Publications by authors named "Hiroyasu Igaki"

64 Publications

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

Mol Clin Oncol 2021 Feb 30;14(2):41. Epub 2020 Dec 30.

Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan.

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 , , , and of each tumor sample from patients with CESCC were analyzed by 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 and its pathway-related gene mutations, the present study detected 15.1% of , 6.0% of , 3.5% of , 3.0% of and 3.0% for 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.
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http://dx.doi.org/10.3892/mco.2020.2205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788557PMC
February 2021

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

J Thorac Dis 2019 Nov;11(11):4654-4662

Cancer Care Center, Kawasaki Saiwai Hospital, Kawasaki, Japan.

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.
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http://dx.doi.org/10.21037/jtd.2019.10.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940259PMC
November 2019

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

Sci Rep 2019 09 16;9(1):13347. Epub 2019 Sep 16.

Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.

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.
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http://dx.doi.org/10.1038/s41598-019-50005-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746740PMC
September 2019

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

Gen Thorac Cardiovasc Surg 2019 May 18;67(5):470-478. Epub 2019 Feb 18.

Department of Esophageal Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

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.
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http://dx.doi.org/10.1007/s11748-019-01070-1DOI Listing
May 2019

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.

Int J Clin Oncol 2019 Jan 14;24(1):60-67. Epub 2018 Aug 14.

Esophageal Surgery Division, National Cancer Center Hospital, Tokyo, Japan.

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.
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http://dx.doi.org/10.1007/s10147-018-1336-xDOI Listing
January 2019

Long-term outcome after resection for recurrent oesophageal cancer.

J Thorac Dis 2018 May;10(5):2691-2699

Cancer Care Center, Kawasaki Saiwai Hospital, Kawasaki, Japan.

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% 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% 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% 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.
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http://dx.doi.org/10.21037/jtd.2018.05.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006052PMC
May 2018

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

Endosc Int Open 2017 Sep 12;5(9):E868-E874. Epub 2017 Sep 12.

Esophageal Surgery Division, National Cancer Center Hospital, Tokyo, Japan.

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.
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http://dx.doi.org/10.1055/s-0043-115388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595573PMC
September 2017

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

Surg Endosc 2018 02 4;32(2):651-659. Epub 2017 Aug 4.

Japan Esophageal Oncology Group of Japan Clinical Oncology Group (JCOG), Tokyo, Japan.

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.
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http://dx.doi.org/10.1007/s00464-017-5716-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772128PMC
February 2018

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).

Int J Clin Oncol 2017 Dec 17;22(6):1042-1049. Epub 2017 Jul 17.

Department of Surgery, Keio University, School of Medicine, Tokyo, Japan.

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.
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http://dx.doi.org/10.1007/s10147-017-1154-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676839PMC
December 2017

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

Anticancer Res 2017 07;37(7):3741-3749

Esophageal Surgery Division, National Cancer Center Hospital, Tokyo, Japan.

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.
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http://dx.doi.org/10.21873/anticanres.11748DOI Listing
July 2017

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).

Jpn J Clin Oncol 2017 Jun;47(6):480-486

Department of Surgery, Keio University School of Medicine, Tokyo.

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.
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http://dx.doi.org/10.1093/jjco/hyx040DOI Listing
June 2017

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

Int J Surg Case Rep 2017 24;33:1-3. Epub 2017 Jan 24.

Department of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan.

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 Bc and Bb+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.
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http://dx.doi.org/10.1016/j.ijscr.2016.11.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334493PMC
January 2017

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

Ann Surg 2016 Dec;264(6):1009-1015

*Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan†Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan‡Esophageal Surgery Division, National Cancer Center Hospital, Tokyo, Japan§Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan¶Department of Surgery, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan||Esophageal Surgery Division, National Cancer Center Hospital East, Kashiwa, Japan**Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan††Gastroenterological Surgery, Toranomon Hospital, Tokyo, Japan‡‡Department of Surgery, Niigata Cancer Center Hospital, Niigata, Japan§§Department of Surgery, Shizuoka General Hospital, Shizuoka, Japan¶¶Japan Clinical Oncology Group Data Center, National Cancer Center, Tokyo, Japan||||Department of Surgery, Keio University, School of Medicine, Tokyo, Japan.

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.
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http://dx.doi.org/10.1097/SLA.0000000000001557DOI Listing
December 2016

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

Ann Surg 2017 06;265(6):1152-1157

*JCOG Data Center/Operations Office, National Cancer Center, Tokyo, Japan †Department of Surgery, Keio University School of Medicine, Tokyo, Japan ‡Esophageal Surgery Division, National Cancer Center Hospital, Tokyo, Japan §Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan ¶Department of Gastrointestinal Surgery, Aichi Cancer Center Hospital, Nagoya, Japan ||Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan **International Goodwill Hospital, Yokohama, Japan.

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.
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http://dx.doi.org/10.1097/SLA.0000000000001828DOI Listing
June 2017

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

Medicine (Baltimore) 2016 May;95(20):e3699

From the Division of Gastrointestinal Oncology (TT) and Division of Esophageal Surgery (YT), Shizuoka Cancer Center, Sunto-gun, Shizuoka; JCOG Data Center/Operation Office, National Cancer Center (JM, KN, HF); Gastrointestinal Medical Oncology Division (KS, YH, KK) and Division of Esophageal Surgery (HI), National Cancer Center Hospital; Department of Thoracic Surgery, Aichi Cancer Center (MS); and Department of Surgery, Keio University School of Medicine (YK) Japan.

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.
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http://dx.doi.org/10.1097/MD.0000000000003699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902424PMC
May 2016

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

Jpn J Clin Oncol 2016 Apr 31;46(4):389-92. Epub 2016 Jan 31.

International Goodwill Hospital, Yokohama, Japan.

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.
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http://dx.doi.org/10.1093/jjco/hyv211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886135PMC
April 2016

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

PLoS One 2016 26;11(1):e0147372. Epub 2016 Jan 26.

Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147372PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728064PMC
July 2016

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

Mol Carcinog 2016 12 12;55(12):2077-2088. Epub 2016 Jan 12.

Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.

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.
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http://dx.doi.org/10.1002/mc.22452DOI Listing
December 2016

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

Int J Clin Oncol 2016 Apr 3;21(2):283-288. Epub 2015 Sep 3.

Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan.

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.
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http://dx.doi.org/10.1007/s10147-015-0899-zDOI Listing
April 2016

Recurrent Laryngeal Nerve Paralysis after Esophagectomy: Respiratory Complications and Role of Nerve Reconstruction.

Tohoku J Exp Med 2015 09;237(1):1-8

Division of Esophageal Surgery, Department of Gastrointestinal Oncology, National Cancer Center Hospital.

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.
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http://dx.doi.org/10.1620/tjem.237.1DOI Listing
September 2015

Prognostic Factors in Patients Receiving Neoadjuvant 5-Fluorouracil plus Cisplatin for Advanced Esophageal Cancer (JCOG9907).

Oncology 2015 16;89(3):143-51. Epub 2015 Apr 16.

Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.

Objective: Neoadjuvant chemotherapy with 5-fluorouracil plus cisplatin and subsequent esophagectomy with two- to three-field lymphadenectomy is a standard treatment for patients with clinical stage II/III squamous cell carcinoma (SCC) of the esophagus. This study investigates the prognostic factors for patients who received neoadjuvant chemotherapy.

Methods: Of 164 patients assigned to receive neoadjuvant chemotherapy in the JCOG9907 trial, multivariate analyses were performed for 159 and 149 patients to evaluate the preoperative and the combined preoperative and postoperative prognostic factors, respectively.

Results: The multivariate analyses using preoperative factors showed that clinical stage T3 [vs. cT1-2; hazard ratio (HR) 3.60, p = 0.0007] and serum albumin (Alb) <4.0 g/dl (vs. ≥ 4.0 g/dl; HR 2.29, p = 0.0005) were associated with a poor prognosis. Four independent prognostic factors were identified by multivariate analysis of both preoperative and postoperative factors: pathological curability B (pB; R0 with stage IV or pD < pN) or pC [microscopic or macroscopic residual tumor (R1/R2)] [vs. pA (R0); HR 1.93, p = 0.015], pathological stage N1 (vs. pN0; HR 3.86, p = 0.0012), cT3 (vs. cT1-2; HR 2.80, p = 0.0073), and serum Alb <4.0 g/dl (vs. ≥ 4.0 g/dl; HR 2.03, p = 0.0069).

Conclusions: Preoperative cT stage, Alb, and postoperative pathological findings are independent prognostic factors for patients undergoing neoadjuvant chemotherapy for advanced thoracic esophageal SCC. This analysis may aid in stratification according to individual patient risk.
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http://dx.doi.org/10.1159/000381065DOI Listing
November 2015

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

Surg Endosc 2015 Dec 13;29(12):3519-26. Epub 2015 Feb 13.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

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.
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http://dx.doi.org/10.1007/s00464-015-4102-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648951PMC
December 2015

ZNF695 methylation predicts a response of esophageal squamous cell carcinoma to definitive chemoradiotherapy.

J Cancer Res Clin Oncol 2015 Mar 2;141(3):453-63. Epub 2014 Oct 2.

Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Purpose: Definitive chemoradiotherapy (dCRT) is one of the standard treatments for esophageal squamous cell carcinoma. Patients with a response to dCRT have a better prognosis than those resistant to dCRT while survival benefits for patients with residual tumors are limited. Nevertheless, few molecular markers to predict the response to dCRT are currently available. Here, we aimed to establish a DNA methylation marker to predict the response to dCRT.

Methods: A total of 104 patients were divided into screening (n = 43) and validation (n = 61) sets. A genome-wide DNA methylation analysis was performed using an Infinium HumanMethylation450 BeadChip array. Methylation levels were measured by quantitative methylation-specific PCR and normalized by the fraction of cancer cells in a sample.

Results: The genome-wide methylation analysis of seven responders and eight non-responders identified 18 genomic regions specifically (un)methylated in the responders. Among these, methylation of the promoter CpG island of ZNF695 was significantly associated with the response to dCRT in the screening set (P = 0.004), and a cutoff value was determined. In the validation set, the association was successfully validated (P = 0.021), and a high specificity (90 %) for the prediction of responders was obtained using the prefixed cutoff value. In addition, a multivariate analysis showed that ZNF695 methylation was an independent predictive factor for the response to dCRT (OR 7.55, 95 % CI 2.12-26.9, P = 0.002).

Conclusion: ZNF695 methylation was significantly associated with the response to dCRT and is a promising predictive marker for the response to dCRT.
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http://dx.doi.org/10.1007/s00432-014-1841-xDOI Listing
March 2015

Prognostic analysis of salvage esophagectomy after definitive chemoradiotherapy for esophageal squamous cell carcinoma: the importance of lymphadenectomy.

J Thorac Cardiovasc Surg 2014 Jun 15;147(6):1805-11. Epub 2014 Jan 15.

Division of Esophageal Surgery, Department of Surgery, National Cancer Center Hospital, Tokyo, Japan.

Objectives: The 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.

Methods: Clinical 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.

Results: Survival 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 < .001; odds ratio [OR], 0.292); complete tumor resection (P < .001; OR, 4.520); N category (P = .089; OR, 1.304); M category (P = .081; OR, 2.215), and total mediastinal dissection with 15 or more dissected mediastinal lymph nodes (P = .034; OR, 0.546).

Conclusions: Salvage indications of recurrence, earlier disease, and complete tumor resection are related to longer survival. The total area of mediastinal dissection with a sufficient number of dissected mediastinal lymph nodes improves survival. Additional neck dissection does not add benefit. The optimal procedure for lymph node dissection in salvage esophagectomy should be established in future studies.
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http://dx.doi.org/10.1016/j.jtcvs.2013.12.040DOI Listing
June 2014

Estimation of the fraction of cancer cells in a tumor DNA sample using DNA methylation.

PLoS One 2013 2;8(12):e82302. Epub 2013 Dec 2.

Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan ; Esophageal Surgery Division, National Cancer Center Hospital, Tokyo, Japan ; Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Contamination of normal cells is almost always present in tumor samples and affects their molecular analyses. DNA methylation, a stable epigenetic modification, is cell type-dependent, and different between cancer and normal cells. Here, we aimed to demonstrate that DNA methylation can be used to estimate the fraction of cancer cells in a tumor DNA sample, using esophageal squamous cell carcinoma (ESCC) as an example. First, by an Infinium HumanMethylation450 BeadChip array, we isolated three genomic regions (TFAP2B, ARHGEF4, and RAPGEFL1) i) highly methylated in four ESCC cell lines, ii) hardly methylated in a pooled sample of non-cancerous mucosae, a pooled sample of normal esophageal mucosae, and peripheral leukocytes, and iii) frequently methylated in 28 ESCCs (TFAP2B, 24/28; ARHGEF4, 20/28; and RAPGEFL1, 19/28). Second, using eight pairs of cancer and non-cancer cell samples prepared by laser capture microdissection, we confirmed that at least one of the three regions was almost completely methylated in ESCC cells, and all the three regions were almost completely unmethylated in non-cancer cells. We also confirmed that DNA copy number alterations of the three regions in 15 ESCC samples were rare, and did not affect the estimation of the fraction of cancer cells. Then, the fraction of cancer cells in a tumor DNA sample was defined as the highest methylation level of the three regions, and we confirmed a high correlation between the fraction assessed by the DNA methylation fraction marker and the fraction assessed by a pathologist (r=0.85; p<0.001). Finally, we observed that, by correction of the cancer cell content, CpG islands in promoter regions of tumor-suppressor genes were almost completely methylated. These results demonstrate that DNA methylation can be used to estimate the fraction of cancer cells in a tumor DNA sample.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0082302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846724PMC
February 2015

A retrospective study on nonmalignant airway erosion after right transthoracic subtotal esophagectomy: incidence, diagnosis, therapy, and risk factors.

Ann Thorac Surg 2014 Feb 20;97(2):467-73. Epub 2013 Nov 20.

Division of Esophageal Surgery, Department of Surgery, National Cancer Center Hospital, Tokyo, Japan.

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<0.001), preoperative radiotherapy (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.
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http://dx.doi.org/10.1016/j.athoracsur.2013.10.017DOI Listing
February 2014

Endoscopic submucosal dissection for gastric tube cancer after esophagectomy.

Gastrointest Endosc 2014 Feb 21;79(2):260-70. Epub 2013 Sep 21.

Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan.

Background: Recent improvements in the survival of patients after esophagectomy have led to an increasing occurrence of gastric tube cancer (GTC). Removal of the reconstructed gastric tube, however, can lead to high morbidity and mortality.

Objective: To assess the feasibility and effectiveness of endoscopic submucosal dissection (ESD) for GTC.

Design: Retrospective study.

Setting: National Cancer Center Hospital, Tokyo, Japan.

Patients: We investigated patients with GTC after esophagectomy undergoing ESD from 1998 to 2011.

Intervention Esd Main Outcome Measurements: Patient characteristics, endoscopic findings, technical results, histopathology including curability and Helicobacter pylori gastritis, and long-term outcomes.

Results: There were 51 consecutive patients with 79 lesions including 38 lesions (48%) meeting the absolute indication, 31 (39%) satisfying the expanded indications, and 10 (13%) falling outside such indications. The median procedure time was 90 minutes. There were 73 en bloc resections (92%), 59 en bloc resections with tumor-free margins (R0 resections, 75%), and 51 curative resections (65%) based on the Japanese Gastric Cancer Association criteria. Fifty patients (98%) were assessed as H pylori gastritis positive. Adverse events included 3 perforations (3.8%) during ESD and 2 delayed perforations (2.5%) without any emergency surgery and 3 delayed bleeding (3.8%). Local recurrence was detected in 4 patients (7.8%), and metachronous GTCs were identified in 18 patients (35%). Five patients (10%) died of GTC including 3 metachronous lesions. The 5-year overall survival rate was 68.4%, and the disease-specific survival rate was 86.7% with 100% for curative and 72.7% for non-curative patients during a median follow-up period of 3.8 years (range, 0-12.1 years).

Limitation: Single-center retrospective study.

Conclusions: ESD for GTC was feasible and effective for curative patients; however, long-term outcomes for non-curative patients were less satisfactory.
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http://dx.doi.org/10.1016/j.gie.2013.07.059DOI Listing
February 2014

Phase II feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma.

Cancer Sci 2013 Nov 18;104(11):1455-60. Epub 2013 Oct 18.

Division of Digestive Endoscopy and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan; Division of Gastroenterology, Saitama Cancer Center, Saitama, Japan.

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).
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http://dx.doi.org/10.1111/cas.12274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654256PMC
November 2013

Diagnosis and surgical outcomes for primary malignant melanoma of the esophagus: a single-center experience.

Ann Thorac Surg 2013 Sep 25;96(3):1002-6. Epub 2013 Jun 25.

Division of Esophageal Surgery, Department of Surgery, National Cancer Center Hospital, Tokyo, Japan.

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.
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http://dx.doi.org/10.1016/j.athoracsur.2013.04.072DOI Listing
September 2013
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