Long-term Results of a Phase II Study of Neoadjuvant SOX for Advanced Gastric Cancer.

BACKGROUND/AIM: This study aimed to evaluate the long-term survival outcomes from our previous study: a phase II study of neoadjuvant chemotherapy with S-1 plus oxaliplatin for cT4 or N2-3 advanced gastric cancer. PATIENTS AND METHODS: The patients with clinical T4 and/or N2 or more lymph nodes received two cycles (3 weeks per cycle) of neoadjuvant chemotherapy with S-1 plus oxaliplatin (oxaliplatin at 130 mg/m2 on day 1 and S-1 at 80-120 mg/day on days 1 to 14), followed by gastrectomy with D2 lymphadenectomy. The final preplanned analysis of long-term outcomes, including overall and relapse-free survival, was performed. This trial has been completed and registered with the University Hospital Medical Information Network Clinical Trials Registry under number UMIN 000024656. RESULTS: Between May 2016 and March 2019, 30 patients were enrolled. All patients completed the protocol. After a median follow-up of 50 months for surviving patients, the 3-year overall and recurrence-free survival rates were 80.0% and 76.7%, respectively, at the last follow-up in March 2023, whereas the 5-year overall and recurrence-free survival rates were 72.7% and 73.0%, respectively. CONCLUSION: The administration of two cycles of neoadjuvant chemotherapy with S-1 plus oxaliplatin, followed by D2 gastrectomy, was associated with relatively good long-term oncologic outcomes for patients with high-risk gastric cancer.

Tumor Depth Prediction of Gastric Cancer With a T4 Score.

BACKGROUND/AIM: Peritoneal metastases are often found at surgery of pT4 gastric cancers, preventing R0 resection. In the event of successful R0 resection, distant metastases still occur in a sizeable proportion of patients. Estimation of the depth of invasion has a relatively low accuracy (57%-86%) compared with pathological findings. This study sought to develop a clinical score to distinguish between pathological stage T4 (pT4) and pT1-3 gastric cancer. PATIENTS AND METHODS: Reviewing the data of 2,771 patients who had undergone gastrectomy at our hospital from January 1996-December 2016, we assessed demographic factors plus tumor markers, diameter, location, histology, and macroscopic type according to the fifth edition (2019) of the WHO classification. Significant factors on multivariate analysis were used to develop a pT4 gastric cancer depth prediction score (T4 score). RESULTS: Multivariate analysis revealed that the clinical factors associated with pT4 disease were CA19-9 elevation, tumor diameter ≥50 mm, poorly cohesive type adenocarcinoma, mucinous adenocarcinoma, and WHO macroscopic types 2-4. The T4 score was obtained by weighing these factors according to the ß-coefficient. The optimum cutoff value of the T4 score was 4 points. A total of 79.4% of cases with a T4 score ≥4 points were stage pT4. A total of 93.9% of cases with a T4 score <4 points were stage pT1-3, with 91.1% sensitivity, 85.3% specificity, 79.4% positive predictive value, and 93.9% negative predictive value. CONCLUSION: T4 scoring can differentiate pT4 gastric cancer from pT1-3 gastric cancer.

Phase II study of neoadjuvant chemotherapy with S-1 plus oxaliplatin for gastric cancer clinical T4 or N2-3.

In Japan, the standard treatment for stage II or III gastric cancer is D2 gastrectomy followed by administration of S-1 for one year. However, patients with stage III disease have unsatisfactory survival rates. The purpose of this study was to evaluate the efficacy and safety of neoadjuvant chemotherapy consisting of S-1 and oxaliplatin for advanced gastric cancer. Patients with cT4 or cN2-3 gastric cancer were scheduled to receive two courses of chemotherapy (130 mg/m2 oxaliplatin on Day 1, 80 mg/m2 S-1 per day twice daily for 14 days) followed by surgery. The primary endpoint was the R0 resection rate. The secondary endpoints were rates of completion of protocol treatment, pathological response, and adverse events; and 3-year overall survival, 5-year overall survival, and 5-year recurrence-free survival. Between May 2016 and March 2019, 30 patients were enrolled in the study, all of whom completed the protocol treatment. The R0 resection rate (primary endpoint) was 93.3% (95% confidence interval: 77.9-99.2). The pathological response rate was 63.3%. Grade 3-4 toxicities included anemia (3.3%), anorexia (6.7%), and fatigue (3.3%). Relative dose intensities were 91.2% and 94.2% for S-1 and oxaliplatin, respectively. Neoadjuvant S-1 and oxaliplatin is highly effective, achieving an acceptable R0 resection rate with relatively few severe toxicities and good compliance.Trial registration: Registry name: A prospective intervention study on the availability of preoperative SOX therapy for T4 or N2-3 gastric cancer. Trial ID: UMIN: UMIN000024656. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R00002836.

Rapid Flow Cytometry of Gastrointestinal Stromal Tumours Closely Matches the Modified Fletcher Classification.

AIM: We aimed to develop a rapid, simple procedure and an algorithm for quantitative analysis and classification of the metastatic risk of gastrointestinal stromal tumours (GIST) for clinical use. MATERIALS AND METHODS: Eighteen specimens from laparoscopic local gastrectomy were assessed by flow cytometry. We devised a new risk classification for GIST by combining flow cytometry parameters with tumour size and evaluated whether the combined parameters correlated with the modified Fletcher risk classification. RESULTS: We found a significant correlation between clinical prognostic factors (mitotic count and Ki-67 labelling index) and the flow cytometry parameters DNA ploidy, DNA index and S-phase fraction. The combined parameters established from tumour size and the flow cytometry parameters showed a high correlation with the modified Fletcher risk classification (p=0.0064). Flow cytometry had to be performed for approximately 10 minutes to determine the metastatic risk. CONCLUSION: Rapid flow cytometry parameters can classify risk without the need for histological analysis.

Staging of gastric cancer with the Clinical Stage Prediction score.

BACKGROUND: Chemotherapy with or without surgery is the first-line treatment for stage III/IV gastric cancer, while surgery is the first-line treatment for stage I/II gastric cancer. Accordingly, it is important to distinguish between stage III/IV and stage I/II gastric cancer, but clinical staging is less accurate than pathological staging. This study was performed to develop a clinical score that could distinguish stage III/IV gastric cancer from stage I/II gastric cancer. METHODS: We reviewed 2722 patients who underwent gastrectomy at our hospital from January 1996 to December 2015. As pretreatment factors potentially related to tumor stage, we assessed age, sex, tumor markers, tumor diameter, tumor location, tumor histology, and macroscopic type. Factors showing significance on multivariate analysis were used to develop the Clinical Stage Prediction score (CSP score), and a cutoff value for the score was determined by receiver operating characteristics analysis. RESULTS: According to multivariate analysis, clinical factors associated with stage III/IV disease were elevation of the carcinoembryonic antigen level, tumor diameter ≥ 60 mm, circumferential gastric involvement, esophageal infiltration, mucinous adenocarcinoma, and macroscopic types 2-4. The CSP score was obtained by weighting these factors according to the non-standardized ß-coefficient. Receiver operating characteristics analysis indicated that the optimum cutoff value of the CSP score was 17 points. Among 1042 patients with a CSP score ≥ 17 points, 820 patients (78.7%) had stage III/IV gastric cancer. Conversely, among 1680 patients with a CSP score < 17 points, 1547 patients (92.1%) had stage I/II gastric cancer. When discrimination of stage III/IV gastric cancer from stage I/II gastric cancer by the CSP score was assessed, the sensitivity was 78.7%, specificity was 92.1%, positive predictive value was 86.0%, and negative predictive value was 87.5%. CONCLUSIONS: The CSP score can be helpful for differentiating stage III/IV gastric cancer from stage I/II gastric cancer based on pretreatment clinical factors.

Columnar metaplasia in the remnant esophagus is a long-term indicator for pneumonia after radical esophagectomy.

BACKGROUND: This study investigated the long-term risk factors for pneumonia after esophageal reconstruction using a gastric tube via the posterior mediastinal route following esophagectomy for esophageal cancer. The influence of columnar metaplasia in the remnant esophagus was specifically assessed. METHODS: Among 225 patients who underwent esophagectomy between January 2004 and December 2010, the subjects were 54 patients who could be followed up for more than 5 years. Routine oncologic follow-up consisted of CT scanning of the abdomen and chest every 4-6 months and annual endoscopy. Data on the occurrence of pneumonia were collected by retrospective review of chest CT scans. Risk factors for pneumonia investigated by univariate and multivariate analyses included the age, gender, diameter of the stapler, length of the intrathoracic remnant esophagus, anastomotic stricture, and presence of columnar metaplasia in the remnant esophagus. RESULTS: The median age was 62.4 years (interquartile range: 55.8-68.0 years). Forty-three patients were men. Pneumonia was detected in 39 patients (72.2%). The incidence of columnar metaplasia in the remnant esophagus increases with time. Anastomotic stricture was significantly related to the absence of columnar metaplasia on endoscopy in the first year after esophagectomy (p = 0.013). Univariate analysis showed that the frequency of pneumonia was significantly related to the intrathoracic remnant esophagus length ≥4.4 cm (p = 0.014), age over 65 years (p = 0.014), and the presence of columnar metaplasia in the remnant esophagus in the fifth year after esophagectomy (p = 0.005). Among them, age over 65 years and the presence of columnar metaplasia in the remnant esophagus in the fifth year after esophagectomy were found to be independent indicators of the postoperative pneumonia by multivariate analysis. CONCLUSION: Pneumonia occurred in 72.2% (39/54) of patients after esophagectomy for esophageal cancer. The presence of columnar metaplasia after esophagectomy is an indicator for pneumonia over the long term.

Incidence of Esophageal Carcinomas After Surgery for Achalasia: Usefulness of Long-Term and Periodic Follow-up.

BACKGROUND Patients with esophageal achalasia are considered to be a high-risk group for esophageal carcinoma, and it has been reported that this cancer often arises at a long interval after surgery for achalasia. However, it is unclear whether esophageal carcinoma is frequent when achalasia has been treated successfully and the patient is without dysphagia. In this study, we reviewed patients with esophageal carcinoma who were detected by regular follow-up after surgical treatment of achalasia.   CASE REPORT Esophageal cancer was detected by periodic upper GI endoscopy in 6 patients. Most of them had early cancers that were treated by endoscopic resection. All 6 patients had undergone surgery for achalasia and the outcome had been rated as excellent or good. Annual follow-up endoscopy was done and the average duration of follow-up until cancer was seen after surgery was 14.3 years (range: 5 to 40 years). Five patients had early cancer. Four cases had multiple lesions.   CONCLUSIONS In conclusion, surgery for achalasia usually improves passage symptoms, but esophageal cancer still arises in some cases and the number of tumors occurring many years later is not negligible. Accordingly, long-term endoscopic follow-up is needed for detection of malignancy at an early stage.

Esophageal metastasis of renal cancer 10 years after nephrectomy.

The patient was a 65-year-old man, who had undergone right nephrectomy for renal cancer in 2002. At that time, histopathological examination revealed clear cell carcinoma (pT3a, pN0, M0, and pStage III). Postoperatively, he received natural interferon alpha (6 million units 3 times a week) from November 2002 to February 2005, and showed no evidence of recurrence. However, he noticed dysphagia in March 2012. Endoscopy revealed a pedunculated polypoid tumor in the mid-esophagus and biopsies were taken showing a clear cell carcinoma. Contrast-enhanced thoracoabdominal CT scanning identified a pedunculated polypoid tumor in the mid-thoracic esophagus and enlargement of a lymph node adjacent to the right main bronchus. With a diagnosis of esophageal and lymph node metastases of renal cancer, the patient underwent esophagectomy with right thoracotomy with reconstruction by a posterior mediastinal stomach tube. Postoperative histopathological examination revealed clear cell carcinoma. Because esophageal metastasis of renal cancer is extremely rare, this case is reported here together with discussions of the relevant literature.

Application of regenerative medical technology using tissue-engineered cell sheets for endoscopic submucosal dissection of esophageal neoplasms.

We have developed a technique for endoscopic transplantation of cultured autologous oral mucosal epithelial cell sheets to an esophageal ulcer following endoscopic submucosal dissection (ESD). The epithelial cell sheets successfully prevented esophageal stricture after ESD. Key technology is that epithelial cell sheets cultured from oral mucosal tissue and attached proteins can be harvested using cell sheet technology and can be transplanted to a wound site without the use of adhesive material. This regenerative procedure can promote the epithelialization of ulceration safely and effectively. In the near future, the development of advanced endoscopic treatment of regenerative medicine shows promise.

Improvement in the postoperative course of salvage esophagectomy after definitive chemoradiotherapy.

BACKGROUND/AIMS: The aim of this study was to assess the outcome of salvage esophagectomy with less extensive lymphadenectomy, which we have performed since 2003 to improve high mortality and morbidity of standard salvage esophagectomy. METHODOLOGY: We retrospectively compared the surgical outcome of 15 patients who underwent standard salvage esophagectomy via right thoracotomy for thoracic esophageal cancer between 1993 and 2002 (earlier period) with the results of 11 patients between 2003 and 2011 (later period). RESULTS: There were two mortalities in the earlier period, whereas no patient died in the later period, and there was a lower rate of morbidity. In the later period, there was a significantly shorter SIRS duration, lower CRP on postoperative days 1-5, and higher lymphocyte count on postoperative days 2-4. Long-term survival showed no significant difference between the two periods. CONCLUSIONS: Salvage esophagectomy with less extensive lymphadenectomy might improve the surgical outcome while maintaining long-term survival.

Primary esophageal mucosa-associated lymphoid tissue lymphoma treated by endoscopic submucosal dissection.

Primary esophageal mucosa-associated lymphoid tissue (MALT) lymphoma is rare. There have been few reports about early primary esophageal MALT lymphoma being treated endoscopically. The clinical profile of primary esophageal MALT lymphoma is currently unclear, so it is important to accumulate more information about early esophageal MALT lymphoma. To achieve early detection of esophageal MALT lymphoma, we need more accurate knowledge and information about the macroscopic and morphological features of this tumor. Endoscopic resection is one of the most effective treatments. With respect to the lateral and vertical margins of the resected specimen, endoscopic submucosal dissection (ESD) may be superior to endoscopic mucosal resection for treating early esophageal MALT lymphoma. Here we report the macroscopic appearance of the tumor which is the first successful case of ESD for early esophageal MALT lymphoma.

Usefulness of clip traction in the early phase of esophageal endoscopic submucosal dissection.

BACKGROUND: The usefulness of clip traction in endoscopic submucosal dissection (ESD) for early esophageal carcinoma was investigated. METHODS: A total of 87 patients who underwent ESD for esophageal squamous cell carcinoma were included in the study. The hook knife method was used for ESD. Twenty patients underwent ESD without clip traction (non-clip group) and 67 underwent procedures in which clip traction was used (clip group). A clip with a string was attached to the oral edge of the lesion after mucosal incision in the clip group. RESULTS: ESD was successful in all cases. Wide exposure of the submucosal tissue below the lesion was obtained by applying tension to the clip traction. The duration of ESD was shorter in the clip group, and there was a significant difference in duration between the non-clip and clip groups. There were no complications of ESD in the clip group, but muscle layer injury occurred in three patients in the non-clip group. CONCLUSION: Clip traction shortens operating time and is safer in esophageal ESD. Clip traction is recommended as a useful auxiliary procedure.

Prevention of esophageal stricture after endoscopic submucosal dissection using tissue-engineered cell sheets.

BACKGROUND & AIMS: The use of esophageal endoscopic submucosal dissection (ESD) to remove superficial esophageal neoplasms is gradually becoming more common in Japan. However, large-scale esophageal ESD often requires subsequent multiple balloon dilations to prevent postoperative esophageal stricture. We investigated the safety and efficacy of endoscopic transplantation of tissue-engineered autologous oral mucosal epithelial cell sheets in preventing formation of strictures after ESD. METHODS: We performed an open-label, single-arm, single-institute study. We collected specimens of oral mucosal tissue from 9 patients with superficial esophageal neoplasms. Epithelial cell sheets were fabricated ex vivo by culturing isolated cells for 16 days on temperature-responsive cell culture surfaces. After a reduction in temperature, these sheets were endoscopically transplanted directly to the ulcer surfaces of patients who had just undergone ESD. All patients were monitored by endoscopy once a week until epithelialization was complete. RESULTS: Autologous cell sheets were successfully transplanted to ulcer surfaces using an endoscope. Complete re-epithelialization occurred within a median time of 3.5 weeks. No patients experienced dysphagia, stricture, or other complications following the procedure, except for one patient who had a full circumferential ulceration that expanded to the esophagogastric junction. CONCLUSIONS: Sutureless, endoscopic transplantation of carrier-free cell sheets composed of autologous oral mucosal epithelial cells safely and effectively promotes re-epithelialization of the esophagus after ESD. Patients in this study did not experience any serious complications. This procedure might be used to prevent stricture formation following ESD and improve patients' quality of life. Further study will be needed to show that stricture formation can be prevented.

[Docetaxel plus S-1 as a second-line chemotherapy for metastasis or recurrence of esophageal cancer].

Although chemotherapy consisting of cisplatin and 5-fluorouracil(CF)has been a standard regimen for esophageal cancer, it might be difficult to use continuously. This study evaluated the response and safety of docetaxel plus S-1 used as a second line therapy. We reviewed 21 patients(postoperatively, 11; after definitive chemoradiotherapy, 8; after chemotherapy, 2) who received chemotherapy between 2006 and 2010. Metastatic or recurrent disease was detected in the organs(n=8), lymph nodes(n=8), main tumors(n=3), mediastinum(n=1), and pleura(n=1). Docetaxel 30mg/m2 was infused every 2 weeks, and S-1 80mg/m2 was taken for 2 weeks, then with 2 weeks rest until progression. Almost all of the patients received docetaxel in the outpatient chemotherapy room. The median number of treatment cycles was 3, ranging from 1-12. Among the 14 patients with a therapeutic response, three(21%)achieved PR, 8 showed SD, and 3 had PD. Toxicity which included grade 3/4 was neutropenia in 6 patients, and anemia in one patient. After a follow-up of over one year, the median overall survival was 10 months, and the one-year survival rate was 38%. Docetaxel plus S-1 might be a feasible regimen as a second-line chemotherapy for metastasis or recurrence of esophageal cancer.

Partial esophagectomy for a superficial carcinoma arising from the mid-esophageal diverticulum.

A 69-year-old man presented with epigastralgia at a local hospital. Endoscopy detected a superficial esophageal carcinoma arising from a mid-esophageal diverticulum with intraepithelial spread. The patient was referred to our hospital for further examination and treatment. Esophagography showed irregularity in the mid-esophageal diverticulum. Endoscopic ultrasonography (EUS) revealed invasion of the tumor into the proper mucosal muscle layer. No lymph node metastasis was detected on computed tomography or EUS. Partial esophagectomy and lymph node dissection in the mediastinum was performed through a right thoracotomy. An esophageal end-to-end anastomosis was constructed by circular stapler inserted from the stomach through a small laparotomy. Pathologic findings were a well-differentiated squamous cell carcinoma slightly invading the submucosal layer without lymph node metastasis. Although the patient did not have postoperative complications and was discharged 3 weeks after the operation, he suffered an anastomotic stricture requiring endoscopic balloon dilatation. He has survived more than 4 years after the operation without recurrence.

Left thoracoabdominal approach for adenocarcinoma of the esophagogastric junction.

BACKGROUND/AIMS: To evaluate usefulness of esophagogastrectomy via left thoracoabdominal (LT) approach for adenocarcinoma of the esophagogastric junction (AEG), the results of surgery stratified by Siewert's classification, were analyzed retrospectively. METHODOLOGY: The tumor diameter, distance of the proximal tumor border from the esophagogastric junction, and length of the esophagus in the resected specimens of consecutive 171 AEG patients were measured. The surgical approach was classified as total esophagectomy (TE), esophagogastrectomy via LT, or transhiatal/abdominal (HA) approach. RESULTS: Sixteen patients underwent TE, 71 had LT, and 84 had HA. Overall survival of the TE and LT groups was significantly lower than that of the HA group. The difference was seen between LT and HA for type II T3 tumors, but the tumor diameter in LT was significantly larger than that in HA. The approach could not be determined by Siewert's classification, but by distance of proximal tumor border from the junction. The tumors with distance over 5cm might be indicated for the TE approach; 5-3cm, the LT; within 3cm, the HA. The percentage of patients in whom the LT approach is indicated might be only 19%. CONCLUSION: Left thoracoabdominal esophagogastrectomy may be valid for some AEG.

Multimodal treatment for lymph node recurrence of esophageal carcinoma after curative resection.

BACKGROUND: Although esophagectomy with extended lymph node dissection can improve survival of patients with esophageal carcinoma, lymph node metastasis has remained one of the main recurrence patterns. The aim of this study was to evaluate the outcome of intensive treatment for recurrent lymph node metastasis. METHODS: Recurrent lymph node metastasis was detected in 68 patients with thoracic esophageal carcinoma after curative esophagectomy (R0, International Union Against Cancer criteria). Multimodal treatment was performed in 41 patients: 19 patients underwent lymphadenectomy with adjuvant therapy, and 22 received definitive chemoradiotherapy and repeated chemotherapy. The remaining 27 patients (40%) received chemotherapy or best supportive care. RESULTS: Survival of the lymphadenectomy and the chemoradiotherapy groups was significantly better than that of the patients who received chemotherapy or best supportive care (P < .0001). Fifteen patients (79%) underwent curative lymph node dissection (R0) in the lymphadenectomy group. Complete response, partial response, and stable disease were obtained in 8 (37%), 10 (45%), and 4 (18%) patients who received chemoradiotherapy, respectively. There was no statistically significant difference in survival between the lymphadenectomy and the chemoradiotherapy groups. Although the location of lymph node metastasis did not influence survival significantly, seven patients with nodes around the abdominal aorta did not survive longer than 3 years. The most common repeat recurrence pattern was organ metastasis after the treatment. Multivariate analysis showed that the number of metastatic nodes and tumor marker were independent prognostic factors. CONCLUSION: Multimodal treatment including lymphadenectomy and chemoradiotherapy could improve survival of the patients with lymph node recurrence of esophageal carcinoma after curative resection.

Chemoradiotherapy with and without esophagectomy for advanced esophageal cancer.

BACKGROUND/AIMS: To evaluate the impact of surgery on survival after chemoradiotherapy, we analyzed the long-term outcome of patients with advanced esophageal cancer. METHODOLOGY: Data on 92 consecutive patients with T3 or T4 esophageal cancer who were initially treated by chemoradiotherapy were reviewed retrospectively. Of 82 patients who completed the planned schedule, 35 patients underwent esophagectomy (CRT+E Group) and 47 patients received definitive chemoradiotherapy (CRT Group). RESULTS: A response to chemoradiotherapy was obtained in 71% of all 92 patients. The 1- and 3-year survival rates in the patients with T3M0 were 87 and 44 percent respectively, while these in the patients with T4 and/or M1(Lymph) disease were 47 and 20 percent. Although there was no difference in overall survival between the CRT+E Group and the CRT Group, the survival of responders in the CRT+E Group was significantly higher than that of those in the CRT Group (P=0.0448). The locoregional recurrence rate of responders in the CRT Group was higher than that in the CRT+E Group. Multivariate analysis showed that the independent prognostic factors were response, M(Lymph), and esophagectomy. CONCLUSIONS: Although this study was retrospective and nonrandomized, esophagectomy after chemoradiotherapy might improve the survival of responders for locoregional control.

[The study of the autopsies of six patients with progressive esophageal cancer to investigate complications caused by esophageal stents].

Endoscopic placement of metal stents are used widely for patients with esophageal obstruction and fistula due to progressive esophageal cancer, but cause high rate of severe complications associated with the immediate causes of death. To determine severe complications caused by stents, we studied clinical data and autopsy of six patients who had been treated with stents for inoperable progressive esophageal cancer. Occording to the clinical records only two patients had severe complications due to stents. But at autopsy, three patients had massive hemorrhage in the stent placement, one patient had mediastinitis, and one patient were in imminent danger of perforation whose stent had been incorporated into the adventitia of the wall. More severe complications were revealed than those expected clinically. Endoscopic placement of metal stents have a great deal for the improvement of quality of life. But we should carefully decide the indication because endoscopic placement of metal stents could cause severe complications associated with the immediate causes of death.