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Abstract Background Leiomyosarcoma (LMS) of the gastrointestinal tract is an extremely rare high-grade neoplasm with poor prognosis. For advanced LMS with distant metastasis, the decision as to the choice of the most appropriate therapeutic strategy, including chemotherapy and surgery, is difficult. Here, we present an unusual case of LMS of the sigmoid colon with liver metastases and gastric cancer. The survival of this patient was prolonged by a combined modality therapy involving chemotherapy and surgery. Case presentation A 66-year-old woman who had been diagnosed with advanced gastric cancer and multiple liver metastases was referred to our hospital. The initial treatment with docetaxel and S-1 considerably reduced both the gastric cancer and liver tumors; consequently we performed surgical resection. Pathological examination revealed that no viable tumor cells remained in the stomach and chemotherapy resulted in complete remission of the gastric cancer. The liver tumors were immunohistochemically diagnosed as LMS. A tumor of the sigmoid colon was subsequently discovered and the liver tumors were found to have recurred. The surgically resected sigmoid colon and liver tumors were all immunohistochemically diagnosed as LMS. These findings indicated that the multiple liver metastases arose from the LMS in the sigmoid colon, and that they were accompanied by advanced gastric cancer. We performed another surgical resection and administered chemotherapy to treat the recurring liver metastases. The patient survived for 4 years and 10 months after initial presentation at our hospital. Conclusion Colonic LMS is rare and its joint occurrence with gastric cancer is extremely unusual. Although LMS is a high-grade neoplasm, a multimodal therapeutic approach can increase patient survival time even when multiple liver metastases are present.

Background: Patients across various cancers who develop immune-related adverse events (irAEs) post-immune checkpoint inhibitor (ICI) treatment tend to experience better tumor response and survival than those who do not. However, studies regarding this association in patients with esophageal squamous cell carcinoma (ESCC) are limited., Methods: We assessed the relationship of irAEs with tumor response and survival in 82 consecutive patients with unresectable advanced or recurrent ESCC treated with second- or later-line nivolumab, an anti-PD-1 antibody, monotherapy., Results: We observed irAEs in 24 (29.3%) patients, with the overall response and disease control rates in the irAE-positive group being significantly better than those in the irAE-negative group (both p < 0.0001). During the entire period and within 8 weeks of nivolumab initiation, progression-free and overall survivals (PFS and OS, respectively) were significantly better in patients with grade1/2 irAEs than in those without. Univariate and multivariate analyses indicated grade1/2 irAEs during the entire period and within 8 weeks as independent covariates for PFS (entire period: hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.16-0.49, p < 0.001; within 8 weeks: HR 0.46, 95% CI 0.23-0.93, p = 0.03) and OS (entire period: HR 0.24, 95% CI 0.13-0.44, p < 0.001; within 8 weeks: HR 0.41, 95% CI 0.18-0.92, p = 0.03)., Conclusions: Grade1/2 irAEs during the entire treatment period and within 8 weeks of nivolumab initiation were significantly associated with improved tumor response and survival in patients with advanced ESCC treated with nivolumab monotherapy. Therefore, mild irAEs may be predictive markers for the response and prognosis of ESCC following ICI treatment.

Background/aim: This study aimed to evaluate the long-term prognosis of definitive chemoradiotherapy and clinical features of postoperative lymph node (LN) recurrence after curative resection of thoracic esophageal squamous cell cancer (ESCC)., Patients and Methods: A total of 586 patients who underwent radical resection of ESCC at the Hiroshima University Hospital from January 2000 to December 2019 were reviewed retrospectively. This study analyzed the clinical characteristics of 54 patients who developed recurrence in a solitary LN by comparing them to 182 patients who experienced total recurrence. Additionally, we analyzed the prognostic factors of 50 patients who received chemo-radiotherapy (CRT)., Results: The results revealed a tendency for a higher incidence of solitary LN recurrence in cases of early esophageal cancer and upper thoracic esophageal cancer among all recurrence cases. The 3-, 5-, and 7-year overall survival (OS) rates were 40.5%, 37.8% and 34.6%, respectively, with a median survival time of 27.9 months. Univariate analysis of OS factors, such as age, depth of the primary tumor at the initial surgery, time to LN recurrence after surgery, site of LN recurrence, and the number of the regional LNs with recurrence showed no significant impact on OS., Conclusion: Approximately 35% of patients with ESCC who experienced LN recurrence after curative resection achieved long-term survival through CRT. Despite the absence of identifiable prognostic factors, CRT proves to be a valuable initial treatment option for LN recurrence., Competing Interests: The Authors declare no conflicts of interest that may have influenced the results of this study., (Copyright 2024, International Institute of Anticancer Research.)

Background: Esophageal fistula (EF) is a serious complication in patients with cT4b esophageal squamous cell carcinoma (ESCC) with adjacent organ involvement. Among EFs, aortoesophageal fistula (AEF), forming a fistula with the aorta, could be fatal. This study aimed to identify the risk factors for AEF in patients with cT4b ESCC with obvious or suspected aortic invasion who underwent definitive radiotherapy (DRT)., Methods: Forty-four patients with cT4b ESCC with obvious or suspected invasion to the aorta who underwent DRT were included. Blood tests and computed tomography (CT) findings before and after DRT were compared between the patients with and without AEF to identify the potential risk factors for AEF., Results: Nine patients (20.5%) developed AEF after DRT. Comparing between patients with and without AEF, pre-DRT white blood cell counts and post-DRT C-reactive protein (CRP) levels were significantly higher in patients with AEF. Furthermore, pre-DRT CT findings were similar between the two groups. However, post-DRT CT findings demonstrated significantly larger picus angle and lower esophageal wall thickness on the aortic side in patients with AEF. Multivariate analysis identified elevated post-DRT CRP levels [<3.3 versus ≥3.3 mg/dL; odds ratio (OR): 30.7; 95% confidence interval (CI): 2.92-323.2; P=0.004] and esophageal wall thinning on post-DRT CT scans (>6 versus ≤6 mm; OR: 13.2; 95% CI: 1.24-140.1; P=0.033) as risk factors for AEF., Conclusions: We found that post-DRT esophageal wall thinning on the aortic side, as observed on CT scans, and elevated CRP levels were predictive factors for AEF in patients with cT4b ESCC with obvious or suspected invasion to the aorta., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-848/coif). The authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Background: Nivolumab is approved in Japan as a second-line treatment for patients with advanced esophageal squamous cell carcinoma (ESCC) resistant to fluoropyrimidine and platinum-based drugs. It is also used in adjuvant and primary postoperative therapies. This study aimed to report real-world data on nivolumab use for esophageal cancer treatment., Methods: In total, 171 patients with recurrent or unresectable advanced ESCC who received nivolumab (n = 61) or taxane (n = 110) were included. We collected real-world data of patients treated with nivolumab as a second- or later-line therapy and evaluated treatment outcomes and safety., Results: Median overall survival was longer and progression-free survival (PFS) was significantly longer (p = 0.0172) in patients who received nivolumab than in patients who received taxane as a second- or later-line therapy. Furthermore, subgroup analysis for second-line treatment only showed the superiority of nivolumab in increasing the PFS rate (p = 0.0056). No serious adverse events were observed., Conclusions: In real-world practice, nivolumab was safer and more effective than taxane in patients with ESCC with diverse clinical profiles who did not meet trial eligibility criteria, including those with poor Eastern Cooperative Oncology Group performance status, comorbidities, and receiving multiple treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ohsawa, Hamai, Emi, Ibuki, Kurokawa, Yoshikawa, Hirohata, Kitasaki and Okada.)

Purpose: Various blood cell parameters have been identified as predictive markers of tumor responses and the survival of patients with cancer treated with immune checkpoint inhibitors. The purpose of this study is to assess the ability of various blood cell parameters to predict therapeutic effects and survival in patients with esophageal squamous cell carcinoma (ESCC) treated with nivolumab monotherapy., Patients and Methods: We evaluated neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR) and lymphocyte-to-monocyte (LMR) ratios as predictive markers of patients' survival and effects of nivolumab monotherapy after one or more prior chemotherapies for unresectable advanced or recurrent ESCC., Results: The objective response and disease control rates were 20.3% and 47.5%, respectively. The LMRs before, and 14 and 28 days after nivolumab initiation were significantly higher in patients with complete response (CR)/partial response (PR)/stable disease (SD) than those with progressive disease (PD). The NLRs at 14 and 28 days after nivolumab initiation were significantly lower in patients with CR/PR/SD than with PD. The optimal cutoffs for these parameters significantly discriminated patients with CR/PR/SD and PD. Univariate and multivariate analyses identified pretreatment NLRs as a significant independent factor for progression-free and overall survival (hazard ratio [HR]: 1.19, 95% confidence interval [CI]: 1.07-1.32, and HR 1.23, 95% CI: 1.11-1.37, respectively; p ≤ 0.001 for both)., Conclusion: The pretreatment LMRs, and NLR and LMR at 14 and 28 days after starting nivolumab monotherapy were significantly associated with the clinical therapeutic effect. The pretreatment NLR was significantly associated with patients' survival. These blood cell parameters before and during the early days of nivolumab monotherapy can help to identify patients with ESCC who would most likely benefit from nivolumab monotherapy., Competing Interests: All authors report no conflicts of interest in this work., (© 2023 Hamai et al.)

Background: Neoadjuvant chemotherapy (NAC) followed by surgery is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). Chemoradiotherapy (CRT) is an alternative treatment approach. However, both treatments are associated with toxicity, and the optimal treatment for older patients with ESCC is unknown. This study aimed to evaluate the treatment strategies and prognosis of older patients with locally advanced ESCC in a real-world setting., Methods: We retrospectively evaluated 381 older patients (≥ 65 years) with locally advanced ESCC (stage IB/II/III, excluding T4) who received anticancer therapy at 22 medical centers in Japan. Based on age, performance status (PS), and organ function, the patients were classified into two groups: clinical trial eligible and ineligible groups. Patients aged ≤ 75 years with adequate organ function and a PS of 0-1 were categorized into the eligible group. We compared the treatments and prognoses between the two groups., Results: The ineligible group had significantly shorter overall survival (OS) than the eligible group (hazard ratio [HR] for death, 1.65; 95% confidence interval [CI], 1.22-2.25; P = 0.001). The proportion of patients receiving NAC followed by surgery was significantly higher in the eligible group than in the ineligible group (P = 1.07 × 10 -11 ), whereas the proportion of patients receiving CRT was higher in the ineligible group than in the eligible group (P = 3.09 × 10 -3 ). Patients receiving NAC followed by surgery in the ineligible group had comparable OS to those receiving the same treatment in the eligible group (HR, 1.02; 95% CI, 0.57-1.82; P = 0.939). In contrast, patients receiving CRT in the ineligible group had significantly shorter OS than those receiving CRT in the eligible group (HR, 1.85; 95% CI, 1.02-3.37; P = 0.044). In the ineligible group, patients receiving radiation alone had comparable OS to those receiving CRT (HR, 1.13; 95% CI, 0.58-2.22; P = 0.717)., Conclusions: NAC followed by surgery is justified for select older patients who can tolerate radical treatment, even if they are old or vulnerable to enrollment in clinical trials. CRT did not provide survival benefits over radiation alone in patients ineligible for clinical trials, suggesting the need to develop less-toxic CRT., (© 2023. The Author(s).)

Background/aim: Neoadjuvant chemotherapy (NAC) followed by surgery is a standard treatment for patients with locally advanced esophageal cancer. This study aimed to identify patients who might be eligible for postoperative adjuvant therapy., Patients and Methods: We reviewed the surgical outcomes of 84 patients who received NAC followed by esophagectomy to treat esophageal squamous cell carcinoma (ESCC) and revealed prognostic factors associated with locally advanced ESCC., Results: Univariate and multivariate analyses revealed the pretreatment level of squamous cell carcinoma-related antigen [SCC-A; hazard ratio (HR)=1.50, p=0.01], ypT ≥3 (HR=2.51; p=0.04), ypN ≥1 (HR=5.87; p=0.01), ypM1 (HR=2.38; p=0.049), and lymphovascular invasion (HR=3.12, p=0.049) as significant independent covariates for recurrence-free survival (RFS). The 5-year RFS rates for patients with 0-1, 2-3, or 4-5 of these indicators of poor prognosis were 97.1%, 51.2%, and 6.7% (p≤0.001 for all). Recurrence rates among these groups also significantly differed at 2.9%, 50.0%, and 93.3% (p<0.0001)., Conclusion: Pretreatment SCC-A, ypT, ypN, ypM, and lymphovascular invasion were significantly associated with RFS in patients with ESCC who received NAC followed by surgery. The status of these prognostic factors in ESCC might indicate a need for postoperative adjuvant therapy after NAC followed by surgery., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The safety and effectiveness of thoracoscopic compared with open esophagectomy remain uncertain. We aimed to clarify the differences between these surgical modalities in patients with esophageal squamous cell carcinoma (ESCC) who underwent neoadjuvant therapy., Patients and Methods: We reviewed surgical outcomes among 133 patients with locally advanced ESCC who underwent neoadjuvant therapy followed by esophagectomy. We compared the operative outcomes, postoperative complications and survival rates between 65 and 68 patients who were respectively treated by open and thoracoscopic esophagectomy., Results: The surgical duration was longer, but blood loss was lower during thoracoscopic, compared with open esophagectomy. The numbers of dissected mediastinal lymph nodes and rates of postoperative complications did not significantly differ between open and thoracoscopic esophagectomy. However, the rates of postoperative pneumonia and recurrent laryngeal nerve paralysis were significantly lower and higher, respectively, after thoracoscopic, compared with open esophagectomy. Overall survival did not significantly differ between the groups., Conclusion: Thoracoscopic esophagectomy is feasible for patients with locally advanced ESCC who undergo neoadjuvant therapy., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: The present study aimed to evaluate the long-term results of definitive chemoradiotherapy (CRT) for unresectable locally advanced esophageal squamous cell carcinoma (LA-ESCC)., Materials and Methods: We analyzed eighty patients with unresectable LA-ESCC, who underwent definitive CRT between 2001 and 2014. The 5-year overall survival (OS), cause-specific survival (CSS), and progression-free survival (PFS) rates were calculated, and we investigated the prognostic factors and adverse events., Results: The median age was 66 years (range, 41-83 years). Histologically, all patients had squamous cell carcinoma. The most common tumor site was the middle thoracic esophagus in 43 (54%) patients. According to the eighth edition of the Union for International Cancer Control TNM classification, sixty-six patients (83%) had T4 disease, 59 (74%) had regional lymph node (LN) metastases, and 35 (44%) had distant LN metastases beyond the regional LN (M1 LYM) disease. Forty-five (56%) and 35 (44%) patients belong to clinical stages IVA and IVB, respectively. The median follow-up period for survivors was 86 months. The 5-year OS, CSS, and PFS rates were 20.2%, 25.7%, and 18.4%, respectively. On univariate analysis, only the performance status score was significantly associated with better overall survival (p = 0.026). Grade 3 or higher late adverse events were observed in 12 (15%) patients, and these included cardiopulmonary adverse events in 6 (8%) patients. Treatment-related death occurred in 3 (4%) patients., Conclusion: We showed the long-term results of definitive CRT for unresectable LA-ESCC. The survivals are still poor and new treatment strategies need to be developed., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background/aim: Intensive trimodal therapy is needed for locally advanced esophageal squamous cell carcinoma (ESCC). The prediction of recurrence is especially required for patients with pathological residual tumors in the resected primary sites and/or lymph nodes [non-pathological complete response (pCR)] who have a high possibility of recurrence after trimodal therapy. We aimed to determine the risk factors for cancer recurrence in ESCC patients diagnosed with non-pCR after trimodal therapy., Patients and Methods: We evaluated the risk factors for recurrence-free survival (RFS) using the multivariate Cox proportional hazards analysis, based on data from 105 ESCC patients diagnosed with non-pCR after neoadjuvant chemoradiotherapy followed by esophagectomy., Results: Univariate analysis revealed that RFS was significantly associated with postoperative complications, pathological T, N, M stage after therapy (ypT, ypN, ypM), tumor differentiation, lymphovascular invasion (LVI), and pathological response of the primary tumor. Subsequent multivariate analysis revealed postoperative complications ypN, tumor differentiation, and LVI as independent variables for RFS. The RFSs significantly differed between patients with and without these risk factors., Conclusion: Severe postoperative complications, ypN 2/3, poor tumor differentiation, and LVI were significantly associated with poor RFS. These factors may be used as prognostic factors in patients with non-pCR after trimodal therapy., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Esophageal perforation in advanced esophageal cancer requires immediate treatment. However, no clear treatment protocol has been established for this condition. We report a case of advanced esophageal cancer with esophageal perforation treated with esophageal bypass surgery and definitive chemoradiotherapy (CRT)., Case Report: A 45-year-old woman was diagnosed with locally advanced esophageal cancer with esophageal perforation. Although the patient's general condition was relatively stable, no improvement was expected through conservative treatment. Esophageal gastric bypass surgery was performed; her symptoms improved postoperatively and oral ingestion became possible. Definitive CRT with 66 Gy radiotherapy and chemotherapy with cisplatin and 5-fluorouracil was administered. A complete clinical response was achieved. The patient is alive and well without recurrence 20 months after treatment., Conclusion: Definitive CRT after esophageal bypass surgery is a potential treatment option for locally advanced esophageal cancer with esophageal perforation to improve treatment response and quality of life., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: MicroRNA (miR)s are promising diagnostic biomarkers of cancer. Recent next generation sequencer (NGS) studies have found that isoforms of micro RNA (isomiR) circulate in the bloodstream similarly to mature micro RNA (miR). We hypothesized that combination of circulating miR and isomiRs detected by NGS are potentially powerful cancer biomarker. The present study aimed to investigate their application in esophageal cancer., Methods: Serum samples from patients with esophageal squamous cell carcinoma (ESCC) and age and sex matched healthy control (HC) individuals were investigated for the expression of miR/isomiRs using NGS. Candidate miR/isomiRs which met the criteria in the 1st group (ESCC = 18 and HC = 12) were validated in the 2nd group (ESCC = 30 and HC = 30). A diagnostic panel was generated using miR/isomiRs that were consistently confirmed in the 1st and 2nd groups. Accuracy of the panel was tested then in the 3rd group (ESCC = 18 and HC = 18). Their use was also investigated in 22 paired samples obtained pre- and post-treatment, and in patients with esophageal adenocarcinoma (EAD) and high-grade dysplasia (HGD)., Results: Twenty-four miR/isomiRs met the criteria for diagnostic biomarker in the 1st and 2nd group. A multiple regression model selected one mature miR (miR-30a-5p) and two isomiRs (isoform of miR-574-3p and miR-205-5p). The index calculated from the diagnostic panel was significantly higher in ESCC patients than in the HCs (13.3±8.9 vs. 3.1±1.3, p<0.001). The area under the receiver operating characteristics (ROC) curves of the panel index was 0.95. Sensitivity and specificity were 93.8%, and 81% in the 1st and 2nd groups, and 88.9% and 72.3% in the 3rd group, respectively. The panel index was significantly lower in patients with EAD (6.2±4.5) and HGD (4.2±1.7) than in those with ESCC and was significantly decreased at post-treatment compared with pre-treatment (6.2±5.6 vs 11.6±11.5, p = 0.03)., Conclusion: Our diagnostic panel had high accuracy in the diagnosis of ESCC. MiR/isomiRs detected by NGS could serve as novel biomarkers of ESCC., Competing Interests: Prof. Hidetoshi Tahara is representative director of a university-originated venture, MiRTeL Co. Ltd., which provides commercial microRNA panel services. The remaining authors declare no potential conflict of interest. MiRTeL Co. Ltd provided support in the form of salaries for an author (H.T), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background/aim: Neoadjuvant therapy followed by surgery is the standard treatment for advanced esophageal cancer. This study aimed to evaluated the potential of 18 F-fluorodeoxyglucose positron-emission tomography to predict the pathological therapeutic effect of neoadjuvant chemotherapy., Patients and Methods: We enrolled 68 patients with advanced esophageal squamous cell carcinoma who underwent 18 F-fluorodeoxyglucose positron-emission tomography before and after neoadjuvant chemotherapy, followed by surgery. Retrospective analysis of the pathological therapeutic effects was performed., Results: The pathological therapeutic effect of good responders was significantly inversely associated with the maximum standardized uptake value (SUVmax) after neoadjuvant chemotherapy and with SUVmax reduction (both p<0.0001). Univariate and multivariate analyses revealed that lower post therapy SUVmax and reduction in SUVmax were independent prognostic factors for relapse-free (p=0.02) and overall survival (p<0.0001)., Conclusion: Post-neoadjuvant chemotherapy SUVmax and SUVmax reduction can predict the pathological therapeutic effect of neoadjuvant chemotherapy., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: An esophagorespiratory fistula (ERF) is a fatal complication for patients with tracheobronchial invasion by esophageal cancer. We report the case of a long-term esophageal cancer survivor treated by esophageal bypass operation for ERF after chemoradiotherapy (CRT)., Case Report: A 44-year-old man was treated with definitive CRT (i.e. 66 Gy radiotherapy, chemotherapy with cisplatin, and 5-fluorouracil) for unresectable locally advanced esophageal cancer with massive invasion of the left main bronchus. Although a complete clinical response was obtained, the patient developed pneumonia due to an ERF. Esophageal bypass operation was performed for symptomatic relief. The patient's symptoms improved and oral ingestion became possible. No recurrence has been seen for 12 years., Conclusion: Esophageal bypass surgery can help in relieving symptoms and might be associated with long-term survival for esophageal cancer patients with ERF after good response to CRT. Thus, bypass surgery is a useful option in the treatment for esophageal cancer with ERF., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Cisplatin (CDDP) is an important chemotherapeutic drug for treating esophageal cancer that often induces nausea and vomiting. Rikkunshito (RKT), a traditional Japanese herbal medicine, can increase levels of plasma ghrelin, which is an orexigenic gut hormone that can alleviate chemotherapy-induced nausea and vomiting (CINV) and anorexia., Methods: This prospective randomized crossover study included 20 patients with esophageal cancer who were administered with CDDP-based chemotherapy. Ten of them were assigned to group A [1st course: with RKT 7.5 g/day on days 1-14; 2nd course: without RKT (control)] and 10 were assigned to group B [1st course: without RKT (control); 2nd course: with RKT 7.5 g/day on days 22-35]. Food intake and levels of plasma acylated ghrelin (AG) were compared between the control and RKT courses., Results: Data from 18 patients were included in this analysis, as chemotherapy was immediately stopped due to deteriorating renal function in one patient and intracerebral bleeding in another. The median rate at which food intake decreased between days 4 and 6 was considerably lower in the course with, than without RKT (2% vs. 30%; P=0.02). Median levels of AG significantly increased from days 3 to 8 in patients in both courses with and without RKT (9.6 to 15.7 fmol/mL, P<0.0001; control, 10.2 to 17.8, P=0.0002). The rate at which median plasma AG levels increased from days 3 to 8 tend to be higher in the RKT, than in the control course (68% vs. 48%, P=0.08)., Conclusions: RKT can improve CDDP-induced, delayed-onset anorexia and increase plasma AG levels among patients with esophageal cancer who undergo highly emetogenic chemotherapy (HEC)., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background/aim: Although locally advanced esophageal squamous cell carcinoma (ESCC) can be controlled and survival can be prolonged by neoadjuvant chemoradiotherapy (NCRT) followed by surgery (trimodal therapy), some patients still develop early recurrence and die of cancer even after such intensive therapy. The present study aimed to determine the factors associated with early recurrence and cancer death for patients with ESCC treated by trimodal therapy., Patients and Methods: We evaluated risk factors for recurrence within 6 months, as well as cancer death within 1 year based on data from 141 patients with ESCC who underwent NCRT followed by curative esophagectomy., Results: The carcinoembryonic antigen level before treatment, postoperative complications, pathology after neo-adjuvant therapy (ypT, ypN), lymphatic invasion, venous invasion and pathological response of the primary tumor were significant factors in a comparison of patients with and without early recurrence. Multivariate analysis subsequently selected ypN [ypN, 0/1 vs. 2/3; hazard ratio (HR)=4.13, 95% confidence interval (CI)=1.25-13.66; p=0.02] as an independent covariate for early recurrence. Postoperative complications, ypT, ypN, poorer tumor differentiation, lymphatic invasion and venous invasion were significant factors in a comparison of patients with and without early cancer death. Multivariate analysis subsequently selected postoperative complications of grade ≥3b (vs. <3b) defined according to the Clavien-Dindo classification (HR=5.9, 95% CI=1.53-23.47; p=0.01) and venous invasion (vs. without: HR=4.80, 95% CI=1.21-19.14; p=0.03) as independent covariates for early cancer death., Conclusion: Further reduction of postoperative complications are needed after NCRT for patients with ESCC. Meticulous surveillance and postoperative adjuvant therapy should be considered for patients with risk factors for early recurrence and cancer death., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Aortoesophageal fistula (AEF) is a fatal complication results in sudden massive hematemesis. Although thoracic endovascular aortic repair (TEVAR) is an established method of treating aortic aneurysms or aortic dissection, the number of AEF after TEVAR is recently increasing due to the spread of TEVAR. However, the therapeutic strategy for AEF remains controversial., Presentation of Case: We describe a 71-year-old man with Stanford B aortic dissection and aortic aneurysm rupture treated by TEVAR who developed AEF between the thoracic aorta and upper thoracic esophagus 20 months thereafter. We applied a three-step surgical procedure for this patient comprising resection of the esophagus as the infectious source, removal of an aortic aneurysm with stent-graft and replacement of the aorta, and final reconstruction of the esophagus. Thereafter, the patient resumed oral intake and has remained relapse-free for 24 months without adverse events., Discussion: Previous reports have described simultaneous resection of the esophagus and aortic stent-graft via a left thoracotomy followed by a two-step surgical reconstruction of the esophagus. We applied a three-step procedure consisting of resections of the esophagus and aortic stent-graft on separate occasions followed by esophageal reconstruction in this patient. The first procedure in the three-step approach is less stressful than that of the two-step approach., Conclusion: The three-step surgical approach to treating AEF after TEVAR resulted in a good outcome for this patient. Thus, this surgical strategy is a useful option for treating AEF after TEVAR., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study retrospectively evaluated the long-term results of neoadjuvant chemoradiotherapy (NCRT) followed by esophagectomy for the patients with resectable, locally advanced esophageal squamous cell carcinoma (ESCC). Altogether, 49 patients treated from 2008 to 2012 were analyzed. Chemotherapy consisted of 5-fluorouracil and cisplatin. Radiotherapy was performed with a total dose of 40 Gy in 20 fractions for primary tumor, metastatic lymph nodes, and elective nodal area. Subsequently, transthoracic esophagectomy with extensive lymphadenectomy was performed. The median follow-up time for the survivors was 86 (range, 55-111) months. Pathological complete response from NCRT was observed in 17 (35%) patients. The 5-year overall survival and relapse-free survival rates were 56% [95% confidence interval (CI): 43-71%] and 55% (95% CI: 41-69%), respectively. The 5-year locoregional control rate was 84% (95% CI: 74-95%). Multivariate analyses revealed body mass index, N-factor, and %ΔSUVmax as significant factors for overall survival. Recurrences and within-irradiation field failure were observed in 16 (31%) and 4 (8%) patients, respectively. Toxicities of NCRT were generally mild. Postoperative Grade IIIb or worse complications were seen in 14% of patients, including one Grade V case (2%). The 5-year incidence rate of late complications of Grade 3 or worse was 22% (95% CI: 7-36%). The cumulative 5-year incidence rate of metachronous malignancies was 13% (95% CI: 1-26%). NCRT followed by esophagectomy for patients with resectable, locally advanced ESCC showed favorable locoregional control and overall survival, with acceptable postoperative complications. Long-term careful follow-up for late complications and metachronous malignancies is needed.

Background/aim: The present study aimed to determine the effects of intervals between neoadjuvant chemoradiotherapy (nCRT) and esophagectomy on therapeutic outcomes in patients with locally advanced esophageal squamous cell carcinoma (ESCC)., Patients and Methods: We analyzed data from 134 consecutive patients who were diagnosed with locally advanced ESCC of the thoracic esophagus and were treated by nCRT followed by esophagectomy between September 2003 and September 2015. We assigned the patients to groups A and B according to whether they underwent esophagectomy ≤8 or >8 weeks after nCRT., Results: The two groups were comparable in terms of age, gender, performance status, comorbidities, tumor location, clinical stage, R0 resection rates and pathological responses to nCRT. The incidences of pneumonia and respiratory failure were significantly higher in group B (p=0.03, p=0.009, respectively). Recurrence-free (RFS) and overall (OS) survival rates did not significantly differ between the two groups. However, RFS was significantly poorer among patients with R0 resection (p=0.04) and those of cStages III and IV (p=0.009) in group B., Conclusion: Esophagectomy should proceed within eight weeks after nCRT from the viewpoints of respiratory morbidity and impact of RFS on patients with R0 resection., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The prognoses of submucosal esophageal squamous cell carcinoma patients vary. Patients with favorable prognoses may receive less invasive or nonsurgical interventions, whereas patients with poor prognoses or advanced esophageal cancer may require aggressive treatments. We sought to identify prognostic factors for patients with submucosal esophageal squamous cell carcinoma, focusing on lymph node metastasis and recurrence., Methods: We included 137 submucosal esophageal squamous cell carcinoma patients who had undergone transthoracic esophagectomy with systematic extended lymph node dissection. Submucosal tumors were classified as SM1, SM2, and SM3 according to the depth of invasion. Prognostic factors were determined by univariable and multivariable analyses., Results: Lymph node metastasis was observed in 18.8%, 30.5%, and 50.0% of SM1, SM2, and SM3 cases, respectively. The overall 5-year recurrence rate was 21.9%; the rates for SM1, SM2, and SM3 tumors were 9.4%, 18.6%, and 34.8%, respectively. The SM1 tumors all recurred locoregionally; distant metastasis occurred in SM2 and SM3 cases. The 5-year overall survival rates were 83%, 77%, and 59% for SM1, SM2, and SM3 cases, respectively. On univariable analysis, lymph node metastasis, depth of submucosal invasion (SM3 versus SM1/2), and tumor location (upper thoracic versus mid/lower thoracic) were poor prognostic factors for overall survival. Multivariable Cox regression analyses identified depth of submucosal invasion (hazard ratio 2.51, 95% confidence interval: 1.37 to 4.61) and tumor location (hazard ratio 2.43, 95% confidence interval: 1.18 to 4.63) as preoperative prognostic factors., Conclusions: Tumor location (upper thoracic) and infiltration (SM3) are the worse prognostic factors of submucosal esophageal squamous cell carcinoma, but lymph node metastasis is not a predictor of poorer prognosis., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background/aim: The TNM staging system for esophageal cancer is designed to predict survival based on pathological stage in patients who have been treated with surgery alone. However, pathological stage can vary considerably after neoadjuvant therapy due to tumor responses., Patients and Methods: We reviewed 110 patients with esophageal squamous cell carcinoma (ESCC) who underwent neoadjuvant chemoradiotherapy (nCRT) followed by surgery, and investigated the effects of nCRT on TNM stage and its prognostic significance., Results: A comparison of pre-treatment clinical and pathological stages (cStage and ypStage, respectively) resulted in 75 (68%) of the patients being down-staged. Good responders (over two-thirds of the primary tumor reduced by nCRT) comprised 100%, 83%, 69%, 52% and 50% of patients with ypStages 0, I, II, III and IV, respectively (p=0.001). In addition, 62 (83%) and 20 (57%) of patients with and without down-staged tumors, respectively, were pathological good responders (p=0.004). We found that cStage did not significantly correlate with survival, whereas univariate analysis significantly associated ypStages III/IV (p=0.003) and down-staged tumors (p=0.04) with overall survival (OS). Multivariate analysis selected ypStage III/IV (HR=3.26; 95% CI=1.52-6.99; p=0.002) and no down-staging (HR=2.06; 95%CI=1.16-3.64, p=0.01) as independent covariates for OS., Conclusion: nCRT could lead to down-staged ESCC tumors for many patients and a good prognosis. The correlation between ypStage and pathological response to nCRT indicated that ypStage could stratify survival and serve as a prognostic predictor after trimodal therapy., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Responses of esophageal cancer to neoadjuvant therapy and patient prognosis are difficult to predict preoperatively. This study aimed to determine the ability of fluorine-18 fluorodeoxyglucose ((18)FDG) positron emission tomography (FDG-PET) to predict outcomes of trimodal therapy on esophageal squamous cell carcinoma (ESCC)., Methods: The responses of 111 patients with ESCC were monitored using FDG-PET before and after neoadjuvant chemoradiotherapy (nCRT) followed by surgical treatment. Associations between the maximum standardized uptake value (SUVmax) and pathologic responses (PRs) and prognosis were analyzed., Results: Responses were significantly associated with SUVmax after nCRT (post-SUVmax) and with the rate of decreases in the SUVmax (%ΔSUVmax) of the primary tumor. The optimal cutoffs for post-SUVmax and %ΔSUVmax determined from receiver operating characteristic (ROC) curves were 2.7 (area under the curve [AUC], 0.68; 95% confidence interval [CI], 0.58-0.78; p = 0.001) and 75 (AUC, 0.64; 95% CI, 0.54-0.75; p = 0.01) for predicting a pathologic complete response (pCR) and 3.7 (AUC, 0.76; 95% CI, 0.63-0.89; p < 0.001) and 70 (AUC, 0.65; 95% CI, 0.52-0.78; p = 0.02) for predicting a good response according to Japan Esophageal Society response criteria. These values reliably separated patients into groups with and without pCR and with and without a good response. Multivariate analysis showed that %ΔSUVmax (≤70 and >70) was an independent prognostic factor for disease-specific survival (hazard ratio [HR], 0.45; 95% CI, 0.21-0.98; p = 0.04)., Conclusions: SUVmax is a valuable preoperative predictor of tumor response and survival among patients who undergo trimodal therapy for ESCC., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Esophageal cancer is most frequently treated with platinum-based chemoradiotherapy (CRT). We previously described a phase I study of definitive CRT with docetaxel (DOC) and 5-fluorouracil (5FU) in patients with advanced esophageal cancer. This regimen had low toxicity and was effective without platinating agents. The present study aims to determine the antitumor effects of neoadjuvant CRT with DOC and 5FU and surgical outcomes., Methods: We reviewed data from 38 patients with locally advanced cancer of the esophagus or esophagogastric junction who underwent trimodality therapy comprising neoadjuvant CRT with DOC and 5FU followed by esophagectomy between 2003 and 2008., Results: Esophagitis was the most common toxicity associated with neoadjuvant CRT (grade 3; 26.3%), and hematologic toxicity was mild. Transthoracic esophagectomy and pharyngolaryngoesophagectomy proceeded in 36 (94.7%) and 2 (5.3%) patients, respectively, and 35 (92.1%) underwent R0 resection. Five (13.2%) patients had complete pathologic responses (pCR) of the primary tumor, and 23 (60.5%) had pathologic reductions of over two-thirds of the primary tumor. The T or N status was also down-staged in 26 (68.4%) patients. Overall postoperative morbidity developed in 21 (55.3%) patients, and mortality due to postoperative morbidity was zero. The 5-year recurrence-free and overall survival rates were 39.5% and 44.7%, respectively., Conclusions: The rates of neoadjuvant CRT toxicity and postoperative complications were acceptable, and the complete resection rate and survival data were favorable. This regimen is promising as neoadjuvant CRT for esophageal cancer and very useful as an alternative regimen for treating patients with esophageal cancer who cannot tolerate cisplatin., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We report a surgical case of tension pyopneumothorax in a patient who was receiving chemotherapy for esophageal cancer. A 68-year-old man who had undergone total gastrectomy with splenectomy for gastric cancer and was receiving chemotherapy for esophageal cancer was presented to our hospital with dyspnea. Left tension pyopneumothorax was diagnosed, and he received left lower lobectomy after pleural drainage. His postoperative course was uneventful, and he is alive without any cancer recurrences 5 years after the lobectomy. Once tension pyopneumothorax has developed from lung abscess, emergent lobectomy may be a useful option to prevent lethal aspiration pneumonia.

Background: In T4 esophageal cancer with tracheobronchial invasion, an esophagorespiratory fistula (ERF) often occurs during or after chemoradiotherapy. We have performed esophageal bypass operations prior to definitive chemoradiotherapy for these patients to increase the chemoradiotherapy completion rate by minimizing the potential effect of an ERF. The aim of this study was to examine the clinical outcome of esophageal bypass surgery prior to chemoradiotherapy., Methods: Between 1997 and 2010, 17 patients underwent esophageal bypass surgery followed by definitive chemoradiotherapy for esophageal cancer with tracheobronchial invasion (bypass group). Ten patients in the same circumstances were treated with chemoradiotherapy alone (control group). Overall survival, the clinical effect of chemoradiotherapy, the ERF incidence rate, and the safety of esophageal bypass surgery were assessed., Results: The overall response rate to chemoradiotherapy was 64.7% in the bypass group and 90.0% in the control group. Except for 2 patients with ERF at initial diagnosis, 4 (26.7%) of the 15 patients developed ERF in the bypass group, and 3 (30.0%) of the 10 patients developed ERF in the control group during or after chemoradiotherapy. The 2-year and 3-year overall survival rates were 17.6% and 17.6% in the bypass group and 20.0% and 0% in the control group, respectively (p = 0.924); long-term survival of more than 3 years was seen only in the bypass group., Conclusions: Esophageal bypass surgery prior to definitive chemoradiotherapy could be performed safely, and this strategy contributed to long-term survival in the patients who achieved a good response to chemoradiotherapy but developed an ERF., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Poly (ADP-ribose) polymerase (PARP) plays a critical role in responding to DNA damage, by activating DNA repair pathways responsible for cellular survival. Inhibition of PARP is used to treat certain solid cancers, such as breast and ovarian cancers. However, its effectiveness with other solid cancers, such as esophageal squamous cell carcinoma (ESCC), has not been clarified. We evaluated the effects of PARP inhibition on the survival of human esophageal cancer cells, with a special focus on the induction and repair of DNA double-strand breaks. The effects were monitored by colony formation assays and DNA damage responses, with immunofluorescence staining of γH2AX and RAD51. We found that PARP inhibition synergized with cisplatin, and the cells were highly sensitive, in a similar manner to the combination of cisplatin and 5-fluorouracil (5-FU). Comparable increases in RAD51 foci formation were observed after each combined treatment with cisplatin and either 3-aminobenzamide (3-AB) or 5-FU in three human esophageal cancer cell lines, TE11, TE14, and TE15. In addition, decreasing the amount of RAD51 by RNA interference rendered the TE11 cells even more hypersensitive to these treatments. Our findings suggested that the homologous recombinational repair pathway may be involved in the synergism between cisplatin and either 3-AB or 5-FU, and that 3-AB and 5-FU may similarly modify the cisplatin-induced DNA damage to types requiring the recruitment of RAD51 proteins for their repair. Understanding these mechanisms could be useful for improving the clinical outcome of ESCC patients who suffer from aggressive disease that presently lacks effective treatment options., (© 2013 Japanese Cancer Association.)

Background/aim: The status of each patient with advanced esophageal cancer varies widely, and the prognosis is generally poor. We aimed to determine which prognostic factors are involved in the management of locally advanced esophageal cancer with adjacent organ invasion., Patients and Methods: We retrospectively investigated the therapeutic outcomes of 74 patients with thoracic esophageal cancer and clinical evidence of adjacent organ invasion but without distant metastasis. The predictive factors for a chemoradiotherapeutic response and survival were evaluated., Results: Definitive chemoradiotherapy (CRT), bypass surgery and CRT, as well as CRT followed by esophagectomy were carried out in 48 (64.9%), 17 (23.0%), and 9 (12.2%) patients, respectively. The median survival time (MST) of patients overall was 11.3 months. The MST of patients after definitive CRT, bypass surgery plus CRT and CRT followed by esophagectomy was 10.4, 11.0 and 16.4 months, respectively; MST did not differ significantly between patients. MST of patients with a complete response (CR), a partial response (PR) and stable (SD)/progressive (PD) disease as clinical outcomes of CRT was 52.6, 11.3 and 6.7 months, respectively; the MST was considerably longer in patients with, than in those without CR (CR vs. SD/PD, p<0.0001; CR vs. PR, p=0.0004). In multivariate analysis, age <60 years [odds ratio (OR)=7.74; 95% confidence interval (CI)=1.85-32.41; p=0.005] and hemoglobin ≥13 g/dl (OR=11.54; 95% CI=1.29-103.21; p=0.03) were independently associated with CR as an outcome of CRT, and serum albumin level ≥3.5 g/dl (OR=2.11; 95% CI=1.09-4.10; p=0.03) was independently associated with prolonged survival., Conclusion: Pre-treatment hemoglobin and albumin levels were valuable predictors of the outcome of CRT and survival, respectively. A better response to CRT as well as improved nutritional status prolonged the survival of patients with advanced esophageal cancer.

We describe the case of an 80-year-old man with hepatocellular carcinoma (HCC) who developed tracheal obstruction due to peritracheal lymph node metastasis. A metastatic tumor that protruded into the airway was ablated using a neodymium yttrium-aluminium-garnet laser and then a self-expandable metallic stent (SEMS) was deployed in the trachea. Stenting resolved symptoms of severe dyspnea upon mild exertion and in the supine position. Three months later, the patient is alive and has resumed normal activities as an outpatient, despite having metastatic HCC. Peritracheal lymph node metastasis arising from HCC is very rare and a polypoid tumor growing from a metastatic lymph node into the trachea is also extremely unusual. Tracheal obstruction in this patient was successfully treated by airway stenting.

We describe a 68-year-old man who was treated by laparoscopic thoracic duct clipping for persistent chylothorax after an extrapleural pneumonectomy for malignant pleural mesothelioma. Initial conservative treatment did not resolve the postoperative chylothorax. A second surgery through the thoracic approach was considered invasive and difficult after extrapleural pneumonectomy. A laparoscopic approach proved effective and resolved the chylothorax. Thus, laparoscopic thoracic duct clipping is considered very useful for treating chylothorax., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Airway stenting is required for the palliative treatment of advanced esophageal cancer. This study retrospectively analyzes the outcomes of airway stenting for esophageal cancer at our institution. Data from nine patients who underwent airway stenting were reviewed. All patients had poor respiratory status due to esophagorespiratory fistula and/or respiratory stenosis. We retrospectively assessed the results of airway stenting as five grades of respiratory symptoms, regarding stent-related complications and clinical course and survival. Six silicone and six covered self-expandable metallic stents were deployed in five and six patients, respectively. Two types of airway stents were deployed in two patients, and double stents were positioned in the airway and in the esophagus of three other patients. The grade of respiratory symptoms improved in seven patients. The mean dyspnea grade was 3.0±0.9 and 1.3±1.3 before and after airway stenting, respectively. Stent-related complications comprised of chest pain, incomplete closure of the ERF, sputum retention and stent migration. The mean±SD survival of all patients was 103±108 (range, 0 to 325) days, and the survival of patients without relapsed cancer at the time of stenting, who underwent cancer-specific therapy after stenting, was prolonged. Although the airway should be stented according to the status and the prognosis of each patient individually stenting can relieve symptoms and improve the prognosis even when esophageal cancer is at very advanced stages. Airway stenting could play a role in the multidisciplinary management of advanced esophageal cancer.

The occurrence of esophageal conduit necrosis after esophagectomy in patients with esophageal cancer is rare, but it is associated with severe and fatal complications, and the subsequent surgical reconstruction required by such patients is challenging. We reconstructed the esophagus using a skin tube prepared from a myocutaneous flap of the anterior chest wall in a patient whose entire thoracic esophagus was missing due to reconstructed conduit necrosis after surgery for esophageal cancer. Four years after skin tube reconstruction, the patient remains free of cancer recurrence with good oral intake and has resumed routine activities. Thus, the skin tube is considered very useful for salvage esophageal reconstruction.

Unlabelled: This phase I study was designed to determine the maximum-tolerated dose (MTD) of docetaxel (TXT) and toxicities of combining weekly administration of TXT and continuous infusion of 5-fluorouracil (5-FU) with concomitant radiotherapy for advanced esophageal cancer., Patients and Methods: Patients received TXT by i.v. infusion over 1 h on days 1, 8, 22 and 29. They were also given 5-FU 250 mg/m2/day by continuous infusion for 24 h on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40 and 43-45. Fractionated radiotherapy was performed on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40 and 43-45, and a total dose of 60 to 66 Gy was delivered. The starting dose level (Level 1) of TXT was set at 7.5 mg/m2. Dose escalation was conducted in increments of 25 mg/m2, until the dose reached Level 4 (15 mg/m2). At least three patients were enrolled at each level., Results: Seven patients (median age, 64 years) were enrolled. Six patients had stage III (T4NIMO) and one had stage IVb (T4N1M1b) esophageal cancer; six had squamous cell carcinoma and one had carcinosarcoma. No patient had received prior chemotherapy or radiotherapy, and two patients had undergone esophageal bypass surgery using a whole stomach tube without resection of primary or metastatic lesions. In the 7patients, the regimen was well-tolerated, with esophagitis as the most common toxicity (grade 3: n=1; grade 4: n=3). In general, hematological toxicity was mild. Dose-limiting toxicity (DLT) was observed at Level 2 (TXT 10 mg/m2) when three patients developed grade 4 esophagitis and this dose was deemed the MTD for this regimen. In the 7 assessable patients, the overall clinical response rate was 85.7%., Conclusion: The MTD of TXT in this regimen was 10 mg/m2 and the recommended dose of TXT was 7.5 mg/m2. Although esophagitis was the dose-limiting and the most frequent toxicity, the regimen was safe and well-tolerated, and demonstrated the possibility of good efficacy in patients with advanced esophageal cancer.

Background: Cell cycle checkpoint dysfunction is often associated with sensitivity to chemotherapeutic agents. In this study, the question of whether DNA methylation of CHFR, a mitotic checkpoint gene, can predict the response of advanced and recurrent gastric cancers (GCs) to docetaxel or paclitaxel was examined., Materials and Methods: In a retrospective study, 41 patients with GC treated with paclitaxel alone (n=12) or a combination of docetaxel and S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine, potassium oxonate) (n=29) were studied. The DNA methylation status of the CHFR gene was examined by combined bisulfite restriction analysis of DNAs from 41 GC tissues and the methylation status was compared to their sensitivity to chemotherapy. The levels of CHFR mRNA were measured by quantitative reverse transcription-PCR., Results: DNA methylation of CHFR was found in 15 (36.6%) out of the 41 GC samples and the levels of CHFR mRNA were associated with the methylation status of CHFR (p = 0.034). In 41 samples of corresponding non-neoplastic mucosae, no DNA methylation of CHFR was detected. Among 12 patients treated with paclitaxel alone, only 1 (20.0%) of the 5 patients with CHFR methylation had a partial response (PR) to paclitaxel, whereas 3 (42.9%) of the 7 patients without CHFR methylation had a PR to paclitaxel (p = 0.836). In 29 patients treated with a combination of S-1 and docetaxel, there was no clear association between the CHFR methylation status and response to chemotherapy (p = 0.092)., Conclusion: We conclude that the DNA methylation of CHFR alone cannot predict the response of advanced and recurrent GC to docetaxel or paclitaxel. Both paclitaxel and docetaxel may be effective for treatment of GC even if CHFR is expressed.

Gastric carcinoma (GC) is one of the most common malignancies worldwide. To better understand the genetic basis of this disease, we performed serial analysis of gene expression (SAGE) on four primary GC samples and one associated lymph node metastasis. We obtained a total of 137,706 expressed tags (Gene Expression Omnibus accession number GSE 545, SAGE Hiroshima gastric cancer tissue), including 38,903 that were unique. Comparing tags from our GC libraries containing different stages and different histologies, we found several genes and tags that are potentially involved in invasion, metastasis, and carcinogenesis. Among these, we selected 27 genes and measured mRNA expression levels in an additional 46 GC samples by quantitative reverse transcription-PCR. Frequently overexpressed genes (tumor/normal ratio > 2) were COL1A1 (percentage of cases with overexpression, 78.3%), CDH17 (73.9%), APOC1 (67.4%), COL1A2 (58.7%), YF13H12 (52.2%), CEACAM6 (50.0%), APOE (50.0%), REGIV (47.8%), S100A11 (41.3%), and FUS (41.3%). Among these genes, mRNA expression levels of CDH17 and APOE were associated with depth of tumor invasion (P = 0.0060 and P = 0.0139, respectively), and those of FUS and APOE were associated with degree of lymph node metastasis (P = 0.0416 and P = 0.0006, respectively). In addition, mRNA expression levels of FUS, COL1A1, COL1A2, and APOE were associated with stage (P = 0.0414, P = 0.0156, P = 0.0395, and P = 0.0125, respectively). Quantitative reverse transcription-PCR analysis also showed a high level of REGIV expression (>100 arbitrary units) in 14 of 46 GC samples (30.4%) but not in noncancerous tissues. We detected V5-tagged RegIV protein in the culture media of cells transfected with pcDNA-RegIV-V5 by Western blot. Our results provide a list of candidate genes that are potentially involved in invasion, metastasis, and carcinogenesis of GC. REGIV may serve as a specific biomarker for GC.

The SWI/SNF proteins are ATP-dependent chromatin remodeling enzymes that have been implicated in the regulation of gene expression. Recent studies have shown that members of the SWI/SNF superfamily can function as tumor suppressor genes. DNA methylation and transcriptional inactivation of the HLTF gene, which is a homologue to the SWI/SNF genes, have been observed in colon cancer. In the present study, we studied the DNA methylation status of the HLTF gene by methylation-specific PCR in 50 gastric carcinoma tissues, and seven gastric carcinoma cell lines and compared the methylation status with the levels of HLTF mRNA expression. DNA methylation of the HLTF gene was found in 25 (50%) of 50 gastric carcinomas, and levels of HLTF mRNA were associated with methylation status of HLTF (P = 0.027; Mann-Whitney U test). No correlations were found between HLTF mRNA levels and DNA methylation and T grade, N grade, tumor stage, or histological type. In corresponding non-neoplastic mucosae, DNA methylation of the HLTF gene was found in 1 (7%) of 15 samples. The methylated allele was not detected in any of 10 normal gastric mucosae from 10 healthy volunteers. Among seven gastric carcinoma cell lines, the KATO-III cell line showed loss of HLTF mRNA expression associated with DNA methylation. This loss was rectified by treatment with both Aza-2'-deoxycytidine, a demethylating agent, and trichostatin A, a histone deacetylase inhibitor. Chromatin immunoprecipitation assay revealed that the acetylation levels of histones H3 and H4 in the 5' CpG island of the HLTF gene were inversely associated with DNA methylation status. These results suggest that transcriptional inactivation of HLTF by aberrant DNA methylation and histone deacetylation may be involved in stomach carcinogenesis through down-regulation of HLTF expression.

A novel preparation technique, so called "Paste Mold," was devised for organ and tissue distribution studies. This is the most powerful by joining with autoradioluminography (ARLG), which was established and validated recently in the working group of Forum '93 of Japanese Society for study of xenobiotics. A small piece (10-50 mg) of each organ or tissue was available for measuring its radioactive concentration and it was sampled from the remains of frozen carcass used for macroautoradiography (MARG). The solubilization of the frozen pieces was performed with mixing a suitable volume of gelatine and strong alkaline solution prior to mild heating kept at 40 degrees C for a few hours. After that, the tissue paste was molded in template pattern to form the small plates. The molded plates were contacted with Imaging plate (IP) for recording their radioactive concentration. The recorded IP was processed by BAS2000. The molded plate was formed in thickness of 200 microns, so called infinit thickness against soft beta rays, and therefore the resulting relative intensities, represented by (PSL-BG)/S values, indicated practically responsible ratio of the radioactive concentration in organs and tissues, without any calibulation for beta-self absorption coefficiency. On the other hand, the left half body of the frozen carcass was used for making whole body autoradiography (WBA) before the Paste-Mold preparation. Comparison was performed for difference in (PSL-BG)/S values of organs and tissues between frozen and dried sections. A good concordance in relative intensities, (PSL-BG)/S by the Paste-Mold preparation was given with those by the frozen sections rather than dried sections.(ABSTRACT TRUNCATED AT 250 WORDS)

Healing processes of the tracheal epithelia after minor mechanical injury in vitro were morphologically investigated by electron microscopy. Actin filaments in the epithelia, at the injured site, were observed by phalliodin. The results are as follows: 1) The injured area was covered with one layer of epithelium within 48 hours and there were no mitotic figures. 2) The epithelial cells at the healing site were squamous and well developed. 3) Actin-filaments could be observed with well developed interdigitation. In conclusion these findings suggest that areas of minor injury heal by sliding of cells surrounding the injured area. The development of interdigitation is considered to play an important role in this process. It seems that actin observed at the site of interdigitation development plays some role in this healing process.

The growth process of tracheal epithelia was observed by primary cell culture method using BrdU. Cells stained with BrdU, that showed mitotic activity, were nonciliary cells and BrdU was not found in ciliated (differentiated) cells. The dividing cells and the mature cells could be distinguished by BrdU. Thus, it was demonstrated that BrdU could be used as an index for investigating the growth process of basal cells. Tissue culture of the tracheal rings after mucosal injury was performed. On the third day post-injury, the cells stained with BrdU and the migrating epithelia were observed in the border region between the non-injury and injury site. On the seventh day post-injury, healing was completed. The tissue culture method using BrdU is useful for observing the healing process of the tracheal mucous membrane.

Long-term culture of the middle ear epithelium of guinea pigs was carried out on reconstituted floating collagen matrix. Fibroblasts established from the abdominal skin dermis of allogenic animals were used to reorganize hydrated collagen gels into a dermal-like matrix. The explants placed on the surface of these matrices were composed of pseudostratified columnar cells with polygonal flat outgrowth sheets, which could be maintained for up to one month. In contrast, with simple hydrated collagen gel, no lysis of the substrate was observed regarding this reorganized collagen gel. In order to examine the growth pattern of these culture cells, 5-bromodeoxyuridine (BrdU) was added to the medium during the entire culture period. The specimens were immunohistologically stained using monoclonal antibodies. Noticeable changes were observed in the marginal portion of the explant where the cell shape changed from cuboidal to squamous. In this transitional area, most cells showed positive staining and consequently high proliferative activity. In the central area of the explants, however, the number of positive cells decreased and the main observation was a few labeled basal cell nuclei. It was suggested that the same regenerative process which usually occurs in normal respiratory epithelia after mechanical injury or other insults, was replayed in this culture system.