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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.

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.

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. 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. 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. 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.

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.

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.

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 (

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 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.

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.The impact of postoperative infectious complications on survival after transthoracic esophagectomy remains controversial.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.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)].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.

Because esophageal carcinosarcoma (ECS) is rare, a treatment strategy similar to that employed in esophageal cancer is usually applied. However, the clinicopathological features and the treatment effects of preoperative chemotherapy or chemoradiotherapy (CT/CRT) are not well known. We retrospectively evaluated clinical and pathological characteristics of consecutive patients with pathologically confirmed ECS who underwent esophagectomy from 1996 to 2011 in our institution, and assessed their pathological response to preoperative CT/CRT in surgically resected specimens. We identified 19 patients with a final diagnosis of ECS who had then undergone curative surgery. In 6 of these, the preoperative pathological diagnosis by biopsy had been squamous cell carcinoma. In 7 of 13 patients treated by surgery alone, clinical T factors were overdiagnosed compared with pathological findings. Of patients who received preoperative CT (5-fluorouracil plus cisplatin) with (n = 2) and without (n = 4) concurrent RT (41.4–50.4 Gy), two had a partial response, in three, the disease remained stable, and one patient had progressive disease. Histopathological evaluation showed a limited pathological response in the sarcomatous component. Median overall survival of patients with and without preoperative treatment was 28.0 and 47.2 months, respectively [HR = 1.55 (95% CI 0.36–6.56)], and median relapse free survival was 13.4 months versus not achieved [HR = 2.06 (95% CI 0.54–7.76)]. The problems associated with clinical T stage diagnosis as well as the lack of evidence for an effect of preoperative treatment, especially on the sarcomatous component, mean that treatment strategies for ECS should be considered with care.

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.

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.

Highlights • In this case, we emphasized the value of Endobronchial Watanabe Spigot (EWS) use in bronchial embolization. • Embolization with EWS is one of the first line options in conservative management of BPF after esophagectomy. • We safely retried the 2nd endoboronchial embolization using the EWS. • The patient with advanced esophageal cancer, clinical stage was cT3N1M0 stage IIIA was referred to our hospital. He underwent esophagectomy with video assisted thoracic surgery accompanied by reconstruction of the stomach through the posterior sternum after induction chemotherapy. The patient was in good condition and there was no recurrence. • The patient was followed six months later, empyema was not occurred and the patient was in good general condition., 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.

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. 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. 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). Preoperative CRT with CF and elective lymph node irradiation showed an acceptable toxicity and promising activity especially in ESCC.

Background Variations in institutional practice may contribute to different outcomes of cancer treatment. The impact of interinstitutional heterogeneity on outcomes between hospitals after oesophagectomy has not been examined previously using data from surgical clinical trials. Methods The data from two phase III trials for oesophageal cancer were used. Japan Clinical Oncology Group (JCOG) 9204 involved oesophagectomy (92-OP) versus oesophagectomy plus postoperative chemotherapy (92-POST), with accrual from 1992 to 1997. JCOG9907 involved postoperative chemotherapy (99-POST) versus preoperative chemotherapy (99-PRE), with accrual from 2000 to 2006. Hospitals contributing fewer than three patients were excluded. The influence of time and preoperative chemotherapy on interinstitutional heterogeneity related to postoperative complications and 5-year overall survival were evaluated by comparisons within and between these trial groups. Heterogeneity was estimated by a mixed-effects model after adjusting for age, sex, performance status, location of the primary tumour and clinical stage. Results Twelve hospitals in 92-OP (114 patients), 13 in 92-POST (114), 19 in 99-POST (158) and 18 in 99-PRE (154) were eligible. There was considerable heterogeneity in predicted postoperative complications in both groups in JCOG9204 (median 31·3 (range 15·0–68·2) per cent), and in 99-PRE (35·2 (22·6–46·6) per cent) but not in 99-POST (27·7 (27·7–27·7) per cent) from JCOG9907. A similar pattern was seen for predicted overall survival (92-POST: 66·4 (range 64·1–68·9) per cent; 99-PRE: 55·9 (54·0–59·7) per cent; 99-POST: 44·4 (44·4–44·4) per cent). Conclusion Interinstitutional heterogeneity regarding complications and survival after oesophagectomy is a problem that merits wider consideration.

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.

Recurrent laryngeal nerve paralysis (RLNP) after esophagectomy is a common complication and associated with aspiration pneumonia. In this study, we assessed the risk of RLNP and the usefulness of immediate reconstruction of recurrent laryngeal nerve (RLN) to prevent respiratory complications after esophagectomy. Seven hundred and eighty-two consecutive patients underwent an esophagectomy with three-field lymph node dissection, simultaneous gastric conduit reconstruction, and cervical anastomosis. Vocal cord function was observed using a flexible laryngoscope. Reconstruction between RLN and ipsilateral vagus nerve was performed during esophagectomy. RLNP was observed in 229 (29.3%) of the patients after esophagectomy: 198 unilateral and 31 bilateral cases. Of the 198 unilateral RLNP, vocal cord paralysis was observed predominantly on the left side (82.7%). RLNP was significantly associated with postoperative respiratory complications (P < 0.001) requiring a tracheotomy (P < 0.001) and mechanical ventilation (P < 0.001) and was also associated with esophagogastric anastomotic leakage (P = 0.015); consequently, the postoperative hospital stay was longer for patients with RLNP (P < 0.001). A longer operation time (P < 0.001) and advanced age (P = 0.038) were identified as significant independent predictors of RLNP. Resection of the RLN together with metastatic nodes was performed in 29 cases. The patients underwent RLN reconstruction (n = 11) had a significantly shorter postoperative hospital stay than those without RLN reconstruction (n = 18) (P = 0.019). In conclusion, RLNP was related to a poorer postoperative course among patients undergoing an esophagectomy. New surgical technologies are recommended for prevention of RLNP.

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.

ObjectivesThe objective of this study was to review the prognostic factors for increased survival after salvage esophagectomy after definitive chemoradiotherapy for esophageal squamous carcinoma and determine the importance of lymphadenectomy from a prognostic view.MethodsClinical data for all patients from January 1999 to December 2012 who underwent salvage esophagectomy for residual tumor or tumor recurrence after definitive chemoradiotherapy were retrospectively collected. Survival was determined and prognostic factors were analyzed with univariate and multivariate analyses.ResultsSurvival after 1, 3, and 5 years postoperatively was 74.4%, 39.8%, and 29.5%, respectively. The independent predictive factors for increased postoperative survival were tumor recurrence rather than residual tumor as the indication for salvage surgery (P

Background This study investigated the incidence, diagnosis, treatment, and risk factors for nonmalignant airway erosion after subtotal esophagectomy for thoracic esophageal carcinoma. Methods Clinical data from all patients with thoracic esophageal carcinoma who underwent right transthoracic subtotal esophagectomy from 2000 to 2012 at our institution were retrospectively reviewed, and the clinical course and outcome of those who developed airway erosion were investigated in detail. Risk factors for airway erosion were calculated by multivariate analysis. Results Of 1,091 patients enrolled, 15 patients (1.4%) developed nonmalignant airway erosion, which occurred at postoperative day (POD) 7 to 92 (median, 24). Anastomotic leakage or gastric-tube necrosis was detected prior to airway erosion in 14 cases (93.3%). Endoscopic and surgical therapy was administrated to 3 patients. Airway erosion was cured in 9 patients (60.0%). Five patients died from airway erosion directly (mortality, 33.3%). Alimentary leakage or necrosis ( p p = 0.004), and reconstruction through the posterior mediastinal route ( p = 0.051) were independent risk factors for airway erosion development. Conclusions Airway erosion is a fatal complication after subtotal esophagectomy. Preoperative radiotherapy dramatically increases the risk of developing airway erosion and reduces the probability of spontaneous healing. Aggressive treatment of alimentary leakage or necrosis and reconstruction through the anterior route help to decrease the risk of airway erosion, especially in high-risk patients.

7 Background: Esophagectomy (E) is the standard of care for stage I esophageal squamous cell carcinoma (ESCC), while chemoradiotherapy (CRT) is a treatment option. A parallel-group controlled trial including randomized arms to confirm the non-inferiority of CRT to E for stage IA ESCC was conducted. Methods: Patients (pts) with thoracic ESCC, adenosquamous cell, or basaloid cell carcinoma with stage IA (T1bN0M0), age 20 to 75, performance status 0 to 1, and adequate organ function were eligible. If pts accepted randomization, they were randomly allocated to E with 2-3 field lymph node dissection (arm A) or CRT (arm B). However, if pts had a preference and refused randomization, they were allocated to pts preference arm, E (arm C) or CRT (arm D). CRT consisted of cisplatin and 5-FU, with radiation at the dose of 60 Gy concurrently. The primary endpoint was overall survival (OS) of arm A and B, secondary endpoint included OS of arm C and D using inverse probability weighting with propensity score. The planned sample size in arm A and B was 114 pts in total with one-sided alpha of 10%, power of 75% and non-inferiority margin of HR as 1.78. The sample size in arm C and D was at least 156 pts in each arm with one-sided alpha of 2.5%, power of 85% and non-inferiority margin of HR as 1.78. Results: Between December 2006 and February 2013, 379 (Arm A: 4, B: 7, C: 209 C, D: 159) pts were enrolled. Primary endpoint was not calculated due to small number of randomized arms. Patients characteristics of arm C and D were as follows; median age: 62 and 65, male (%): 82.8 and 88.1, PS 0 (%): 99.5 and D 98.1. All histologic type was SCC except one basaloid cell carcinoma in arm C. The 3- and 5-year OS were 94.7% and 86.5% in arm C, and 93.1% and 85.5% in arm D (adjusted HR 1.05; 95% CI 0.67-1.64 [< 1.78]).Treatment related death were observed in two pts in arm C and none in arm D. Conclusions: Though the accrual of randomized arms was shortened, CRT showed trend toward non-inferiority compared to E in pts preference arms. CRT is considered as a treatment option for stage IA ESCC with organ preservation. Clinical trial information: UMIN000000551.

The combination of docetaxel, cisplatin, and 5-fluorouracil (DCF) as preoperative treatment for esophageal squamous cell carcinoma (ESCC) has not been investigated. We carried out a multicenter phase II feasibility study of preoperative chemotherapy with DCF for ESCC. Patients with clinical stage II/III ESCC (International Union Against Cancer TNM classification system, 6th edition) were eligible. Chemotherapy consisted of i.v. docetaxel (70-75 mg/m(2)) and cisplatin (70-75 mg/m(2)) on day 1, and continuous infusion of fluorouracil (750 mg/m(2)/day) on days 1-5. Antibiotic prophylaxis on days 5-15 was mandatory. This regimen was repeated every 3 weeks with a maximum of three cycles allowed. After completion of chemotherapy, esophagectomy with extended lymphadenectomy was carried out. The primary endpoint was the completion rate of protocol treatment. Forty-two eligible patients were enrolled. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (83%), anorexia (7%), and stomatitis (5%). Forty-one (98%) patients underwent surgery. The completion rate of protocol treatment was 90.5% (38/42). No treatment-related death was observed and the incidence of operative morbidity was tolerable. According to RECIST, the overall response rate after the completion of DCF was 64.3%. Pathological complete response was achieved in 17%. The estimated 2-year progression-free survival and overall survival were 74.5% and 88.0%, respectively. Although these data are preliminary, preoperative DCF was well tolerated. Antitumor activity was highly promising and warrants further investigation. This trial was registered with University Hospital Medical Information Network (no. UMIN000002396).

Background We summarize the experience of diagnosis and surgical therapy for primary malignant melanoma of the esophagus (PMME). Methods Clinical data of 13 patients diagnosed as having PMME treated by surgery as their primary therapy from 2000 to 2012 were retrospectively analyzed, and survival information was collected through follow-up. Results The average age (± standard deviation) of participants in this study was 66.4 ± 7.6 years, and 84.6% were male. Overall, 61.5% of tumors were located in the lower thoracic esophagus. The accuracies of clinical T stage, N stage, and TNM stage were 53.9%, 46.2%, and 38.5%, respectively, compared with pathological staging (kappa = 0.252, p = 0.023). Surgical mortality and morbidity were 7.7% and 53.9%, respectively. The incidence of lymph node metastasis for patients with tumor invading within the mucosa was 0, but increased to 42.9% (3 of 7) with tumor invading to the submucosal layer. Primary malignant melanoma of the esophagus in the mid third of the thoracic esophagus had a greater chance to metastasize to perigastric lymph nodes (2 of 5) than to middle mediastinal lymph nodes (1 of 5). For PMME located at the lower third of the thoracic esophagus, upper mediastinal lymph node metastasis was more likely to occur (2 of 4) with tumor invasion penetrating the proper muscle layer. Recurrence occurred within 1 year in all patients with tumor later than Stage Ib. The most common recurrent organ was the liver. The overall 1-year and 5-year postoperative survival rates were 54.0% and 35.9%, respectively, and lymph node metastasis was the independent predictive factor for postoperative survival ( p = 0.013; odds ratio, 15.05). Conclusions Despite the similarity in lymph node metastatic patterns to squamous cell carcinoma, PMME is more inclined to distant metastasis. Clinical staging was inconsistent with pathological staging for PMME based on endoscopy and computed tomography. Surgical therapy was the optimal treatment for PMME at an earlier stage. Early diagnosis and aggressive lymph node dissection were beneficial for accurate staging, potentially reducing recurrence and thus improving survival.

A three-arm Phase III trial was started in November 2012. Preoperative chemotherapy with cisplatin plus 5-fluorouracil is the current standard treatment for locally advanced esophageal cancer in Japan, while preoperative chemoradiotherapy with cisplatin plus 5-fluorouracil is the standard in Western countries. Preoperative chemotherapy with docetaxel, cisplatin plus 5-fluorouracil is another promising regimen. The purpose of this study is to confirm the superiority of docetaxel, cisplatin plus 5-fluorouracil over cisplatin plus 5-fluorouracil and the superiority of cisplatin plus 5-fluorouracil with chemoradiotherapy over cisplatin plus 5-fluorouracil as preoperative therapy for squamous cell carcinoma of esophagus. A total of 501 patients will be accrued from 41 Japanese institutions within 6.25 years. The primary endpoint is overall survival and the secondary endpoints include progression-free survival, %R0 resection, response rate, pathologic complete response rate and adverse events.

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.

To evaluate the sites and frequencies of overall and initial lymph node (LN) metastases (LNMs) of clinical T1N0 esophageal cancer.The sites and frequencies of initial LNMs and sentinel LNs (SLNs) of esophageal cancer remain unclear.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.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%.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.

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.

Aberrant hypermethylation of specific genes is present in esophageal squamous cell carcinomas (ESCCs). Such hypermethylation is also present in normal-appearing esophageal mucosae of ESCC patients and is considered to contribute to the formation of a field for cancerization. On the other hand, the presence of global hypomethylation in ESCCs or in their background esophageal mucosae is unknown. We collected 184 samples of esophageal mucosae (95 normal mucosae from healthy subjects, and 89 non-cancerous background mucosae from ESCC patients) and 93 samples of ESCCs. Methylation levels of repetitive elements (Alu, LINE1) and cancer/testis antigen genes (NY-ESO-1, MAGE-C1) were measured by bisulfite pyrosequencing and quantitative methylation-specific PCR, respectively. Methylation levels of Alu, LINE1, NY-ESO-1, and MAGE-C1 were significantly lower in ESCCs than in their background and normal mucosae. Also, in the background mucosae, a significant decrease of the Alu methylation level compared with the normal mucosae was present. In ESCCs, methylation levels of the two repetitive elements and the two cancer/testis antigen genes were correlated with each other. This is the first study to show the presence of global hypomethylation in ESCCs, and even in their non-cancerous background mucosae. Alu hypomethylation might reflect the severity of an epigenetic field for cancerization.

Patients with esophageal carcinoma receiving postoperative chemotherapy showed superior disease-free survival than those receiving surgery alone in a Japan Clinical Oncology Group trial (JCOG9204). The purpose of this study was to evaluate optimal perioperative timing—that is, before or after surgery—for providing chemotherapy in patients with locally advanced esophageal squamous cell carcinoma. Eligible patients with clinical stage II or III, excluding T4, squamous cell carcinoma were randomized to undergo surgery followed (group 1) or preceded (group 2) by chemotherapy consisting of two courses of cisplatin plus 5-fluorouracil. The primary end point was progression-free survival. We randomized 330 patients, with 166 assigned to group 1 and 164 to group 2, between May 2000 and May 2006. The planned interim analysis was conducted after completion of patient accrual. Progression-free survival did not reach the stopping boundary, but overall survival in group 2 was superior to that of group 1 (P = 0.01). Therefore, the Data and Safety Monitoring Committee recommended early publication. Updated analyses showed the 5-year overall survival to be 43% in group 1 and 55% in group 2 (hazard ratio 0.73, 95% confidence interval 0.54–0.99, P = 0.04), where the median follow-up of censored patients was 61.6 months. Concerning operative morbidity, renal dysfunction after surgery in group 2 was slightly higher than in group 1. Preoperative chemotherapy with cisplatin plus 5-fluorouracil can be regarded as standard treatment for patients with stage II/III squamous cell carcinoma.

症例は67歳の男性で，2008年7月に右開胸開腹食道亜全摘術，3領域郭清術，胸骨後経路頸部胃管吻合術を施行した．術後3日目に腹痛出現し，術後4日目の検査にて胸骨後経路に横行結腸が陥入した内ヘルニアによるイレウスと診断した．術後6日目に緊急開腹手術を施行し内ヘルニアを修復した．術後は経過良好にて再手術後39日目に退院した．現在までに7か月経過も再発の所見はない．食道がん術後にはまれに再建経路を通って内ヘルニアが起こることが知られているがその頻度は極めて少なく，本邦では今症例を含めて報告があるのは8例を数えるのみである．そのうち7例は後縦隔経路に陥入したもので，胸骨後経路に陥入したものは我々の報告が初めてであり，極めてまれな症例であったため報告する．

The recent anatomical studies of the esophagus showed that submucosal longitudinal lymphatic vessels connect to the superior mediastinal and the paracardial lymphatics and lymphatic routes to periesophageal nodes originate from the muscle layer. Using clinical data for lymph node metastasis, we verify these anatomical bases to clarify the rational areas of lymph node dissection in esophageal cancer surgery. Analysis was performed on 356 consecutive patients who underwent esophagectomy with three-field dissection. Patients were divided into those with tumor limited within the submucosal layer and those with tumor invading or penetrating the muscle layer. Frequency of node metastasis was compared according to supraclavicular, upper mediastinum, mid-mediastinum, lower mediastinum, perigastric and celiac areas. In patients with tumor limited to the submucosal layer, node metastasis was more frequent in the upper mediastinum and perigastric area than the mid- or lower mediastinum. Even in patients with tumor located in the lower esophagus, node metastasis was more frequent in the upper mediastinum than the mid-mediastinum or lower mediastinum. In patients with tumor located in the mid-esophagus, node metastasis was more frequent in the supraclavicular area than the mid-mediastinum or lower mediastinum. In patients with tumor invading or penetrating the muscle layer, node metastasis in the mid- and lower mediastinum increased dramatically, but was still less frequent than those in the upper mediastinum or the perigastric area. Postoperative survival curves did not differ among the involved areas. The most predictive factor associated with lymph node metastasis for postoperative survival was not the area of involved nodes, but the number of involved nodes by multivariate analyses. These clinical results verify recent anatomical observations. The lack of difference in survival rates among the involved areas suggests that these areas should be staged equivalently. For adequate nodal staging, the upper mediastinum should be dissected for the lower esophageal tumor and supraclavicular areas should be dissected for the mid-esophageal tumor even in patients with tumor limited to within the submucosal layer.

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 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.

Purpose: To assess the performance of our health risk appraisal (HRA) models for screening individuals at high risk of esophageal/pharyngeal squamous cell carcinoma (EPSCC). Methods: Based on the results of our previous case-control study, we invented HRA models that enable screening for EPSCC cases in Japanese men with high sensitivity and specificity based on either their aldehyde dehydrogenase-2 genotype (HRA-G model) or alcohol flushing (HRA-F model) and drinking, smoking, and dietary habits. Follow-up endoscopy combined with esophageal iodine staining (median follow-up period: 5.0 years) was done on 404 Japanese men (50-78 years) who were registered as cancer-free controls in the previous study. Results: The follow-up endoscopy resulted in a diagnosis of 6 esophageal SCC (Tis in 5 and T1 in 1), 1 hypopharyngeal SCC (T2), and 1 oropharyngeal SCC (T2). Seven and 6 of the 8 EPSCC cases were in the top 10% risk group at baseline according to the HRA-G and HRA-F models, respectively. The EPSCC detection rates per 100 person-years in the top 10% risk groups by the HRA-G and HRA-F models were 4.38 (95% confidence interval, 1.76-9.01) and 3.48 (95% confidence interval, 1.28-7.58), respectively. Their age-adjusted relative risk was 95.1- and 26.3-fold, respectively (P < 0.0001), higher than in the bottom 90% risk groups. Conclusions: The high detection rates for EPSCC in the top 10% risk group of this preliminary follow-up study were in good agreement with those predicted by the HRA models and thus encouraged the screening based on our HRA models in larger populations of Japanese men. (Cancer Epidemiol Biomarkers Prev 2009;18(2):651–5)

Background: Because early squamous cell carcinoma (SCC) of the esophagus is detectable by endoscopic esophageal iodine staining with high accuracy and is easily treated by endoscopic mucosectomy, it is important to develop efficient methods for screening candidates for the endoscopic examination. Inactive aldehyde dehydrogenase-2 (ALDH2) is a very strong risk factor for esophageal SCC in alcohol drinkers and thus may be suitable as a screening tool. Purpose: To assess the performance of health risk appraisal (HRA) models in screening for esophageal SCC in the Japanese male population. Methods: Two types of HRA models were developed based on our previous case-control study, which included assessment of ALDH2 activity and selected risk factors (HRA-G and HRA-F: activities of ALDH2 assessed by genotype and questionnaire for alcohol flushing, respectively). Each individual's risk of esophageal SCC was calculated quantitatively as a risk score. The sensitivity and specificity of the HRA models at various cutoff values of risk score was estimated by a leave-one-out cross-validation. The positive predictive value was estimated assuming the prevalence of esophageal SCC in the whole population to be 0.17% or 0.39% according to literatures. Results: When individuals ranked in the top 10% of the HRA-F risk score was screened, the sensitivity was 57.9% and positive predictive value was 0.93% or 2.12% according to the above assumptions, respectively. The sensitivity was slightly better by the HRA-G model than by the HRA-F model. Conclusion: The HRA models may provide an important approach to early intervention strategies to control esophageal SCC in Japanese men. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2846–54)

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.

Background: Aldehyde dehydrogenase-2 (ALDH2) is the key enzyme for elimination of acetaldehyde, an established animal carcinogen produced after drinking. In persons with inactive ALDH2, the body fails to metabolize acetaldehyde rapidly, leading to excessive accumulation of acetaldehyde. Inactive heterozygous ALDH2 enhances the risk of esophageal squamous cell carcinoma (SCC) in Japanese male drinkers. Methods: We studied whether this is the case for women. The risk factors of esophageal SCC were examined in 52 Japanese women with esophageal SCC and 412 cancer-free Japanese women. Results: The increasing trend in cancer risk according to the quantity of alcohol consumption was significantly steeper in women with inactive heterozygous ALDH2 than in those with active ALDH2 [adjusted odds ratios (ORs) (95% confidence intervals (CIs)) per +7 U/wk increment of alcohol drinking were 3.91 (2.09–7.31) and 1.39 (0.92–2.09), respectively; p=0.006 for difference in OR; 1 Ut=22 g of ethanol]. The results obtained using an alcohol-flushing questionnaire were essentially comparable with those obtained by ALDH2 genotyping [adjusted ORs (95% CIs) per +7 U/wk increment of alcohol drinking were 3.94 (1.87–8.31) and 1.46 (0.96–2.23) in those with and without flushing, respectively; p=0.021 for difference in OR]. The risk of esophageal cancer was markedly higher in heavy drinkers with ALDH2*1/*2 than in never/rare drinkers with ALDH2*1/*1 [adjusted OR (95% CI)=59.1 (4.65–750)]. Other independent significant risk factors of esophageal SCC were smoking, a preference for hot food or drinks, and lower intake of green and yellow vegetables. Conclusions: Japanese men and women shared several common risk factors of esophageal SCC, including drinking with inactive heterozygous ALDH2.

No previous reports on lymph-node metastasis (LNM) from superficial squamous cell carcinoma of the esophagus have proposed definite criteria for additional treatment after endoscopic mucosal resection (EMR). We investigated the association between histopathological factors and LNM in 464 consecutive patients with superficial squamous cell carcinoma of the esophagus who had undergone a radical esophagectomy with lymph-node dissection (14 'M1' lesions: intraepithelial tumors, 36 'M2' lesions: tumors invading the lamina propria, 50 'M3' lesions: tumors in contact with or invading the muscularis mucosa, 32 'SM1' lesions: tumors invading the most superficial 1/3 of the submucosa and 332 'SM2/3' lesions: tumors invading deeper than SM1 level). Histopathological factors including invasion depth, size, lymphatic invasion (LY), venous invasion, tumor differentiation, growth pattern, degree of nuclear atypia and histological grade were assessed for their association with LNM in 82 M3 or SM1 lesions to determine which patients need additional treatment after EMR. LNM was found in 0.0, 5.6, 18.0, 53.1 and 53.9% of the M1, M2, M3, SM1 and SM2/3 lesions, respectively. A univariate analysis showed that each of the following histopathological factors had a significant influence on LNM: invasion depth (M3 vs SM1), LY, venous invasion and histological grade. Invasion depth and LY were significantly associated with LNM in a multivariate analysis. Four out of 38 patients (10.3%) with M3 lesions without LY had LNM, whereas five out of 12 patients (41.7%) with M3 lesions and LY had LNM. Only patients with M1/2 lesions are good candidates for EMR. Invading the muscularis mucosa (M3) is a high-risk condition for LNM the same as submucosal invasion, but M3 lesions without LY can be followed up after EMR without any additional treatment.

Carcinomas of the thoracic esophagus throughout the world have remained in dismal prognosis despite improvements of surgical technique, perioperative care, and multi-modality treatment approach. During the past 2 decades, prevalence of carcinomas, especially adenocarcinoma, of the lower thoracic esophagus has increased drastically in the Western countries.1,2 Many are associated with gastroesophageal reflux and Barrett esophagus. In the East, the most frequent location of esophageal carcinomas is the middle thoracic esophagus and histologic type is mainly squamous cell carcinoma that originates from esophageal squamous epithelium; most are associated with alcohol and tobacco abuse.3–5 Differences of the tumor characteristics between the Western and Eastern countries cause various attitudes in the surgical approach to esophageal carcinomas. The majority of Western surgeons have advocated limited surgical resections such as transhiatal esophagectomy.6 Because they consider esophageal carcinomas to have poor prognosis or being already systemic when lymph node metastases exist, the primary goal of surgical intervention is palliative, with low operative morbidity and mortality rates. Furthermore, controversy has persisted about the extent of resection. Transhiatal resection only performs sampling the lower mediastinal or celiac axis nodes.7 Esophagectomy with extensive lymphadenectomy such as en bloc resection does not remove the upper mediastinal lymph nodes as a standard practice.8 In the East, especially in Japan, extensive lymph node dissection, including not only the abdominal and lower mediastinal but also the upper, middle mediastinal and occasionally cervical lymph nodes, has been advocated as a standard surgical procedure with curative intent, because systematic dissection of metastatic nodes may improve survival and lead to potential cure.9 We perform a right transthoracic esophagectomy with extensive lymph node dissection for all surgical candidates with carcinomas of the thoracic esophagus regardless of tumor location. The aim of the present study was to evaluate our results with 2-field and 3-field lymph node dissection for patients with squamous cell carcinoma of the lower thoracic esophagus.

Objectives: Adenosquamous carcinoma (ASC) of the esophagus is an uncommon form of esophageal cancer. Despite isolated case reports on this tumor type, no large clinicopathologic series appears to have been studied at a single institution. Methods: At our institution, 20 cases of ASC were diagnosed pathologically between 1970 and 2001 (20/2,056 total esophageal cancers; 1.0%). Excluding 2 patients who received preoperative radiation therapy, 18 were selected for review of their clinicopathologic features, including survival time, in comparison with those of patients with conventional squamous cell carcinomas (SCCs; n = 850) and adenocarcinomas (ACs; n = 40) of the esophagus. Results: The location and macroscopic type of the ASCs were similar to those of the SCCs. ASC tumors were significantly smaller than SCC (p = 0.004) and AC (p = 0.012) tumors, and the depth of invasion of ASCs was significantly less than that of SCCs (p = 0.028). Lymphatic permeation and blood vessel invasion were seen in 14 (77.8%) and 7 (38.9%) of the 18 patients with ASCs, respectively, and intraepithelial carcinoma contiguous to the main lesion was evident in 10 cases (56.6%). The cumulative postoperative survival rates of patients with ASC at 3, 5 and 10 years were 71.5, 63.6 and 47.7%, respectively, the outcome being significantly better than for patients with either SCC (p = 0.027) or AC (p = 0.013). Conclusion: In the esophagus, ASCs have better prognosis than conventional SCCs or ACs, probably due to their smaller size and lower stage.

Background Pulmonary complications are a major component of morbidity and mortality after esophagectomy, and have not been well studied after extended lymphadenectomy. Methods Four hundred forty-one patients underwent three-field lymph node dissection and were retrospectively reviewed. Pulmonary complications developed in 32 patients (7.3%) and resulted in 11 deaths (34.4% of pulmonary complications were fatal, and 62.4% of all mortality was caused by pulmonary complications). Pulmonary complications were divided into primary (group A) and secondary pulmonary morbidities (group B), and analyzed separately. Perioperative arterial blood gases on room air were compared with a matched control group (group C). Results All primary complications occurred in the first postoperative week, whereas secondary complications were distributed evenly after operation. The incidence of serious infection (60% versus 23.5%, p = 0.041) and respiratory failure (70.6% versus 31.6%, p = 0.045) was significantly higher in group B as compared with group A and was associated with a higher death rate (47.1% versus 15.8%, p = 0.047). Changes in arterial blood gases were similar in groups A and C, both PaO 2 and pH were reduced in group B, and PaCO 2 was increased. Independent risk factors for primary pulmonary complications were history of major operation, abnormal spirometry, and chronic renal dysfunction. Predictive factors for secondary pulmonary complications were old age, concomitant total gastrectomy, major anastomotic leakage, and bilateral vocal cord palsy. Conclusions Pulmonary complications can be kept at a low level, but they still account for most of the mortality after three-field lymph node dissection. Primary and secondary pulmonary complications are two distinct entities that should be managed differently. Arterial blood gases on room air are helpful in the management of pulmonary complications.

Multiple cancers frequently occur in the upper aerodigestive tract. The high incidence rate of multiple carcinomas in this region is often explained in terms of involvement of the same underlying risk factors. It has been reported that the oral bacterium Streptococcus anginosus (S. anginosus) is associated with esophageal, gastric, and pharyngeal cancer tissues. In this study, a highly specific quantification method for S. anginosus DNA using real-time PCR was established. We employed this assay to determine whether S. anginosus is also associated with oral cancer tissues. This precise quantification method revealed different degrees of infection with S. anginosus in esophageal cancer and oral cancer. We assayed 10 ng of genomic DNA from cancer tissues, and found that eight of 18 samples (44%) from the esophagus contained a detectable level (>10 fg) of S. anginosus DNA, whereas this was the case for only five of 38 samples (13%) of oral cancer. The quantity of S. anginosus DNA in the esophageal cancer tissues was significantly higher than in oral cancer. The maximum amount of S. anginosus DNA was approximately ten times higher in esophageal than in oral cancer tissues. In addition, none of the five different oral cancer sites (floor of the mouth, mandibular gingival, maxillary gingival, buccal mucosal, and tongue) showed significant signs of S. anginosus infection. On the other hand, most non-cancerous tissues of the esophagus and tongue showed an undetectable level of S. anginosus. These results suggest that S. anginosus is associated with esophageal cancer, but is not closely related with oral cancer.

Background. Clinicopathologic characteristics and outcomes with clinical T1 and T2 squamous cell carcinomas requiring surgical resection have not been well investigated. The purpose of this study was to evaluate results for patients undergoing 3-field lymph node dissection and to elucidate predictors of survival. Methods. From January 1988 to January 1998, 336 patients with carcinomas of the thoracic esophagus underwent transthoracic esophagectomy with 3-field lymph node dissection. Of these, 325 (97%) patients had squamous cell carcinomas. A total of 139 (41%) with clinical T1 and T2 tumors were retrospectively analyzed based on the prospectively established database. Results. Among the 139 patients with clinical T1 and T2 squamous cell carcinomas, 90 (65%) had T1 and 49 (35%) had T2 tumors. The operative morbidity, and 30-day and in hospital mortality rates were 70%, 0%, and 2%, respectively. Macroscopic and microscopic complete resection of the primary tumor and removal of metastatic nodes were accomplished in 90% of the cases. The overall 1-, 3-, and 5-year survival rates were 88%, 72%, and 61%. Significant prognostic factors, determined by multivariate analysis, were number of lymph node metastases, pathologic T status, and completeness of resection. Number of lymph node metastases most strongly affected survival. Eighty-six percent of patients with 5 or more metastatic nodes occurred recurrence of disease. Conclusion. Esophagectomy with 3-field lymph node dissection accomplishes a high feasibility of complete resection of primary tumor and removal of metastatic nodes in patients with clinical T1 and T2 squamous cell carcinomas. Five or more metastatic nodes can be considered as an indicator of systemic disease with a high likelihood of distant organ metastasis. This variable must be taken into consideration for deciding clinical disease stage and treatment strategy. (Surgery 2003;133:368-74.)