Clinicopathological, molecular, and prognostic features of colorectal carcinomas with KRAS c.34G>T (p.G12C) mutation.

Evidence indicates that combinations of anti-EGFR antibodies and KRAS p.G12C (c.34G>T) inhibitors can be an effective treatment strategy for advanced colorectal cancer. We hypothesized that KRAS c.34G>T (p.G12C)-mutated colorectal carcinoma might be a distinct tumor subtype. We utilized a prospective cohort incident tumor biobank (including 1347 colorectal carcinomas) and detected KRAS c.34G>T (p.G12C) mutation in 43 cases (3.2%) and other KRAS mutations (in codon 12, 13, 61, or 146) in 467 cases (35%). The CpG island methylator phenotype (CIMP)-low prevalence was similarly higher in KRAS c.34G>T mutants (52%) and other KRAS mutants (49%) than in KRAS-wild-type tumors (31%). KRAS c.34G>T mutants showed higher CIMP-high prevalence (14%) and lower CIMP-negative prevalence (33%) compared with other KRAS mutants (6% and 45%, respectively; p = 0.0036). Similar to other KRAS mutants, KRAS c.34G>T-mutated tumors were associated with cecal location, non-microsatellite instability (MSI)-high status, BRAF wild type, and PIK3CA mutation when compared with KRAS-wild-type tumors. Compared with BRAF-mutated tumors, KRAS c.34G>T mutants showed more frequent LINE-1 hypomethylation, a biomarker for early-onset colorectal carcinoma. KRAS c.34G>T mutants were not associated with other features, including the tumor tissue abundance of Fusobacterium nucleatum (F. animalis), pks+ Escherichia coli, Bifidobacterium, or (enterotoxigenic) Bacteroides fragilis. Among 1122 BRAF-wild-type colorectal carcinomas, compared with KRAS-wild-type tumors, multivariable-adjusted colorectal cancer-specific mortality hazard ratios (95% confidence interval) were 1.82 (1.05-3.17) in KRAS c.34G>T (p.G12C)-mutated tumors (p = 0.035) and 1.57 (1.22-2.02) in other KRAS-mutated tumors (p = 0.0004). Our study provides novel evidence for clinical and tumor characteristics of KRAS c.34G>T (p.G12C)-mutated colorectal carcinoma.

Minimally Invasive Esophagectomy Provides Better Short- and Long-Term Outcomes Than Open Esophagectomy in Locally Advanced Esophageal Cancer.

BACKGROUND: Minimally invasive esophagectomy (MIE) has been increasingly performed for locally advanced esophageal cancer in place of open transthoracic esophagectomy (OE). This study explored the significance of MIE for esophageal squamous cell carcinoma (ESCC), focusing mainly on the depth of primary esophageal tumors. METHODS: This study retrospectively assessed short- and long-term outcomes of patients who underwent esophagectomy for ESCC from 2005 through 2021. The inverse probability of the treatment-weighting (IPTW) method was used to compare the outcomes between OE and MIE. The outcomes also were evaluated in the subgroups stratified by cT category. RESULTS: Among 1117 patients, 447 (40%) underwent OE and 670 (60%) underwent MIE. After IPTW adjustment, the incidence of any postoperative complications was significantly higher in the OE group than in the MIE group (60.8% vs 53.7%; p = 0.032), whereas the R0 resection rate was significantly higher in the MIE group (98.6% vs 92.7%; p < 0.001). The MIE group showed better 3 year overall and cancer-specific survival than the OE group (p < 0.001). The incidence of locoregional recurrence within the surgical field was significantly more frequent in the OE group (p < 0.001). In the subgroup analysis stratified by cT category, the R0 resection rate was significantly higher and the incidence of locoregional recurrence was lower in the MIE group among the patients with cT3-4 tumors. In the patients with cT1-2 tumors, MIE showed no significant benefit over OE. CONCLUSIONS: For the patients with cT3-4 tumors, MIE showed fewer postoperative complications, better locoregional control, and better prognosis than OE. Compared with OE, MIE is beneficial, especially for locally advanced ESCC.

Development and Validation Study of the Prognostic Impact of Deep Learning-Determined Myxoid Stroma After Neoadjuvant Chemotherapy in Patients with Esophageal Squamous Cell Carcinoma.

PURPOSE: This study was designed to investigate the prognostic significance of artificial intelligence (AI)-based quantification of myxoid stroma in patients undergoing esophageal squamous cell carcinoma (ESCC) surgery after neoadjuvant chemotherapy (NAC) and to verify its significance in an independent validation cohort from another hospital. METHODS: We evaluated two datasets of patients with pathological stage II or III ESCC who underwent surgery after NAC. Cohort 1 consisted of 85 patients who underwent R0 surgery for the primary tumor after NAC. Cohort 2, the validation cohort, consisted of 80 patients who received same treatments in another hospital. AI-based myxoid stroma was evaluated in resected specimens, and its area was categorized by using the receiver operating characteristic curve for overall survival (OS) of cohort 1. RESULTS: The F1 scores, which are the degree of agreement between the automatically detected myxoid stroma and manual annotations, were 0.83 and 0.79 for cohorts 1 and 2. The myxoid stroma-high group had a significantly poorer prognosis than the myxoid stroma-low group in terms of OS, disease-specific survival (DSS), and recurrence-free survival (RFS) in cohort 1. Comparable results were observed in cohort 2, where OS, DSS, and RFS were significantly affected by myxoid stroma. Multivariate analysis for RFS revealed that AI-determined myxoid stroma-high was one of the independent prognostic factors in cohort 1 (hazard ratio [HR] 1.97, p = 0.037) and cohort 2 (HR 4.45, p < 0.001). CONCLUSIONS: AI-determined myxoid stroma may be a novel and useful prognostic factor for patients with pathological stage II or III ESCC after NAC.

Anatomical factor associated with thoracic procedural difficulty in robot-assisted minimally invasive esophagectomy.

BACKGROUND: Robotic surgical systems with full articulation of instruments, tremor filtering, and motion scaling can potentially overcome the procedural difficulties in endoscopic surgeries. However, whether robot-assisted minimally invasive esophagectomy (RAMIE) can overcome anatomical difficulties during thoracoscopic esophagectomy remains unclear. This study aimed to clarify the anatomical and clinical factors that influence the difficulty of RAMIE in the thoracic region. METHODS: Forty-five patients who underwent curative-intent RAMIE with upper mediastinal lymph node dissection for esophageal cancer were included. Using preoperative computed tomography images, we calculated previously reported anatomical indices to assess the upper mediastinal narrowness and vertebral body projections in the middle thoracic region. The factors influencing thoracic operative time were then investigated. RESULTS: During the thoracic procedure, the median operative time was 215 (124-367) min and the median blood loss was 20 (5-190) mL. Postoperatively, pneumonia, anastomotic leakage, and recurrent laryngeal nerve palsy occurred in 17.8%, 2.2%, and 6.7% of the patients, respectively. The multiple linear regression model revealed that a narrow upper mediastinum and greater blood loss during the thoracic procedure were significant factors associated with a prolonged thoracic operative time (P = 0.025 and P < 0.001, respectively). Upper mediastinal narrowing was not associated with postoperative complications. CONCLUSIONS: A narrow upper mediastinum was significantly associated with a prolonged thoracic operative time in patients with RAMIE.

Gastric conduit reconstruction after esophagectomy.

A high risk of complications still accompanies gastric conduit reconstruction after esophagectomy. In this narrative review, we summarize the technological progress and the problems of gastric conduit reconstruction after esophagectomy. Several types of gastric conduits exist, including the whole stomach and the narrow gastric tube. The clinical outcomes are similar between the two types of conduits. Sufficient blood supply to the conduit is mandatory for a successful esophageal reconstruction. Recently, due to the availability of equipment and its convenience, indocyanine green angiography has been rapidly spreading. When the blood perfusion of the planning anastomotic site is insufficient, several techniques, such as the Kocher maneuver, pedunculated gastric tube with duodenal transection, and additional microvascular anastomosis, exist to decrease the risk of anastomotic failure. There are two different anastomotic sites, cervical and thoracic, and mainly two reconstructive routes, retrosternal and posterior mediastinal routes. Meta-analyses showed no significant difference in outcomes between the anastomotic sites as well as the reconstructive routes. Anastomotic techniques include hand-sewn, circular, and linear stapling. Anastomoses using linear stapling is advantageous in decreasing anastomosis-related complications. Arteriosclerosis and poorly controlled diabetes are the risk factors for anastomotic leakage, while a narrow upper mediastinal space and a damaged stomach predict leakage. Although standardization among the institutional team members is essential to decrease anastomotic complications, surgeons should learn several technical options for predictable or unpredictable intraoperative situations.

Quantitative Evaluation of Periodontitis for Predicting the Occurrence of Postoperative Pneumonia After Oncologic Esophagectomy.

BACKGROUND: Periodontitis is a biofilm-associated inflammatory periodontal disease associated with postoperative complications after esophagectomy. However, few studies have evaluated the inflammatory burden posed by periodontitis quantitively for patients undergoing oncologic esophagectomy. This study aimed to clarify the relationship between periodontitis and postoperative pneumonia using periodontal inflammatory surface area (PISA). METHODS: The study analyzed 251 patients who underwent esophagectomy for esophageal cancer. The patients were classified into low-PISA and high-PISA groups according to preoperative PISA, and the relationship between the occurrence and severity of postoperative pneumonia was investigated. RESULTS: The high-PISA group (n = 69) included more males (P < 0.001) and patients with poor performance status (P < 0.024). Postoperative pneumonia occurred more frequently in the high-PISA group than in the low-PISA group (31.9 % vs. 15.9 %; P = 0.008), whereas the incidences of other complications did not differ significantly. In addition, the incidence of severe pneumonia was significantly higher in the high-PISA group (7.2 % vs. 1.6 %; P = 0.038). In the multivariable analysis for adjustment of preoperative confounders, age older than 70 years (odds ratio [OR], 2.62; P = 0.006), high PISA (OR, 2.45; P = 0.012), and smoking history (OR, 2.78; P = 0.006) were the independent variables predicting postoperative pneumonia. CONCLUSION: Preoperative higher PISA was significantly associated with the occurrence of overall and severe postoperative pneumonia. The quantitative evaluation of periodontitis using PISA is a useful measure for predicting postoperative pneumonia, and intensive periodontal intervention may contribute to decreasing postoperative pneumonia.

Genomic features of Helicobacter pylori-naïve diffuse-type gastric cancer.

Helicobacter pylori (HP) is a major etiologic driver of diffuse-type gastric cancer (DGC). However, improvements in hygiene have led to an increase in the prevalence of HP-naïve DGC; that is, DGC that occurs independent of HP. Although multiple genomic cohort studies for gastric cancer have been conducted, including studies for DGC, distinctive genomic differences between HP-exposed and HP-naïve DGC remain largely unknown. Here, we employed exome and RNA sequencing with immunohistochemical analyses to perform binary comparisons between 36 HP-exposed and 27 HP-naïve DGCs from sporadic, early-stage, and intramucosal or submucosal tumor samples. Among the samples, 33 HP-exposed and 17 HP-naïve samples had been preserved as fresh-frozen samples. HP infection status was determined using stringent criteria. HP-exposed DGCs exhibited an increased single nucleotide variant burden (HP-exposed DGCs; 1.97 [0.48-7.19] and HP-naïve DGCs; 1.09 [0.38-3.68] per megabase; p = 0.0003) and a higher prevalence of chromosome arm-level aneuploidies (p < 0.0001). CDH1 was mutated at similar frequencies in both groups, whereas the RHOA-ARHGAP pathway misregulation was exclusive to HP-exposed DGCs (p = 0.0167). HP-exposed DGCs showed gains in chromosome arms 8p/8q (p < 0.0001), 7p (p = 0.0035), and 7q (p = 0.0354), and losses in 16q (p = 0.0167). Immunohistochemical analyses revealed a higher expression of intestinal markers such as CD10 (p < 0.0001) and CDX2 (p = 0.0002) and a lower expression of the gastric marker, MUC5AC (p = 0.0305) among HP-exposed DGCs. HP-naïve DGCs, on the other hand, had a purely gastric marker phenotype. This work reveals that HP-naïve and HP-exposed DGCs develop along different molecular pathways, which provide a basis for early detection strategies in high incidence settings. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

McKeown Versus Ivor-Lewis Esophagectomy for Patients with a History of Total Pharyngolaryngectomy: A Comparison Study.

BACKGROUND: Oncologic esophagectomy in patients with a history of total pharyngolaryngectomy (TPL) is challenging. There are two different esophagectomy procedures: total esophagectomy with cervical anastomosis (McKeown) and subtotal esophagectomy with intrathoracic anastomosis (Ivor-Lewis). Differences in outcomes between McKeown and Ivor-Lewis esophagectomies for patients with this history remain unclear. METHODS: We retrospectively reviewed 36 patients with a history of TPL who underwent oncologic esophagectomy and compared the clinical outcomes between the procedures. RESULTS: Twelve (33.3%) and 24 (66.7%) patients underwent McKeown and Ivor-Lewis esophagectomies, respectively. McKeown esophagectomy was more frequently performed for the supracarinal tumors (P = 0.002). Other baseline characteristics, including the history of radiation therapy, were comparable between the groups. Postoperatively, the incidences of pneumonia and anastomotic leakage were higher in the McKeown group than in the Ivor-Lewis group (P = 0.029 and P < 0.001, respectively). Neither tracheal necrosis nor remnant esophageal necrosis was observed. The overall and recurrence-free survival rates were comparable between the groups (P = 0.494 and P = 0.813, respectively). CONCLUSIONS: When performing esophagectomy for patients with a history of TPL, if it is oncologically acceptable and technically available, Ivor-Lewis is preferable over McKeown esophagectomy for avoiding postoperative complications.

Prognostic significance of circulating basophil counts in patients who underwent esophagectomy for esophageal cancer.

PURPOSE: Recent reports have suggested that basophils influence allergic reactions and tumor immunity. In this study, we aimed to elucidate the association between preoperative circulating basophil (CB) counts and the outcomes of patients who underwent esophagectomy for esophageal cancer. METHODS: A total of 783 consecutive patients who underwent esophagectomy for esophageal cancer were eligible. The clinicopathological factors and prognoses were compared between the groups stratified by the preoperative counts of CB. RESULTS: There were more advanced clinical T and N stages in the low CB group than in the high CB group (P = 0.01 and = 0.04, respectively). The incidences of postoperative complications were comparable between the groups. The low CB count was associated with unfavorable overall and recurrence-free survivals (P = 0.04 and 0.01, respectively). In the multivariate analysis, low CB count was one of the independent prognostic factors for poor recurrence-free survival (HR 1.33; 95% CI 1.04-1.70; P = 0.02). In addition, hematogenous recurrence occurred more frequently in the low CB group than in the high CB group (57.6% vs. 41.4%, P = 0.04). CONCLUSION: A preoperative low CB count was an unfavorable prognosticator in patients who underwent esophagectomy for esophageal cancer.

Fecal Microbes Associated with the Outcomes After Esophagectomy in Patients with Esophageal Cancer.

BACKGROUND: Although accumulating evidence suggests that an imbalanced gut microbiota leads to cancer progression, few studies demonstrated the implication in patients who underwent oncologic esophagectomy. This study aimed to elucidate the association between gut microbes and the outcomes after oncologic esophagectomy, as well as the host's inflammatory/nutritional status. METHODS: Overall, 783 consecutive patients who underwent oncologic esophagectomy were eligible. We investigated the microbiota detected by fecal culture tests and then assessed the association between the gut microbiota and patient characteristics, short-term outcomes, and long-term survival. RESULTS: Seventeen different species could be cultivated. We comprehensively examined the impact of each detected microbe on survival. The presence of Bacillus species (Bacillus sp.; 26.8%) was associated with favorable prognosis on overall and cancer-specific survival (p = 0.02 and 0.02, respectively). Conversely, the presence of Proteus mirabilis (P. mirabilis; 3.4%) was associated with unfavorable overall and recurrence-free survivals (p = 0.02 and < 0.01, respectively). Multivariate analysis showed that the presence of P. mirabilis was one of the independent prognostic factors for poor recurrence-free survival (p < 0.01). Patients with Bacillus sp. had lower modified Glasgow prognostic score and better response to preoperative treatment than those without (p = 0.01 and 0.03, respectively). Meanwhile, patients with P. mirabilis were significantly associated with higher systemic inflammation scores and increased postoperative pneumonia incidence than those without (p = 0.01 and 0.02, respectively). CONCLUSIONS: Preoperative fecal microbiota was associated with the host's inflammatory and nutritional status and may influence the outcomes after oncologic esophagectomy.

Prediction of tissue origin of adenocarcinomas in the esophagogastric junction by DNA methylation.

BACKGROUND: Prediction of tissue origin of esophagogastric junction (EGJ) adenocarcinomas can be important for therapeutic decision, but no molecular marker is available. Here, we aimed to develop such a marker taking advantage of tissue-specific profiles of DNA methylation. METHODS: DNA methylation profiles of gastric adenocarcinomas (GACs) were obtained by an Infinium HumanMethylation450 BeadChip array, and those of esophageal adenocarcinoma (EACs) were obtained from the TCGA database. DNA from formalin-fixed paraffin-embedded (FFPE) samples was analyzed by bisulfite pyrosequencing. RESULTS: In the screening set, 51 of 145,841 CpG sites in CpG islands were methylated at significantly higher levels in 30 GACs compared to those in 30 EACs. Among them, SLC46A3 and cg09177106 were unmethylated in all the 30 EACs. Predictive powers of these two markers were successfully confirmed in an independent validation set (18 GACs and 18 EACs) (SLC46A3, sensitivity = 77.8%, specificity = 100%; cg09177106, sensitivity = 83.3%, specificity = 94.4%), and could be applied to FFPE samples (37 GACs and 18 EACs) (SLC46A3, P = 0.0001; cg09177106, P = 0.0028). On the other hand, EAC-specific markers informative in the FFPE samples could not be isolated. Using these GAC-specific markers, nine of 46 (19.6%) TCGA EGJ adenocarcinomas were predicted to be GACs. CONCLUSIONS: Two GAC-specific markers, SLC46A3 and cg09177106, had a high specificity for identifying the tissue origin of EGJ adenocarcinoma.

Is Prophylactic Cervical Drainage Effective in Patients Undergoing McKeown Esophagectomy Reconstructed Through the Retrosternal Route with Two-Field Lymphadenectomy?

BACKGROUND: McKeown esophagectomy with two-field lymphadenectomy is the treatment of choice for oncologic esophagectomy. A cervical drain is placed in cases after modern two-field lymph node dissection (M2FD) to provide information on anastomotic leakage. However, the necessity of prophylactic cervical drainage during surgery remains unknown. This study aimed to clarify the clinical significance of cervical drainage in patients who underwent McKeown esophagectomy with M2FD. METHODS: A total of 293 patients underwent McKeown surgery with two-field lymphadenectomy at our institute between January 2013 and December 2019. We compared the day of drain removal, amount of drainage volume, and the appearance of drainage fluid between patients with and without anastomotic leakage. RESULTS: McKeown esophagectomy reconstructed through the retrosternal route is 203 patients (69.3%) of all. Nineteen patients (6.5%) experienced anastomotic leakage. The amount of cervical drain discharge was comparable between patients with and without anastomotic leakage. In addition, no purulent or salivary discharge was observed in patients with anastomotic leakage. There was no difference in the median day of drain removal between the groups. The initial clinical findings for the diagnosis of anastomotic leakage were surgical site infection in 10 (52.6%), fever in 5 (26.3%), prolonged inflammation in a blood test in 3 (15.8%), and bloody discharge from the chest tube in 1 (5.3%). There was no mortality due to any cause. CONCLUSION: A prophylactic cervical drain may not be mandatory in patients with esophageal cancer undergoing McKeown esophagectomy reconstructed through the retrosternal route with two-field lymphadenectomy.

C-reactive protein to prealbumin ratio: a useful inflammatory and nutritional index for predicting prognosis after curative resection in esophageal squamous cell carcinoma patients.

PURPOSE: Although C-reactive protein to prealbumin ratio (CPR) can predict the outcomes of several types of cancer surgeries, little is known about the implication of CPR in patients undergoing esophagectomy for esophageal squamous cell carcinoma (ESCC). METHODS: Between 2009 and 2018, 682 consecutive ESCC patients who underwent curative esophagectomy were enrolled. The clinicopathological factors and prognoses were compared between the groups stratified by preoperative CPR levels. A logistic regression model was used to determine the risk factors of postoperative pneumonia. Survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model was used to elucidate prognostic factors. RESULTS: There were more elderly patients, more males, and more advanced clinical T and N categories in the high CPR group than in the low CPR group. Also, the incidence of postoperative pneumonia was significantly higher in the high CPR group than in the low CPR group (32.4% vs. 20.3%, p < 0.01). In multivariate analyses, high CPR was one of the independent predictive factors for postoperative pneumonia (OR, 1.71; 95% CI, 1.15-2.54; p < 0.03). Moreover, high CPR was an independent prognostic factor for overall, cancer-specific, and recurrence-free survivals (HR 1.62; 95% CI 1.18-2.23; p < 0.01, HR 1.57; 95% CI 1.08-2.32; p = 0.02, HR 1.42; 95% CI 1.06-1.90; p = 0.02). CONCLUSION: Preoperative CPR was found to be a useful inflammatory and nutritional indicator for predicting the occurrence of pneumonia and prognosis in patients with ESCC undergoing esophagectomy.

Long-Term Insufficiency of Oral Intake after Esophagectomy: Who Needs Intense Nutritional Support after Esophagectomy?

BACKGROUND: Patients with esophageal cancer are at a high risk of malnutrition after esophagectomy, and nutritional support may at times be required for several months following surgery. In this study, we aimed to clarify the clinical features and preoperative risk factors of patients with long-term insufficiency of oral intake after esophagectomy by evaluating the duration of feeding enterostomy placement. METHODS: A total of 306 patients who underwent esophagectomy, reconstruction with gastric conduit, and feeding enterostomy creation were retrospectively reviewed. We analyzed the clinical features and preoperative risk factors for long-term placement of feeding enterostomy. RESULTS: The feeding enterostomy tube was removed less than 90 days after esophagectomy in 234 patients (76.5%) (short group), whereas 72 patients still needed enteral nutrition after 90 days (23.5%; long group). Although severe malnutrition was observed more frequently in the long group compared with the short group (p = 0.021), overall survival time was comparable between the groups (p = 0.239). Multivariate analysis revealed that higher age (odds ratio [OR] 1.04; 95% confidence interval [CI], 1.01-1.07; p = 0.021), poor performance status (OR 2.94; 95% CI, 1.10-7.87; p = 0.032), and lower preoperative body weight (BW) (OR 0.96; 95% CI, 0.94-0.99; p = 0.009) were the independent variables predicting the long-time placement of feeding enterostomy. CONCLUSION: Nutritional support via feeding enterostomy for more than 90 days after esophagectomy was required in 23.5% of patients. The elderly, poor performance status, and lower BW were the independent preoperative factors for predicting the long-term placement of feeding enterostomy.

Current status of robot-assisted minimally invasive esophagectomy: what is the real benefit?

Robot-assisted minimally invasive esophagectomy (RAMIE) for esophageal cancer has been performed increasingly frequently over the last few years. Robotic systems with articulated devices and tremor filtration allow surgeons to perform such procedures more meticulously than by hand. The feasibility of RAMIE has been demonstrated in several retrospective comparative studies, which showed similar short-term outcomes to conventional minimally invasive esophagectomy (cMIE). Considering the number of harvested lymph nodes, RAMIE may be superior to cMIE in terms of left upper mediastinal lymph node dissection. However, whether or not the addition of a robotic system to cMIE can help improve perioperative and oncological outcomes remains unclear. Given the lack of established evidence from randomized controlled trials, we must await the results of ongoing studies to reach any meaningful conclusions. Further advancements in robotic platforms, as well as the reduction in medical expenses, will be essential to demonstrate the real benefit of RAMIE.

Treatment strategies and outcomes for elderly patients with locally advanced squamous cell carcinoma of the esophagus.

PURPOSE: A multidisciplinary treatment strategy for locally advanced esophageal squamous cell carcinoma (ESCC) is required to achieve prolonged survival. We aimed to clarify the differences in treatment strategies for locally advanced ESCC and the outcomes of elderly (aged ≥ 75 years) vs. younger patients (aged < 75 years). METHODS: We compared the treatment strategy selection and the outcomes of 40 elderly and 160 younger patients with cStage II/III ESCC diagnosed between January, 2014 and December, 2016. RESULTS: Nineteen (47.5%) of the elderly patients and 144 (90.0%) of the younger patients underwent esophagectomy and 9 (22.5%) of the elderly patients and 131 (81.9%) of the younger patients received neoadjuvant chemotherapy. Ivor-Lewis or transhiatal esophagectomy was performed more frequently in the elderly group than in the younger group (P = 0.0096). The survival rate after esophagectomy was higher in the younger group than in the elderly group. The overall survival rate of the elderly patients who underwent esophagectomy was significantly higher than that in those who did not. CONCLUSIONS: Esophagectomy is a practical choice for elderly patients with locally advanced ESCC, although reduced treatment intensity may impact long-term survival.

Clinical features and risk factors for early recurrence after esophagectomy following neoadjuvant chemotherapy for esophageal cancer.

PURPOSE: The purpose of this study was to clarify the clinical features and outcomes of patients with recurrence after esophagectomy following neoadjuvant chemotherapy (NAC) related to the timing of recurrence. METHODS: We reviewed 240 consecutive patients who underwent NAC followed by esophagectomy for clinical stage II/III esophageal squamous cell carcinoma between 2009 and 2014. We compared the clinical features and survival after recurrence among groups of patients stratified by the timing of recurrence diagnosis and identified the risk factors for early recurrence (ER). RESULTS: Recurrence was identified within 1 year in 61 patients and after 1 year in 23 patients. Significant differences were observed between the patients with recurrence within 1 year (early recurrence; ER) and those with recurrence after 1 year (late recurrence; LR). The ER patients had more advanced tumors and higher pretreatment serum squamous cell antigen (SCC-Ag) levels and less experienced downstaging than patients without recurrence (no recurrence; NR). Overall survival was significantly worse for the ER patients than for the LR patients. Multivariate analysis revealed that cN2-3, increased serum SCC-Ag levels, and clinical response to NAC were independent predictors of ER. CONCLUSION: The ER patients had distinctive clinical features from the LR and NR patients. Extensive lymph node metastasis, an elevated SCC-Ag, and inadequate response to NAC were identified as predictors of ER.

Immunogenic characteristics of microsatellite instability-low esophagogastric junction adenocarcinoma based on clinicopathological, molecular, immunological and survival analyses.

Microsatellite instability (MSI) is categorized by mutation frequency: high MSI (MSI-H), low MSI (MSI-L) and microsatellite stable (MSS). MSI-H tumors have a distinct immunogenic phenotype, with immunotherapies using checkpoint inhibitors already approved for the treatment of MSI-H gastroesophageal adenocarcinoma (GEA); this is not observed for MSI-L or MSS. Here, we tested the hypothesis that MSI-L tumors are also a distinct phenotype and potentially immunogenic. MSI-PCR assays (BAT25, BAT26, BAT40, D2S123, D5S346 and D17S250) were performed on 363 Epstein-Barr virus-negative, surgically resected esophagogastric junction (EGJ) adenocarcinoma samples. Tumors were characterized as MSI-H (≥2 markers), MSI-L (1 marker) or MSS (0 markers). CD8+ cell counts, PD-L1 and HER2 expression levels, TP53 mutations, epigenetic alterations and prognostic significance were also examined. All pathological and molecular experiments were conducted using serial, whole-tumor sections of chemo-naïve surgical specimens. MSI-H and MSI-L were assigned to 28 (7.7%) and 24 (6.6%) cases, respectively. Compared to MSS cases, MSI-L cases had significantly higher intratumoral CD8+ cell infiltration (P = .048) and favorable EGJ cancer-specific survival (multivariate hazard ratio = 0.35, 95% CI, 0.12-0.82; P = .012). MSI-L tumors were also significantly associated with TP53-truncating mutations as compared to MSI-H (P = .009) and MSS (P = .012) cases, and this trend was also observed in GEA data from The Cancer Genome Atlas (TCGA). Indel mutational burden among TCGA MSI-L tumors was significantly higher than that of MSS tumors (P = .016). These results suggest that MSI-L tumors may have a distinct tumor phenotype and be potentially immunogenic in EGJ adenocarcinoma.

Clinical Significance of Serum Squamous Cell Carcinoma Antigen for Patients with Recurrent Esophageal Squamous Cell Carcinoma.

BACKGROUND: Squamous cell carcinoma antigen (SCC-Ag) is a widely used tumor marker of SCC. However, the clinical significance of serum SCC-Ag levels in recurrent esophageal SCC (ESCC) remains unclear. This study aimed to investigate the clinical relevance of serum SCC-Ag levels in patients with recurrent ESCC after surgery. METHODS: This study retrospectively analyzed 208 patients who experienced recurrence after curative resection for ESCC. Serum SCC-Ag levels at the time of recurrence were collected from the patients' records. The patients were classified into tertiles based on the serum SCC-Ag values (low, middle, and high), and the clinical characteristics and outcomes were compared among the groups. RESULTS: Significant differences in sex (p = 0.001), pathologic T (p = 0.034), and N stages of primary cancer (p = 0.015) were observed among the groups. Although the recurrence patterns did not differ significantly, a high SCC-Ag was significantly associated with multiple recurrences (p = 0.019). The high-SCC-Ag group patients demonstrated a shorter time to recurrence than the other groups (p = 0.044). The SCC-Ag levels were significantly associated with overall survival after recurrence (p = 0.036). Multivariate analysis showed that serum SCC-Ag value at recurrence was an independent poor prognosticator (p = 0.031). CONCLUSION: Elevated serum SCC-Ag levels at recurrence were significantly associated with a reduced time to recurrence, multiple recurrences, and a poor prognosis after recurrence. An alternative to the current standard treatment is required to improve the outcome for patients with high serum SCC-Ag levels at recurrence.

Influence of Damaged Stomach on Anastomotic Leakage following Cervical Esophagogastrostomy in Patients with Esophageal Cancer.

BACKGROUND: Anastomotic leakage (AL) is one of the most common complications after esophagectomy. Although some patients have a history of peptic ulcers or other prior stomach diseases, the influence of a damaged stomach (DS) on AL incidence remains unclear. Therefore, we investigated the association between DS and incidence of AL in patients who underwent esophagectomy. PATIENTS AND METHODS: Between 2015 and 2019, a total of 447 consecutive patients who underwent cervical esophagogastrostomy using gastric tube following esophagectomy were enrolled. DS was defined on the basis of endoscopic findings of ulcers or scars due to medical history or prior treatment. We compared the incidence of AL between patients with DS and those with a healthy stomach (HS). Univariate and multivariate logistic regression analyses were used to identify factors that could predict AL incidence. RESULTS: Fifty-one patients (11.4%) had DS. Causes of DS included peptic ulcer (n = 36), endoscopic resection for early gastric cancer (n = 9), percutaneous endoscopic gastrostomies (n = 5), and post-chemotherapy scar for gastric malignant lymphoma (n = 1). Overall, AL occurred in 35 patients (7.8%). The incidence of AL in the DS group was significantly higher than in the HS group (15.7 vs. 6.8%, p = 0.03). DS was one of the independent predictive factors for AL (odds ratio, 2.75; 95% confidence interval, 1.10-6.92; p = 0.03) on multivariate analysis. Further, the diseases in the lower third of the conduit were associated with AL. CONCLUSIONS: Presence of DS can predict AL in patients who underwent cervical esophagogastrostomy after esophagectomy.