B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity.

Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu1-3. Here we identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8+ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses. Our study reveals that, in addition to cytokines and membrane proteins, small metabolites derived from B-lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses.

Definitive chemoradiotherapy with paclitaxel for locally advanced esophageal squamous cell carcinoma in older patients (PARADISE-1): a phase I trial.

BACKGROUND: In older patients, esophageal squamous cell carcinoma (ESCC) is difficult to treat using standard therapies, including surgery and cisplatin-based chemoradiotherapy. Paclitaxel (PTX) has radiosensitizing activity. We conducted a phase I trial of PTX combined with radiotherapy to establish a standard therapy for locally advanced ESCC in older patients. METHODS: Enrollment was conducted at six centers in Japan from April 2016 to September 2019. The participants were aged ≥ 70 years, had locally advanced ESCC, and were intolerant to surgery or unwilling. A fixed 60-Gy radiation dose was administered in 30 fractions. PTX dosing levels started at 30 mg/m2 weekly for 6 weeks. Depending on the number of DLTs, the dose was set to be increased by 10 mg/m2 or switched to biweekly. A geriatric assessment was performed before treatment using the Geriatric-8 screening tool. The primary endpoint was dose-limiting toxicity (DLT). RESULTS: We enrolled 24 patients (6 per group); DLT was observed in one (grade 4 hypokalemia), one (grade 3 aspiration), two (grade 3 radiodermatitis, grade 3 esophageal hemorrhage), and two (grade 3 anorexia, grade 5 pneumonitis) patients in the weekly PTX 30, 40, 50, and 60 mg/m2 groups, respectively. All adverse events, except death in the 60 mg/m2 group, showed reversible improvement, and the safety profile was considered acceptable. The 2-year survival and complete response rates were 40.0% and 54.2%, respectively. There was a significant difference in survival between favorable and unfavorable Geriatric-8 scores. CONCLUSIONS: The recommended PTX dose with concomitant radiation was determined to be 50 mg/m2 weekly. Phase II trials at this dose are underway.

Risk of stricture after endoscopic submucosal dissection in the cervical esophagus and efficacy of local steroid injection for stricture prevention.

BACKGROUND AND AIMS: There is a high incidence of stricture after endoscopic submucosal dissection (ESD) for cervical esophageal cancer. We aimed to elucidate the risk factors for stricture and evaluate the efficacy of steroid injection for stricture prevention in the cervical esophagus. METHODS: We retrospectively analyzed 100 patients who underwent ESD for cervical esophageal cancer to: (1) identify the factors associated with stricture among patients who did not receive steroid injection; (2) compare the incidence of stricture between patients with and without steroid injection. RESULTS: Among 48 patients who did not receive steroid injection, there were significant differences in tumor size (P = .026), resection time (P = .028), and circumferential extent of the mucosal defect (P = .005) between patients with stricture (n = 5) and without stricture (n = 43). Compared with patients without steroid injection, patients with steroid injection had a significantly lower incidence of stricture when the post-ESD mucosal defect was < 3/4 and ≥ 1/2 (40% versus 8%, P = .039). As for the patients with a post-ESD mucosal defect of ≥ 3/4 (n = 13), local steroid injection was performed for all the patients, and 6 patients (46%) developed stricture. CONCLUSIONS: Patients who underwent ≥ 1/2 circumferential resection were at high risk of cervical esophageal stricture. Steroid injection had a stricture-prevention effect in patients with < 3/4 and ≥ 1/2 circumferential resection, but seemed to be insufficient in preventing stricture in patients with ≥ 3/4 circumferential resection.

Classification of fundic gland polyps for predicting gastric neoplasms in Helicobacter pylori-negative patients with familial adenomatous polyposis.

BACKGROUND: In familial adenomatous polyposis (FAP) patients, fundic gland polyps (FGPs) have been considered a risk factor for gastric neoplasms. We speculated that FGPs in FAP patients spread directionally from the greater to the lesser curvature of the gastric body and investigated the relationship between the distribution of FGPs and gastric neoplasm development. METHODS: We extracted 195 FAP patients from two institutions and reviewed their medical records. Gastric polyposis was classified based on the FGP distribution (P0, no FGPs; P1, localized in the fundus or greater curvature of the gastric body; P2, spreading to the anterior or posterior wall; P3, involving the proximal half of the lesser curvature; and P4, spreading from P3 to the anal side of the lesser curvature). RESULTS: The 195 eligible patients were divided into the neoplasm group (n = 54, 28%) and the non-neoplasm group (n = 141, 72%). Overall, 24% of the patients were Helicobacter pylori (H. pylori)-positive. In the FGP distribution, the rate of patients with gastric neoplasm tended to increase significantly with each step towards an increasingly wide distribution from P0 to P4 in H. pylori-negative patients, but not in H. pylori-positive ones. In addition, in H. pylori-negative patients, the likelihood of neoplasm increased consistently from P0 to P4, with the highest odds ratio (95% confidence interval) at P4 of 14.1 (2.5-154.4). Furthermore, multivariate analysis showed P4 and Spigelman stage ≥III were significantly associated with gastric neoplasm development. CONCLUSION: FGP distribution was correlated with gastric neoplasm development in FAP patients.

Multiple foci of dilated vessels as a new predictor of metachronous esophageal cancer.

OBJECTIVES: Prediction of the risk of esophageal squamous cell carcinoma (SCC) by endoscopic findings without iodine staining, which is irritating to the esophagus, would be beneficial. In a previous retrospective study, we found that multiple foci of dilated vascular areas (MDV) of the esophageal mucosa, seen in narrow-band imaging (NBI)/blue laser imaging (BLI), are associated with iodine-unstained lesions and, thus, may be a predictor of esophageal SCC. This prospective study aimed to investigate the association between MDV and metachronous esophageal SCC. METHODS: Patients with a history of endoscopic resection for esophageal SCC were included in the study. First, evaluation of the MDV using NBI or BLI was conducted during the initial endoscopy. The patients were then monitored for metachronous esophageal SCC by endoscopic surveillance. The association between the number of MDV and incidence of metachronous esophageal SCC was investigated. RESULTS: From February 2018 to May 2019, 206 patients were enrolled and 201 patients were included in the analysis. Patients were followed up until October 2022. The median (interquartile range) endoscopic follow-up period was 1260 (1105-1348) days. The incidence of metachronous esophageal SCC at 2 years was 7.1% in patients with MDV ≤4 and 13.9% in patients with MDV ≥5 (P < 0.01). In the multivariate analysis, MDV was an independent predictor of metachronous esophageal SCC, with an odds ratio (95% confidence interval) of 2.37 (1.06-5.31). CONCLUSION: Multiple foci of dilated vascular area is a useful predictor for stratifying the risk of metachronous esophageal SCC.

Efficacy and survival of nivolumab treatment for recurrent/unresectable esophageal squamous-cell carcinoma: real-world clinical data from a large multi-institutional cohort.

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.

Predictors of technical difficulty for trainees in esophageal endoscopic submucosal dissection.

BACKGROUND: Esophageal endoscopic submucosal dissection (ESD) is technically challenging, especially for trainees, and requires a safe training system. This study aimed to identify predictors of technical difficulty facing trainees performing esophageal ESD to establish such system. METHODS: This was a single-center retrospective study of patients with esophageal cancer who underwent ESD performed by trainees between January 2010 and August 2022. Technical difficulties were defined as muscularis propria exposure and long procedure time (≥ 90 min). Factors associated with these technical difficulties were investigated. RESULTS: A total of 798 lesions in 721 patients were evaluated. Muscularis propria exposure occurred in 298 lesions (37.3%), including 10 perforations (1.3%). The procedure time was ≥ 90 min in 134 lesions (16.8%). In the multivariate analysis, tumor size ≥ 20 mm, tumors ≥ 1/2 of the circumference, and those close to previous treatment scars significantly increased the incidence of both difficulties, whereas tumors in the upper esophagus significantly decreased this incidence. Furthermore, female sex and tumors in the left wall were independent predictors of muscularis propria exposure, and elevated morphology was an independent predictor of long procedure time. Muscularis propria exposure and long procedure time occurred in more than half of the cases with three or more predictors of each difficulty. CONCLUSIONS: Large tumors and tumors close to previous treatment scars increase technical difficulties for trainees in esophageal ESD. Conversely, tumors in the upper esophagus reduce these difficulties. These results enable us to predict the difficulty level preoperatively and select appropriate cases in stepwise training.

Remarkable response as a new indicator for endoscopic evaluation of local efficacy of non-surgical treatments for esophageal cancer.

In Japan, standard of care of the patients with resectable esophageal cancer is neoadjuvant chemotherapy (NAC) followed by esophagectomy. Patients unfitted for surgery or with unresectable locally advanced esophageal cancer are generally indicated with definitive chemoradiotherapy (CRT). Local disease control is undoubtful important for the management of patients with esophageal cancer, therefore endoscopic evaluation of local efficacy after non-surgical treatments must be essential. The significant shrink of primary site after NAC has been reported as a good indicator of pathological good response as well as favorable survival outcome after esophagectomy. And patients who could achieve remarkable shrink to T1 level after CRT had favorable outcomes with salvage surgery and could be good candidates for salvage endoscopic treatments. Based on these data, "Japanese Classification of Esophageal Cancer, 12th edition" defined the new endoscopic criteria "remarkable response (RR)", that means significant volume reduction after treatment, with the subjective endoscopic evaluation are proposed. In addition, the finding of local recurrence (LR) at primary site after achieving a CR was also proposed in the latest edition of Japanese Classification of Esophageal Cancer. The findings of LR are also important for detecting candidates for salvage endoscopic treatments at an early timing during surveillance after CRT. The endoscopic evaluation would encourage us to make concrete decisions for further treatment indications, therefore physicians treating patients with esophageal cancer should be well-acquainted with each finding.

T-cell deficiency induces deficits in social behavior and dyslipidemia in mice.

Patients with neuropsychiatric disorders often exhibit an altered metabolic status. However, the underlying factors that induce behavioral and metabolic dysfunctions remain poorly understood. Therefore, we investigated whether behavioral and metabolic alterations could be induced in immunodeficient conditions. We found that T-cell-deficient Cd3e-/- mice exhibit deficits in social behavior associated with dyslipidemia. Cd3e-/- mice exhibited abnormal social novelty preference, but normal anxiety-like behavior. We also detected decreases in the concentrations of plasma triglyceride and the lipid transporter molecule fatty acid-binding protein 2. Furthermore, the adoptive transfer of T-cells to Cd3e-/- mice ameliorated the deficits in social behavior and recovered plasma triglyceride concentration. Thus, we found that T-cell disruption can induce defects in social behavior and systemic lipid homeostasis in mice. Given these findings, we believe that Cd3e-/- mice represent a useful tool for investigating the mechanisms of causal relationships among immune dysfunction, behavior, and metabolism.

Predictors of stricture after non-circumferential endoscopic submucosal dissection of the esophagus and single-dose triamcinolone injection immediately after the procedure.

BACKGROUND AND AIMS: Local triamcinolone (TA) injection is widely used to prevent stricture formation after endoscopic submucosal dissection (ESD). However, stricture develops in up to 45% of patients despite this prophylactic measure. We therefore conducted a single-center prospective study to identify predictors of stricture after esophageal ESD and local TA injection. METHODS: Patients who underwent esophageal ESD and local TA injection and who were comprehensively assessed for lesion- and ESD-related factors were included in the study. Multivariate analyses were conducted to identify the predictors of stricture. RESULTS: A total of 203 patients were included in the analysis. Multivariate analysis identified residual mucosal width ≤5 mm (odds ratio [OR], 29.0; P < .0001) or 6 to 10 mm (OR, 3.7; P = .04), history of chemoradiotherapy (OR, 5.1; P = .045), and tumor in the cervical or upper thoracic esophagus (OR, 3.8; P = .018) as independent predictors of stricture. Based on the ORs of the predictors, patients were stratified into 2 groups according to stricture risk: patients in the high-risk group (residual mucosal width ≤5 mm or 6-10 mm with another predictor) had a stricture rate of 52.5% (31 of 59 cases), and patients in the low-risk group (residual mucosal width ≥11 mm or 6-10 mm without other predictors) had a stricture rate of 6.3% (9 of 144 cases). CONCLUSIONS: We identified predictors of stricture after ESD and local TA injection. Local TA injection prevented stricture formation after ESD in low-risk patients but was not sufficient to prevent stricture in high-risk patients. Additional interventions should thus be considered in high-risk patients. (University Hospital Medical Network Clinical Trials Registry number: UMIN 000028894.).

Efficacy and safety of intensive downstaging polypectomy (IDP) for multiple duodenal adenomas in patients with familial adenomatous polyposis: a prospective cohort study.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) risk developing multiple duodenal adenomas (MDAs), leading to duodenal cancer and death. We investigated the efficacy and safety of intensive downstaging polypectomy (IDP) for MDAs integrated with new-generation procedures. METHODS: This prospective phase II study, conducted at a tertiary cancer center, enrolled patients with FAP who had MDAs. We performed IDP including cold snare/forceps polypectomy (CSP/CFP) and underwater endoscopic mucosal resection (UEMR). The primary end point was the downstaging of Spigelman stage at 1-year follow-up. RESULTS: 2424 duodenal polyps in 58 patients with FAP underwent IDP, including 2413 CSPs in 57 patients, seven CFPs in one patient, and four UEMRs in four patients. Only one major adverse event was observed (grade 3 hyperamylasemia) without clinical manifestations. We performed additional UEMR, CSP, and CFP for one, 12, and 22 patients, respectively, during initial follow-up. Overall, 55 patients completed protocol examination; the Spigelman stage was significantly reduced at the 1-year follow-up endoscopy (P < 0.001), with downstaging observed in 39 patients (71 %). Among the 26 patients with Spigelman stage IV at initial examination and protocol completion, 23 (88 %) showed downstaging. There was no major change in Spigelman stages from 1-year follow-up esophagogastroduodenoscopy to a median of 37 months (range 3-56). CONCLUSIONS: IDP, including new-generation procedures, showed significant downstaging with acceptable adverse events for MDA in patients with FAP, even those with advanced-stage disease. Lesion selection for different resection techniques may be important for suitable and sustainable management of MDA in patients with FAP.

A single-center prospective study evaluating the usefulness of artificial intelligence for the diagnosis of esophageal squamous cell carcinoma in a real-time setting.

BACKGROUND: Several pre-clinical studies have reported the usefulness of artificial intelligence (AI) systems in the diagnosis of esophageal squamous cell carcinoma (ESCC). We conducted this study to evaluate the usefulness of an AI system for real-time diagnosis of ESCC in a clinical setting. METHODS: This study followed a single-center prospective single-arm non-inferiority design. Patients at high risk for ESCC were recruited and real-time diagnosis by the AI system was compared with that of endoscopists for lesions suspected to be ESCC. The primary outcomes were the diagnostic accuracy of the AI system and endoscopists. The secondary outcomes were sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and adverse events. RESULTS: A total of 237 lesions were evaluated. The accuracy, sensitivity, and specificity of the AI system were 80.6%, 68.2%, and 83.4%, respectively. The accuracy, sensitivity, and specificity of endoscopists were 85.7%, 61.4%, and 91.2%, respectively. The difference between the accuracy of the AI system and that of the endoscopists was - 5.1%, and the lower limit of the 90% confidence interval was less than the non-inferiority margin. CONCLUSIONS: The non-inferiority of the AI system in comparison with endoscopists in the real-time diagnosis of ESCC in a clinical setting was not proven. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs052200015, 18/05/2020).

Feasibility of underwater endoscopic mucosal resection for endoscopic management of gastric neoplasms in patients with familial adenomatous polyposis.

BACKGROUND: Underwater endoscopic mucosal resection (UEMR) has been developed as an effective endoscopic intervention for colon, rectum, and duodenum neoplasms. However, there are no comprehensive reports regarding the stomach, and its safety and efficacy are unknown. We aimed to examine the feasibility of UEMR for gastric neoplasms in patients with familial adenomatous polyposis (FAP). METHODS: We retrospectively extracted data of patients with FAP who underwent endoscopic resection (ER) for gastric neoplasms at Osaka International Cancer Institute from February 2009 to December 2018. Elevated gastric neoplasms of ≤ 20 mm in diameter were extracted, and conventional endoscopic mucosal resection (CEMR) and UEMR were compared. Furthermore, outcomes after ER until March 2020 were examined. RESULTS: 91 endoscopically resected gastric neoplasms were extracted from 31 patients with 26 pedigrees, and 12 neoplasms underwent CEMR and 25 neoplasms underwent UEMR was compared. The procedure time was shorter for UEMR than for CEMR. There was no significant difference between en bloc resection and R0 resection rates by EMR methods. CEMR and UEMR showed postoperative hemorrhage rates of 8% and 0%, respectively. Residual/local recurrent neoplasms were identified in four lesions (4%), but additional endoscopic intervention (three UEMR and one cauterization) resulted in a local cure. CONCLUSION: UEMR was feasible in gastric neoplasms of FAP patients, especially in elevated lesions and those of ≤ 20 mm in diameter.

Influence of radiation dose and predicted tumor invasion depth on local recurrence after definitive chemoradiotherapy for stage 0-I esophageal squamous cell carcinoma: a propensity score-weighted, retrospective, observational study.

BACKGROUND: The optimal radiation dose for treating non-metastatic superficial esophageal squamous cell carcinoma is unknown. In this retrospective observational study, we investigated the influence of radiation dose and pretreatment endoscopic prediction of tumor invasion depth on local recurrence after definitive chemoradiotherapy in patients with superficial esophageal squamous cell carcinoma. METHODS: We analyzed 134 patients with clinical Tis-T1N0M0 esophageal squamous cell carcinoma who underwent chemoradiotherapy at our institution between 2006 and 2019. Patients were grouped into standard-dose (50.0-50.4 Gy) and high-dose (60.0 Gy) radiotherapy groups. The outcomes of interest were local recurrence and major local recurrence (endoscopically unresectable local recurrent tumors). Kaplan-Meier analysis and the log-rank test were used with propensity score and inverse probability of treatment weighting. Cox proportional hazards analysis was performed to identify predictors of local recurrence and major local recurrence. RESULTS: The median follow-up times were 52 and 84 months for the standard-dose and high-dose groups, respectively. The adjusted 3-year local recurrence and major local recurrence rates in the standard-dose and high-dose groups were 33.8 and 9.6% (adjusted hazard ratio, 4.00 [95% confidence interval: 1.64-9.73]; adjusted log-rank p = 0.001) and 12.5 and 4.7% (adjusted hazard ratio, 3.13 [95% confidence interval: 0.91-10.81]; adjusted log-rank p = 0.098), respectively. Cox proportional hazards analysis showed that standard-dose radiotherapy and endoscopic findings of deep submucosal invasion are independently associated with local recurrence and major local recurrence. CONCLUSIONS: High-dose radiotherapy is more beneficial for local tumor control than standard-dose radiotherapy in patients with non-metastatic superficial esophageal squamous cell carcinoma. The use of high-dose radiotherapy may merit consideration for tumors with deep submucosal invasion.

Indication of emergency colonoscopy after colorectal endoscopic submucosal dissection: A proposal of hematochezia scale.

BACKGROUND AND AIM: Hematochezia is a major adverse event associated with colorectal endoscopic submucosal dissection (ESD). This study aimed to distinguish between hematochezia that required endoscopic hemostasis and hematochezia that required no hemostasis. METHODS: This retrospective study included consecutive patients who underwent ESD for colorectal tumors at the Osaka International Cancer Institute between September 2017 and August 2020. The exclusion criteria were as follows: patients with coexisting advanced colorectal cancers or inflammatory bowel diseases, patients who received incomplete ESD or emergency surgery, or patients who underwent ESD for multiple lesions. We evaluated whether the patients had hematochezia and underwent emergency colonoscopy and hemostasis during hospitalization. The degree of hematochezia in the saved photographs was assessed using the hematochezia scale and classified as mild, moderate, or severe. Blood pressure, heart rate, time from ESD to first hematochezia, and total number of hematochezia episodes were also evaluated. RESULTS: Among the 437 patients who underwent ESD, 44 were excluded, and 393 patients were evaluated. Hematochezia was observed in 100 patients (25%). Emergency colonoscopy was performed in 12 patients (3%), and hemostasis was required in six patients (2%). For patients with hematochezia, only mild hematochezia and hematochezia that developed ≤ 48 h after ESD were significantly associated with no intervention for hemostasis. The positive predictive value for no intervention for hemostasis was 100% (93-100%) for mild hematochezia and 98% (93-100%) for hematochezia ≤ 48 h. CONCLUSIONS: Mild hematochezia and hematochezia ≤ 48 h were negative predictors of hemostasis, in which emergency colonoscopy may be avoided.

Impact of endoscopic surveillance on mortality of metachronous esophageal and head and neck cancer after esophageal endoscopic resection.

BACKGROUND AND AIM: As more superficial esophageal cancer (EC) patients are being treated with endoscopic resection (ER), it is important to understand the outcomes, including survival data, of patients who develop metachronous EC and head and neck cancer (HNC). We aimed to evaluate the long-term surveillance and survival outcomes of metachronous EC and HNC after esophageal ER. METHODS: This study included 627 patients who underwent ER of superficial esophageal squamous cell carcinoma from 2008 to 2016 and were generally followed by annual or biannual esophagogastroduodenoscopy up to 2019 at Osaka International Cancer Institute. Data on metachronous cancer development and causes of death were collected from an integrated database of hospital-based cancer registry and Vital Statistics of Japan. RESULTS: During a median (range) follow-up period of 67.4 (3.8-142.7) months, 230 patients (36.7%) developed 500 metachronous ECs and 126 patients (20.1%) developed 239 metachronous HNCs, post-ER of index EC. The 3-year, 5-year, and 7-year cumulative incidences were 25.8%, 36.0%, and 43.6% for metachronous EC and 10.9%, 16.0%, and 26.9% for metachronous HNC, respectively. No patients died of metachronous EC, and only seven patients (1.1%) died of metachronous HNC. The 3-year, 5-year, and 7-year disease-specific survival rates were 99.8%, 99.6%, and 98.6%, respectively. CONCLUSIONS: The incidences of metachronous EC and HNC increase with time over 5 years after esophageal ER; therefore, surveillance endoscopy should be continued over 5 years. Endoscopic surveillance is useful for survivors after esophageal ER given the high incidence and extremely low mortality of metachronous EC and HNC.

Positive predictive value of the clinical diagnosis of T1a-epithelial/lamina propria esophageal cancer depends on lesion size.

OBJECTIVES: Endoscopic resection (ER) is a minimally invasive treatment for esophageal squamous cell carcinoma (ESCC). However, stricture may develop after ER for widespread lesions. Application of ER is justified if these cancers are pathological T1a-epithelial/lamina propria (pEP/LPM) cancers that can be cured by ER. We conducted a study to clarify the association between pathological invasion depth and lesion size or circumference in clinical (c) EP/LPM cancers. METHODS: From our database, we identified patients diagnosed with cEP/LPM ESCC via endoscopic examination who underwent endoscopic or surgical tumor resection. The accuracy of the cEP/LPM ESCC diagnosis was determined by histologically diagnosing cancer invasion depth as a reference standard. RESULTS: Between January 2015 and December 2019, 1271 cancer patients were diagnosed with cEP/LPM ESCC, of which 1195 (94.0%) were correctly diagnosed with pEP/LPM cancer. The positive predictive value (PPV) classified according to lesion sizes of ≤25, 26-49, and ≥50 mm was 95.8% (981/1024 lesions), 89.7% (191/213 lesions), and 67.6% (23/34 lesions), respectively. PPV according to the circumferential extent of <3/4, ≥3/4, and <1, and whole was 94.6% (1164/1230 lesions), 75.0% (24/32 lesions), and 77.8% (7/9 lesions), respectively. In multivariate analysis, the PPV of cEP/LPM ESCC was significantly associated with lesion size (P < 0.001) and male sex. CONCLUSIONS: Between January 2015 and December 2019, 1271 cancer patients were diagnosed with cEP/LPM ESCC, of which 1195 (94.0%) were correctly diagnosed with pEP/LPM cancer. The PPV of cEP/LPM ESCC was related to lesion size. Treatment should be determined considering the high risk of cancer invasion into the muscularis mucosa or deeper in cEP/LPM cancers with a lesion size of ≥50 mm.

Clinical Outcome of Additional Esophagectomy After Endoscopic Treatment for Superficial Esophageal Cancer.

BACKGROUND: Endoscopic treatment is one of the options for superficial esophageal cancer, but additional therapy such as esophagectomy or chemoradiotherapy (CRT) is sometimes needed due to noncurative resection. However, the outcome of additional therapy after endoscopic treatment has not been fully evaluated. METHODS: In 160 patients with superficial esophageal cancer, including 37 patients who underwent esophagectomy and 123 patients who underwent CRT after noncurative endoscopic resection, outcomes were investigated. RESULTS: The CRT group included more elderly patients than the surgery group, although there were no significant differences in tumor depth or lymphovascular invasion between the two groups. Overall survival was significantly better in the surgery group than in the CRT group (5-year overall survival: 94.3% vs. 79.9%; p = 0.039). Two (5.4%) patients in the surgery group who developed lymph node recurrence achieved complete response by chemotherapy or CRT, and 9 of 16 patients (13.0%) in the CRT group who developed recurrence underwent salvage esophagectomy or lymphadenectomy. As a result, the 5-year cause-specific survival was 100% in the surgery group and 92.8% in the CRT group. SM2 invasion (≥ SM2) was significantly associated with recurrence after CRT, while lymphatic invasion was associated with lymph node metastasis in the surgery group. CONCLUSION: Endoscopic treatment combined with esophagectomy or CRT can be a curative treatment option in patients with superficial esophageal cancer. However, esophagectomy rather than CRT should be recommended for patients with massive submucosal tumor invasion due to the risk of recurrence after CRT.

Endoscopic Features of Superficial Esophageal Squamous Cell Carcinoma in Patients with Very Low Risk Factors (Female, Nondrinking, and Nonsmoking): A Case-Control Study.

BACKGROUND: Although esophageal squamous cell carcinoma (ESCC) is more likely to develop in patients with any risk factor (male, drinking, or smoking), it is sometimes detected in patients with very low risk factors (female, nondrinking, and nonsmoking). We examined the endoscopic features of superficial ESCC in patients with very low risk factors. METHODS: In this single-center case-control study, 666 patients with 666 superficial ESCC lesions were divided into 2 groups: those with very low risk factors (very low-risk group, n = 34) and those with any risk factors (any-risk group, n = 632). After case-control selection at a 1:5 ratio, the very low-risk group comprised 34 patients and the any-risk group comprised 170 patients. We compared the baseline characteristics, endoscopic findings, and treatment results (including pathological diagnosis) between the 2 groups. RESULTS: There were no statistically significant differences between the 2 groups in age, tumor size, tumor location, tumor morphology, or treatment results (including tumor depth and lymphovascular invasion). A longitudinal lesion with an attachment of white keratinized epithelium was more likely to be detected in the very low-risk group than the any-risk group (61.8 vs. 17.6%, respectively; p < 0.001). CONCLUSIONS: ESCC in patients with very low risk factors is rare but can be encountered in daily practice. A longitudinal lesion with an attachment of white keratinized epithelium is its main characteristic, which is slightly different from that of patients with any risk factors.

Features of Esophageal Adenocarcinoma in Magnifying Narrow-Band Imaging.

BACKGROUND: Several endoscopic classifications for esophageal adenocarcinoma have been proposed; however, gastric adenocarcinoma is much more common than esophageal or esophagogastric junctional (EGJ) adenocarcinoma in East Asian countries. We, therefore, investigated whether an endoscopic diagnostic algorithm for gastric adenocarcinoma could be used for esophageal or EGJ adenocarcinoma. METHODS: One hundred eighteen consecutive patients who underwent endoscopic resection or surgery for intramucosal esophageal or EGJ adenocarcinoma, at the Osaka International Cancer Institute between January 2006 and December 2017, were included in this retrospective study. Their lesions were classified as Siewert type 1 or 2, and the presence of endoscopic magnifying narrow-band imaging findings for diagnosing gastric adenocarcinoma was evaluated. RESULTS: We evaluated 125 adenocarcinomas in 118 patients (29 type 1 and 96 type 2). Demarcation lines (DLs) were seen in 7 (24%) type 1 and 53 (55%) type 2 lesions. Irregular mucosal patterns were present in 2 (7%) type 1 and 22 (23%) type 2 lesions. Irregular vascular patterns were present in 26 (90%) type 1 and 50 (52%) type 2 lesions. According to the magnifying endoscopy diagnostic algorithm for gastric adenocarcinoma, only 7 (24%) type 1 and 52 (54%) type 2 lesions were correctly diagnosed as cancers (p = 0.005). CONCLUSION: The magnifying endoscopy diagnostic algorithm for gastric cancer may not be useful for esophageal or EGJ adenocarcinomas because of the low visibility of DLs, especially in Siewert type 1 adenocarcinoma.