A Single-Arm Confirmatory Study of Definitive Chemoradiation Therapy Including Salvage Treatment for Clinical Stage II/III Esophageal Squamous Cell Carcinoma (JCOG0909 Study).

PURPOSE: Definitive chemoradiotherapy (CRT) is the standard treatment for patients with locally advanced esophageal cancer (EC) who refuse surgery as the initial therapy. However, poor survival, a high incidence of late toxicities, and severe complications after salvage surgery remain issues to be resolved. This single-arm multicenter trial (JCOG0909) aimed to confirm the efficacy of CRT modifications, including salvage treatment for reducing CRT-related toxicities and facilitating salvage treatment for improved survival. METHODS AND MATERIALS: Patients with clinical stage II/III EC (International Union Against Cancer sixth edition, non-T4) were eligible. Chemotherapy comprised cisplatin (75 mg/m2 on days 1 and 29) and 5-fluorouracil (1000 mg/m2/d on days 1-4 and 29-32). Radiation therapy was administered at a total dose of 50.4 Gy. Good responders received 1 to 2 additional cycles of chemotherapy. For residual or recurrent disease, salvage endoscopic resection or salvage surgery was performed based on specific criteria. The primary endpoint was 3-year overall survival (OS). The calculated sample size was 95 patients, with a 1-sided alpha of 5% and a power of 80%. The expected and threshold 3-year OS were 55% and 42%, respectively. RESULTS: Overall, 96 patients were enrolled, and 94 were included in the efficacy analysis. A complete response was achieved in 55 patients (59%). Salvage endoscopic resection and salvage surgery were performed in 5 (5%) and 25 patients (27%), respectively. R0 resection by salvage surgery was achieved in 19 patients (76%). Five patients (20%) showed grade 3 or 4 early operative complications, and 9 patients (9.6%) showed grade 3 late toxicities during the long-term follow-up. The 3-year OS was 74.2% (90% confidence interval, 65.9%-80.8%). CONCLUSION: The combination of definitive CRT and salvage treatment has lower CRT-related toxicities and yields good OS, thus making it a promising novel treatment option for patients with locally advanced EC.

Second primary malignancies in patients with clinical T1bN0 esophageal squamous cell carcinoma after definitive therapies: supplementary analysis of the JCOG trial: JCOG0502.

BACKGROUND: Previous studies have suggested that patients with esophageal squamous cell carcinoma (ESCC) are still at a high risk of developing second primary malignancies (SPMs) after definitive therapies. We evaluated the development of SPMs and explored its risk factors in patients with clinical T1bN0 ESCC. METHODS: JCOG0502 prospectively compared esophagectomy with definitive chemo-radiotherapy for clinical T1bN0 ESCC. Here, we reviewed all JCOG0502 patients' data for SPMs and investigated the risk factors for SPMs using uni-variable and multivariable analyses by Fine and Gray model. RESULTS: Among 379 enrolled patients, 213 underwent esophagectomy and 166 received chemo-radiotherapy. Patient characteristics were male (85%); median age [63 (range 41-75) years; location of the primary tumor (upper/middle/lower thoracic esophagus, 11%/63%/27%, respectively]; alcohol consumption history (79%); smoking history (66%); prevalence of no/several/many/unknown Lugol-voiding lesions (LVLs) (45%/36%/8%/11%, respectively). In a median follow-up of 7.1 years, 118 SPMs occurred in 99 (26%) patients. Cumulative incidences of SPMs after 3, 5, and 10 years were 9%, 15%, and 36%, respectively. The most common primary tumor sites were the head and neck (35%), stomach (20%) and lungs (14%). In multivariable analyses, compared to no LVLs, several LVLs [hazard ratio (HR) 2.24, 95% confidential interval (CI) 1.32-3.81] and many LVLs (HR 2.88, 95% CI 1.27-6.52) were significantly associated with the development of SPMs. Sixteen patients died due to the SPMs. CONCLUSION: The incidence of SPMs was high. The presence of LVLs, which was a predictive factor for SPMs, may be useful for surveillance planning.

Prognostic biomarker study in patients with clinical stage I esophageal squamous cell carcinoma: JCOG0502-A1.

We undertook genomic analyses of Japanese patients with stage I esophageal squamous cell carcinoma (ESCC) to investigate the frequency of genomic alterations and the association with survival outcomes. Biomarker analysis was carried out for patients with clinical stage T1bN0M0 ESCC enrolled in JCOG0502 (UMIN000000551). Whole-exome sequencing (WES) was performed using DNA extracted from formalin-fixed, paraffin-embedded tissue of ESCC and normal tissue or blood sample. Single nucleotide variants (SNVs), insertions/deletions (indels), and copy number alterations (CNAs) were identified. We then evaluated the associations between each gene alteration with a frequency of 10% or more and progression-free survival (PFS) using a Cox regression model. We controlled for family-wise errors at 0.05 using the Bonferroni method. Among the 379 patients who were enrolled in JCOG0502, 127 patients were successfully analyzed using WES. The median patient age was 63 years (interquartile range, 57-67 years), and 78.0% of the patients ultimately underwent surgery. The 3-year PFS probability was 76.3%. We detected 20 genes with SNVs, indels, or amplifications with a frequency of 10% or more. Genomic alterations in FGF19 showed the strongest association with PFS with a borderline level of statistical significance of P = .00252 (Bonferroni-adjusted significance level is .0025). Genomic alterations in FGF4, MYEOV, CTTN, and ORAOV1 showed a marginal association with PFS (P < .05). These genomic alterations were all CNAs at chromosome 11q13.3. We have identified new genomic alterations associated with the poor efficacy of ESCC (T1bN0M0). These findings open avenues for the development of new potential treatments for patients with ESCC.

Long-term survival of patients with T1bN0M0 esophageal cancer after thoracoscopic esophagectomy using data from JCOG0502: a prospective multicenter trial.

BACKGROUND: Thoracoscopic esophagectomy (TE) is considered the standard surgery for esophageal cancer because of its superiority over open esophagectomy (OE) in terms of short-term outcomes. However, few prospective multicenter studies have evaluated its long-term survival after TE. This study aimed to investigate whether the prognosis for patients with T1bN0M0 esophageal cancer after TE is not inferior to OE using data from the Japan Clinical Oncology Group Study (JCOG0502), a prospective multicenter trial comparing esophagectomy with chemoradiotherapy. METHODS: Data of patients in JCOG0502 after esophagectomy were used to compare the overall survival (OS) and relapse-free survival (RFS) after OE versus TE. OE or TE was selected at the surgeon's discretion. A hazard ratio and 95% confidence interval (CI) were calculated via Cox proportional-hazards model. RESULTS: Of the 210 patients who underwent esophagectomy, 109 underwent OE, whereas 101 underwent TE. The 5-year OS was 88.9% after OE and 85.0% after TE. The hazard ratio of TE for OS was 1.53 (95% CI, 0.84-2.78; p = 0.16) and 1.10 (95% CI, 0.52-2.35; p = 0.80) in the univariable and multivariable analyses, respectively. The 5-year RFS was 85.3% after OE and 79.1% after TE. The hazard ratio of TE for RFS was 1.39 (95% CI, 0.81-2.38; p = 0.23) and 0.88 (95% CI, 0.44-1.74; p = 0.70) in the univariable and multivariable analyses, respectively. CONCLUSION: The prognosis for patients with T1bN0M0 esophageal cancer after TE was not inferior to OE.

Severe reflux esophagitis after total gastrectomy successfully treated by transposition of the jejunojejunal anastomosis: a report of two cases.

BACKGROUND: Reflux esophagitis after total gastrectomy is often difficult to treat. In this report, we describe two cases of reflux esophagitis that were refractory to medical therapy and successfully treated by transposition of the jejunojejunal anastomosis. CASE PRESENTATION: Case 1: A 66-year-old man underwent total gastrectomy and cholecystectomy for gastric cancer, and Roux-en-Y (RY) reconstruction was performed. The pathological diagnosis was T4aN3aM0 stage IIIC. Five months later, esophagogastroduodenoscopy identified reflux esophagitis. Although he was treated with various oral medications and was hospitalized six times, he lost 19 kg of weight. Finally, the patient was reoperated 3 years postoperatively. Intraoperative findings showed that there was no evidence of recurrence or severe adhesions that could have caused obstruction, and the anastomotic distance between the esophagojejunostomy and the jejunojejunostomy was approximately 40 cm. The jejunojejunostomy was re-anastomosed to increase the distance to 100 cm. Two years and 6 months after the reoperation, there was no recurrence of reflux esophagitis, and the patient's weight increased by 14 kg. Case 2: A 68-year-old woman underwent total gastrectomy and cholecystectomy for gastric cancer, and RY reconstruction was performed. The pathological diagnosis was T4aN0M0 stage IIB. Similar to Case 1, the patient was diagnosed with reflux esophagitis 5 months later. She lost 23 kg of weight and was reoperated at 6 months postoperatively. Intraoperative findings showed that there was no evidence of recurrence or severe adhesions, and transposition of the jejunojejunostomy was performed to increase the distance between anastomoses from 40 to 100 cm. Two years and 8 months after the reoperation, there was no recurrence of reflux esophagitis, and her weight increased by 15 kg. CONCLUSIONS: Transposition of the jejunojejunostomy was an effective treatment for medication-resistant severe reflux esophagitis after total gastrectomy.

Parallel-Group Controlled Trial of Surgery Versus Chemoradiotherapy in Patients With Stage I Esophageal Squamous Cell Carcinoma.

BACKGROUND & AIMS: Surgery is the standard of care for T1bN0M0 esophageal squamous cell carcinoma (ESCC), whereas chemoradiotherapy (CRT) is a treatment option. This trial aimed to investigate the noninferiority of CRT relative to surgery for T1bN0M0 ESCC. METHODS: Clinical T1bN0M0 ESCC patients were eligible for enrollment in this prospective nonrandomized controlled study of surgery versus CRT. The primary endpoint was overall survival, which was determined using inverse probability weighting with propensity scoring. Surgery consisted of an esophagectomy with 2- or 3-field lymph node dissection. CRT consisted of 2 courses of 5-fluorouracil (700 mg/m2) on days 1-4 and cisplatin (70 mg/m2) on day 1 every 4 weeks with concurrent radiation (60 Gy). RESULTS: From December 20, 2006 to February 5, 2013, a total of 368 patients were enrolled in the nonrandomized portion of the study. The patient characteristics in surgery arm and CRT arm, respectively, were as follows: median age, 62 and 65 years; proportion of males, 82.8% and 88.1%; and proportion of performance status 0, 99.5% and 98.1%. Comparisons were made using the nonrandomized groups. The 5-year overall survival rate was 86.5% in the surgery arm and 85.5% in the CRT arm (adjusted hazard ratio, 1.05; 95% confidence interval, 0.67-1.64 [<1.78]). The complete response rate in the CRT arm was 87.3% (95% confidence interval, 81.1-92.1). The 5-year progression-free survival rate was 81.7% in the surgery arm and 71.6% in the CRT arm. Treatment-related deaths occurred in 2 patients in the surgery arm and none in the CRT arm. CONCLUSIONS: CRT is noninferior to surgery and should be considered for the treatment of T1bN0M0 ESCC.

The association of primary tumor site with acute adverse event and efficacy of definitive chemoradiotherapy for cStage II/III esophageal cancer: an exploratory analysis of JCOG0909.

BACKGROUND: JCOG0909 is a phase II trial of definitive chemoradiotherapy including salvage treatment for cStage II-III thoracic esophageal cancer; the radiation field for elective regional lymph node irradiation, which can affect patient outcome and adverse event, varied based on the primary tumor site, i.e., upper (Ut), middle (Mt), and lower thoracic (Lt) esophagus. The impact of different primary sites on the safety and efficacy of definitive chemoradiotherapy in JCOG0909 is not well characterized. METHODS: Patients were categorized into three groups (Ut, Mt, and Lt) according to the primary tumor location. We compared acute adverse events during definitive chemoradiotherapy, complete response (CR) rate, 3-year progression-free survival (PFS), and overall survival (OS) among the 3 groups. RESULTS: Out of the 96 patients enrolled in JCOG0909 between April 2010 and August 2014, 94 patients (16, 59, and 19 patients in the Ut, Mt, and Lt groups, respectively) were included in this exploratory analysis. The proportion of patients with cStage III was 25% in the Ut, 37% in the Mt, and 47% in the Lt group. Grade 3-4 leukopenia, neutropenia, and thrombocytopenia were more frequently observed in the Mt (66%, 54%, and 15%) and Lt groups (84%, 68%, and 16%) than in the Ut group (38%, 44%, and 0%). There was no significant between-group difference with respect to 3-year OS (73.3%, 77.9%, and 57.9%), 3-year PFS (60.0%, 59.3%, and 47.4%), or CR rate (62.5%, 62.7%, and 42.1%). CONCLUSIONS: In JCOG0909, the incidence of severe hematological toxicity had a trend toward higher in the Mt and Lt than the Ut esophageal cancer; however, no remarkable difference by primary sites was observed with respect to efficacy endpoints.

Rare squamous cell carcinoma arising from a presacral epidermoid cyst: A case report.

INTRODUCTION: Presacral epidermoid cysts are uncommon, usually benign cysts caused by developmental abnormalities in the fetal period. We present a rare case of squamous cell carcinoma arising from a presacral epidermoid cyst. PRESENTATION OF CASE: A 59-year-old woman complained of tenesmus and discomfort in the buttocks. Computed tomography revealed a 50-mm well-defined cystic mass in the presacrum and a 70-mm solid mass extending from the cyst into the rectum, vagina, and left sciatic spine. On T1-weighted magnetic resonance images, the cyst was unilocular and the mass was marginated with low intensity. On T2-weighted images, the mass had high intensity. A malignant presacral developmental cyst was diagnosed, without obvious metastasis. Using abdominal and parasacral approaches, Hartmann's operation was performed with multiorgan resection, including the sacrum, coccyx, left sciatic spine, internal obturator muscle, rectum, and uterine appendage. Histopathology of the excised specimen revealed a squamous cell carcinoma originating from the presacral epidermoid cyst. DISCUSSION: Reports of malignant transformation of epidermoid cysts in the presacral space, as in the present case, are extremely rare. Because of their unusual location and slow growth, epidermoid cysts tend to remain asymptomatic. Because the patient had a malignant tumor with suspected invasion of adjacent organs, combination surgery was selected. CONCLUSION: Although further research is required, presacral epidermoid cysts are extremely rare and may be malignant. Thorough preoperative image evaluation is crucial for complete resection.

Concordance of clinical diagnosis of T classification among physicians for locally advanced unresectable thoracic esophageal cancer.

BACKGROUND: We conducted a multicenter phase II trial assessing chemoselection with docetaxel plus 5-fluorouracil and cisplatin induction chemotherapy and subsequent conversion surgery for locally advanced, unresectable esophageal cancer. The aim of this study was to validate the concordance of clinical T diagnosis among physicians in the cases of this trial. METHODS: Computed tomography scans and esophagoscopic images of 48 patients taken at baseline were centrally reviewed by 6 senior physicians with experience in esophageal oncology. Individual reviewers voted for definitive T4, relative T4, relative T3, or definitive T3. Discordant diagnoses between reviewers were resolved by the majority opinion. The reviewers were blinded to patient clinical outcome data and to the vote of the other reviewers. RESULTS: Ninety percent of cases were diagnosed as clinical T4 by investigators, while 33.3-75.0% (median 70.8%) of cases were judged to be T4 by 6 reviewers. Discordant diagnosis between investigators and reviewers occurred in 33% (16/48) of all cases (Cohen's kappa coefficient 0.0519), including 12 cases where curative resection was considered possible (48%, n = 25) and 4 cases where curative resection was considered impossible (17%, n = 23). Critical discordance (one reviewer voted for definitive T3 but the other voted for definitive T4, and vice versa) between reviewers occurred in 0-12.5% of cases (median 2.1%). CONCLUSIONS: There were inter-observer variations in clinical diagnosis of the T category of locally advanced, unresectable esophageal cancer. Accurate clinical diagnosis of T classification is required for determining the optimum treatment for each patient.

Impact of laparoscopy on the prevention of pulmonary complications after thoracoscopic esophagectomy using data from JCOG0502: a prospective multicenter study.

BACKGROUND: Postoperative pulmonary complications (PPCs) are the most common causes of serious morbidity after esophagectomy, which involves both thoracic and abdominal incisions. Although the thoracoscopic approach decreases PPC frequency after esophagectomy, it remains unclear whether the frequency is further decreased by combining it with laparoscopic gastric mobilization. This study aimed to determine the impact of laparoscopy on the prevention of PPCs after thoracoscopic esophagectomy using data from the Japan Clinical Oncology Group Study 0502 (JCOG0502). METHODS: JCOG0502 is a four-arm prospective study comparing esophagectomy with definitive chemo-radiotherapy. The use of thoracoscopy and/or laparoscopy was decided at the surgeon's discretion. PPCs were defined as one or more of the following postoperative morbidities grade ≥2 (as per Common Terminology Criteria for Adverse Events v3.0): pneumonia, atelectasis, and acute respiratory distress syndrome. RESULTS: A total of 379 patients were enrolled in JCOG0502. Of these, 210 patients underwent esophagectomy via thoracotomy with laparotomy (n = 102), thoracotomy with laparoscopy (n = 7), thoracoscopy with laparotomy (n = 43), and thoracoscopy with laparoscopy (n = 58). PPC frequency was reduced to a greater extent by thoracoscopy than by thoracotomy (thoracoscopy 15.8%, thoracotomy 30.3%; p = 0.015). However, following thoracoscopic esophagectomy, laparoscopy failed to further decrease the PPC frequency compared with laparotomy (laparoscopy 15.5%, laparotomy 16.3%; p = 1.00). Univariable analysis showed that thoracoscopy (shown above) and less blood loss (<350 mL 16.3%, ≥350 mL 30.2%; p = 0.022) were associated with PPC prevention, whereas laparoscopy showed a borderline significant association (laparoscopy 15.4%, laparotomy 26.9%; p = 0.079). Multivariable analysis also showed that thoracoscopy and less blood loss were associated with PPC prevention. CONCLUSION: Thoracoscopic approach to esophagectomy significantly reduced PPC frequency with minimal additional effect from laparoscopic gastric mobilization.

The Prevalence of Overall and Initial Lymph Node Metastases in Clinical T1N0 Thoracic Esophageal Cancer: From the Results of JCOG0502, a Prospective Multicenter Study.

OBJECTIVE: To evaluate the sites and frequencies of overall and initial lymph node (LN) metastases (LNMs) of clinical T1N0 esophageal cancer. BACKGROUND: The sites and frequencies of initial LNMs and sentinel LNs (SLNs) of esophageal cancer remain unclear. METHODS: The Japan Clinical Oncology Group JCOG0502 trial was a 4-arm prospective study that compared esophagectomy with chemoradiotherapy for clinical T1N0 esophageal cancer in both randomized and patient-preference arms. The preoperative diagnostic accuracy was evaluated for patients assigned to the surgery arm. Patients who withdrew consent and who were not treated were excluded. All patients underwent esophagectomy with D2 or greater LN dissection. From the pathologic findings, sites and frequencies of LNMs and SLNs were assessed and the frequency of skip LNMs was calculated. RESULTS: In total, 211 patients underwent LNM and SLN analysis. Regarding N-factor accuracy, 57 (27.0%) of 211 clinical N0 cases had pathologic LNMs. The upper mediastinal and mediastinal/abdominal regions were frequent sites of LNMs in upper and lower thoracic cases, respectively. However, in middle thoracic cases, LNMs were observed in the neck, mediastinal, and abdominal regions, and pathologic SLN spread to all 3 fields. The frequency of skip LNMs was 36.7%. CONCLUSIONS: A clinical diagnosis of T1N0 is not sufficiently accurate, and therefore, it is unacceptable to omit LN dissection or minimize the prophylactic radiation field. SLNs, which are not location restricted, should be surveyed in all 3 fields.

Theoretical therapeutic impact of lymph node dissection on adenocarcinoma and squamous cell carcinoma of the esophagogastric junction.

BACKGROUNDS: The aim of this study was to evaluate the theoretical therapeutic impact of dissecting each lymph node station for adenocarcinoma and squamous cell carcinoma of the esophagogastric junction. METHODS: This multicenter study included 431 junctional cancer patients (381 adenocarcinomas and 50 squamous cell carcinomas) who fulfilled the following criteria: (1) the center of the tumor was located between 1 cm above and 2 cm below the esophagogastric junction, and (2) the tumor invaded the junction. The theoretical therapeutic impact of dissecting each lymph node station was evaluated based on the therapeutic value index calculated by multiplying the frequency of metastasis to each station and the 5-year survival rate of patients with metastasis to that station. RESULTS: The 5-year overall survival rates (95% confidence interval) were 60.4% (55.1-65.7) in the adenocarcinoma cases and 52.3% (35.6-69.0) in the squamous cell carcinoma cases. The nodal stations showing the first to fifth highest index were the paracardial and lesser curvature nodes (nos. 1, 2 and 3), nodes at the root of the left gastric artery (no. 7) and lower mediastinal lymph nodes, regardless of the histology. CONCLUSIONS: Nodal dissection achieved by proximal gastrectomy and lower esophagectomy should be the minimal requirement for junctional cancer regardless of the histology, considering the therapeutic value indices for the relevant lymph node stations.

Evaluation of safety profile of thoracoscopic esophagectomy for T1bN0M0 cancer using data from JCOG0502: a prospective multicenter study.

BACKGROUND: Thoracoscopic esophagectomy is rapidly and increasingly being used worldwide because it is a less invasive alternative to open esophagectomy. However, few prospective multicenter studies have evaluated its safety profile. This study aimed to evaluate the safety profile of thoracoscopic esophagectomy using perioperative data from the Japan Clinical Oncology Group Study (JCOG0502). METHODS: JCOG0502 is a four-arm prospective study comparing esophagectomy with chemoradiotherapy for esophageal cancer, with randomized and patient preference arms. Patients with clinical stage T1bN0M0 esophageal cancer were enrolled until patient accrual was completed. Open or thoracoscopic esophagectomy was selected at the surgeon's discretion. Perioperative complications were defined as adverse events of ≥grade 2 as per Common Terminology Criteria for Adverse Events ver. 3.0. RESULTS: A total of 379 patients were enrolled between December 2006 and February 2013. Of the 210 patients who underwent surgery, 109 patients underwent open esophagectomy, and 101 patients underwent thoracoscopic esophagectomy. Although thoracoscopic esophagectomy decreased the incidence of postoperative atelectasis (open: 22.0%, thoracoscopy: 10.9%; P = 0.041), reoperation was more frequent in the thoracoscopy group (open: 1.8%, thoracoscopy: 9.9%; P = 0.016). The incidence of overall complications did not differ between the two groups (open: 44.0%, thoracoscopy: 44.6%; P = 1.00). There was one in-hospital death in each group (open: 0.9%, thoracoscopy: 1.0 %; P = 1.00). CONCLUSIONS: Thoracoscopic esophagectomy is a safe procedure with morbidity and mortality comparable with those of open esophagectomy. However, it is associated with a higher frequency of reoperation.

Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial.

BACKGROUND: The prognosis for locally advanced gastric cancer is poor despite advances in adjuvant chemotherapy. We did the Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) to assess the superiority of sequential treatment (paclitaxel then tegafur and uracil [UFT] or paclitaxel then S-1) compared with monotherapy (UFT or S-1) and also the non-inferiority of UFT compared with S-1. METHODS: We did this randomised phase 3 trial with a two-by-two factorial design at 230 hospitals in Japan. We enrolled patients aged 20-80 years with T4a or T4b gastric cancer, who had had D2 dissection and a ECOG performance score of 0-1. Patients were randomly assigned to one of four treatment groups with minimisation for tumour size, lymph node metastasis, and study site. Patients received UFT only (267 mg/m(2) per day), S-1 only (80 mg/m(2) per day) for 14 days, with a 7-day rest period or three courses of intermittent weekly paclitaxel (80 mg/m(2)) followed by either UFT, or S-1. Treatment lasted 48 weeks in monotherapy groups and 49 weeks in the sequential treatment groups. The primary endpoint was disease-free survival assessed by intention to treat. We assessed whether UFT was non-inferior to S-1 with a non-inferiority margin of 1·33. This trial was registered at UMIN Clinical Trials Registry, number C000000082. FINDINGS: We randomly assigned 1495 patients between Aug 3, 2004, and Sept 29, 2009. 374 patients were assigned to receive UFT alone, 374 to receive S-1 alone, 374 to received paclitaxel then UFT, and 373 to receive paclitaxel then S-1. We included 1433 patients in the primary analysis after at least 3 years of follow-up (359, 364, 355, and 355 in each group respectively). Protocol treatment was completed by 215 (60%) patients in the UFT group, 224 (62%) in the S-1 group, 242 (68%) in the paclitaxel then UFT group, and 250 (70%) in the paclitaxel then S-1 group. 3-year disease-free survival for monotherapy was 54·0% (95% CI 50·2-57·6) and that of sequential treatment was 57·2% (53·4-60·8; hazard ratio [HR] 0·92, 95% CI 0·80-1·07, p=0·273). 3-year disease-free survival for the UFT group was 53·0% (95% CI 49·2-56·6) and that of the S-1 group was 58·2% (54·4-61·8; HR 0·81, 95% CI 0·70-0·93, p=0·0048; pnon-inferiority=0·151). The most common grade 3-4 haematological adverse event was neutropenia (41 [11%] of 359 patients in the UFT group, 48 [13%] of 363 in the S-1 group, 46 [13%] of 355 in the paclitaxel then UFT group, and 83 [23%] of 356 in the paclitaxel then S-1 group). The most common grade 3-4 non-haematological adverse event was anorexia (21 [6%], 24 [7%], seven [2%], and 18 [5%], respectively). INTERPRETATION: Sequential treatment did not improve disease-free survival, and UFT was not non-inferior to S-1 (and S-1 was superior to UFT), therefore S-1 monotherapy should remain the standard treatment for locally advanced gastric cancer in Japan. FUNDING: Epidemiological and Clinical Research Information Network.

Hand-sewn anastomotic technique after esophageal cancer resection.

BACKGROUND/AIMS: Mechanical stapled anastomosis can be performed easily and quickly in esophagogastrostomy after esophageal cancer resection. However, we have performed cervical hand-sewn anastomosis in the esophagogastrostomy. Here we introduce the surgical technique and report the outcomes after the anastomosis. METHODOLOGY: The gastric tube is pulled up via the posterior mediastinal route. A single layer of Gambee sutures is used to approximate the cervical esophagus and the posterior wall of the gastric tube in end-to-side fashion. After the anastomosis, the redundant part in the gastric tube apex is removed. We analyzed 152 consecutive patients who underwent this anastomosis in our institute from 1999 to 2012. RESULTS: There was no postoperative mortality. We experienced anastomotic leakage in 7 patients (5%) and anastomotic stenosis in 5 patients (3%). CONCLUSIONS: The anastomotic complication rates in the hand-sewn anastomosis were comparable to those of the mechanical stapled anastomosis in the previous reports.

Incidence of metachronous gastric cancer in the remnant stomach after synchronous multiple cancer surgery.

BACKGROUND: In the preoperative evaluation for gastric cancer, high-resolution endoscopic technologies allow us to detect small accessory lesions. However, it is not known if the gastric remnant after partial gastrectomy for synchronous multiple gastric cancers has a greater risk for metachronous cancer. The purpose of this study was to determine the incidence of metachronous cancer in this patient subset compared with that after solitary cancer surgery. METHODS: Data on a consecutive series of 1,281 patients gastrectomized for early gastric cancer from 1991 to 2007 were analyzed retrospectively. The 715 gastric remnants after distal gastrectomy were periodically surveyed by endoscopic examination in Shikoku Cancer Center. Among those surveyed cases, 642 patients were pathologically diagnosed with solitary lesion (SO group) and 73 patients with synchronous multiple lesions (MU group) at the time of the initial surgery. RESULTS: In the follow-up period, 15 patients in the SO group and 3 patients in the MU group were diagnosed as having metachronous cancer in the gastric remnant. The cumulative 4-year incidence rate was 1.9 % in the SO group and 5.5 % in the MU group. The difference did not reach the significant level by the log-rank test. CONCLUSIONS: The incidence of metachronous cancer is higher after multiple cancer surgery; however, the difference is not statistically significant.

SPRR2A expression in cholangiocarcinoma increases local tumor invasiveness but prevents metastasis.

Cholangiocarcinoma morbidity and mortality is attributable to local invasiveness and regional lymph node and distant organ metastasis. Cholangiocarcinoma progression follows a series of sequential events that resemble wound healing reactions: local invasion resembles the epithelial migration phase involving epithelial-mesenchymal transition (EMT); colonization at distant sites resembles epithelial restitution seen during the reverse process, mesenchymal-epithelial transition (MET). In this study we compare the in vivo local and metastatic growth potential of cholangiocarcinoma cell lines with respect to expression of a novel pSTAT3-dependent, biliary epithelial cell wound healing protein, small proline-rich protein 2A (SPRR2A). SPRR2A has been associated with local aggressiveness, but decreased metastatic capabilities in other cancers. Stable SPRR2A transfection into two cholangiocarcinoma cell lines (SG231 and HuCCT-1), previously shown by us to induce permanent EMT, resulted in local aggressiveness but an inability to form metastases. In contrast, SPRR2A-negative epithelial control cells showed relatively poor local aggressiveness, but readily formed metastatic tumors. Post-intrasplenic injection cell tracking showed that: (a) mesenchymal (SPRR2A+) cells were not trapped in the liver, but were rapidly cleared through mesenteric lymph nodes and did not form metastases; whereas (b) epithelial (SPRR2A-) controls were primarily entrapped within MUC-1-associated liver "micro-infarcts" that later evolved into metastatic colonies. SPRR2A-associated tumor behavior was mimicked by MUC1 shRNA, which induced EMT and, like SPRR2A+ cells, showed reduced metastatic capabilities. Cholangiocarcinoma local invasion involves EMT processes, whereas MET and MUC1 expression promote metastasis. A better understanding of disease progression should help target treatment for this deadly neoplasm.

[A case of reversible encephalopathy syndrome caused by hyponatremia during neoadjuvant 5-FU+CDDP therapy for esophageal cancer].

We present a case of reversible encephalopathy syndrome caused by hyponatremia during neoadjuvant chemotherapy with 5-FU+CDDP for esophageal cancer. A 52-year-old woman visited another hospital with the complaint of discomfort during swallowing. Upper gastrointestinal endoscopy revealed an ulcerated lesion in the lower thoracic esophagus, which was pathologically diagnosed as squamous cell carcinoma. She was admitted to our institution, and the diagnosis of esophageal cancer Mt-Lt, type 2, cT2N1M0, stage II was made. We obtained informed consent for her treatment with both CRT and surgery, and she selected surgery. Therefore, she was administered neoadjuvant chemotherapy with 5-FU+CDDP therapy. On day 4, abnormalities of the central nerve, such as unconsciousness, difficulty in speaking, and muscle cramps were, observed. After the examinations she was diagnosed with encephalopathy. It should be noted that hyponatremia induced by renal sodium wasting syndrome(RSWS)was considerd to be the cause, and we report our case with the literature cited.

Long-term outcome after proximal gastrectomy with jejunal interposition for gastric cancer compared with total gastrectomy.

BACKGROUND: Proximal gastrectomy (PG) has been widely accepted as treatment for early gastric cancer located in the upper third of the stomach. Reconstruction by jejunal interposition has been known to reduce reflux esophagitis for PG patients. The aim of this study was to compare the long-term outcomes of patients who underwent PG with jejunal interposition with those treated by total gastrectomy (TG). METHODS: Data on 102 cases of PG with jejunal interposition and 49 cases of TG with Roux-Y reconstruction for gastric cancer were analyzed retrospectively in terms of overall survival, weight maintenance, anemia and nutritional status, and endoscopic findings. RESULTS: Median follow-up time was 59 months in the both groups. There was no significant difference in the overall 5-year survival rate between the PG group (94%) and the TG group (84%). The PG group showed significantly better body weight maintenance at the first year. The laboratory blood tests showed that the PG group had a significantly better red blood cell count and hemoglobin and hematocrit levels at the second and third year. However, postoperative endoscopic surveillance detected reflux esophagitis (3%), peptic ulcer (9%), and metachronous gastric cancer (5%) in the PG group. CONCLUSIONS: Proximal gastrectomy maintains comparable oncological radicality to TG and is preferred over TG in terms of preventing postoperative anemia. However, periodic endoscopic follow-up is necessary to monitor the upper gastrointestinal tract.