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Background: S-588410, a cancer peptide vaccine (CPV), comprises five HLA-A*24:02-restricted peptides from five cancer-testis antigens. In a phase 2 study, S-588410 was well-tolerated and exhibited antitumor efficacy in patients with urothelial cancer. Therefore, we aimed to evaluate the efficacy, immune response, and safety of S-588410 in patients with completely resected esophageal squamous cell carcinoma (ESCC)., Methods: This phase 3 study involved patients with HLA-A*24:02-positive and lymph node metastasis-positive ESCC who received neoadjuvant therapy followed by curative resection. After randomization, patients were administered S-588410 and placebo (both emulsified with Montanide™ ISA 51VG) subcutaneously. The primary endpoint was relapse-free survival (RFS). The secondary endpoints were overall survival (OS), cytotoxic T-lymphocyte (CTL) induction, and safety. Statistical significance was tested using the one-sided weighted log-rank test with the Fleming-Harrington class of weights., Results: A total of 276 patients were randomized (N = 138/group). The median RFS was 84.3 and 84.1 weeks in the S-588410 and placebo groups, respectively (P = 0.8156), whereas the median OS was 236.3 weeks and not reached, respectively (P = 0.6533). CTL induction was observed in 132/134 (98.5%) patients who received S-588410 within 12 weeks. Injection site reactions (137/140 patients [97.9%]) were the most frequent treatment-emergent adverse events in the S-588410 group. Prolonged survival was observed in S-588410-treated patients with upper thoracic ESCC, grade 3 injection-site reactions, or high CTL intensity., Conclusions: S-588410 induced immune response and had acceptable safety but failed to reach the primary endpoint. A high CTL induction rate and intensity may be critical for prolonging survival during future CPV development., (© 2024. The Author(s).)

Background: The association between recurrence timing and prognosis in patients with locally advanced resectable esophageal cancer undergoing neoadjuvant chemotherapy (NAC) followed by esophagectomy remains unclear. This study aimed to clarify this association using multicenter prospective clinical trial data., Methods: Among 162 patients enrolled in a NAC phase II study comparing the efficacy of cisplatin and fluorouracil plus docetaxel with cisplatin and fluorouracil plus adriamycin, 64 patients with recurrence after R0 resection were included in this study. We evaluated the association between recurrence timing and overall survival after recurrence (OSr), along with clinicopathological factors associated with recurrence timing and OSr., Results: Among 64 patients, 46 (71.9%) and 59 (92.2%) experienced recurrence within 1 and 2 years after surgery, respectively. Groups based on recurrence timing, including ≤ 6, 6-12, and > 12 months, had median OSr of 3.6, 13.9, and 13.4 months, respectively. The prognosis was significantly poorer for patients with recurrence ≤ 6 months after surgery than for other patients (P < 0.001). Multivariate analysis revealed pathological lymph node staging as an independent factor associated with early recurrence (odds ratio: 3.46, 95% confidence interval: 1.47-8.02, P = 0.0045). On the other hand, multivariate analysis for factors associated with OSr revealed pT (hazard ratio [HR]: 1.91, 95%CI 1.26-2.88, P = 0.0022), early recurrence (HR: 6.88, 95%CI 2.68-17.6, P < 0.001), and treatment after recurrence, with both local treatment (HR: 0.47, 95%CI 0.22-0.98, P = 0.043) and chemotherapy (HR: 0.25, 95%CI 0.11-0.58, P = 0.0011) as independent prognostic factors., Conclusion: Patients with advanced esophageal cancer experiencing recurrence within 6 months after esophagectomy following NAC have an extremely poor prognosis, suggesting that an advanced pN stage is associated with early recurrence., (© 2024. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background/aim: We herein examined T cell immunity in esophageal cancer patients with and without Helicobacter pylori infection to establish a foundation for immunotherapeutic strategies targeting esophageal cancer in the presence of H. pylori infection., Materials and Methods: Twenty-six patients with esophageal squamous cell carcinoma between 2015 and 2017 were enrolled in the present study. Serum antibodies against H. pylori were measured. Fresh tumor tissues were obtained by endoscopic biopsy or from surgical resection. A cell suspension of these tissues was subjected to a flow cytometric analysis., Results: Among the 26 patients analyzed, 10 (38.5%) were seropositive for H. pylori. The flow cytometric analysis of tumor-infiltrating lymphocytes revealed that the percentage of CD103 + CD4 + T cells in esophageal tumors was significantly lower in H. pylori-positive patients than in H. pylori-negative patients (p=0.0105). Conversely, the percentage of CD45RA-CD25hi effector Treg cells in esophageal tumors was significantly higher in H. pylori-positive patients than in H. pylori-negative patients (p=0.0022), indicating an immunosuppressive tumor microenvironment in the former. Following neoadjuvant chemotherapy, the number of CD45RA-CD25hi effector Treg cells decreased (p=0.0248)., Conclusion: The tumor immune microenvironment of esophageal cancer patients with H. pylori infection exhibited an immunosuppressive phenotype. The targeting of Treg cells has potential in immunotherapy for this patient population., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Real-world clinical outcomes of and prognostic factors for nivolumab treatment for esophageal squamous-cell carcinoma (ESCC) remain unclear. This study aimed to evaluate real-world outcomes of nivolumab monotherapy in association with relevant clinical parameters in recurrent/unresectable advanced ESCC patients., Methods: This population-based multicenter cohort study included a total of 282 patients from 15 institutions with recurrent/unresectable advanced ESCC who received nivolumab as a second-line or later therapy between 2014 and 2022. Data, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively collected from these patients., Results: Objective response and disease control rates were 17.0% and 47.9%, respectively. The clinical response to nivolumab treatment significantly correlated with development of overall immune-related adverse events (P < .0001), including rash (P < .0001), hypothyroidism (P = .03), and interstitial pneumonia (P = .004). Organ-specific best response rates were 20.6% in lymph nodes, 17.4% in lungs, 15.4% in pleural dissemination, and 13.6% in primary lesions. In terms of patient survival, the median OS and PFS was 10.9 and 2.4 months, respectively. Univariate analysis of OS revealed that performance status (PS; P < .0001), number of metastatic organs (P = .019), C-reactive protein-to-albumin ratio (CAR; P < .0001), neutrophil-lymphocyte ratio (P = .001), and PMI (P = .024) were significant. Multivariate analysis further identified CAR [hazard ratio (HR) = 1.61, 95% confidence interval (CI) 1.15-2.25, P = .0053)] in addition to PS (HR = 1.65, 95% CI 1.23-2.22, P = .0008) as independent prognostic parameters., Conclusions: CAR and PS before nivolumab treatment are useful in predicting long-term survival in recurrent/unresectable advanced ESCC patients with second-line or later nivolumab treatment., Trial Registration: UMIN000040462., (© 2024. The Author(s).)

Background: First-line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab-containing regimens in many countries. We report longer-term follow-up data., Methods: This open-label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression-free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD-L1) expression of ≥1% and then in the overall population., Results: A total of 970 patients were randomly assigned. After 29 months of minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46-0.76]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65-0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48-0.80]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65-0.92]). In patients with tumor cell PD-L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51-0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79-1.36]). Among all treated patients (n = 936), Grade 3-4 treatment-related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients., Conclusions: Nivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow-up, further supporting use as first-line standard treatment options for patients with advanced ESCC., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The standard treatment for advanced esophageal cancer with synchronous distant metastasis is systemic chemotherapy or immunotherapy. Conversion surgery is not established for esophageal cancer with synchronous distant metastasis. This study aimed to investigate the clinical impact of conversion surgery for esophageal cancer with synchronous distant metastasis after induction therapy., Methods: This multi-institutional retrospective study enrolled 66 patients with advanced esophageal cancer, including synchronous distant metastasis, who underwent induction chemotherapy or chemoradiotherapy followed by conversion surgery between 2005 and 2021. Short- and long-term outcomes were investigated., Results: Distant lymph node (LN) metastasis occurred in 51 patients (77%). Distant organ metastasis occurred in 15 (23%) patients. There were 41 patients with metastatic para-aortic LNs, and 10 patients with other metastatic LNs. Organs with distant metastasis included the lung in seven patients, liver in seven patients, and liver and lung in one patient. For 61 patients (92%), R0 resection was achieved. The postoperative complication rate was 47%. The in-hospital mortality rate was 1%, and the 3- and 5-year overall survival (OS) rates for all the patients were 32.4% and 24.4%, respectively. The OS rates were similar between the patients with distant LN metastasis and the patients with distant organ metastasis (3-year OS: 34.9% vs. 26.7%; P = 0.435). Multivariate analysis showed that pathologic nodal status is independently associated with a poor prognosis (hazard ratio, 2.43; P = 0.005)., Conclusions: Conversion surgery after chemotherapy or chemoradiotherapy for esophageal cancer with synchronous distant metastasis is feasible and promising. It might be effective for improving the long-term prognosis for patients with controlled nodal status., (© 2024. Society of Surgical Oncology.)

Purpose: To investigate the indications for neoadjuvant chemotherapy (NAC) in esophageal cancer patients aged 75 years or older., Methods: We analyzed data, retrospectively, from 155 patients over 75 years old, who underwent esophagectomy for esophageal cancer between 2010 and 2020. Forty-one patients underwent upfront surgery (US group) and 114 were treated with NAC followed by surgery (NAC group). We compared the patient backgrounds and perioperative outcomes including prognosis, between the two groups., Results: The NAC group patients were significantly younger and had significantly more advanced clinical stage disease than the US group patients. The incidence of postoperative complications was similar in the two groups. Patients with a good pathological response to NAC had a significantly better prognosis than those with a poor response and those in the US group. Among patients with a performance status (PS) of 0, the 5-year OS rate was 56.5% in the NAC group and 38.1% in the US group (HR = 0.63, 95% CI 0.35-1.12). Among those with a PS of 1-2, the 5-year OS rates were 28.1% and 57.1%, respectively (HR = 1.69, 95% CI 0.99-2.89; P = 0.037 for interaction)., Conclusions: NAC did not improve the postoperative prognosis of older esophageal cancer patients with a PS of 1 or higher., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: Multidisciplinary treatment combining chemotherapy, chemo radiation therapy (CRT), and surgery has been utilized for advanced esophageal cancer. However, preoperative treatment could cause postoperative inflammation and complications. We hypothesized that fibrosis surrounding tumor tissue caused by preoperative treatment could induce postoperative systemic inflammation and influence postoperative complications., Methods: Surgical specimens from patients with thoracic esophageal cancer who underwent preoperative CRT (38 cases) or chemotherapy (77 cases) and those who received no preoperative treatment (49 cases) were evaluated to measure the fibrotic area adjacent to the tumor (10 mm from the tumor edge) by applying Azan staining. Pleural effusion and peripheral blood serum interleukin-6 levels were analyzed to evaluate local and systemic postoperative inflammation in 37 patients., Results: The fibrotic areas around the tumors were significantly larger in patients who underwent preoperative CRT than in patients who underwent chemotherapy (p < 0.001) or who had received no preoperative therapy (p < 0.001). Infectious complications were higher in patients who underwent preoperative CRT than chemotherapy (p = 0.047) or surgery alone (p < 0.001). The patients with larger fibrotic areas had more infectious complications (p = 0.028). Multivariate analysis showed that both a large fibrotic area and preoperative CRT were correlated with infectious complications, but not significantly. Pleural effusion interleukin-6 was significantly higher in patients who underwent preoperative CRT than in patients who received no preoperative therapy (p = 0.013)., Conclusions: A large fibrotic peritumoral esophageal tissue area after preoperative treatment could cause postoperative inflammatory response and infectious complications., (© 2024 International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Background: The surgical procedure for esophagogastric junction (EGJ) adenocarcinoma usually depends on the location of its epicenter or proximal margin, but accurate evaluation of these positions is often difficult. The usefulness of positron emission tomography-computed tomography (PET-CT) for this purpose is unknown., Methods: Between June 2005 and February 2015, we enrolled 30 patients with cT2-4 EGJ adenocarcinoma (Siewert type I/II) who underwent surgical resection. We ascertained the sensitivity and specificity of preoperative PET-CT for identifying the primary tumor and regional lymph node metastasis, and compared PET-CT and pathological findings in terms of the distance from the EGJ to the tumor epicenter or proximal tumor margin., Results: PET-CT detected the primary tumor with a sensitivity of 97% (29/30), and detected lymph node metastasis with a sensitivity and specificity of 22% (4/18) and 100% (8/8), respectively. No significant association was observed between the maximal standardized uptake value and histological type, tumor size, or pT status. Regarding the accuracy of evaluating tumor location, the median differences between PET-CT and pathological measurements were .6 cm for the tumor epicenter and .5 cm for the proximal margin from the EGJ. PET-CT and pathological findings showed agreement regarding Siewert classification type (I or II) and lengths of esophageal involvement exceeding 4 cm or 2 cm in 77% (10/13), 85% (11/13), and 85% (11/13) of cases, respectively., Discussion: PET-CT had high sensitivity for primary EGJ adenocarcinoma. It may effectively locate the tumor epicenter and proximal margin and thus help clinicians determine the optimal surgical procedure., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Opportunities for T4b esophageal cancer patients to receive curative surgery are increasing with the development of multidisciplinary treatments. However, the best modality to accurately diagnose infiltration to the organs surrounding T4b esophageal cancer is still unknown. The aim of this study was to determine the performance of CT and MRI in diagnosing T stage in T4b esophageal cancer, with reference to the pathological diagnosis., Methods: A retrospective medical records review of patients with T4b esophageal cancer patients from January 2017 to December 2021 was conducted. Among 125 patients who were treated for cT4b esophageal cancer in Osaka University Hospital, 30 patients were diagnosed with cT4b esophageal cancer by CT, ycT staging with CT (contrast-enhanced images) and MRI (T2-FSE images), and curative R0 resection was performed. Preoperative MRI staging was independently performed by two experienced radiologists. The diagnostic performance of CT and MRI were examined using McNemar's test., Results: Nineteen and 12 patients were diagnosed with ycT4b by CT and MRI, respectively. Combined T4b organ resection was performed in 15 patients. A pathological diagnosis of ypT4b was made in 11 cases. In comparison to CT, MRI showed a higher diagnostic performance, specificity (47% vs. 89%, p = 0.013), and accuracy (60% vs. 90%, p = 0.015) for CT vs. MRI., Conclusions: Our results-with reference to the pathological diagnosis-revealed that MRI had a superior diagnostic performance to CT for diagnosing T4b esophageal cancer invading the surrounding organs. An accurate diagnosis of T4b esophageal cancer may facilitate the implementation of appropriate treatment strategies., (© 2023. The Author(s) under exclusive licence to The Japan Esophageal Society.)

This systematic review was performed to investigate the superiority of proton beam therapy (PBT) to photon-based radiotherapy (RT) in treating esophageal cancer patients, especially those with poor cardiopulmonary function. The MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases were searched from January 2000 to August 2020 for studies evaluating one end point at least as follows; overall survival, progression-free survival, grade ≥ 3 cardiopulmonary toxicities, dose-volume histograms, or lymphopenia or absolute lymphocyte counts (ALCs) in esophageal cancer patients treated with PBT or photon-based RT. Of 286 selected studies, 23 including 1 randomized control study, 2 propensity matched analyses, and 20 cohort studies were eligible for qualitative review. Overall survival and progression-free survival were better after PBT than after photon-based RT, but the difference was significant in only one of seven studies. The rate of grade 3 cardiopulmonary toxicities was lower after PBT (0-13%) than after photon-based RT (7.1-30.3%). Dose-volume histograms revealed better results for PBT than photon-based RT. Three of four reports evaluating the ALC demonstrated a significantly higher ALC after PBT than after photon-based RT. Our review found that PBT resulted in a favorable trend in the survival rate and had an excellent dose distribution, contributing to reduced cardiopulmonary toxicities and a maintained number of lymphocytes. These results warrant novel prospective trials to validate the clinical evidence., (© 2023. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: Three-course neoadjuvant chemotherapy (NAC) followed by surgery has become a standard of care for locally advanced esophageal cancer (EC). However, some patients occasionally experience a poor tumor response to the third course and have a poor clinical outcome., Methods: An exploratory analysis of data from the authors' recent multicenter randomized phase 2 trial compared patients with locally advanced EC who received two courses (n = 78) and those who received three courses (n = 68) of NAC. The association between tumor response and clinico-pathologic factors, including survival, was evaluated to identify risk factors in the three-course group., Results: Of 68 patients who received three courses of NAC, 28 (41.2%) had a tumor reduction rate lower than 10% during the third course. This rate was associated with unfavorable overall survival (OS) and progression-free survival (PFS) compared with a tumor reduction rate of 10% or higher (2-year OS rate: 63.5% vs. 89.3%, P = 0.007; 2-year PFS rate: 52.6% vs. 79.7%, P = 0.020). The independent prognostic factors for OS were tumor reduction rate lower than 10% during the third course (hazard ratio [HR], 2.735; 95% confidence interval [CI] 1.041-7.188; P = 0.041) and age of 65 years or older (HR, 9.557, 95% CI 1.240-73.63; P = 0.030). Receiver operating characteristic curve and multivariable logistic regression analyses identified a tumor reduction rate lower than 50% after the first two courses as an independent predictor of a tumor reduction rate lower than 10% during the third course of NAC (HR, 4.315; 95% CI 1.329-14.02; P = 0.015)., Conclusion: Continuing NAC through a third course may worsen survival for patients who do not experience a response to the first two courses in locally advanced EC., (© 2023. Society of Surgical Oncology.)

Background: The optimal treatment strategy for cT4b esophageal cancer has not been established yet. Although curative surgery is sometimes performed after induction treatments, the prognostic factor of cT4b esophageal cancer cases who underwent R0 resection remains unknown., Methods: A total of 200 patients with cT4b esophageal cancer who underwent R0 resection after induction treatments between 2001 and 2020 in our institute were included in the present study. The relationship between clinicopathological factors and patient survival is evaluated to identify useful prognostic factors., Results: The median and 2-year overall survival were 40.1 months and 62.8%, respectively. Disease recurrence occurred in 98 (49%) patients after surgery. Compared to induction chemotherapy alone, chemoradiation-based induction treatments were associated with decreased locoregional recurrence (34.0% vs 60.8%, P = .0077) but increased pulmonary metastases (27.7% vs 9.8%, P = .0210) and dissemination (19.1% vs 3.9%, P = .0139) after surgery. Multivariate analysis of overall survival identified the preoperative C-reactive protein/albumin ratio (hazard ratio 1.7957, P = .0031), response to induction treatments (hazard ratio 2.9663, P = .0009), postoperative pneumonia (hazard ratio 2.3784, P = .0010), and pN (2-3) (hazard ratio 1.5693, P = .0355) as independent prognostic factors. Preoperative C-reactive protein/albumin ratio (hazard ratio 1.6760, P = .0068) and postoperative pneumonia (hazard ratio 1.8365, P = .0200) were also independent prognostic factors for recurrence-free survival., Conclusion: Curative surgery after induction therapy for cT4b esophageal cancer achieved favorable survival. Preoperative C-reactive protein/albumin ratio, postoperative pneumonia, response to induction treatments, and pN were useful prognostic factors., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Although intramural metastasis (IM) in esophageal cancer is considered a poor prognostic factor, there are only limited reports detailing its clinicopathologic characteristics and prognostic impact., Patients and Methods: We retrospectively included patients with esophageal squamous cell carcinoma (ESCC) with esophagectomy at our institution between 2010 and 2016. We compared patients with intramural metastases (IMs) (IM group) versus those without IMs (non-IM group) to clarify the clinical significance of intramural metastasis in ESCC., Results: A total of 23 (3.9%) out of all 597 patients were identified to have IM. The IMs were located on the cranial side in 13 (56.5%) and caudal side in 10 (43.5%) of the primary tumor, with two multiple cases. The IM group, compared with the non-IM group, was associated with higher percentage of cN-positive (91.3 versus 67.9%, P = 0.02), pN-positive (82.6 versus 55.9%, P = 0.04), and pM(lym)-positive (30.4 versus 12.5%, P = 0.02) cases. Five-year recurrence-free survival (RFS) was significantly worse in the IM group than the non-IM group (14.9 versus 55.0 %, P < 0.001). Multivariable analysis of recurrence-free survival identified pT (HR 1.74, 95% CI 1.36-2.23, P < 0.001), pN (HR 2.11, 95% CI 1.60-2.78, P < 0.001), histological classification (HR 1.68, 95% CI 1.21-2.35, P = 0.002), and pM(LYM) (HR 1.64, 95% CI 1.64-2.95, P < 0.001), along with presence of IM (HR 2.24, 95% CI 1.37-3.64, P < 0.001) to be independent prognostic factors. Lymphatic (65.2 versus 24.9%, P < 0.001) and hepatic (26.1 versus 6.8%, P = 0.005) recurrences were significantly more common in the IM group than in the non-IM group., Conclusions: IM was shown to be associated with dismal survival after surgery. A treatment strategy emphasizing more intensive systemic control should be considered for patients with ESCC with IM., (© 2023. The Author(s).)

Purpose: This study aimed to characterize postoperative blood glucose fluctuation in patients who underwent esophagectomy for esophageal cancer, and to define its impact on complications and prognosis., Methods: The subjects of this retrospective study were 284 patients who underwent esophagectomy at Osaka University Hospital between 2015 and 2017. Data analyzed included clinicopathological background, the immediate postoperative blood glucose level (IPBG), postoperative blood glucose variability (PBGV), insulin dosage, postoperative complications, and prognosis., Results: The median IPBG and PBGV were 170 (64-260) mg/dl and 64.5 (11-217) mg/dl, respectively. Postoperative pneumonia was more common in patients with PBGV > 100 mg/dl (P = 0.015). Patients with IPBG < 170 mg/dl had significantly worse 5-year overall survival (OS) and 5-year recurrence-free survival (RFS) than those with IPBG > 170 mg/dl (54.5% vs. 80.4%, respectively, [P < 0.001] and 44.3% vs. 69.3%, respectively, [P = 0.001]). The 5-year OS rates were 43.5%, 68.3%, 80.6%, and 79.0% for patients with IPBG < 154, 154-170, 170-190, and ≥ 190 mg/dl, respectively. The corresponding 5-year RFS rates were 38.1%, 52.4%, 77.0%, and 61.3%, respectively. Multivariate analysis revealed that IPBG < 154 mg/dl and pathological stage were independent poor prognostic factors for OS., Conclusion: PBGV was associated with postoperative pneumonia, and low IPBG was an independent poor prognostic factor for patients with esophageal cancer., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: The optimal extent of lymph-node (LN) dissection in esophageal cancer has not been established. Although the frequency and patterns of recurrence in each regional LN station after radical dissection are important in determining the regional LNs of thoracic esophageal cancer to be routinely dissected, this information has not been investigated sufficiently. We studied the significance of dissection at each LN station based on their recurrence patterns., Methods: Six hundred and twelve patients with esophageal cancer who underwent curative esophagectomy were studied. The incidence and pattern of recurrence (systemic or non-systemic) at each regional LN station were analyzed. To compare the significance of dissection among regional LNs, the efficacy index (EI) was also calculated., Results: Regional LN recurrence was diagnosed in 101 (16.5%) patients. Among the regional LNs, recurrent laryngeal nerve, paraesophageal, and perigastric LNs showed higher EIs (3.1-6.7). Pretracheal and posterior thoracic para-aortic LNs showed low EIs (0-0.2). Supraclavicular LNs had moderate EIs (1.7-2.0). The recurrence rate was highest in the pretracheal LN, followed by the supraclavicular LNs. The majority (81.8%) of the pretracheal LN had a systemic recurrence, while about half (right: 60.0%, left: 43.8%) of the supraclavicular LNs had a systemic recurrence., Conclusion: Due to the high incidence of systemic recurrence or low EI for pretracheal and posterior thoracic para-aortic LNs, we suggest that these LN stations be regarded as non-regional LNs and be excluded from routine dissection. Supraclavicular LNs may also be excluded from routinely dissected stations., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: We report the long-term results as primary endpoint in a multicentre randomized prospective Phase 2 trial which compared chemoradiotherapy (CRT) and triplet chemotherapy (CT) as the initial therapy for conversion surgery (CS) in T4b esophageal cancer (EC)., Methods: Patients with T4b EC were randomly assigned to the CRT group or CT group as initial treatment. CS was performed if resectable after initial or secondary treatment. The primary endpoint was 2-year overall survival, analysed by intention-to-treat., Results: The median follow-up period was 43.8 months. The 2-year survival rate was higher in the CRT group (55.1%; 95% CI: 41.1-68.3%) compared to the CT group (34.7%; 95% CI: 22.8-48.9%), although the difference was not significant (P = 0.11). Local and regional lymph node recurrence in patients undergoing R0 resection was significantly higher in the CT group compared to the CRT group (local: 30% versus 8%, respectively, P = 0.03; regional: 37% versus 8%, respectively, P = 0.002)., Conclusions: Upfront CT was not superior to upfront CRT as induction therapy for T4b EC in terms of 2-year survival and was significantly inferior to upfront CRT in terms of local and regional control., Registration: The Japan Registry of Clinical Trials (s051180164)., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background/aim: Monoclonal antibodies (mAbs) that target tumor antigens have recently been developed. Their antitumor activity is mainly achieved through antibody-dependent cellular cytotoxicity (ADCC) via effector cells such as tumor-infiltrated macrophages and natural killer (NK) cells. CpG oligodeoxynucleotides (ODNs) have potent antitumor activity and are considered to increase the tumor infiltration of macrophages and NK cells; however, a completely solubilized novel CpG-schizophyllan (SPG) complex, K3-SPG, displays more potent antitumor activity. We recently reported the significant antitumor activity of anti-glypican-1 (GPC1) mAb against GPC1-positive esophageal squamous cell carcinoma (ESCC) via ADCC. The aim of this study was to evaluate the potential synergistic antitumor activity of anti-GPC1 mAb and K3-SPG and elucidate the underlying mechanisms using a xenograft model of GPC1-positive human ESCC cells., Materials and Methods: The established human esophageal cancer cell line TE14 was subcutaneously injected into SCID mice. Xenograft mice were treated with anti-GPC1 mAb, K3-SPG, or their combination. Antitumor activity was evaluated by measuring the tumor volume. For FACS analysis, agents were administrated, and tumors were resected 1 day after the final treatment., Results: Anti-GPC1 mAb or K3-SPG monotherapy showed dose-dependent antitumor activity, and combination therapy with anti-GPC1 mAb and K3-SPG showed antitumor activity (p=0.0859). Flow cytometry revealed significantly increased numbers of macrophages (p=0.0133) and of the ratio of activated NK cells/total NK cells (p=0.0058) following K3-SPG or combination therapy., Conclusion: Combination therapy with K3-SPG and anti-GPC1 mAb or another antitumor mAb may represent a new cancer treatment option acting via ADCC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates in non-lymphoid tissues, which are associated with improved prognosis in some cancer types. This study aimed to investigate the clinical significance of TLSs in oesophageal cancer (EC)., Methods: In a series of 316 EC surgical specimens from two different institutes, we evaluated the density and maturity of peritumoral TLSs using haematoxylin/eosin, immunohistochemistry, and multiplex immunofluorescence staining. We analysed the association between TLSs and clinicopathological parameters. The clinical significance of TLSs was further evaluated in a different cohort of 34 patients with recurrent EC treated with anti-PD-1 antibody., Results: Tumours with high TLS density predominantly consisted of matured TLSs. High TLS density was significantly associated with less advanced tumour stage, absence of lymphatic/vascular invasion, better serum nutrition parameters (neutrophils count, albumin, neutrophil-to-lymphocyte ratio, and prognostic nutritional index), and prolonged survival. This survival trend was more remarkable in cases with matured TLSs, which represented an increased population of CD138 + plasma cells. In the second EC cohort, TLS density predicted the clinical response to anti-PD-1 antibody and patient survival., Conclusion: The density and maturity of peritumoral TLSs are useful parameters for predicting long-term survival and response to anti-PD-1 antibody treatment in EC patients., (© 2023. The Author(s).)

Background: The efficacy of neoadjuvant chemotherapy (NACT) correlates with patient survival in oesophageal squamous cell carcinoma (OSCC), but optimal evaluation of the treatment response based on PET-CT parameters has not been established., Methods: We analysed 226 OSCC patients who underwent PET-CT before and after NACT followed by surgery. We assessed SUVmax, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) for the primary tumour and the number of PET-positive lymph nodes before and after NACT to predict patient survival., Results: In a stepwise analysis, we defined 60%, 80%, and 80% as the optimal cut-off values for SUVmax, MTV, and TLG reduction, respectively, to distinguish responders and non-responders to NACT. In the ROC analysis, the TLG reduction rate was the best predictor of recurrence among PET-CT parameters. The TLG responders achieved significantly more favourable prognoses than non-responders (2-year progression-free survival [PFS] rate: 64.1% vs. 38.5%; P = 0.0001). TLG reduction rate (HR 2.58; 95% CI 1.16-5.73) and the number of PET-positive lymph nodes after NACT (HR 1.79; 95% CI 1.04-3.08) were significant independent prognostic factors., Conclusions: TLG reduction is the best predictor of prognosis. Preoperative PET-CT evaluation of both the primary tumour and lymph nodes could accurately stratify risk in OSCC patients., (© 2023. The Author(s).)

Background: Neoadjuvant therapy followed by surgery is the standard treatment for locally advanced esophageal cancers. During neoadjuvant therapy, tumor-induced esophageal stenosis or adverse events often cause weight loss. However, little is known about the effects of weight loss during neoadjuvant therapy on postoperative complications or prognosis. We investigated the association between weight loss during neoadjuvant chemotherapy, postoperative infectious complications, and prognosis., Methods: Data from OGSG1003, a randomized phase-II trial comparing two regimens of neoadjuvant chemotherapy, cisplatin and fluorouracil plus Adriamycin and cisplatin and fluorouracil plus docetaxel, for locally advanced esophageal squamous cell carcinoma were used. Body weight was measured before neoadjuvant chemotherapy and esophagectomy. Multivariate analysis for infectious complications and prognosis was performed., Results: The study included 134 patients. The median weight loss during neoadjuvant chemotherapy was 2.83% (-2.07% to 6.29%). Postoperative infectious complications were observed in 37 patients who had a significantly higher weight loss during neoadjuvant chemotherapy (5.18% vs. 1.90%, P = 0.002). Multivariate analysis revealed that > 5% of weight loss during neoadjuvant chemotherapy was the only independent factor associated with postoperative infectious complications (odds ratio 2.69, 95% confidence interval 1.12-6.46, P = 0.027). Weight loss during neoadjuvant chemotherapy was significantly associated with worse recurrence-free survival in the univariate analysis (log-rank test, P = 0.002), but this association was marginal in the multivariate analysis (hazard ratio 1.73, 95% confidence interval 0.98-3.08, P = 0.058)., Conclusions: Severe weight loss during neoadjuvant chemotherapy was an independent risk factor for postoperative infectious complications. Weight maintenance during neoadjuvant chemotherapy may reduce the incidence of postoperative infectious complications., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Objectives: Tumor-infiltrating lymphocytes (TILs) have long been recognized as playing an important role in tumor immune microenvironment. Lately, the Immunoscore (IS) has been proposed as a new method of quantifying the number of TILs in association with patient survival in several cancer types., Methods: In 300 preoperatively untreated esophageal cancer (EC) patients who underwent curative resection at two different institutes, immunohistochemical staining using CD3 and CD8 antibodies was performed to evaluate IS, as objectively scored by auto-counted TILs in the tumor core and invasive margin. In addition, in pre-neoadjuvant chemotherapy (pre-NAC) endoscopic biopsies of a different cohort of 146 EC patients who received NAC, CD3, and CD8 were immunostained to evaluate TIL density., Results: In all cases, the IS-high (score 3-4) group tended to have better survival [5-year overall survival (OS) of the IS-high vs low group: 77.6 vs 65.8%, P = 0.0722] than the IS-low (score 1-2) group. This trend was more remarkable in cStage II-IV patients (70.2 vs 54.5%, P = 0.0208) and multivariate analysis of OS further identified IS (hazard ratio 2.07, P = 0.0043) to be an independent prognostic variable. In preNAC biopsies, NAC-responders had higher densities than non-responders of both CD3 + ( P = 0.0106) and CD8 + cells ( P = 0.0729) and, particularly CD3 + cell density was found to be an independent prognostic factor (hazard ratio 1.75, P = 0.0169)., Conclusions: The IS signature in surgical specimens and TIL density in preNAC- biopsies could be predictive markers of clinical outcomes in EC patients., Competing Interests: The authors report no conflict of interests., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Preoperative risk assessment is important in older patients because they often have comorbidities and impaired organ function. We performed preoperative comprehensive geriatric assessment (CGA) for older patients with esophageal cancer., Patients and Methods: A total of 217 patients over 75 years old who underwent esophagectomy for thoracic esophageal cancer were analyzed. The CGA was performed preoperatively and included the Mini-Mental State Examination (MMSE), Geriatric Depression Score (GDS), vitality index, Barthel index, and instrumental activities of daily living (IADL). We defined the robust group as patients with normal function on every instrument, and the pre-frail and frail groups as those with functional impairment on one instrument or two or more instruments, respectively. We assessed how the CGA correlated with postoperative complications and prognosis., Results: Of the 217 patients, 86 (39.6%) were in the robust group, 68 (31.3%) in the pre-frail group, and 63 (29.0%) in the frail group. Postoperative pneumonia (P = 0.026) and anastomotic leakage (P = 0.032) were significantly more common in the frail group. The frail group had a significantly longer postoperative hospitalization period (P = 0.016) and significantly lower rate of discharge to home (P = 0.016). Overall survival (OS) was significantly worse in the frail group (5-year overall survival rate, frail group versus others, 37.8% versus 52.0%, P = 0.046), but it was not significant on multivariate analysis., Conclusions: The preoperative CGA in older patients with esophageal cancer was associated with risk of postoperative complications., (© 2022. Society of Surgical Oncology.)

Background: Total gastrectomy with jejunum or colon reconstruction after esophagectomy is commonly performed in patients with esophageal cancer who have a history of distal gastrectomy. In this study, we examined the safety and effectiveness of double-tract reconstruction (DTR) with preservation of the remnant stomach for said patient population., Methods: Twenty-seven esophageal cancer patients with a history of distal gastrectomy who underwent transthoracic esophagectomy between 2010 and 2020 in our institution were retrospectively analyzed; 15 of these patients underwent DTR, whereas 12 underwent completion gastrectomy with jejunal Roux-en-Y reconstruction (RYR). Short-term outcomes, postoperative nutritional indexes, and ghrelin levels were evaluated. Moreover, abdominal lymph-node metastasis and recurrence, which were removed by total residual gastrectomy, were examined to determine the oncological validity of residual stomach preservation., Results: There was no metastasis and recurrence in abdominal lymph nodes, such as #4sa or #11d, which were removed by total residual gastrectomy. Total operation time did not differ between the groups (P = 0.4247). The blood loss for the DTR group was 495 ± 446 mL, whereas that for the RYR group was 844 ± 575 mL (P = 0.0168). Clavien-Dindo grade III or higher complications were not significantly different between the groups (P = 0.7063). The rates of serum total protein values at 6 months in the DTR and RYR groups were 112% ± 12.2% and 102.6% ± 10.7% (P = 0.0403), respectively. The prognostic nutritional indexes at 6 months in the DTR and RYR groups were 108.6% ± 14.5% and 83.2% ± 42.6% (P = 0.0376), respectively., Conclusions: DTR in esophagectomy is safe and effective for patients with a history of distal gastrectomy., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Surgical treatment of gastric tube cancer after thoracic gastrectomy is highly invasive, especially for gastric tube cancer of the posterior mediastinal tract, and in some cases, a reduction surgery is an option. We have experienced 4 cases of posterior mediastinal reconstructive gastric tube cancer in which local resection by thoracoscopic and endoscopic cooperative surgery( TECS)was conducted. All cases had undergone video-assisted thoracoscopic subtotal esophagectomy and posterior mediastinal gastric tube reconstruction for thoracic esophageal cancer. In 1 case, endoscopic submucosal dissection was performed, but it showed positive for vertical margins. Other cases were not indicated for endoscopic resection. Considering the patient's background, we decided to preserve the gastric tube and planned local resection by TECS. One patient was transferred to open thoracotomy due to severe adhesion, and 1 patient underwent segmental resection and 2-stage reconstruction due to narrowing of the gastric tube lumen at the suture closure. In all cases, the resection margins were negative and the patients are alive without recurrence of gastric tube cancer. Local resection of gastric tube with TECS for posterior mediastinal tract reconstructive gastric tube cancer may be useful as a less invasive surgical treatment.

Background: Surgery for esophageal cancer (EC) causes morphological and functional changes in the upper gastrointestinal tract, resulting in postoperative weight loss (PWL). PWL has been shown to lead to poor nutritional status and immunocompetence, which may worsen the prognosis for several types of cancer. However, few reports have examined the relationship between weight loss (WL) in the early postoperative period and cancer prognosis., Methods: A total of 421 esophageal cancer patients underwent curative esophagectomy at Osaka University Hospital from 2010 to 2016. Based on the patients' body weight 1.5 months after surgery, they were classified into severe WL (n = 50) and slight-moderate WL (n = 371) groups., Results: The 5-year overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were significantly lower in the severe WL group than the slight-moderate WL group (p = 0.0002, p < 0.0001, and p = 0.0004, respectively). In the multivariate analysis, tumor invasion depth (pT3, 4), lymph node metastasis (pN2, 3), preoperative Prognostic Nutrition Index (< 45), postoperative complications (≥ G3), and severe WL were independent prognostic factors for CSS (hazard ratio [HR] 2.5, 95% confidence interval [CI] 1.7-3.7; HR 1.6, 95% CI 1.1-2.4; HR 1.9, 95% CI 1.3-2.8; HR 1.6, 95% CI 1.1-2.4; and HR 2.7, 95% CI 1.7-4.2, respectively). In a multivariate analysis of risk factors leading to severe WL, thoracotomy (VATS) and postoperative MAX CRP (high) were independent risk factors (odds ratio [OR 0.48, 95% CI 0.24-0.97; OR 1.9, 95% CI 1.0-3.5)., Conclusion: Early PWL would be a useful marker of poor cancer prognosis in EC patients. Highly inflammatory conditions due to surgical invasion and postoperative complications may contribute to early PWL., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Backgrounds: Since the prognosis of patients with adenocarcinoma of the esophagogastric junction (AEG) remains poor, more intensive treatments, including neoadjuvant chemotherapy (NAC), should be developed. We retrospectively examined whether neoadjuvant docetaxel, oxaliplatin, and S‑1 (DOS) combination chemotherapy resulted in a favorable clinical response and acceptable toxicity in patients with AEG., Methods: This retrospective cohort study included 36 consecutive patients with cStage IIB-IV AEG (Siewert types I-III). Regarding stage IV disease, patients with resectable distant lymph node metastasis (M1-LYM) were eligible. Patients underwent three 3-week cycles of docetaxel (40 mg/m 2 ) and oxaliplatin (100 mg/m 2 ) on day 1 plus oral S-1 (80-120 mg according to body surface area) from day 1 to 14. Surgical resection was performed within 2-4 weeks after completion of NAC., Results: Three cycles of neoadjuvant DOS were completed in 28 (78%) patients. Grade 3-4 neutropenia, anorexia, and diarrhea were observed in 26 (72%), 7 (19%), and 4 (11%) patients, respectively. Febrile neutropenia occurred in six (17%) patients. There were no treatment-related deaths. R0 resection was achieved in 35 (97%) patients, and postoperative morbidities of Clavien-Dindo grade III or higher were observed in 6 (17%) patients. Pathological complete response was observed in 11 (31%) of 36 patients. Pathological response rates of grade ≥ 2 and grade ≥ 1b were 47 and 72%, respectively. Two-year progression-free and overall survival rates were 60.1 and 81.2%, respectively., Conclusions: Neoadjuvant DOS therapy for AEG produced high pathological response rates with an acceptable safety profile, and may be a promising treatment strategy., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: Outcomes of salvage surgery after failed definitive chemoradiation (CRT) for esophageal cancer have been well defined. However, only a few studies have focused on salvage esophagectomy for recurrent disease after CRT., Methods: In 227 patients with esophageal cancer who underwent salvage esophagectomy after definitive CRT, consisting of 116 patients who underwent esophagectomy for persistent disease (the persistent group) and 111 patients who underwent esophagectomy for recurrent disease (the recurrent group), the short- and long-term outcomes were investigated., Results: The rates of any postoperative complication were similar between the groups (49.1% in the persistent group vs. 49.5% in the recurrent group, p = 0.951), although there was a higher rate of anastomotic leakage in the recurrent group (p = 0.027). Thirty-day mortality was also similar between the groups (1.7% in the persistent group vs. 0.9% in the recurrent group, p = 0.587). The 3-year and 5-year overall survival rates were 33.7% and 28.0% in the persistent group and 48.7% and 41.7% in the recurrent group, respectively (p = 0.0175). In the recurrent group, clinically nodal status before CRT as well as pathologically nodal status and time to relapse were identified as independent prognostic factors. In the persistent group, pT and resection margin were identified as independent factors associated with survival., Conclusions: The present study showed that salvage surgery for recurrent disease can provide acceptable short- and long-term outcomes. Considering clinically and pathologically nodal status and time to relapse, adjuvant therapy might be offered for patients who underwent salvage esophagectomy for recurrent disease after definitive CRT., (© 2022. Society of Surgical Oncology.)

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most severe cancers and is characterized by chemotherapy resistance and poor prognosis associated with epithelial-mesenchymal transition (EMT). In a previous study, a low mitochondrial DNA (mtDNA) copy number was associated with poorer prognosis and induced EMT in ESCC. However, the detailed mechanism related to mtDNA copy number and EMT is unclear. The aim of this study was to clarify the mechanism by which a change in mtDNA copy number contributes to EMT and to examine treatment of chemotherapy resistance in ESCC., Methods: The association between low mtDNA copy number and chemotherapy resistance was investigated using specimens from 88 patients who underwent surgery after neoadjuvant chemotherapy. Then, the mtDNA content of human ESCC cell lines, TE8 and TE11, was depleted by knockdown of mitochondrial transcription factor A expression. The present study focused on modulation of mitochondrial membrane potential (MMP) and DNA methylation as the mechanisms by which mtDNA copy number affects EMT. mRNA and protein expression, chemotherapy sensitivity, proliferation, MMP and DNA methylation were evaluated, and in vitro and in vivo assays were conducted to clarify these mechanisms., Results: ESCC patients with decreased mtDNA copy number who underwent R0 resection after neoadjuvant chemotherapy had significantly worse pathological response and recurrence-free survival. Additionally, low mtDNA copy number was associated with resistance to chemotherapy in vitro and in vivo. mtDNA controlled MMP, and MMP depolarization induced EMT. Depletion of mtDNA and low MMP induced DNA methylation via a DNA methylation transcription factor (DNMT), and a DNMT inhibitor suppressed EMT and improved chemotherapy sensitivity in mtDNA-depleted ESCC cells, as shown by in vitro and in vivo assays., Conclusion: This study showed that decreased mtDNA copy number induced EMT via modulation of MMP and DNA methylation in ESCC. Therapeutic strategies increasing mtDNA copy number and DNMT inhibitors may be effective in preventing EMT and chemosensitivity resistance., (© 2022. The Author(s).)

Endoscopic diagnosis of the invasion depth of superficial esophageal squamous cell carcinoma (ESCC) is an important determinant of the treatment strategy. The three endoscopic imaging modalities commonly used to predict the invasion depth of superficial ESCC in Japan are non-magnifying endoscopy (non-ME), magnifying endoscopy (ME), and endoscopic ultrasonography (EUS). However, which of these three modalities is most effective remains unclear. We performed a systematic review of the literature to compare the diagnostic accuracy of the three modalities for prediction of the invasion depth of superficial ESCC. We used Medical Subject Heading terms and free keywords to search the PubMed, Cochrane Central, and Ichushi databases to identify direct comparison studies published from January 2000 to August 2020. The results of direct comparison studies were used to compare the diagnostic accuracy of each modality. The primary outcome was defined as the proportion of overdiagnosis of pT1b-SM2/3 cancers, and the main secondary outcome was the proportion of underdiagnosis of pT1b-SM2/3 cancers. Other secondary outcomes were the sensitivity and specificity values of the modalities. Four articles were finally selected for qualitative evaluation. Although ME showed no significant advantages over non-ME in terms of sensitivity and specificity, it had a slightly lower proportion of overdiagnosis. EUS had sensitivity and specificity similar to those of non-ME and ME, but EUS had a higher proportion of overdiagnosis. Non-ME and ME are useful for the diagnosis of cancer invasion depth. EUS may increase overdiagnosis, and caution is required in determining its indications., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: Ghrelin has been reported to reduce postoperative weight loss by improving appetite and food intake in patients undergoing upper gastrointestinal surgery., Objective: We aimed to investigate whether growth hormone induction, another essential effect of ghrelin, may attenuate skeletal muscle loss in patients during postoperative starvation., Methods: Esophageal cancer patients were randomized to receive a continuous intravenous infusion of high-dose ghrelin (HD; 0.5 µg/kg/h), low-dose ghrelin (LD; 0.25 µg/kg/h), or placebo for 7 days after surgery. During this period, oral feeding was not introduced but the patients received the same parenteral and enteral nutrition. We investigated the effects of ghrelin on body weight, skeletal muscle mass, nutritional status, and hormone levels., Results: Overall, 73 patients were enrolled in this study. The rate of weight loss on postoperative day (POD) 7 relative to that before surgery was significantly lower in the HD group than in the placebo group (HD vs. placebo: -0.61% vs. 1.8%, p = 0.030). The rate of muscle loss in the erector spinae muscle on POD 7 in the HD and LD groups was significantly lower than that in the placebo group (HD vs. placebo: 2.8% vs. 8.5%, p < 0.001; LD vs. placebo: 4.9% vs. 8.5%, p = 0.028). The levels of growth hormone on PODs 1, 3, and 7, and insulin-like growth factor 1 on PODs 3, 7, and 14 were significantly higher in patients who received ghrelin., Conclusion: Continuous ghrelin administration could attenuate skeletal muscle loss in esophageal cancer patients during postoperative starvation., (© 2022. Society of Surgical Oncology.)

Background: The optimal number of neoadjuvant chemotherapy (NAC) cycles remains to be established for treating oesophageal squamous cell carcinoma (ESCC). We compared two versus three courses of NAC for treating locally advanced ESCC in a multi-institutional, randomised, Phase II trial., Methods: We randomly assigned 180 patients with locally advanced ESCC at 6 institutions to either two (N = 91) or three (N = 89) courses of DCF (docetaxel 70 mg/m 2 , cisplatin 70 mg/m 2 i.v. on day 1, fluorouracil 700 mg/m 2 continuous infusion for 5 days) every 3 weeks, prior to surgery. The primary endpoint was 2-year progression-free survival (PFS) with an intention-to-treat analysis., Results: Patient background parameters were well-balanced. The R0 resection rates were 98.9 and 96.5% in the two- and three-course groups, respectively (P = 0.830). In resected cases, the two- and three-course groups had comparable pN0 rates (P = 0.225) and histological responses (P = 0.898). The 2-year PFS rate was also comparable between the two groups (71.4 vs. 71.1%, P = 0.669). Among subgroups based on baseline characteristics, only patients aged under 65 years old showed a tendency for better survival with the three-course treatment (hazard ratio = 2.612, 95% confidence interval: 1.012-7.517)., Conclusions: Two courses of a DCF regimen showed potential as an optional NAC treatment for locally advanced ESCC., Clinical Trial Registration: University Hospital Medical Information Network Clinical Trials Registry of Japan (identification number UMIN 000015788)., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: To evaluate pathological response to NAC in metastatic LNs, and assess its clinical prognostic significance in patients with EC., Summary of Background Data: The pathological response to preoperative treatment is commonly evaluated in the PT. However, LN metastases strongly correlate with systemic micro-metastases. Thus, pathological evaluation of LN response could more accurately predict prognosis in EC patients undergoing NAC before surgery., Methods: We enrolled 371 consecutive patients who underwent triplet NAC followed by surgery for EC between January 2010 and December 2016. Pathological LN regression grade was defined by the proportion of viable tumor area within the whole tumor bed area for all metastatic LNs: grade I, >50%; II, 10%-50%; III, <10%; and IV, 0%. We analyzed the correlation of grade with clinico-pathological parameters., Results: Among 319 patients with clinically positive LNs, pathological LN regression grades were I/II/III/IV in 115/51/58/95 patients, and 191 patients (59.9%) showed discordance between the PT and LN pathological regression grades. LN regression grade significantly correlated with cN positive number, ypTNM, lymphovascular invasion, and clinical/pathological PT response. Multivariate analysis for recurrence-free survival revealed that LN regression grade [hazard ratio (HR) = 2.25, P < 0.001], ypT (HR = 1.65, P = 0.005), and ypT (HR = 1.62, P = 0.004) were independent prognostic factors, but not pathological PT regression grade (P = 0.67)., Conclusions: Compared to PT response, pathological LN response better predicted long-term survival in EC patients who received NAC plus curative surgery., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: Established supportive care to reduce the toxicity of neoadjuvant chemotherapy (NAC) is lacking. This multicenter randomized study compared the administration of synbiotics combined with enteral nutrition (EN) versus that of prophylactic antibiotics as supportive care treatment for patients with esophageal cancer undergoing NAC., Methods: Patients with advanced esophageal cancer scheduled to receive NAC were randomly administered either prophylactic antibiotics (antibiotic group) or synbiotics combined with EN (Syn + EN group). The primary endpoint was the febrile neutropenia (FN) incidence during the first course, and the secondary endpoints were other adverse events, changes in intestinal environment, including fecal microbiota, organic acid concentrations, pH, and chemotherapy tolerability., Results: Eighty-one patients were enrolled. The FN incidence was nonsignificantly lower (P = 0.088) in the Syn + EN group. The incidences of grade 4 neutropenia and grades 2-4 diarrhea were significantly lower in the Syn + EN group (P = 0.014 and 0.033, respectively). Relative dose intensity was significantly higher in the Syn + EN group (92.0 ± 10.9%) than in the antibiotic group (83.2 ± 18.2%) (P = 0.01). Alpfa diversity was significantly higher in the Syn + EN group than in the antibiotic after chemotherapy (P = 0.002). The numbers of Bifidobacterium (P < 0.05), Lacticaseibacillus (P < 0.001), and Enterobacteriaceae (P < 0.001) and the concentration of acetic acid (P < 0.001) were significantly higher in the Syn + EN group than in the antibiotic group after chemotherapy. The severity of diarrhea and occurrence of FN were significantly correlated with Clostridioides difficile abundance and were significantly inversely correlated with acetic acid concentration after chemotherapy., Conclusions: Synbiotics combined with EN may be an alternative supportive care treatment to prophylactic antibiotics in patients with cancer undergoing toxic chemotherapy (https://jrct.niph.go.jp; jRCTs051180153)., Competing Interests: Conflicts of interest The authors declare no competing interests., (Copyright © 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Purpose: To evaluate if nutritional supplements can attenuate postoperative catabolism in esophageal cancer patients after radical esophagectomy., Methods: We analyzed data prospectively from 30 patients who underwent curative esophagectomy for esophageal cancer between August and December, 2019. We compared postoperative nitrogen balance and changes in body composition between patients who received protein-enhanced enteral feeds (PEF) or other enteral feeds (OF)., Results: Postoperative enteral feeding was administered safely to all patients. The average nitrogen balance was significantly higher in the PEF group than in the OF group on postoperative days (PODs) 3 (2.41 vs. - 1.50 g, P = 0.002), 4 (3.74 vs. - 0.08 g, P = 0.006), and 5 (3.27 vs. 0.11 g, P = 0.031). The cumulative nitrogen balance in the 7 days after surgery was significantly higher in the PEF group than in the OF group (6.12 vs. - 8.40 g, P = 0.025). The bodyweight loss and lean body mass loss on POD 14 were equivalent in the two groups (bodyweight loss 3.70 vs. 2.87%, P = 0.25; lean body mass loss, 4.34 vs. 1.91%, P = 0.33)., Conclusions: PEF improved the postoperative nitrogen balance significantly in patients who underwent esophagectomy., (© 2021. Springer Nature Singapore Pte Ltd.)

Background: First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma., Methods: In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients)., Results: A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone., Conclusions: Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.)., (Copyright © 2022 Massachusetts Medical Society.)

Alcohol consumption is a major risk factor for esophageal cancer. In Asia, heavy drinkers are considered to have a higher risk of esophageal cancer than nondrinkers and light drinkers. However, no study has shown an association between alcohol reduction and the morbidity of esophageal cancer in Asian heavy drinkers. Therefore, this study investigated the significance of reducing alcohol consumption to prevent esophageal cancer in Asian heavy drinkers by conducting a systematic review and meta-analysis. The MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases were searched from January 1995 to December 2020. The hazard ratio (HR) and 95% confidence interval (CI) were calculated using a random-effects model. I 2 statistics were used to detect heterogeneity. This study included 21 articles in the qualitative synthesis. Light drinkers and heavy drinkers were categorized based on alcohol consumption amount as ≤ 25 ethanol g/day and ≥ 66 ethanol g/day, respectively, as described in many previous studies, and five cohort studies were eligible for this meta-analysis. The HR of esophageal cancer among heavy drinkers versus nondrinkers was 4.18 (95% CI 2.34-7.47, I 2  = 74%). On the other hand, the HR of esophageal cancer among light drinkers was 1.82 compared with nondrinkers (95% CI 1.57-2.10, I 2  = 0%). Heavy drinkers have a higher esophageal cancer incidence than light drinkers and nondrinker. It is possible that alcohol reduction may decrease the risk of esophageal cancer in Asian heavy drinkers., (© 2021. The Japan Esophageal Society.)

Background: Various functions in elderly patients with esophageal cancer deteriorate easily and their quality of life can be adversely affected by treatment. The age groups covered in previous studies are wide, and the impact on the elderly individuals is unknown. This study examined changes in quality of life scores after preoperative chemotherapy to clarify aspects of physical, psychological, and social quality of life in elderly patients with esophageal cancer., Methods: Thirty-six patients aged over 65 years, who were scheduled to undergo preoperative chemotherapy for esophageal cancer surgery, were enrolled. The survey questionnaire comprised the EORTC QLQ-C30 Japanese Language Version, EORTC QLQ-OES 18 Japanese Language Version, and G8. The surveys were conducted before chemotherapy (pre-CT) and after chemotherapy (post-CT)., Results: In the functional scale of QLQ-C 30, physical functioning decreased significantly, while emotional functioning increased significantly post-CT (p = 0.021, p = 0.030, respectively). Global health status was not changed. In QLQ-OES18, the mean symptom scale score decreased significantly for dysphagia, trouble swallowing saliva, choking, eating, reflux, and pain post-CT (p = 0.014, p = 0.034, p = 0.033, p = 0.022, p = 0.026, p = 0.016, respectively). The mean G8 score decreased significantly from 11.7 to 10.7 (p = 0.022) post-CT, but the proportion of patients with dysfunction decreased., Conclusions: Quality of life scores of elderly patients with esophageal cancer who received preoperative chemotherapy decreased in terms of physical function but improved in terms of esophageal cancer symptoms and mental function. Our results suggest that alleviation of symptoms contributed to the improvements in mental health., (© 2021. The Japan Esophageal Society.)

The consumption of fruit and vegetables was reported to be associated with a reduced risk of esophageal cancer (EC) in many studies of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) from different regions worldwide. Therefore, to provide precise information to reduce the risk of EC in Asia, we performed a systematic review and meta-analysis of studies conducted in the Asian region about fruit and vegetable consumption and the risk of EC. We searched the MEDLINE (PubMed) and ICHUSHI (Japana Centra Revuo Medicina) databases from January 2010 to December 2020. The summary relative risk (SRR) and 95% CI were calculated using a random-effects model. In addition, I 2 statistics were used to detect heterogeneity. Twenty-two studies were eligible for meta-analysis (16 case-control studies and 6 cohort studies). The SRR for the lowest versus highest fruit consumption was 0.64 (95% CI 0.53-0.77, I 2  = 82%). That for the lowest versus highest vegetable consumption was 0.61 (95% CI 0.50-0.74, I 2  = 81%). Based on subgroup analysis, a validated Food Frequency Questionnaire (FFQ) was significantly associated (SRR for fruit: 0.54; 95% CI 0.40-0.74, SRR for vegetable: 0.60; 95% CI 0.48-0.76) with low heterogeneity (I 2  = 48% for fruit, I 2  = 0% for vegetables). Egger's funnel plot asymmetry test demonstrated publication bias (P < 0.001 for fruit, P = 0.009 for vegetables). Fruit and vegetable consumption might be associated with a lower risk of EC in the Asian region. However, further substantial prospective studies with a validated FFQ and well-controlled important confounding factors are required to confirm the association., (© 2021. The Japan Esophageal Society.)

Background: Mutations in p53, identified in 90% of oesophageal squamous cell carcinoma (ESCC), are associated with unfavourable prognosis and chemo-resistance. APR-246 induces apoptosis by restoring transcriptional ability of mutant p53, and may be a promising therapeutic agent to overcome chemo-resistance in ESCC., Methods: In ESCC cell lines differing in p53 status, we performed in vitro cell viability and apoptosis assays, evaluated reactive oxygen species (ROS) generation, and assessed signal changes by western blot after APR-246 administration with/without chemo-agent. Antitumour effects and signal changes were evaluated in in vivo experiments using xenograft and patient-derived xenograft (PDX) mouse models., Results: APR-246 administration induced significant apoptosis by upregulating p73 and Noxa via ROS induction in ESCC cell lines harbouring p53 missense mutations. Moreover, APR-246 plus chemotherapy exerted combined antitumour effects in ESCC with p53 missense mutations. This effect was also mediated through enhanced ROS activity, leading to massive apoptosis via upregulation of p73 and Noxa. These findings were confirmed by xenograft and PDX models with p53 mutant ESCC., Conclusion: APR-246 strongly induced apoptosis by inducing ROS activity and p73-Noxa signalling, specifically in ESCC with p53 missense mutation. This antitumour effect was further enhanced by combination with 5-FU, which we first confirmed in ESCC preclinical model., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The Charlson Comorbidity Index (CCI), an indicator that objectively quantifies comorbidities, reduces nutritional status; however, the impact of the CCI on the postoperative nutrition indexes of patients with esophageal cancer remains unclear., Methods: In total, 336 patients with esophageal cancer who underwent surgery between January 2011 and April 2017 were included in this study. We investigated the relationship between the CCI and postoperative nutrition indexes., Results: Patients were divided into two groups: CCI ≤1 (low CCI group) and CCI ≥2 (high CCI group). A high CCI was significantly associated with shortened overall survival (OS; 3-year OS rate of 77.9% in the low CCI group versus 59.7% in the high CCI group; p = 0.008). Nutritional indexes, such as the Prognostic Nutritional Index (PNI), at 1 month after esophagectomy were significantly lower in the high CCI group than in the low CCI group (p = 0.031); however, the PNI at 6 months after surgery was similar between the high and low CCI groups. Multivariate analysis identified high CCI as an independent risk factor associated with PNI <45 in esophageal cancer patients at 1 month after esophagectomy (p = 0.047)., Conclusion: This study showed that CCI ≥2 was significantly associated with poor PNI at 1 month after surgery for esophageal cancer, indicating that it is necessary to administer effective nutritional interventions for patients with postoperative malnutrition, especially those with multiple comorbidities., (© 2021. Society of Surgical Oncology.)

Background: Sarcopenia was previously linked to clinical outcomes for several cancer types, including esophageal cancer (EC), but most studies only measured the quantity of skeletal muscle mass. We aim to assess the clinical significance of evaluating the quantity and quality of skeletal muscle in patients with EC who underwent neoadjuvant chemotherapy (NAC) followed by esophagectomy., Methods: We included 333 consecutive patients with EC who underwent NAC followed by esophagectomy. The psoas muscle index (PMI) and intracellular muscle adipose tissue content (IMAC) were measured by computed tomography. We defined low PMI combined with high IMAC as severe sarcopenia, and assessed its impact on clinical outcomes., Results: Thirty-seven patients (11.1%) had severe sarcopenia. Compared with patients without severe sarcopenia, those with severe sarcopenia showed a significantly worse NAC response rate (54.1% vs 74.7%; P = 0.008), worse pathological response rate (24.3% vs 40.2%, P = 0.061), higher morbidity rate (67.6% vs 38.5%; P = 0.001), particularly for pneumonia (32.4% vs 14.9% P = 0.007) and expectoration disorder (37.8% vs 13.5% P < 0.001), and unfavorable survival (3-year overall survival rate: 54.1% vs 66.6% P = 0.027). Multivariable analysis of overall survival showed that severe sarcopenia (HR 1.68, P = 0.025) and cT (HR 1.52, P = 0.032) were independent prognostic factors of poor outcome., Conclusions: PMI combined with IMAC represents a new criterion for sarcopenia that might be useful for predicting NAC response, postoperative complications, and long-term survival in patients with EC undergoing multidisciplinary treatments., (© 2021. Society of Surgical Oncology.)