 of the 100 patients (47%), with downstaging in 3 (3.0%) and upstaging in 44 (44%). Peritoneal deposits were found in 7 patients with peritoneal dissemination diagnosed by conventional examination. An unsuspected peritoneal deposit was found in 21 of 93 patients (22.6%), and unsuspected free cancer cells without deposits were found in 27 of 93 patients (29.0%). Gastrectomy after staging laparoscopy was performed in 39 patients. Laparoscopy showed no peritoneal deposits in any of these patients. Free cancer cells were found in 9 patients (23.1%), but 4 of these had peritoneal deposits at operation. R0 resection was performed in 34 of the 39 patients (87.2%). Neoadjuvant chemotherapy after staging laparoscopy was performed in 35 patients. All 35 patients underwent gastrectomy, which resulted in 27 R0 and 8 R2 resections. Of 18 patients with positive cytology at laparoscopy, 11 had no free cancer cells at operation. Neoadjuvant chemotherapy induced downstaging of the disease in 11 of the 18 patients with positive cytology (61.1%). Of 26 patients with massive peritoneal deposits, 4 underwent palliative resection because of pyloric stenosis. Twenty-two patients (22.0%) were able to avoid unnecessary laparotomy because of the staging laparoscopy.ConclusionStaging laparoscopy with peritoneal lavage cytology is a safe, effective tool in patients with locally advanced gastric cancer, especially in patients receiving neoadjuvant chemotherapy.

The Significance of Splenectomy for Advanced Proximal Gastric Cancer

Objectives. The significance of splenectomy in advanced proximal gastric cancer is examined retrospectively. Methods. From 1994 to 2004, 505 patients with advanced proximal gastric cancer underwent curative total gastrectomy with preserving spleen (T) for 264 patients and total gastrectomy with splenectomy (ST) for 241 patients. Results. Patients who underwent splenectomy showed more advanced lesions. The metastatic rate of lymph node (LN) in the splenic hilus (No. 10) in ST was 18.3%. As for the incidence of surgical complications, there was not statistically difference except for pancreatic fistula. The index of estimated benefit of (No. 10) LN was 4.2, which was similar to that of (No. 9), (No. 11p), (No. 11d), and (No. 16) LNs. 5-year survival rate of (No. 10) positive group was 22.2%. 5-year survival rates of pSE and pN2 in T group were better than that of pSE and pN2 in ST, respectively. The superiority of ST was not confirmed even in Stage II, IIIA, and IIIB. Conclusion. Splenectomy was not effective for patients with (No. 10) metastasis in long-term survival. Spleen-preserving total gastrectomy will be feasible and be enough to accomplish radical surgery for locally advanced proximal gastric cancer.

Neoadjuvant chemotherapy in advanced gastric cancer with non-curative factors: a Phase II study with 5-fluorouracil, leucovorin, and cisplatin

Background. Neoadjuvant chemotherapy (NAC) has recently received increasing attention in an attempt to increase the rate of complete tumor resections, reduce systemic metastases, and prolong survival in patients with advanced gastric cancer. Methods. Since 1993, 21 patients with unresectable or non-curative resectable gastric cancer received NAC, consisting of 5-fluorouracil, leucovorin, and cisplatin (FLP) with at least two cycles before surgery. Results. All except 2 patients underwent surgical treatment, and resection was performed in 18 (85.7%). There were no deaths and no major morbidity following operation. There was no complete response (CR), but 12 patients (57.1%) had a partial response (PR), the response rate was 47.6% for the primary region, 64.7% for abdominal para-aortic (No.16) lymph node metastasis, 40.0% for liver metastasis, and 11.1% for peritoneal dissemination. One-year survival of the 21 patients was 40.5%, and median survival time (MST) was 322 days. MST in the responders was 571 days, and that in non-responders was 199 days (P < 0.01). MST was 835 days in patients who underwent curative resection and 310 days in those who underwent non-curative surgery (P < 0.01). There was no grade 4 toxicity, but grade 3 leukopenia occurred in 4 patients (19.0%), grade 3 anemia occurred in 3 patients (14.3%), and grade 3 stomatitis in 2 patients (9.5%). There were no serious renal disorders and no treatment-related death. Conclusions. The combination of FLP for NAC was feasible and useful for tumor reduction, especially for No.16 lymph node metastasis. There was a survival benefit in patients whose tumor had PR or who had had curative resection. We should confirm the effect and survival benefit of FLP for NAC by a prospectively randomized clinical controlled study.

Comparison of the surgical treatment strategies for Siewert type II squamous cell carcinoma in the same area as esophagogastric junction carcinoma: data from a single Japanese high-volume cancer center

PurposeSiewert type II esophagogastric junction adenocarcinoma (ADC) and squamous cell carcinoma (SCC) existing in the same area have distinct clinicopathological characteristics. The objective of this study was to examine differences in the surgical treatment and survival data, according to the histological subtype, in a single high-volume cancer center.MethodsWe retrospectively examined data from a total of 123 patients. Seventy-two patients with Siewert type II ADC and 51 patients with SCC in the same area.ResultsIn terms of the clinicopathological factors, the SCC patients had more advanced stage disease and thoracotomy was more frequently performed than in the ADC patients. The 5-year overall survival (OS) rates did not differ significantly between SCC and ADC, regardless of whether or not mediastinal, splenic hilum and para-aortic lymph node dissection was performed. Based on the calculated index for the frequency of nodal metastasis and the five-year OS rate for involvement at each level, only node nos. 1, 2, 3 and 7 had a high index (>5) in both groups. The multivariate Cox regression analysis showed that only age (<65), the pN category and residual tumor classification were independently associated with the outcome.ConclusionsDifferences in the histological type of esophagogastric junction cancer were not independent prognostic factors for survival, and there appears to be a benefit to dissecting the number 1, 2, 3 and 7 lymph nodes.

Long-term clinical outcome and survival after pylorus-preserving gastrectomy.

BACKGROUND/AIMS Pylorus-preserving gastrectomy (PPG) was introduced as a function preserving and minimally-invasive surgery for early gastric cancer (ECG). We investigated the long-term clinical and oncological outcomes of the procedure. METHODOLOGY A total of 433 patients who underwent PPG between 1993 and 2009 were assessed retrospectively. RESULTS The accuracy of the preoperative diagnosis of EGC was 93.1%. The incidence of lymph node metastasis was 3.7%. The median follow-up period was 77 (9-201) months. The overall 5-year survival rate was 96.6%. Three patients with advanced cancer developed recurrence and died. Thirteen patients developed a second primary gastric cancer in the remnant stomach. Four patients were treated by endoscopic resection, and nine underwent gastrectomy all with curative intent. The incidence of regurgitation and gastric-fullness at 5 years after PPG were 6.1% and 1.5%. Endoscopic findings of residual food, gastritis, bile reflex and reflux esophagitis were 19.1%, 11.0%, 3.0%, 10.0%, respectively. The mean relative body weight recovered up to 94.0% of that prior to surgery after 1 year and maintained. CONCLUSIONS PPG is a safe operative procedure for patients with EGC. It is important to improve the accuracy of preoperative diagnosis, and patients should be carefully followed-up to detect remnant stomach cancer.

Prognostic analysis of submucosa-invasive gastric cancer with lymph node metastasis

BACKGROUND The aims of this study were to identify prognostic factors of patients with submucosa-invasive (T1b) gastric cancer and to verify the validity of adjuvant chemotherapy for this disease. METHODS We retrospectively examined the cases of 1,236 consecutive patients in our prospectively maintained database with T1b gastric cancer who underwent gastrectomy in 1995-2012. We used 11 clinicopathologic characteristics to identify prognostic factors by univariate and multivariate analyses. We compared the survival of the 160 node-positive T1b gastric cancer patients with that of 133 patients in the same database who had node-positive muscularis propria-invasive (T2) gastric cancer and had undergone gastrectomy without adjuvant chemotherapy during the same period, as a reference cohort. RESULTS The 5-year overall survival rate was 91.4% for all 1,236 patients. Advanced age (hazard ratio [HR] 4.51; 95% confidence interval [CI] 3.26-6.24; P < .01), male sex (HR 2.26; 95% CI 1.56-3.26; P < .01), and the presence of lymph node metastasis (HR 1.89; 95% CI 1.33-2.70; P < .01) were independent prognostic factors. The 5-year overall survival rates were 92.5% in node-negative patients, 84.5% in patients with 1 or 2 metastatic nodes, and 80.1% in patients with 3 or more metastatic nodes (P < .01). The 5-year overall survival rates of the node-positive T1b and T2 gastric cancer patients were 83.6% and 81.2%, respectively (P = .73). CONCLUSION The prognosis of node-positive T1b gastric cancer patients after curative gastrectomy was unsatisfactory. Adjuvant chemotherapy should be considered for these patients, especially those with 3 or more metastatic nodes.

Rapid-growth carcinosarcoma of the esophagus arising from 0-IIc squamous cell carcinoma after definitive chemoradiotherapy: a case report

A case of carcinosarcoma arising from the area of intraepithelial spread of relapsed esophageal squamous cell carcinoma (SCC) after definitive chemoradiotherapy (CRT) is reported herein. A 71-year-old man was referred to our hospital because of a superficial esophageal carcinoma. Definitive CRT was performed because the patient refused surgical treatment. Complete response was recognized after CRT, but tumor relapse was diagnosed 3 months later. The relapsed tumor initially revealed a minimal depression with a small white nodule. This nodule developed to a sessile elevated mass after 1 month and finally to a polypoid tumor 3.2 × 2.3 × 1.5 cm in size within 125 days. A subtotal esophagectomy with two-field lymph node dissection was performed. Histologically, the polypoid tumor was composed mainly of spindle-shaped sarcomatous cells and invaded the muscularis propria of the esophageal wall. An area of intraepithelial spread of SCC was found at the base of its stalk. No lymph node metastases were found. The postoperative course was uneventful, and the patient has remained free of disease for 45 months. To our knowledge, this is the only reported case of esophageal carcinosarcoma arising from an area of intraepithelial spread of relapsed SCC that showed such rapid growth by serial endoscopies.

Augmentation of 5-fluorouracil cytotoxicity by epidermal growth factor in a newly established human signet-ring cell carcinoma of the stomach in culture

A cell line designated TSG6 was established from a signet-ring cell gastric carcinoma developed in a 57-year-old female patient. The TSG6 cells had well preserved the features of signet-ring cell carcinoma based on morphology. The cells exhibited both epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) immunoreactivities, and also secreted EGF. Moreover, the growth of TSG6 cells was stimulated in the presence of exogenous EGF. These results suggest that the possible presence of an EGF/EGFR autocrine growth mechanism is expressed in the TSG6 cells. The simultaneous treatment with EGF and 5-fluorouracil (5-FU) produced a nearly 2.4-fold enhancement of 5-FU cytotoxicity against TSG6 cells. A bromodeoxyuridine/DNA How cytometry analysis revealed that EGF augmented 5-FU cytotoxicity by inducing the accumulation of S phase cells which might be more susceptible to 5-FU. Moreover, we found that the incorporation of 5-FU into the TSG6 cells was increased with the addition of EGF. These data indicate that EGF may be a potent agent as a biological response modifier for 5-FU against the tumors which express the EGF/EGFR autocrine mechanism, and that the TSG6 cell line is useful in furthering our understanding of the interaction between anticancer drugs and EGF.

Pathogenic Germline BRCA1/2 Mutations and Familial Predisposition to Gastric Cancer

Most gastric cancers (GCs) are considered sporadic, however familial aggregation occurs in 10% of cases1, 2. Approximately 5% of GCs are caused by an autosomal dominant inherited trait, with carriers having a strongly increased risk of GC and other cancers3. Clinical criteria for this entity were defined by the International Gastric Cancer Linkage Consortium (IGCLC)4. Among these, hereditary diffuse gastric cancer (HDGC) is a well-known type of familial GC (FGC). About 40% of families fulfilling the clinical criteria for HDGC have germline CDH1 mutations5. A subset of the remaining families of HDGC, and ones fulfilling the criteria of other familial GC, harbor pathogenic germline mutation in other genes which associated with hereditary cancer predisposition syndromes4. Hereditary breast and ovarian cancer (HBOC) is one of the best-described inherited cancer predisposition syndromes, caused by pathogenic germline BRCA1 or BRCA2 (BRCA1/2) mutations6–9. The increased risks of cancers other than breast and ovarian cancers were observed in the carriers10. The association between germline BRCA1/2 mutation and increased risk of GC were demonstrated in previous studies for HBOC families11–14. Regarding FGC, a recent large-scale study demonstrated that germline BRCA2 mutations were identified in patients who had a family history which fulfilled the criteria of HDGC, but lacking CDH1 mutations15. Therefore, it is possible that germline BRCA1/2 mutations may cause familial predisposition to GC. Recent advances of comprehensive genomic analysis enable us to identify the genomic alterations in GC16. BRCA1/2 mutations were shown in the subset of GC tumor tissues, however the association between germline BRCA1/2 mutations and familial predisposition to GC were not fully understood. Previously we performed genomic sequencing of 207 Japanese GCs using 435-gene panel, and identified BRCA1/2 mutations in tumor17. In this study, we conducted BRCA1/2 genetic testing in seven Japanese GC patients whose tumor had BRCA1/2 mutations. We identified pathogenic germline BRCA1/2 mutations in three patients, who have a familial component of GC.

A phase III trial to confirm modified S-1 adjuvant chemotherapy for pathological stage II/III vulnerable elderly gastric cancer patients who underwent gastric resection (JCOG1507, BIRDIE)

Adjuvant chemotherapy with S-1 is a standard treatment for patients with stage II/III gastric cancer after D2 gastrectomy; however, this is not uniformly applicable in older patients. The Stomach Cancer Study Group of the Japan Clinical Oncology Group conducted a questionnaire survey on older patients aged ≥80 years and revealed wide heterogeneity among older patients of similar chronological age. This randomized trial aims to confirm the superiority of modified S-1 treatment (reduced initial dose of S-1 by ≥ 1 level compared with the standard dose) versus surgery alone in vulnerable older (≥80 years old) patients with pathological stage II/III gastric cancer after curative resection. A total of 370 patients will be enrolled from 62 institutions over 4.5 years. The primary endpoint of this study is overall survival. This trial has been registered in the UMIN Clinical Trials Registry with code UMIN000025742 [http://www.umin.ac.jp/ctr/index.htm].