Fuyumi Isayama

Study of abnormal chromosome regions in esophageal squamous cell carcinoma by comparative genomic hybridization: relationship of lymph node metastasis and distant metastasis to selected abnormal regions

Squamous cell carcinoma of the esophagus (ESCC) has a poor prognosis among digestive tract cancers. Lymph node metastasis and distant metastasis are the major factors determining its prognosis. We used comparative genomic hybridization (CGH) to evaluate primary tumor lymph nodes and metastatic areas from ESCC patients in order to determine the relationship between abnormal chromosome regions and outcome. Tumor tissues and lymph nodes were collected from 51 patients with ESCC, and abnormal chromosome regions were detected by CGH. We searched for regions that were significantly more common in patients with lymph nodes metastases (n>/= 6) or distant metastases, and correlated those chromosomal changes with survival. Regions showing amplification in more than 65% of esophageal squamous cell cancers were as follows: 17q12 (90.2%), 17q21 (86.3%), 3q29 (82.4%), 3q28 (78.4%), 8q24.2 (76.5%), 22q12 (76.5%), 3q27 (74.5%), 8q24.3 (74.5%), 1q22 (70.6%), 5p15.3 (70.6%), 22q13 (70.6%), 3q26.3, 8q23, 8q24.1, 9q34, 11q13, 17p12, 17q25, 20q12, 20q13.1 (68.6%), 1q32, 1q42, and 20q13.2 (66.7%). Regions showing deletion in more than 50% of the tumors were as follows: Yp11.3 (62.7%), 3p26 (56.9%), Yq12 (54.9%), 13q21 (52.9%), 4q32 (51.0%), and 13q22 (51.0%). When Fishers test was used to assess associations of these regions with metastases to lymph nodes, amplification at 2q12-14 (P= 0.012), 3q24-26 (P= 0.005), and 7q21-31 (P= 0.026) were significant. Survival was worse for patients with amplification at all 3 regions. In patients with distant organ metastases, amplification at 7p13-21 was significant (P= 0.008), and survival was worse. Chromosomal amplifications in ESCC at 2q12-14, 3q24-26, and 7q21-31 were associated with lymph node metastasis, while amplification at 7p13-21 was related to distant metastasis. Amplification at these regions correlated with worse survival. Genes involved in the phenotype of ESCC may exist in these regions. Identification of these genes is a theme for future investigation.

Size analysis of lymph node metastasis in esophageal cancer: diameter distribution and assessment of accuracy of preoperative diagnosis

BackgroundIn esophageal cancer, lymphatic spread occurs more frequently and at an earlier stage than in other gastrointestinal cancers, and both preoperative and intraoperative diagnoses of lymph nodes metastases are sometimes incorrect. Our objective was to measure the sizes of lymphatic metastases and to examine the accuracy of clinical diagnosis of lymphatic spread in patients with squamous cell carcinoma of the esophagus.MethodsThe sizes of 320 metastatic lymph nodes of 9254 dissected nodes from 92 consecutive esophagectomy patients over 1 year were measured and compared with the sizes of the actual metastases within the nodes. These data allowed investigation of the correct rate of preoperative diagnosis of lymph node metastasis.ResultsThe mean diameter of the metastases was 4.8 mm, which was significantly smaller than that of the involved lymph nodes. Among the metastatic lymph nodes, 37.2% were less than 5 mm in diameter, and 63.1% of the metastases were less than 5 mm in diameter. The true-positive and true-negative diagnosis rate for all lymph node stations in three fields (neck, thorax, and abdomen) was only 23.2%, and the false-negative rate for diagnosis of lymph node metastasis was 53.7%.ConclusionsTwo-thirds of involved lymph nodes had very small metastases (<5 mm), suggesting that limited confidence should be placed in the preoperative diagnosis of lymphatic spread. Therefore, extensive lymph node dissection appears appropriate in esophageal cancer surgery, given the small sizes of many metastases and the difficulty with preoperative diagnosis.

Relational topographical anatomy between right bronchial artery and thoracic duct

Thoracic duct injury leads to “chylothorax”. We found a close relationship of topographical anatomy between right bronchial artery and thoracic duct from esophageal cancer operations. We retrospectively analyzed topographical anatomy of right bronchial artery and location of thoracic duct in 124 cases operated in 2012. Of 124 cases, we recognized 8 cases of anomalous right bronchial artery. In these cases, the right bronchial artery originated directly from descending aorta without connections with third intercostal artery. When the right bronchial artery has a connection with third intercostal artery, the thoracic duct was located within the loop of the right bronchial artery. However, in these 8 anomalous cases, thoracic duct was located dorsally outside the loop of the right bronchial artery without exceptions. We have to be very careful in exploring the thoracic duct when we notice the anomalous right bronchial artery during esophageal cancer operation.

Utility of weekly docetaxel combined with preoperative radiotherapy for locally advanced esophageal cancer from pathological analysis.

Esophageal squamous cell cancer (ESCC) is a high-grade carcinoma that is treated with multidisciplinary approaches, including chemoradiotherapy (CRT) followed by surgery. Despite some success with these therapies, overall survival remains poor. In order to investigate a newer CRT regimen, we designed a comparative study to evaluate preoperative CRT using docetaxel (DOC) or 5-Fluorouracil and cisplatin (FU+CDDP [FP] therapy) for treatment of resectable ESCC. In a retrospective review of patients with resectable, locally advanced ESCC, 95 patients received preoperative CRT between 2001 and 2007. CRT was administered using either FP (n = 40) or DOC (n = 55). Pathological response and clinical outcomes were compared between the two groups. Hazard ratios and time-to-event analyses were used to assess outcomes; the ratios were controlled by multivariate logistic regression analysis of potential prognostic factors, and survival was presented with Kaplan-Meier curves. In the FP group, a significant curative effect was observed on the basis of pathological examination of postoperative lesions. However, the DOC group presented a significantly better prognosis on the basis of cumulative survival rates. Logistic regression analysis revealed that the presence of five or more lymph node metastases was an independent predictor of reduced survival. Patients with lymph node metastasis exhibited a better prognosis in the DOC group than those in the FP group. Preoperative CRT for locally advanced esophageal cancer using DOC results in similar or better long-term outcomes compared with FP-based CRT. Therefore, CRT using DOC is a promising therapy option for esophageal cancer.

Transthoracic esophagectomy of adenocarcinoma in Barrett’s esophagus in Japanese patients: analysis of localization of lymph node metastases in 19 cases

BackgroundThe incidence of esophageal adenocarcinoma is only 1%–2% in Japan. For this reason, many aspects of this disease have not been clarified, such as its generation, progress, and the potential of malignancy. It is necessary to investigate the strategy for treating this disease.MethodsBetween 1998 and 2008, 19 cases were diagnosed as adenocarcinoma with Barrett’s esophagus and treated with esophagectomy at Juntendo University: 13 cases were early stage and 6 cases were advanced stage. Distribution of lymph node metastasis and prognosis were investigated.ResultsThe incidence of lymph node metastases of adenocarcinoma is statistically lower (15.4%) compared with that of squamous cell carcinoma (SCC) (44.0%) (P = 0.034) when the depth of the tumor is not beyond the submucosal layer. Even in the early stages of adenocarcinoma, positive nodes were found in the lower mediastinum and gastric cardia. In advanced cases, cancer had spread randomly to the upper mediastinum or celiac region. Mean survival time of superficial and advanced adenocarcinoma after esophagectomy was 3,517.5 ± 330.6 and 2,061.4 ± 451.3 days, respectively, whereas that of SCC was 2,794.7 ± 131.0 and 1,669.1 ± 101.5 days, respectively. Overall survival of superficial or advanced adenocarcinoma was better than that of SCC but was not statistically superior.ConclusionsEndoscopic mucosal resection is limitedly proposed for mucosal tumors. Esophagectomy with a mediastinal lymphadenectomy should be conducted for tumors invading the submucosa. An individualized strategy is required that could approach the upper mediastinum based on staging and location of lymph node metastases.

Utility of weekly docetaxel combined with preoperative radiotherapy for locally advanced esophageal cancer from pathological analysis: Chemoradiotherapy for esophageal cancer

Esophageal squamous cell cancer (ESCC) is a high-grade carcinoma that is treated with multidisciplinary approaches, including chemoradiotherapy (CRT) followed by surgery. Despite some success with these therapies, overall survival remains poor. In order to investigate a newer CRT regimen, we designed a comparative study to evaluate preoperative CRT using docetaxel (DOC) or 5-Fluorouracil and cisplatin (FU+CDDP [FP] therapy) for treatment of resectable ESCC. In a retrospective review of patients with resectable, locally advanced ESCC, 95 patients received preoperative CRT between 2001 and 2007. CRT was administered using either FP (n = 40) or DOC (n = 55). Pathological response and clinical outcomes were compared between the two groups. Hazard ratios and time-to-event analyses were used to assess outcomes; the ratios were controlled by multivariate logistic regression analysis of potential prognostic factors, and survival was presented with Kaplan-Meier curves. In the FP group, a significant curative effect was observed on the basis of pathological examination of postoperative lesions. However, the DOC group presented a significantly better prognosis on the basis of cumulative survival rates. Logistic regression analysis revealed that the presence of five or more lymph node metastases was an independent predictor of reduced survival. Patients with lymph node metastasis exhibited a better prognosis in the DOC group than those in the FP group. Preoperative CRT for locally advanced esophageal cancer using DOC results in similar or better long-term outcomes compared with FP-based CRT. Therefore, CRT using DOC is a promising therapy option for esophageal cancer.

Setting of the candidate exposure conditions in an individualized tumor response testing (ITRT) toward an individual chemotherapy for esophageal cancer

BackgroundTo apply the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) technique to individualized tumor response testing (ITRT) in esophageal cancer, optimal exposure conditions that would permit us to predict the clinical response to the low-dose cisplatin (CDDP)/5-fluorouracil (5-FU) regimen and docetaxel (DOC) regimen were determined.MethodsCD-DST was performed on 35 surgical specimens and 27 endoscopic biopsy samples from patients with esophageal squamous cell cancer. The reported blood AUC values were reproduced, or an in vitro concentration-response curve was constructed, for each regimen to determine exposure conditions using surgical specimens. For endoscopic samples, we estimated the evaluation rate (of CD-DST) and compared in vitro sensitivity with clinical response in measurable lesions to validate the exposure conditions determined.ResultsOverall, data were evaluated in 75.8% of the cases (94.3% in surgical specimens and 51.9% in endoscopic biopsy samples). Modeled exposure conditions were 5-FU 2.0 μg/ml/120 h with a cutoff inhibition rate (IR) of 50% for the low-dose CDDP/5-FU regimen and DOC 0.04 μg/ml/120 h with a cutoff IR of 50% for the DOC regimen.ConclusionsAlthough the study failed to compare in vitro results with clinical outcomes in measurable lesions, and the practical usefulness and applicability of the technique remain to be demonstrated, CD-DST might be a useful tool in selecting optimal chemotherapeutic agents.