Relationship between cervical esophageal squamous cell carcinoma and human papilloma virus infection and gene mutations.

Cervical esophageal squamous cell carcinoma (CESCC) is rare, accounting for 5% of all esophageal carcinomas. Several diagnostic and predictive markers have been studied. However, to the best of our knowledge, no biomarker is known to determine patient management except the clinical stage. The present study aimed to evaluate whether human papilloma virus (HPV) infection, epidermal growth factor receptor (EGFR) and its pathway-related gene mutations, known to be sensitive biomarkers of oropharyngeal carcinomas, could be used as biomarkers for the prediction of the prognosis of patients with CESCC. The present retrospective study included patients with CESCC who received chemoradiotherapy or surgery. HPV infection and the genomic status of EGFR, KRAS, BRAF, NRAS and PIK3CA of each tumor sample from patients with CESCC were analyzed by in situ hybridizations (ISH) and PCR methods, respectively. The present study included 33 patients with CESCC (male/female, 29/4; median age, 62 years; age range, 41-86 years; clinical stage I/II/III/IV, 2/6/10/15). The present study detected HPV in one patient (3.0%) by ISH and PCR. Concerning the investigation of EGFR and its pathway-related gene mutations, the present study detected 15.1% of EGFR, 6.0% of NRAS, 3.5% of BRAF, 3.0% of KRAS and 3.0% for PIK3CA mutations, with no significant relationship between any gene mutations and the clinical prognostic factors. The HPV-infected patient did not exhibit any gene mutations. The present study indicated that HPV infection, EGFR and its pathway-related gene mutations rarely exist in patients with CESCC. The relationship between these biomarkers and the prognosis in patients with CESCC is still unclear.

FGF5 methylation is a sensitivity marker of esophageal squamous cell carcinoma to definitive chemoradiotherapy.

Definitive chemoradiotherapy (dCRT) is the major treatment for esophageal squamous cell carcinoma (ESCC), and prediction of the response to dCRT is important so as not to miss an opportunity to cure an ESCC. Nevertheless, few validated markers are available. Here, we aimed to identify a highly reproducible marker using multi-layer omics analysis. 117 ESCC samples from 67 responders and 50 non-responders were divided into screening, validation, and re-validation sets. In the screening cohort (n = 41), somatic mutations in 114 genes showed no association with dCRT response. Genome-wide DNA methylation analysis using Infinium HumanMethylation450 BeadChip array identified four genic regions significantly associated with dCRT response. Among them, FGF5 methylation was validated to be associated with dCRT response (n = 34; P = 0.001), and further re-validated (n = 42; P = 0.020) by bisulfite-pyrosequencing. The sensitivity and specificity in the combined validation and re-validation sets (n = 76) were 45% and 90%, respectively, by using the cut-off value established in the screening set, and FGF5 methylation had predictive power independent from clinicopathological parameters. In ESCC cell lines, FGF5 promoter methylation repressed its expression. FGF5 expression was induced by cisplatin (CDDP) treatment in three unmethylated cell lines, but not in two methylated cell lines. Exogenous FGF5 overexpression in a cell line with its methylation conferred resistance to CDDP. In non-cancerous esophageal tissues, FGF5 was not expressed, and its methylation was present in a small fraction of cells. These results showed that FGF5 methylation is a validated marker for ESCC sensitivity to dCRT.

Efficacy of preserving the residual stomach in esophageal cancer patients with previous gastrectomy.

OBJECTIVE: There is no consensus concerning whether the residual stomach should be preserved after esophagectomy for thoracic esophageal cancer patients with previous distal or segmental gastrectomy. The purpose of this retrospective study was to assess the efficacy of preserving the residual stomach after esophagectomy in patients with previous gastrectomy. METHODS: Between 2000 and 2015, 45 consecutive thoracic esophageal cancer patients with previous distal or segmental gastrectomy underwent esophagectomy followed by colon reconstruction. Patients were assigned to two groups according to how the residual stomach was treated (preservation group, n = 11; resection group, n = 34). We compared surgical outcomes and alterations of nutrition status, including the skeletal muscle area, between the two groups. In addition, we investigated the distribution of abdominal lymph node metastases in the resection group. RESULTS: Operative time and blood loss tended to be lower in the preservation group compared to the resection group. However, the difference did not reach statistical significance. The rate of patients decreasing skeletal muscle area after surgery was significantly higher in the resection group (88% vs 50%, P = 0.03). There were no patients with metastatic abdominal lymph nodes when the previous gastrectomy had been performed for gastric cancer and the esophageal cancer was located at the upper or middle esophagus in the resection group. CONCLUSIONS: Preservation of the residual stomach after esophagectomy in esophageal cancer patients with previous gastrectomy may influence the postoperative nutrition status and can be selectively approved.

Comparison of long-term outcomes between radical esophagectomy and definitive chemoradiotherapy in patients with clinical T1bN0M0 esophageal squamous cell carcinoma.

BACKGROUND: Long-term outcomes of patients with clinical T1bN0M0 thoracic esophageal squamous cell carcinoma (ESCC) treated using radical esophagectomy were compared with those treated using definitive chemoradiotherapy (dCRT). METHODS: A total of 320 consecutive patients with clinical T1bN0M0 thoracic ESCC who initially underwent radical esophagectomy or chemoradiotherapy during 2001-2011 were deemed eligible. Of these patients, 102 and 218 underwent radical esophagectomy and dCRT, respectively. Overall survival (OS) and causes of death were compared between the esophagectomy group and the chemoradiotherapy group. RESULTS: Five-year OS in the esophagectomy group was significantly better than that of the chemoradiotherapy group in both the overall sample and a subset of patients aged ≥70 years (P=0.004 and P=0.040). Male patients appeared to benefit more from radical esophagectomy (P=0.005). Until 2006, radical esophagectomy yielded superior results relative to dCRT (P=0.009). However, the survival outcomes after chemoradiotherapy were non-inferior to those after esophagectomy since 2007 (P=0.255). Up to 2006, esophagectomy and chemoradiotherapy groups exhibited significant differences in the causes of death (P=0.024), such that the latter group had a significantly higher rate of deaths due to respiratory complications (P=0.025). However, the introduction of 3-dimensional radiation with CT guided planning in 2007 resolved this inter-group difference (P=0.460). CONCLUSIONS: The appreciable developments in radiation technology have enabled the achievement of comparable long-term outcomes in the chemoradiotherapy group compared with the esophagectomy group in patients with clinical T1bN0M0 thoracic ESCC.

Phase II feasibility study of preoperative concurrent chemoradiotherapy with cisplatin plus 5-fluorouracil and elective lymph node irradiation for clinical stage II/III esophageal squamous cell carcinoma.

BACKGROUND: Preoperative chemoradiotherapy (CRT) is a standard treatment for stage II/III esophageal cancer. Preoperative chemotherapy is also considered a standard treatment for stage II/III esophageal squamous cell carcinoma (ESCC) in patients who undergo radical lymph node dissection. We conducted a feasibility study of preoperative CRT with cisplatin plus 5-fluorouracil (CF) and elective lymph node irradiation followed by esophagectomy with radical lymph node dissection in patients with stage II/III ESCC. METHODS: Patients with clinical stage II/III, excluding T4, ESCC (International Union Against Cancer TNM classification system, 6th edition) were eligible. Chemotherapy comprised two courses of CF infusion repeated after 4-weeks. Radiation therapy was concurrently administered to the primary tumor, metastatic lymph nodes, and regional lymph nodes at a dose of 41.4 Gy. After the completion of CRT, transthoracic esophagectomy with 2-3 fields lymphadenectomy was performed. The primary endpoint was the completion rate of protocol treatment with R0 resection. RESULTS: Thirty-one eligible patients were enrolled. During CRT, the most common grade 3 or 4 toxicities were leukopenia (65%), neutropenia (65%), anemia (13%), thrombocytopenia (13%), febrile neutropenia (13%), anorexia (16%), esophagitis (16%) and hyponatremia (16%). Thirty patients (96.8%) underwent surgery. One patient received palliative chemotherapy because of appearance of lung metastasis during CRT. The completion rate of protocol treatment was 93.5% (29/31). There was one treatment-related death after surgery. Pathological complete response was achieved in 42% (13/30). CONCLUSION: Preoperative CRT with CF and elective lymph node irradiation showed an acceptable toxicity and promising activity especially in ESCC.

Long-term outcome after resection for recurrent oesophageal cancer.

BACKGROUND: The efficacy of surgical resection for lymph node (LN) or distant recurrence of oesophageal cancer has not been sufficiently investigated. The objective of this study was to reveal appropriate indications for a surgical approach. METHODS: A total of 42 patients who underwent resection for recurrent or residual oesophageal squamous cell carcinoma after surgery or definitive chemoradiotherapy (dCRT) between April 2004 and August 2016 were identified. These resections did not include salvage oesophagectomy. The long-term outcomes of these patients were retrospectively analysed. RESULTS: Thirty-three patients underwent LN resection, 6 patients underwent lung resection, and 3 patients underwent resection for other recurrent tumours. The 5-year overall survival (OS) of patients who underwent salvage abdominal lymphadenectomy after dCRT was significantly better than that of patients who underwent salvage cervical or mediastinal lymphadenectomy (46.9% vs. 0.0%, P=0.006). The 5-year OS of patients who underwent salvage resection for LNs outside the radiation field was significantly better than that of patients who underwent resection inside the radiation field (47.6% vs. 8.9%, P=0.027). The 5-year OS of patients who underwent salvage resection for recurrent LNs was significantly better than that of patients who underwent salvage resection for residual LNs (21.7% vs. 0.0%, P<0.001). Among the 42 patients, 9 survived more than 3 years: 4 after salvage abdominal lymphadenectomy, 3 after resection for solitary lung recurrence, and 2 others. CONCLUSIONS: The use of the appropriate surgical approach might improve the prognosis of patients with abdominal LN recurrence, LN recurrence outside the radiation field, or a solitary lung recurrence of oesophageal cancer.

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.

Tumor location is a risk factor for lymph node metastasis in superficial Barrett's adenocarcinoma.

BACKGROUND AND STUDY AIMS: Endoscopic treatment is indicated for superficial Barrett's adenocarcinoma (BA) with a negligible risk of lymph node metastasis (LNM). However, risk factors associated with LNM in superficial BA are still not well characterized. The aim of the current study was to clarify risk factors for LNM of superficial BA. PATIENTS AND METHODS: A retrospective study was conducted in 87 consecutive patients with BA that was resected at National Cancer Center Hospital, Tokyo, Japan between 1990 and 2013. We assessed tumor size, macroscopic type, histological type, tumor depth of invasion, lymphovascular invasion and tumor location to analyze factors associated with LNM. Tumor location was classified into following 2 groups according to Siewert classification: 1) BA of the esophagogastric junction (EGJ-BA) as those having their center within 1 cm proximal from the EGJ; and 2) Esophageal-BA as those having their center at 1 cm or more proximal to the EGJ. EGJ was defined as distal end of the palisade vessels. RESULTS: LNM was detected in 10 (11 %) patients. Univariable analysis revealed that tumor size, tumor depth of invasion, histological type of mixed differentiated and undifferentiated-type adenocarcinoma, lymphovascular invasion and tumor location of esophageal-BA were significantly associated with LNM. Multivariable analysis revealed that tumor location of esophageal-BA [odds ratio 7.8 (95 %CI: 1.3 - 48.1)] was a potential risk factor for LNM. CONCLUSIONS: The current study demonstrated that tumor location is a potential risk factor for LNM in BA. Therefore, indications for endoscopic treatment of esophageal-BA and EGJ-BA could be different.

Clinical Outcomes of Resectable Esophageal Cancer with Supraclavicular Lymph Node Metastases Treated with Curative Intent.

BACKGROUND: In the seventh edition of the Union for International Cancer Control (UICC) TNM classification, supraclavicular lymph node (SCLN) in regard to thoracic esophageal cancer (EC) is regarded as a distant organ, therefore, if resectable, SCLN metastasis is considered a candidate for systemic chemotherapy. The purpose of this study was to clarify the survival outcome in patients with resectable thoracic EC with SCLN metastases (M1LYM) treated with curative intent. PATIENTS AND METHODS: Clinical outcomes in patients with resectable thoracic EC with SCLN metastases (M1LYM) treated by esophagectomy or definitive chemoradiotherapy (dCRT) were retrospectively analyzed. RESULTS: A total of 102 patients were divided in three groups: Surgery with perioperative therapy, n=45; surgery alone, n=19; and dCRT, n=38. Overall, median progression-free survival and median survival time were 9.3 and 26.7 months, respectively. The median survival time was 27.5 months in the group treated with surgery with perioperative treatment, 50.6 months in those treated with surgery alone, and 22 months in the dCRT group. No significant survival difference was seen among the three groups. CONCLUSION: Over 30% of patients with resectable M1LYM treated with curative intent achieved long-term survival.

Esophageal stenosis and the Glasgow Prognostic Score as independent factors of poor prognosis for patients with locally advanced unresectable esophageal cancer treated with chemoradiotherapy (exploratory analysis of JCOG0303).

BACKGROUND: The aim of this study was to investigate the possible prognostic factors and predictive accuracy of the Glasgow Prognostic Score (GPS) for patients with unresectable locally advanced esophageal squamous cell carcinoma (LAESCC) treated with chemoradiotherapy. METHODS: One hundred forty-two patients were enrolled in JCOG0303 and assigned to the standard cisplatin and 5-fluorouracil (PF)-radiotherapy (RT) group or the low-dose PF-RT group. One hundred thirty-one patients with sufficient data were included in this analysis. A Cox regression model was used to analyze the prognostic factors of patients with unresectable LAESCC treated with PF-RT. The GPS was classified based on the baseline C-reactive protein (CRP) and serum albumin levels. Patients with CRP ≤1.0 mg/dL and albumin ≥3.5 g/dL were classified as GPS0. If only CRP was increased or only albumin was decreased, the patients were classified as GPS1, and the patients with CRP >1.0 mg/dL and albumin <3.5 g/dL were classified as GPS2. RESULTS: The patients' backgrounds were as follows: median age (range), 62 (37-75); male/female, 119/12; ECOG PS 0/1/2, 64/65/2; and clinical stage (UICC 5th) IIB/III/IVA/IVB, 3/75/22/31. Multivariable analyses indicated only esophageal stenosis as a common factor for poor prognosis. In addition, overall survival tended to decrease according to the GPS subgroups (median survival time (months): GPS0/GPS1/GPS2 16.1/14.9/8.7). CONCLUSIONS: Esophageal stenosis was identified as a candidate stratification factor for randomized trials of unresectable LAESCC patients. Furthermore, GPS represents a prognostic factor for LAESCC patients treated with chemoradiotherapy. CLINICAL TRIAL INFORMATION: UMIN000000861.

Effective treatment of empyema with bronchopleural fistula after esophagectomy by endobronchial embolization using endobronchial Watanabe Spigots.

INTRODUCTION: Empyema and bronchopleural fistula are well known complications after thoracic surgery. We report a case of refractory air leakage of bronchopleural fistula in a patient with empyema that was successfully treated by endobronchial embolization using Endobronchial Watanabe Spigots (EWSs). PRESENTATION OF CASE: A 71-year-old man underwent esophagectomy for primary esophageal cancer. A right empyema with bronchopleural fistula (BPF) developed four months after surgery. Right thoracic drainage tube was inserted. Although the empyema was treated by drainage and anti-biotics therapy, the air leakage was apparent. The chest computed tomography (CT) scan revealed that the bronchopleural fistula existed in the segment 6 and 10. Endobronchial embolization was performed to the responsible bronchus using EWSs. After the EWSs of middle and large sizes were inserted into the B6c and B10b+c, the air leakage was stopped. The thoracic tube of drainage was removed after endobronchial embolization. Complications due to the EWSs insertion were not observed, and the patient was discharged. DISCUSSION: The management of BPF has evolved over the years. Surgical approach is frequently needed to control the BPF, though endobronchial embolization is effective in closing the BPF in some patients. In our case, EWSs of middle and large size were useful to control air leakage. We safely retried the 2nd endoboronchial embolization using the EWS. The patient had no complication after insertion the EWS again. CONCLUSION: Endobronchial embolization using EWSs was an effective treatment of an empyema with bronchopleural fistula after esophagectomy.

Comparison between neoadjuvant chemotherapy followed by surgery and definitive chemoradiotherapy for overall survival in patients with clinical Stage II/III esophageal squamous cell carcinoma (JCOG1406-A).

BACKGROUND: Neoadjuvant chemotherapy followed by surgery (NAC-S) represents the standard treatment for patients with Stage II/III esophageal squamous cell carcinoma (ESCC) in Japan. Chemoradiotherapy (CRT) is performed in patients who refuse or have contraindications to surgery. However, randomized clinical trials that compare NAC-S with CRT have not been conducted. The aim of this study was to explore subgroups of patients undergoing CRT to identify those with survival outcomes potentially equivalent to NAC-S. METHODS: Pooled data from two clinical trials in patients with Stage II/III ESCC, the JCOG9907 trial and the JCOG9906 trial were used. JCOG9907 demonstrated that NAC-S resulted in superior overall survival (OS) compared with surgery followed by adjuvant chemotherapy. JCOG9906 was a single-arm trial that explored the efficacy and safety of CRT. The eligibility criteria in the two trials were almost identical. Subgroup analyses of clinical data (serum albumin, cT, cN, cstage and tumor location) were conducted with Cox proportional hazards regression models for patients assigned to receive NAC-S in JCOG9907 and patients in JCOG9906. RESULTS: The analysis comprised 163 patients from JCOG9907 in NAC-S arm (NAC-S group) and 73 patients from JCOG9906 who received CRT (CRT group). Baseline characteristics were similar between the two groups. OS was better in the NAC-S group than the CRT group (adjusted hazard ratio 1.72; 95% confidence interval 1.19-2.50). All subgroups in the NAC-S group had longer OS compared with those in the CRT group. CONCLUSIONS: OS was superior after NAC-S rather than CRT. None of the CRT subgroups had similar OS to the NAC-S groups.

Prognostic Impact of Postoperative Morbidity After Esophagectomy for Esophageal Cancer: Exploratory Analysis of JCOG9907.

OBJECTIVE: To investigate the influence of infectious complications on the outcome of current standard preoperative chemotherapy followed by surgery for clinical stage II/III esophageal cancer. BACKGROUND: The impact of postoperative infectious complications on survival after transthoracic esophagectomy remains controversial. METHODS: Data from a randomized controlled trial (JCOG9907) were used. Infectious complications were classified into three groups: pneumonia, anastomotic leakage, and others. Univariate and multivariate analyses using the Cox proportional hazard model were performed. RESULTS: Among the 152 analyzed patients, the incidence of pneumonia, leakage, and overall infectious complication were 22 (14%), 21 (14%), and 54 (36%). Overall survival (OS) of patients with any infectious complication was shorter than that of patients without infectious complication [hazard ratio, HR 1.66, 95% confidence interval, CI, (1.02-2.71)] and progression-free survival (PFS) also tended to be shorter in patients with any infectious complication [HR 1.44, (0.92-2.24)]. The OS of patients with pneumonia was shorter than that of patients without pneumonia [HR 1.82, (1.01-3.29)], and PFS also tended to be shorter in patients with pneumonia [HR 1.50, (0.85-2.62)]. The OS of patients with anastomotic leakage (n = 21) was nearly identical to that for patients without leakage [HR 1.06, (0.52-2.13)] and PFS showed the same tendency [HR 1.28, (0.71-2.32)]. Multivariate analysis revealed that pneumonia tended to compromise OS and PFS [HR 1.66, (0.87-3.17) and HR 1.37, (0.75-2.51)]. CONCLUSIONS: These results indicate that postoperative infectious complications may worsen patient prognosis after esophagectomy. Performing esophagectomy without postoperative complications, especially pneumonia, may be beneficial for improving survival outcomes.

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.

Risk Factors for Esophageal Fistula Associated With Chemoradiotherapy for Locally Advanced Unresectable Esophageal Cancer: A Supplementary Analysis of JCOG0303.

Esophageal fistula is a critical adverse event in patients treated with chemoradiotherapy (CRT) for locally advanced esophageal cancer. However, risk factors associated with esophageal fistula formation in patients receiving CRT have not yet been elucidated.We retrospectively analyzed data obtained from 140 patients who were enrolled in a phase II/III trial comparing low-dose cisplatin with standard-dose cisplatin administered in combination with 5-flurouracil and concomitant radiotherapy. Inclusion criteria were performance status (PS) 0 to 2 and histologically proven thoracic esophageal cancer clinically diagnosed as T4 and/or unresectable lymph node metastasis for which definitive CRT was applicable. Risk factors for esophageal fistula were examined with univariate analysis using Fisher exact test and multivariate analysis using logistic regression models.Esophageal fistula was observed in 31 patients (22%). Of these, 6 patients developed fistula during CRT. Median time interval between the date of CRT initiation and that of fistula diagnosis was 100 days (inter quartile range, 45-171). Esophageal stenosis was the only significant risk factor for esophageal fistula formation both in univariate (P = 0.026) and in multivariate analyses (odds ratio, 2.59; 95% confidence interval, 1.13-5.92, P = 0.025). Other clinicopathological factors, namely treatment arm, age, sex, PS, primary tumor location, T stage, lymph node invasion to adjacent organs, blood cell count, albumin level, and body mass index, were not risk factors fistula formation.Esophageal stenosis was a significant risk factor for esophageal fistula formation in patients treated with CRT for unresectable locally advanced thoracic esophageal squamous cell carcinoma.

Inter-institutional survival heterogeneity in chemoradiation therapy for esophageal cancer: exploratory analysis of the JCOG0303 study.

It is important to examine variation in the treatment effects of patients with esophageal cancer in order to generalize treatment outcomes. We aimed to investigate the range of prognostic differences among hospitals in the treatment of locally advanced esophageal cancer. The JCOG0303 study compared the efficacy of radiotherapy plus low-dose cisplatin and 5-fluorouracil with that of high-dose cisplatin and 5-fluorouracil for unresectable esophageal cancer. Of 32 institutions participating in the JCOG0303 study, the 18 institutions that enrolled three or more patients were included in this study. We predicted the 1-year survival in each institution by using a mixed-effect model. We found that the predicted 1-year survival in the 18 institutions with three or more patients was a median of 60.9%, with a range of 60.9-60.9%. This study is the first to investigated heterogeneity of survival in patients who received definitive chemoradiotherapy for locally advanced esophageal squamous cell carcinoma.

Early-Stage Induction of SWI/SNF Mutations during Esophageal Squamous Cell Carcinogenesis.

The SWI/SNF chromatin remodeling complex is frequently inactivated by somatic mutations of its various components in various types of cancers, and also by aberrant DNA methylation. However, its somatic mutations and aberrant methylation in esophageal squamous cell carcinomas (ESCCs) have not been fully analyzed. In this study, we aimed to clarify in ESCC, what components of the SWI/SNF complex have somatic mutations and aberrant methylation, and when somatic mutations of the SWI/SNF complex occur. Deep sequencing of components of the SWI/SNF complex using a bench-top next generation sequencer revealed that eight of 92 ESCCs (8.7%) had 11 somatic mutations of 7 genes, ARID1A, ARID2, ATRX, PBRM1, SMARCA4, SMARCAL1, and SMARCC1. The SMARCA4 mutations were located in the Forkhead (85Ser>Leu) and SNF2 family N-terminal (882Glu>Lys) domains. The PBRM1 mutations were located in a bromodomain (80Asn>Ser) and an HMG-box domain (1,377Glu>Lys). For most mutations, their mutant allele frequency was 31-77% (mean 61%) of the fraction of cancer cells in the same samples, indicating that most of the cancer cells in individual ESCC samples had the SWI/SNF mutations on one allele, when present. In addition, a BeadChip array analysis revealed that a component of the SWI/SNF complex, ACTL6B, had aberrant methylation at its promoter CpG island in 18 of 52 ESCCs (34.6%). These results showed that genetic and epigenetic alterations of the SWI/SNF complex are present in ESCCs, and suggested that genetic alterations are induced at an early stage of esophageal squamous cell carcinogenesis.

Integrated analysis of DNA methylation and mutations in esophageal squamous cell carcinoma.

The recent development of next-generation sequencing technology for extensive mutation analysis, and beadarray technology for genome-wide DNA methylation analysis has made it possible to obtain integrated pictures of genetic and epigenetic alterations, using the same cancer samples. In this study, we aimed to characterize such a picture in esophageal squamous cell carcinomas (ESCCs). Base substitutions of 55 cancer-related genes and copy number alterations (CNAs) of 28 cancer-related genes were analyzed by targeted sequencing. Forty-four of 57 ESCCs (77%) had 64 non-synonymous somatic mutations, and 24 ESCCs (42%) had 35 CNAs. A genome-wide DNA methylation analysis using an Infinium HumanMethylation450 BeadChip array showed that the CpG island methylator phenotype was unlikely to be present in ESCCs, a different situation from gastric and colon cancers. Regarding individual pathways affected in ESCCs, the WNT pathway was activated potentially by aberrant methylation of its negative regulators, such as SFRP1, SFRP2, SFRP4, SFRP5, SOX17, and WIF1 (33%). The p53 pathway was inactivated by TP53 mutations (70%), and potentially by aberrant methylation of its downstream genes. The cell cycle was deregulated by mutations of CDKN2A (9%), deletions of CDKN2A and RB1 (32%), and by aberrant methylation of CDKN2A and CHFR (9%). In conclusion, ESCCs had unique methylation profiles different from gastric and colon cancers. The genes involved in the WNT pathway were affected mainly by epigenetic alterations, and those involved in the p53 pathway and cell cycle regulation were affected mainly by genetic alterations. © 2016 Wiley Periodicals, Inc.

Accuracy of preoperative diagnosis of lymph node metastasis for thoracic esophageal cancer patients from JCOG9907 trial.

BACKGROUND: Accurate clinical evaluation of lymph nodes is crucial for selection of the optimum treatment strategy for individual esophageal cancer patients. This study investigated the accuracy of preoperative clinical diagnosis of lymph node metastasis for patients with clinical stage II/III esophageal squamous cell carcinoma. METHODS: Patients assigned to receive surgery and postoperative chemotherapy in JCOG9907 trial were studied to evaluate the concordance between clinical and pathological nodes. Preoperative diagnosis was based on computed tomography or magnetic resonance imaging. RESULTS: Among 166 patients in the postoperative group, 160 with sufficient pathological data were studied. The patient background characteristics were: male/female, 147/13; median age, 61 years (range 39-75 years); primary tumor site (upper/middle/lower), 15/76/69; cN0/cN1, 53/107. The sensitivity and specificity of clinical nodes for diagnosis of pathological nodes were 72.7 and 51.3 %, respectively; the positive and negative predictive values were 82.2 and 37.7 %, respectively. The lymph nodes overestimated in the preoperative diagnosis included thoracic paratracheal lymph nodes (#106) (n = 8), middle thoracic paraesophageal lymph nodes (#108) (n = 4), lymph nodes along the lesser curvature (#3) (n = 4), right cardiac lymph nodes (#1) (n = 3), and left cardiac lymph nodes (#2) (n = 2). CONCLUSION: Diagnosis of clinical nodes has low specificity and low negative predictive value for prediction of pathological node category in the preoperative diagnosis of lymph node metastasis for patients with locally advanced resectable esophageal cancer. Clinical staging techniques must therefore be improved for accurate preoperative diagnosis.