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Background Immune checkpoint inhibitors targeting the programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have demonstrated antitumor effects in patients with various malignancies, including esophageal cancer. Thus, a better understanding of local immunity in esophageal cancer is crucial for improving treatment and clinical outcomes. Methods We evaluated PD-1 expression on tumor-infiltrating lymphocytes (TILs), as well as PD-L1 expression on cancer cells, by immunohistochemistry and immunofluorescence using a nonbiased database of 433 curatively resected esophageal cancers. With the idea of application as liquid biopsy, PD-1 expression status on peripheral lymphocytes was evaluated by flow cytometry. Results The cutoff value of PD-1 expression was the median PD-1 count. Compared with cases of low PD-1 expression (n = 219), cases with high levels of PD-1 expression (n = 213) showed significantly worse overall survival (log-rank P = .0017). The prognostic effect of PD-1 differed according to the preoperative treatment status (P for interaction = .040); PD-1 expression was associated with high overall mortality among patients without preoperative therapy, while no such association was present among those with preoperative treatment. A stratification based on PD-1 and PD-L1 status was also significantly associated with overall survival (log-rank P = .0005). PD-1 expression on TILs was significantly associated with that on peripheral lymphocytes (P Conclusions PD-1 expression on TILs was associated with an unfavorable clinical outcome in esophageal cancer, supporting its role as a prognostic biomarker. The combination of PD-1 and PD-L1 expression enabled further classification of patients according to clinical outcome.

Aim Digestive reconstruction after pharyngolaryngectomy with total esophagectomy (PLTE) remains challenging, with the optimal method remaining unclear. The current study aimed to clarify the short‐term outcomes after PLTE and determine the optimal digestive reconstruction method. Methods Based on a nationwide survey of 151 patients who underwent PLTE, outcomes of digestive reconstruction methods are described. Results Among digestive reconstruction methods, a simple gastric tube was most frequently used (37.1%), followed by gastric tube combined with free graft transfer (FGT) (35.1%), gastric tube with microvascular anastomosis (22.5%), and other procedures (5.3%). Intraoperative evaluation of microcirculation (IOEM) was utilized in 29 patients (19.2%). Among the included patients, 66.9% developed any‐grade complications, 41.0% developed severe complications, and 23.8% developed digestive reconstruction‐related complications (DRRCs; leakage or necrosis). Reoperation within 30 days for any complications and DRRCs was required in 13.9% and 8.6% of the patients, respectively. Mortality within 90 days was observed in 4.6%. Among the three major methods, gastric tube combined with FGT promoted the least DRRCs in the gastric tube (P = .005), although the overall incidence of DRRCs was comparable. The use of IOEM was significantly associated with a reduction of severe DRRCs (P = .005). Conclusions Pharyngolaryngectomy with total esophagectomy is a high‐risk surgery significantly associated with the occurrence of postoperative morbidity and mortality. Nonetheless, the addition of FGT can help prevent gastric tip complications, while IOEM can be an effective method for improving outcomes., In this nationwide survey on digestive reconstruction following pharyngolaryngectomy with total esophagectomy, reconstruction using a gastric tube with free graft transfer was significantly associated with fewer digestive reconstruction‐related complications (DRRCs) in the gastric tube. However, it did not decrease overall and severe DRRCs. Intraoperative evaluation of microcirculation significantly reduced severe DRRCs.

Immune checkpoint inhibitors have shown efficacy in various cancers. Although programmed death ligand 1/2 (PD-L1/L2) expressions have been demonstrated as predictive biomarkers of response to immune checkpoint inhibitors and prognostic markers, whether PD-L1/L2 expression is altered in esophageal squamous cell carcinoma during the therapeutic course is unclear. Whether PD-L1/L2 expression in metastatic or recurrent lesions is consistent with that in primary tumors is also unknown. This study included 561 surgically resected esophageal squamous cell carcinomas and PD-L1/L2 expression was evaluated by immunohistochemistry. We investigated the influence of chemotherapeutic drugs (cisplatin and fluorouracil) on PD-L1/L2 expression and PD-L1/L2-related pathways in vitro. We also examined PD-L1/L2 expression in 18 surgically resected lymph node metastases and 10 recurrent lesions compared with primary lesions. The positive rate of PD-L1 was significantly higher in patients with preoperative chemotherapy than in those without preoperative therapy. The positive rate of PD-L2 expression showed no significant difference between patient groups. Cisplatin increased PD-L1 expression in cancer cell lines in vitro, but decreased PD-L2 in some cell lines. The effects of cisplatin on phosphorylated signal transducer and activator of transcription 1/3 (pSTAT1/3) also differed depending on cell lines. Fluorouracil increased PD-L1 and PD-L2 expression. PD-L1/L2 expression in lymph node metastases and recurrent lesions did not always match expression in primary lesions. PD-L1/L2 expression may be altered by preoperative chemotherapy, and PD-L1 /L2 expression in primary lesions does not always match that of metastatic/recurrent lesions. Thus, one-time evaluation is not sufficient to evaluate PD-L1/L2 expression as a biomarker in 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.

OBJECTIVES Endoscopic resection (ER) is indicated for a wide range of superficial esophageal squamous cell carcinomas (ESCCs). We examined the long-term outcomes in patients with pathological (p) invasion of ESCC into the T1a-muscularis mucosae (MM) and T1b-submucosa (SM) after ER, for which data on prognosis are limited. METHODS Of the 1217 patients with superficial ESCC who underwent ER, 225 patients with a pathological diagnosis of ESCC invasion into the MM, minute submucosal invasion ≤200 µm (SM1), or massive submucosal invasion (SM2) were included. In patients with lymphovascular invasion, droplet infiltration, or SM2 invasion, additional treatments, including chemoradiation (CRT) or esophagectomy with two- to three-field lymph node dissection, were recommended. The median observation period was 66 months (interquartile range 48-91 months). RESULTS In total, there were 151, 28, and 46 pT1a-MM, pT1b-SM1, and pT1b-SM2 cases, respectively. Metastatic recurrence was observed in 1.3%, 10.7%, and 6.5% patients with pT1a-MM, pT1b-SM1, and pT1b-SM2 ESCCs, respectively. Of the eight patients with metastatic recurrence, six were successfully treated, and two died of ESCC. The 5-year overall survival rates were 84.1%, 71.4%, and 67.4%, the 5-year relapse-free survival rates were 82.8%, 64.3%, and 65.2%, and the 5-year disease-specific survival rates were 100%, 96.4%, and 99.1% in patients with pT1a-MM, pT1b-SM1, and pT1b-SM2 ESCCs, respectively. Multivariate analysis showed that additional CRT and esophagectomy, and T1b-SM2 were positively and negatively associated with overall survival, respectively. CONCLUSIONS Endoscopic resection preceding appropriate additional treatments resulted in favorable outcomes. Many cases of metastatic recurrence in this cohort could be successfully treated.

The presence of tertiary lymphoid structure (TLS) in tumor tissues has been reported to be a factor associated with a good prognosis in several types of cancers. However, the relationship between TLS formation and peripheral blood findings remains unclear. The purposes of the study were to evaluate the effect of the presence of TLS on survival and determine the peripheral blood characteristics associated with TLS formation in non-small cell lung cancer (NSCLC) patients. A total of 147 consecutive NSCLC patients who underwent lung resection at Fukushima Medical University Hospital between 2013 and 2017 were enrolled. TLS expression was evaluated, and the relationships between clinical parameters and outcomes were analyzed. Peripheral blood mononuclear cells (PBMCs) were further analyzed by mass cytometry to characterize the TLS-positive microenvironment. Forty-six patients had high TLS expression, and the remaining 101 patients had low TLS expression. In stage II to IV patients (n = 35), disease-free survival was longer in the high TLS expression group (p = 0.027). A low neutrophil to lymphocyte ratio (NLR)

Background The registration committee for esophageal cancer in the Japan Esophageal Society (JES) has collected the patients' characteristics, treatment, and outcomes annually. Methods We analyzed the data of patients who had visited the participating hospitals in 2014. We collected the data with a web-based data collection system using the National Clinical Database. We used the Japanese Classification of Esophageal Cancer 10th edition by JES and the TNM classification 7th edition by the Union of International Cancer Control (UICC) for cancer staging. Results A total of 9026 cases were registered from 344 institutions in Japan. Squamous cell carcinoma and adenocarcinoma accounted for 87.9% and 7.1%, respectively. The 5-year survival rates of patients treated using endoscopic resection, concurrent chemoradiotherapy, radiotherapy alone, and esophagectomy were 87.1%, 33.7%, 25.3%, and 59.3%, respectively. Esophagectomy was performed in 5204 cases. Concerning the approach used for esophagectomy, 48.1% of the cases were treated thoracoscopically. The operative mortality (within 30 days after surgery) was 0.75%, and the hospital mortality was 2.0%. The survival curves showed an excellent discriminatory ability both in the clinical and pathologic stages by the JES system. The survival of pStage IV was better than IIIC in the UICC system, because pStage IV included the patients with supraclavicular lymph-node metastasis (M1 LYM). Conclusion We hope that this report contributes to improving all aspects of diagnosing and treating esophageal cancer in Japan.

Echinoderm microtubule‐associated protein‐like 4‐anaplastic lymphoma kinase (EML4‐ALK) rearrangements are found in ~ 5% of patients with non‐small cell lung cancer (NSCLC). Several tyrosine kinase inhibitors (TKIs) have been developed for treatment of so‐called ALK‐positive NSCLC. In cases of tumor progression during treatment with second‐generation ALK‐TKIs, such as alectinib, brigatinib, or ceritinib, National Comprehensive Cancer Network guidelines propose a switch to lorlatinib, a third‐generation ALK‐TKI, or to cytotoxic chemotherapy. However, they do not mention switching to other second‐generation ALK‐TKIs. Here, we present a rare case of a 53‐year‐old Japanese woman, who had never smoked, with ALK‐positive lung adenocarcinoma who survived alectinib‐resistant postoperative recurrence for 4 years by switching to ceritinib. She underwent curative resection for lung adenocarcinoma, but the cancer recurred at the bronchial stump and mediastinal lymph nodes. After platinum‐doublet chemotherapy, the patient still had a single growing liver metastasis, but the tumor was found to harbor EML4‐ALK rearrangement. Therefore, the patient started to take ALK‐TKIs. Alectinib was the second ALK‐TKI used to treat this patient. Alectinib shrank the liver metastasis, which was surgically resected. The tumor relapsed again during continued treatment with alectinib, which was switched to ceritinib. Ceritinib was effective for the relapsed tumor and treatment continued well for 4 years. This case report suggests that, in case of tumor progression during treatment with a second‐generation ALK‐TKI, switching to another second‐generation ALK‐TKI may be one of the treatment options. Further analyses are warranted to find robust markers to determine which ALK‐TKI is best for each patient., Clinical course of the patient. A 53‐year‐old Japanese woman underwent curative resection for lung adenocarcinoma in 2005. The tumor recurred 4 years later and liver metastasis persisted despite cytotoxic chemotherapy. However, EML4‐ALK rearrangement was detected from the tumor, so ALK‐TKIs treatment began in 2013. For the alectinib‐resistant relapse in 2016, ceritinib was started for the treatment, which has been effective for 4 years.

Background The adapted systemic inflammation score (aSIS), calculated from serum albumin and the lymphocyte‐to‐monocyte ratio, has been reported to be a novel prognostic marker for some types of cancers. However, the prognostic impact of aSIS in patients with esophageal squamous cell carcinoma (ESCC) remains controversial. This study aimed to examine the prognostic effects of aSIS in a large cohort of 509 ESCC patients. Methods Preoperative aSIS was retrospectively calculated for 509 ESCC patients who underwent curative resection. Time‐dependent receiver operating characteristics (t‐ROC) curves were used for comparing the prognostic impact. Results Patients with high aSIS showed significantly poorer overall survival (OS) than patients with low aSIS (log rank P, This study examined the prognostic effects of the adapted systemic inflammation score (aSIS), calculated from serum albumin and the lymphocyte‐to‐monocyte ratio, in a large cohort of 509 esophageal squamous cell carcinoma (ESCC) patients. ESCC patients with high aSIS showed significantly poorer overall survival than patients with low aSIS. aSIS was more sensitive than other nutritional prognostic factors (controlling for nutritional status, systemic inflammation score, and the neutrophil‐to‐lymphocyte ratio).

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. 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. 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. Presence of DS can predict AL in patients who underwent cervical esophagogastrostomy after esophagectomy.

Chronic obstructive pulmonary disease (COPD) is known to be a risk factor of pneumonia after esophagectomy. In this study, we investigated the relationship of airflow limitation with the occurrence and the severity of pneumonia in esophageal cancer patients who underwent esophagectomy. We enrolled 844 patients who underwent curative esophagectomy between 2009 and 2018. The airflow limitation was evaluated using the percent-predicted forced expiratory volume at 1 s (%FEV1) with spirometry. There were 597 (70.7%), 141 (16.7%), 68 (8.1%), and 38 patients (4.5%) with %FEV1 of ≥ 90%, 80–90%, 70–80%, and

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. 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. 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). 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.

This study evaluates surgical outcomes of Ivor Lewis esophagectomy (ILE) in our institution, with the transition from open ILE to hybrid or totally minimally invasive ILE (MI-ILE). Selected patients who underwent ILE for esophageal cancer between 2013 and 2020 were included. We retrospectively investigated the patients’ background characteristics and the short-term surgical outcomes. In this period, among a total of 858 esophagectomies, selected seventy-one patients (8.3%) underwent ILE, consisted of 17 cases with completely open procedures, 27 with hybrid MI-ILE, and 27 with total MI-ILE. The major indications for ILE were adenocarcinoma of the distal esophagus or esophagogastric junction (33.8%) and patients with prior treatment of head and neck cancer (31.0%). Among these approaches, there were no significant differences in the characteristics including age, body mass index (BMI), tumor location, preoperative therapy, and clinical TNM stage, except for histology. Compared to the completely open and hybrid groups, incidences of both total and severe complications in the total MI-ILE group were significantly lower (total 70.6 vs. 66.6 vs. 37.0%, p=0.036; severe 35.3 vs. 44.4 vs. 11.1%, p=0.023), and also, those of pneumonia (41.2 vs. 29.6 vs. 7.4%, p=0.026) and postoperative stricture (11.8 vs. 18.5 vs. 0%, p=0.001) were significantly fewer in the total MI-ILE group. We have been able to achieve the transition from completely open to total MI-ILE with better short-term outcomes. Total MI-ILE with linear-stapled anastomosis can be a good alternative to open procedures for the selected patients with reducing the incidence of postoperative pneumonia and anastomotic stricture.

Objectives Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand known to be expressed in several cancers but whose role in lung cancer is not yet fully understood. We sought to confirm DLK1 expression in small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and to examine DLK1’s clinical significance. Furthermore, we examined the possible utility of DLK1 as a novel target in radioimmunotherapy (RIT). Methods We retrospectively assessed the correlation between clinical features and DLK1 expression by immunohistochemistry in resected specimens from 112 patients with SCLC and 101 patients with NSCLC. Moreover, we performed cell and animal experiments, and examined the possibility of RIT targeting DLK1 in SCLC using iodine-125 (125I) -labeled anti-DLK1 antibody, knowing that 125I can be replaced with the alpha-particle-emitter astatine-211 (211At). Results In SCLC and NSCLC, 20.5 % (23/112) and 16.8 % (17/101) of patients (respectively) had DLK1-positive tumors. In NSCLC, DLK1 expression was associated with recurrence-free survival (P Conclusion A proportion of SCLC and NSCLC exhibits DLK1 expression. As a clinical feature, DLK1 expression could be a promising prognostic factor for recurrence in patients with resected NSCLC. In addition, DLK1 could serve as a new therapeutic target, including RIT, as suggested by our pilot study using a radiolabeled anti-DLK1 antibody in SCLC.

Chemoradiotherapy is an alternative to surgery for esophageal cancer, with a putatively equivalent outcome. However, disease recurrence after a complete response is common and if follow-up surveillance detects recurrence, salvage treatments for potentially curable disease must follow. We conducted a nation-wide questionnaire survey of institutions in Japan certified by the Japanese Esophageal Society to investigate outcomes of primary thoracic esophageal cancer patients initially treated by chemoradiotherapy with complete response diagnoses. The primary endpoint was overall survival, the secondary endpoint disease recurrence. Outcomes of patients who had undergone salvage treatments were also investigated. Cases were excluded from analysis if endoscopic study, endoscopic biopsy, or computed tomography data were lacking. At 41 institutes 544 case records were collected; valid data on 392 patients were obtained; 5-year survival was 74.8%, 5-year disease-free survival, 66.8%. Clinical staging before treatment significantly affected both overall and disease-free survival rates, but differences between adjoining stages were unexpectedly small. The primary relapse site was classified as primary site (n = 58), regional lymph nodes (n = 36), or distant disease (n = 34). Salvage treatments with curative intent (surgery, endoscopic treatments, and additional radiation) were performed on 38, 23, and 4 cases; 5-year survival after esophagectomy (n = 22), endoscopic treatment (n = 23), and lymphadenectomy (n = 9) was 47.4%, 70.9%, and 33.3%, respectively. A quarter of patients developed recurrent disease, mostly locoregional, after complete response. Complete response patients with originally advanced stage disease had fair clinical outcomes; salvage treatments after locoregional recurrence achieved modest long-term survival.

Esophagectomy with lymph node dissection is a choice of additional treatment after noncurative endoscopic resection (ER) of T1N0 esophageal squamous cell carcinoma (ESCC). The efficacy and safety of esophagectomy in this situation remain unclear when compared with upfront esophagectomy. We investigated the short- and long-term outcomes of 321 patients with clinical T1N0M0 ESCC who underwent curative esophagectomy, and compared the status of lymph node metastasis, surgical results, and the prognosis between the ER and non-ER groups. The ER group consisted of 57 patients (17.8%), while the non-ER group consisted of 264 patients (82.2%). The incidence of lymph node metastasis was not significantly different between the ER (24.6%) and non-ER groups (30.7%), and there was no significant difference in surgical outcomes between the groups. The distribution of metastatic lymph nodes was very similar between the groups. However, 13 of 14 patients (93%) with lymph node metastasis in the ER group and 63 of 82 patients (77%) with lymph node metastasis in the non-ER group had pN1 disease, while the remaining 18 patients (23%) with lymph node metastasis in the non-ER group had pN2 or N3 disease. Overall and relapse-free survival rates were significantly better in the ER group than in the non-ER group (p

Extracorporeal membrane oxygenation for cardiopulmonary arrest due to left ventricular free wall rupture is considered effective, because it enables rapid cardiopulmonary support and introduction of targeted temperature management.

Background Predicting the prognosis of intensive care unit (ICU) patients is crucial because it may lead to patient stratification that would in turn help in appropriately distributing limited medical resources. This study, therefore, aimed to investigate the use of the urinary liver-type fatty acid-binding protein (L-FABP) semi-quantitative kit in rapidly predicting the prognosis of patients admitted to the ICU. Methods We conducted a single-center, prospective, observational study wherein 100 consecutive patients admitted to the ICU with an indwelling bladder catheter were enrolled between April and October 2020. Urine specimens were collected at the time of admission (T1) and after 6 h (T2), and urinary L-FABP levels were semi-quantitatively measured. Based on the results, an L-FABP variation was defined as the change in L-FABP (negative, weakly positive, or strongly positive) from T1 to T2. Patients were divided into three groups (L-FABP decreased group, unchanged group, or increased group), following which we compared their 14-day mortality. Results Finally, a total of 79 patients were included in the analysis. In multivariate analysis, urinary L-FABP variation [Odds ratio (OR) = 14.327, 95% confidence interval (CI) = 1.819–112.868, p = 0.01] and lactate (OR = 1.234, 95%CI = 1.060–1.437, p = 0.01) were significantly associated with 14-day mortality. Conclusion Urinary L-FABP variation at 6 h after admission was significantly associated with 14-day mortality.

The use of plasma filtration with dialysis (PDF) may be considered when treating the acute phase of capillary leak syndrome (CLS). To the best of our knowledge, this is the first report using PDF for CLS.

The incidence of esophagogastric junction (EGJ) adenocarcinoma has been gradually increasing in Asia, just like in Western countries a few decades ago. Despite recent advances in next‐generation sequencing and multimodal treatments, EGJ adenocarcinoma is still an aggressive malignancy with poor outcomes. Clinically, EGJ adenocarcinoma can be separated into Barrett's adenocarcinoma and cardiac adenocarcinoma, with frequent similarities observed. Barrett's adenocarcinoma is likely to be of gastric origin in terms of its premalignant background, risk factors, and stem cell regulators. Recent comprehensive genomic analyses suggest that immunotherapy may be essential for high‐level microsatellite instability (MSI‐H)‐ and Epstein‐Barr virus (EBV)‐associated subtypes, and against the immunosuppressive phenotype in genomically stable (GS) subtypes, in the treatment of EGJ and gastric adenocarcinoma. Although the chromosomal instability (CIN) subtype dominates EGJ adenocarcinoma, there is still a need to investigate the other molecular subtypes and their targets. Because of the distinctive characteristics of tumor location of EGJ adenocarcinoma, we also described the results of a multicenter cohort study of EGJ adenocarcinoma, comparing Siewert type I (distal esophagus), II (cardia of the stomach), and III (subcardia) tumors. We show that type I tumors were frequently accompanied by Barrett's esophagus (78%, P, In this review article, we discussed future therapeutic targets of adenocarcinoma of esophagogastric junction (EGJ) according to the four molecular subtypes by TCGA. We also referred to the current understanding of the similarity between Barrett's adenocarcinoma and cardiac carcinoma, and added our own analysis examining prognostic differences between those two tumors using a multicenter cohort in Japan.

OBJECTIVE This study aimed to elucidate the residual disease distribution and recurrence patterns in patients with ESCC responding to NAC. SUMMARY BACKGROUND DATA To appropriately plan a prospective trial for the organ preservation approach which includes additional chemoradiotherapy in patients who responded to NAC, the distribution of residual disease needs to be elucidated. Given that the residual tumor is located in the regional field, chemoradiotherapy can be safely added to eliminate the residual disease. METHODS Overall, 483 patients with resectable ESCC who received NAC followed by transthoracic esophagectomy at 2 high-volume centers were reviewed. The recurrence-free survival, overall survival (OS), and residual and recurrent tumor patterns were compared among the pathological responses. RESULTS Compared with nonpathological responders, pathological responders exhibited significantly longer recurrence-free survival [hazard ratio of Grade 1b/2/3 compared with Grade 0; 0.25 (P < 0.001) /0.17 (P < 0.001) /0.16 (P = 0.003)] and OS [hazard ratio of Grade 1b/2/3 compared with Grade 0; 0.26 (P < 0.001) /0.12 (P < 0.001) /0.11 (P = 0.003)]. In terms of the distribution of recurrence, the percentages of solitary recurrence in the regional field out of all recurrence was significantly higher in patients with Grade 1b (60%) / 2 (67%) / 3 (67%) whereas less than 25% in Grade 0 or 1a. CONCLUSIONS It was found that postoperative recurrence in responders occurred in the regional field mostly as a solitary lesion without the distant failure, indicating that the residual tumor cells can be eliminated by additional chemoradiotherapy.

Early provision of a high-protein nutrition improves the prognosis of patients in intensive care units (ICUs). However, high protein intake increases blood urea nitrogen (BUN). No study has compared outcomes according to protein intake, and the clinical significance of changes in BUN (ΔBUN) in ICU patients is unclear. Here, we investigated the association of high protein intake with outcomes and BUN and assessed the clinical significance of ΔBUN.This was a single-center retrospective cohort study. Between 1 January 2016 and 30 September 2019, 295 ICU patients received enteral nutrition for at least 3 days while undergoing mechanical ventilation. After applying the exclusion criteria of an age of18 years, gastrointestinal disease, maintenance dialysis, renal replacement therapy after admission, kidney transplantation, and death within 7 days of commencing enteral nutrition, 206 patients remained.Participants were divided into those receiving1.2 g/kg/day of protein (high-protein group; n = 111) and those receiving ≤1.2 g/kg/day of protein (non-high-protein group; n = 95). The groups were balanced by propensity score matching. The primary endpoint was 28-day mortality, and the secondary endpoints were 90-day mortality, length of ICU stay, number of ventilator-free days in the first 28 days, and ΔBUN.The high-protein group had significantly lower 28- and 90-day mortality and significantly greater ΔBUN, including after propensity score matching. ΔBUN might not be associated with outcomes.Provision of1.2 g/kg/day of protein may be associated with lower mortality of tube-fed and mechanically ventilated patients. Furthermore, while high protein intake may be associated with higher BUN, these changes may not be adversely associated with outcomes.

Introduction: Pneumonia is one of the most frequently occurring complications after esophagectomy and is associated with increased operative mortality. Chronic obstructive pulmonary disease (COPD) is known to be a risk factor for pulmonary complications and operative mortality. However, in COPD patients preparing for esophagectomy, preventive measures against postoperative pneumonia have not yet been discovered. In this study, we evaluate the effect of perioperative inhaled tiotropium, a long-acting, antimuscarinic bronchodilator used in the management of COPD, on patients with COPD who undergo esophageal cancer surgery. Methods/Design: This study investigates the effect of perioperative inhaled tiotropium on patients with COPD who undergo esophagectomy. It is an open-label, randomized controlled trial conducted in a single center (EPITOPE study). A total of 32 enrolled patients are randomly assigned in a 1:1 ratio to either conventional management or inhalation of tiotropium in addition to the conventional management. Patients included in the intervention group receive tiotropium Respimat 5 μg (two inhalations of 2.5 μg) for at least 2 weeks before the esophagectomy. Following the esophagectomy, tiotropium is re-delivered, starting as early as possible and continuing until the postoperative evaluation (between 30 and 44 days after the operation). The primary outcome is the incidence of pneumonia within 30 days after esophagectomy. Secondary outcomes are the incidence of cardiovascular complications within 30 days after esophagectomy, the incidence of any postoperative complications within 30 days after esophagectomy, pulmonary function (preintervention, preoperative, and postoperative), walking distance in the incremental shuttle walking test (preintervention, preoperative, and postoperative), the incidence of adverse events, and mortality within 30 days after esophagectomy. Discussion: The EPITOPE study is the first pilot study on the effects of perioperative inhaled tiotropium on patients with COPD undergoing esophagectomy. After completing this study, we will plan a multicenter RCT with the appropriate outcomes in the future.

Patients with vertebral artery injury from penetrating neck trauma may not present with signs of vascular injury because of anatomical characteristics and concomitant conditions, such as hypothermia and shock. If patients are hemodynamically stable, imaging tests should be performed to examine the posterior components, including the vertebral artery., Although the “zone” approach may be useful for the surgical treatment of injuries to the anterior components of the neck, the “no zone” approach using imaging techniques should be applied when searching for posterior components, including the vertebral artery.

Background/aim Treatments containing ipilimumab have shown a good outcome in patients with non-small cell lung cancer (NSCLC) regardless of the PD-L1 tumor proportion score (TPS). However, the association between PD-L1 TPS and the expression of CTLA-4 in tumor-infiltrating lymphocytes is unknown. Patients and methods Fifty-five NSCLC patients who underwent surgery in our hospital were included in this study. We measured the proportions of CTLA-4+ regulatory T cells, and CTLA-4+ CD8 T cells, and statistically analyzed their correlations with the PD-L1 TPS. Results Statistical correlations were found neither between the proportion of CTLA-4+ regulatory T cells to CD8 T cells and the PD-L1 TPS (p=0.2859) nor between the proportion of CTLA-4+ cells in CD8 T cells and the PD-L1 TPS (p=0.1919). Conclusion The proportions of CTLA-4+ regulatory T cells to CD8 T cells and CTLA-4+ cells in CD8 T cells were irrelevant to the PD-L1 TPS in NSCLC patients.

The optimal treatment strategy for patients with borderline resectable (BR) esophageal squamous cell carcinoma (ESCC), in which tumors grow very close to the adjacent vital organs, remains unclear. This study evaluated the efficacy of neoadjuvant chemoradiotherapy (NACRT) with cisplatin plus fluorouracil (CF) and irradiation (40 Gy) for these patients. The study cohort included 50 patients with BR-ESCC who received NACRT as the initial treatment and were allocated to one of two groups: patients who achieved curative resection (R0 group) or those who did not (Non-R0 group). The overall survival (OS), relapse-free survival (RFS), and pre-therapeutic predictive factors for Non-R0 were evaluated. Among the 50 patients, 22 (44%) achieved curative resection clinically. The median OS was significantly better in the R0 group than in the Non-R0 group (2.4 vs 0.8 years; hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.12–0.67; p

Abnormal function of human body enzymes and epigenetic alterations such as DNA methylation have been shown to lead to human carcinogenesis. Lysyl oxidase (LOX) enzyme has attracted attention due to its involvement in tumor progression in various cancers. The purpose of this study was to clarify the clinical importance of LOX expression and its epigenetic regulation in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Using a database of 284 ESCCs, we examined LOX expression and its prognostic characteristics. The functional role of LOX was assessed by in vitro growth, migration, and invasion assays. The relationship between LOX expression, global DNA hypomethylation (ie, LINE‐1 methylation), and LOX promoter methylation was evaluated by using mRNA expression arrays and pyrosequencing technology. High LOX expression cases had a significantly shorter overall survival and cancer‐specific survival (log‐rank, P, This is the first study to provide the evidence for the relationship between lysyl oxidase (LOX) expression, poor prognosis, and aggressive phenotype in esophageal cancer. In addition, we revealed that LOX expression was regulated epigenetically by genome‐wide hypomethylation using in vitro assay and integrated gene analysis in tissues and cell lines.

Background In 2009, the Japan Esophageal Society (JES) established a system for certification of qualified surgeons as “Board Certified Esophageal Surgeons” (BCESs) or institutes as “Authorized Institutes for Board Certified Esophageal Surgeons” (AIBCESs). We examined the short-term outcomes after esophagectomy, taking into consideration the certifications statuses of the institutes and surgeons. Methods This study investigated patients who underwent esophagectomy for thoracic esophageal cancer and who were registered in the Japanese National Clinical Database (NCD) between 2015 and 2017. Using hierarchical multivariable logistic regression analysis adjusted for patient-level risk factors, we determined whether the institute’s or surgeon’s certification status had greater influence on surgery-related mortality or postoperative complications. Results Enrolled were 16,752 patients operated on at 854 institutes by 1879 surgeons. There were significant differences in the backgrounds and incidences of postoperative complications and surgery-related mortality rates between the 11,162 patients treated at AIBCESs and the 5590 treated at Non–AIBCESs (surgery-related mortality rates: 1.6% vs 2.8%). There were also differences between the 6854 patients operated on by a BCES and the 9898 treated by a Non-BCES (1.7% vs 2.2%). Hierarchical logistic regression analysis revealed that surgery-related mortality was significantly lower among patients treated at AIBCESs. The institute’s certification had greater influence on short-term surgical outcomes than the operating surgeon’s certification. Conclusions The certification system for surgeons and institutes established by the JES appears to be appropriate, as indicated by the improved surgery-related mortality rate. It also appears that the JES certification system contributes to a more appropriate medical delivery system for thoracic esophageal cancer in Japan.

Esophageal cancer is one of the most aggressive gastrointestinal cancers. This review focuses on eight topics within the multidisciplinary approach for esophageal cancer. As esophagectomy is highly invasive and likely to impair quality of life, the development of less invasive strategies is expected. Endoscopic resection (ER) of early esophageal cancer is a less invasive treatment for early esophageal cancer. A recent phase II trial revealed that combined ER and chemoradiotherapy (CRT) is efficacious as an esophagus-preserving treatment for cT1bN0 squamous cell carcinoma (SCC). Esophagectomy and definitive CRT are equally effective for patients with clinical stage I SCC in terms of long-term outcome. For locally advanced resectable cancers, multidisciplinary treatment strategies have been established through several clinical trials of neoadjuvant or perioperative treatment. Minimally invasive esophagectomy may improve the outcomes of patients and CRT is a curative-intent alternative to esophagectomy. CRT with 50.4 Gy radiotherapy combined with salvage surgery is a promising option to preserve the esophagus. Induction chemotherapy followed by esophagectomy may improve the outcomes of patients with locally advanced unresectable tumors. Immune checkpoint inhibitors are effective for esophageal cancer, and their introduction to clinical practice is awaited.

Esophagectomy for esophageal cancer is a very invasive surgery that induces an intense systemic inflammatory response. Postoperative infectious complications worsen survival after esophagectomy through inflammatory responses, and this study aimed to investigate the impact of the response on disease recurrence. We assessed 230 patients who underwent curative minimally invasive esophagectomy for esophageal squamous cell carcinoma. The area under the curve of serum C-reactive protein levels from preoperative day through postoperative day 7 was defined as the cumulative magnitude of postoperative inflammatory response. Relapse-free survival was compared among quartiles of the area, and fourth quartile showed the worst relapse-free survival. Patients in the fourth quartile were the high group, and others were low group. Compared with low group (n = 173), high group (n = 57) showed significantly worse relapse-free survival and overall survival (P = 0.014 and 0.028, respectively). Multivariate analyses found that high group (P = 0.048) was an independent risk factor for recurrence but not overall survival. Higher body mass index (P

Background This study’s aim is to measure liver-type fatty acid-binding protein (L-FABP) levels in urine using a rapid semiquantitative assay kit in the emergency department and to investigate whether the onset of acute kidney injury (AKI) after hospitalization can be predicted. Methods This was a prospective observation study. Patients transferred to the emergency and critical care center were divided into two groups: urinary L-FABP negative and positive groups. The status and severity of AKI were evaluated for the respective patients based on the Kidney Disease: Improving Global Outcome (KDIGO) classification. We compared the proportion of AKI patients in the two groups. Results In the urine L-FABP-positive group, many patients had a significant onset of AKI (p