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Abstract Background Peritoneal metastasis, a major complication of colorectal cancer (CRC), often leads to poor quality of life and unfavorable outcomes. Despite numerous studies characterizing its biological features in CRC, intratumor heterogeneity and interactions between cancer cells and tumor microenvironment cells remain poorly understood. Methods To explore these aspects, we performed single-cell transcriptome analysis of matched primary tumor and peritoneal metastasis samples from a treatment-naïve patient. Results Our analysis revealed enrichment of “tip” endothelial cells in the primary tumor, driving angiogenic sprouting, whereas these cells were absent in peritoneal metastases. Moreover, cancer cells in peritoneal metastasis displayed a distinct expression signature associated with epithelial–mesenchymal transition and tumor invasiveness. Analysis of cell–cell communication between endothelial and tumor cells revealed decreased VEGF signaling and increased CXCL–ACKR1 interactions in peritoneal metastasis. Conclusions Although limited by its N-of-1 design and requiring further validation, our study provides preliminary observations suggesting that alterations in cancer-endothelial cell interactions could reduce dependence on VEGF signaling and influence immune cell infiltration in CRC peritoneal metastasis.

Abstract Positive peritoneal washing cytology is an indicator of poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC); however, its sensitivity is relatively low. This study evaluated the performance of peptide nucleic acid (PNA)-directed PCR clamping as a molecular-based peritoneal washing cytology for sensitive detection of KRAS mutation in PDAC. Intraoperative peritoneal washing fluid (IPWF) obtained from patients with PDAC who underwent surgery was analyzed. PNA-directed PCR clamping was performed on DNA extracted from IPWF. Among 54 patients enrolled, threshold cycle (Ct) was significantly lower in patients with positive peritoneal washing cytology than in those with negative peritoneal washing cytology (P

Abstract Aim The coronavirus disease 2019 (COVID‐19) pandemic greatly impacted medical resources such as cancer screening, diagnosis, and treatment given to people for various diseases. We surveyed the impacts of the pandemic on the incidence of complications and mortality following pancreaticoduodenectomy for pancreatic cancer in Japan. Methods Data on patients who underwent pancreaticoduodenectomy for pancreatic cancer were extracted from the Japanese National Clinical Database (NCD) between 2018 and 2021. The number of the pancreaticoduodenectomy for pancreatic cancer were obtained and then the morbidity and mortality rates were evaluated using a standardized morbidity/mortality ratio (SMR), which is the ratio of the observed number of incidences to the expected number of incidences calculated by the risk calculator previously developed by the NCD. Results This study included 22 255 cases. The number of pancreaticoduodenectomies exhibited an increasing trend even during the COVID‐19 pandemic. The mean observed incidence rates of Grade C pancreatic fistula and Clavien–Dindo grade ≥4 complications, and the 30‐day mortality and surgical mortality rates were 0.8%, 1.8%, 0.8% and 0.9%, respectively. The standardized morbidity ratios did not increase during the COVID‐19 pandemic. The standardized mortality ratios remained within the range of variations observed before the COVID‐19 pandemic. Conclusion The increasing trend in the number of pancreaticoduodenectomies and favorable short‐term outcomes even in the COVID‐19 pandemic suggest the medical care for pancreatic cancer in Japan functioned well during the pandemic.

Abstract Background Due to the coronavirus disease 2019 (COVID‐19) pandemic, cancer screening, diagnosis, and treatment have changed. This study aimed to investigate the impact of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection prior to gastroenterological cancer surgeries on postoperative complications using data from a nationwide database in Japan. Methods Data on patients who underwent surgery for cancer including esophageal, gastric, colon, rectal, liver, and pancreatic cancer between July 1, 2019, and September 300, 2022, from real‐world sources in Japan were analyzed. The association between preoperative SARS‐CoV‐2 infection and short‐term postoperative outcomes was evaluated. A similar analysis stratified according to the interval from SARS‐CoV‐2 infection to surgery (4 weeks) was conducted. Results In total, 60 604 patients were analyzed, and 227 (0.4%) patients were diagnosed with SARS‐CoV‐2 infection preoperatively. The median interval from SARS‐CoV‐2 infection to surgery was 25 days. Patients diagnosed with SARS‐CoV‐2 infection preoperatively had a significantly higher incidence of pneumonia (odds ratio: 2.05; 95% confidence interval: 1.05–3.74; p = 0.036) than those not diagnosed with SARS‐CoV‐2 infection based on the exact logistic regression analysis adjusted for the characteristics of the patients. A similar finding was observed in patients who had SARS‐CoV‐2 infection

Abstract Aim To examine the potential negative effects of the COVID‐19 pandemic on short‐term postoperative outcomes of emergency surgery for gastroduodenal perforation in Japan. Methods A total of 7973 cases of gastroduodenal perforation from 2019 to 2021 were retrieved from the National Clinical Database (NCD), which includes >95% of surgical cases in Japan. Data were analyzed nationally and in subgroups for subjects in areas with high infection levels (HILs). Postoperative 30‐d mortality, surgical mortality, and complications (Clavien–Dindo (CD) grade ≥3) were examined. Months were considered to have significantly high or low mortality or complication rates, if the 95% confidence interval (CI) of the standardized mortality (morbidity) ratio (SMR) does not contain 1. Results Nationally, data from 2019 vs 2020 and 2021 showed 30‐d mortality of 175 (6.7%) vs 398 (7.4%), surgical mortality of 250 (9.5%) vs 537 (10.1%), and complications (CD ≥3) of 558 (21.2%) vs 1163 (21.8%). Among these data, the only significantly high SMR was found for complications in July 2020 (1.36 [95% CI: 1.001–1.80]). In areas with HILs, data from 2019 vs 2020 and 2021 indicated 30‐d mortality of 91 (6.3%) vs 215 (7.3%), surgical mortality of 135 (9.4%) vs 294 (10.0%), and complications (CD ≥3) of 304 (21.1%) vs (23.1%). In these data, no month had a significantly high SMR. Conclusion The COVID‐19 pandemic had few negative effects on outcomes after surgery for gastroduodenal perforation. These findings suggest that the emergency system for gastroduodenal perforation in Japan was generally maintained during the pandemic.

Abstract 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.

Abstract Aim Serum cholinesterase (ChE) levels are considered to reflect nutritional status. Although ChE has been well documented as a prognostic factor for some cancers, no clear consensus on its use for colorectal cancer (CRC) has been reached. The aim of this study was to investigate the relationship between preoperative serum ChE and postoperative long‐term prognosis in CRC patients. Methods A total of 1053 CRC patients who underwent curative surgery were included in this study. The correlations between the preoperative ChE value and overall survival (OS) or cancer‐specific survival (CSS) were assessed. By dividing patients into two groups according to their ChE value, OS and CSS were compared between the groups. Results Multivariate analysis revealed that the continuous ChE value was a significant predictor of OS (hazard ratio, 0.996; 95% CI, 0.993–0.998; p = 0.002) and CSS (hazard ratio, 0.994; 95% CI, 0.991–0.998; p = 0.001), independent of other variables. The low‐ChE (≤234 U/L) group had a significantly poorer prognosis than the high‐ChE (>234 U/L) group for both OS (5‐year OS for low ChE and high ChE: 79.8% and 93.3%, respectively; p

Abstract Introduction Complexities of robotic distal gastrectomy (RDG) give reason to assess physician's surgical skill. Varying levels in surgical skill affect patient outcomes. We aim to investigate how a novel artificial intelligence (AI) model can be used to evaluate surgical skill in RDG by recognizing surgical instruments. Methods Fifty‐five consecutive robotic surgical videos of RDG for gastric cancer were analyzed. We used Deeplab, a multi‐stage temporal convolutional network, and it trained on 1234 manually annotated images. The model was then tested on 149 annotated images for accuracy. Deep learning metrics such as Intersection over Union (IoU) and accuracy were assessed, and the comparison between experienced and non‐experienced surgeons based on usage of instruments during infrapyloric lymph node dissection was performed. Results We annotated 540 Cadiere forceps, 898 Fenestrated bipolars, 359 Suction tubes, 307 Maryland bipolars, 688 Harmonic scalpels, 400 Staplers, and 59 Large clips. The average IoU and accuracy were 0.82 ± 0.12 and 87.2 ± 11.9% respectively. Moreover, the percentage of each instrument's usage to overall infrapyloric lymphadenectomy duration predicted by AI were compared. The use of Stapler and Large clip were significantly shorter in the experienced group compared to the non‐experienced group. Conclusions This study is the first to report that surgical skill can be successfully and accurately determined by an AI model for RDG. Our AI gives us a way to recognize and automatically generate instance segmentation of the surgical instruments present in this procedure. Use of this technology allows unbiased, more accessible RDG surgical skill.

Abstract Aim The existing predictive risk models for the surgical outcome of acute diffused peritonitis (ADP) need renovation by adding relevant variables such as ADP's definition or causative etiology to pursue outstanding data collection reflecting the real world. We aimed to revise the risk models predicting mortality and morbidities of ADP using the latest Japanese Nationwide Clinical Database (NCD) variable set. Methods Clinical dataset of ADP patients who underwent surgery, and registered in the NCD between 2016 and 2019, were used to develop a risk model for surgical outcomes. The primary outcome was perioperative mortality. Results After data cleanup, 45 379 surgical cases for ADP were derived for analysis. The perioperative and 30‐day mortality were 10.6% and 7.2%, respectively. The prediction models have been created for the mortality and 10 morbidities associated with the mortality. The top five relevant predictors for perioperative mortality were age >80, advanced cancer with multiple metastases, platelet count of

Abstract Background Renal impairment is a predictor of coronavirus disease (COVID-19) severity. No studies have compared COVID-19 outcomes in patients with chronic kidney disease (CKD) and patients with impaired renal function without a prior diagnosis of CKD. This study aimed to identify the impact of pre-existing impaired renal function without CKD on COVID-19 outcomes. Methods This retrospective study included 3,637 patients with COVID-19 classified into three groups by CKD history and estimated glomerular filtration rate (eGFR) on referral: Group 1 (n = 2,460), normal renal function without a CKD history; Group 2 (n = 905), impaired renal function without a CKD history; and Group 3 (n = 272), history of CKD. We compared the clinical characteristics of these groups and assessed the effect of CKD and impaired renal function on critical outcomes (requirement for respiratory support with high-flow oxygen devices, invasive mechanical ventilation, or extracorporeal membrane oxygen, and death during hospitalization) using multivariable logistic regression. Results The prevalence of comorbidities (hypertension, diabetes, and cardiovascular disease) and incidence of inflammatory responses (white blood counts, and C-reactive protein, procalcitonin, and D-dimer levels) and complications (bacterial infection and heart failure) were higher in Groups 2 and 3 than that in Group 1. The incidence of critical outcomes was 10.8%, 17.7%, and 26.8% in Groups 1, 2, and 3, respectively. The mortality rate and the rate of requiring IMV support was lowest in Group 1 and highest in Group 3. Compared with Group 1, the risk of critical outcomes was higher in Group 2 (adjusted odds ratio [aOR]: 1.32, 95% confidence interval [CI]: 1.03–1.70, P = 0.030) and Group 3 (aOR: 1.94, 95% CI: 1.36–2.78, P

Abstract Development of subclassification of intermediate-stage hepatocellular carcinoma (HCC) by treatment suitability is in demand. We aimed to identify predictors that define treatment refractoriness against locoregional(transarterial chemoembolization(TACE) or thermal ablation) and surgical therapy. This multicenter retrospective study enrolled 1167 HCC patients between 2015 and 2021. Of those, 209 patients were initially diagnosed with intermediate-stage HCC. Treatment refractoriness was defined as clinical settings that meets the following untreatable progressive conditions by TACE (1) 25% increase of intrahepatic tumor, (2) transient deterioration to Child–Pugh class C, (3) macrovascular invasion or extrahepatic spread, within one year. We then analyzed factors contributing to treatment refractoriness. The Child–Pugh score/class, number of tumors, infiltrative radiological type, and recurrence were significant factors. Focusing on recurrence as a predictor, median time to untreatable progression (TTUP) was 17.2 months in the recurrence subgroup whereas 35.5 months in the initial occurrence subgroup (HR, 2.06; 95% CI, 1.44–2.96; P = 0.001). Median TTUP decreased in cases with more later times of recurrence (3–5 recurrences, 17.3 months; ≥ 6 recurrences, 7.7 months). Recurrence, even more at later times, leads to increased treatment refractoriness. Early introduction of multidisciplinary treatment should be considered against HCC patients after multiple recurrent episodes.

Abstract Aim Possible negative effects of the COVID‐19 pandemic on short‐term postoperative outcomes for colorectal perforation in Japan were examined in this study. Methods The National Clinical Database (NCD) is a large‐scale database including more than 95% of surgical cases in Japan. We analyzed 13 107 cases of colorectal perforation from 2019 to 2021. National data were analyzed, and subgroup analyses were conducted for subjects in prefectures with high infection levels (HILs) and metropolitan areas (Tokyo Met. and Osaka Pref.). Postoperative 30‐day mortality, surgical mortality, and postoperative complications (Clavien–Dindo grade ≥3) were examined. Months were considered to have significantly high or low mortality or complication rates, if the 95% confidence interval (CI) of the standardized mortality (morbidity) ratio (SMR) does not contain 1. Results In the NCD, postoperative 30‐day mortality occurred in 1371 subjects (10.5%), surgical mortality in 1805 (13.8%), and postoperative complications in 3950 (30.1%). Significantly higher SMRs were found for 30‐day mortality in November 2020 (14.6%, 1.39 [95% CI: 1.04–1.83]) and February 2021 (14.6%, 1.48 [95% CI: 1.10–1.96]), and for postoperative complications in June 2020 (37.3%, 1.28 [95% CI: 1.08–1.52]) and November 2020 (36.4%, 1.21 [95% CI: 1.01–1.44]). The SMRs for surgical mortality were not significantly high in any month. In prefectures with HILs and large metropolitan areas, there were few months with significantly higher SMRs. Conclusions The COVID‐19 pandemic had limited negative effects on postoperative outcomes in patients with colorectal perforation. These findings suggest that the emergency system for colorectal perforation in Japan was generally maintained during the pandemic.

Abstract Background Anemia has negative effects on long‐term outcomes of rectal cancer patients; however, its status as a risk factor for severe complications is disputed. Perioperative risks may differ based on the severity of pre‐surgical anemia; nonetheless, no previous study has investigated these differences. This study identified risks of severe postoperative complications in rectal cancer patients based on severity of their pre‐surgical anemia. Materials and Methods This study enrolled patients who underwent low anterior resection for rectal cancer and were registered in the Japanese National Clinical Database (NCD) between 2017 and 2019. Anemia severity was categorized into three levels: mild, moderate, and severe. A logistic regression model was applied to calculate the risk‐adjusted odds ratio (OR) of severe complications after surgery. Results This study analyzed a cohort of 51 765 rectal cancer patients who underwent low anterior resection. Results showed that severe complications occurred in 10.9% of patients and were significantly more frequent in patients with anemia (13.6%) than those with normal hemoglobin levels (9.2%). Risk‐adjusted ORs of severe complications in the severe, moderate, and mild anemia groups versus the normal group for males were 1.19 (95% confidence interval [CI]: 0.89–1.58), 1.47 (1.34–1.62), and 1.21 (1.12–1.31), respectively. Those for females were 1.39 (0.90–2.15), 1.64 (1.37–1.97), and 1.36 (1.16–1.58), respectively. Conclusions According to this large cohort study, pre‐surgical anemia significantly increases the risk of severe postoperative complications in rectal cancer patients. Even mild anemia presents a significant risk.

Abstract Background The COVID‐19 outbreak made conventional medical care impossible, forcing changes in both healthcare providers and patients. In Japan, COVID‐19 infection began spreading in earnest in 2020 and exploded in 2021. There was concern that the medical impact of COVID‐19 in 2021 would differ from that in 2020. We aimed to clarify the impact of COVID‐19 on mortality and anastomotic leakage in laparoscopic surgery for gastric cancer and rectal cancer in Japan using the National Clinical Database (NCD). Methods We collected data from patients who underwent laparoscopic distal gastrectomy (LDG) and laparoscopic low anterior resection (LLAR) from January 2018 to December 2021 from the NCD, a web‐based surgical registration system in Japan. The number of surgical cases, monthly incidence of mortality and morbidity (anastomotic leakage), standardized mortality ratio (SMR), and standardized morbidity‐leakage ratio (SMLR [ratio of observed patients to expected patients calculated using the risk calculator established in the NCD]) were evaluated. Results The numbers of LDG and LLAR cases continued to decline in the first year of the pandemic in 2020 and were as low in 2021 as in 2020. Although the numbers of robot‐assisted LDG and LLAR cases increased, the growth rate was lower than the rate of increase prior to the pandemic. Mortality and anastomotic leakage, two of the most important complications, as assessed by SMR and SMLR, did not worsen during the pandemic in comparison to the pre‐pandemic period. Conclusions Laparoscopic surgeries were performed safely in Japan and were not affected by the COVID‐19 pandemic.

Abstract Understanding the factors that influence people’s decisions regarding vaccination is essential to promote vaccination. We aimed to clarify the motivations for receiving booster vaccines. We conducted a paper-based questionnaire distributed during January–February 2022 involving students and faculty staff who received the first COVID-19 vaccination at the mass vaccination program during June–September 2021 at Keio University. A total of 1725 participants were enrolled, and all completed the survey. Among these, 64.9% reported a significant adverse event (AEs) affecting daily life after the second vaccine. “Fear of severe COVID-19 illness” (72.6%) was the most common reason for getting vaccinated, followed by “concern of infecting others” (68.4%) and “fear of COVID-19 infection itself” (68.3%). Television emerged as the most influential source of information (80%), followed by university information (50.2%) and social networking sites (42.8%). Multivariate analysis revealed “fear of severe COVID-19 illness”, “fear of COVID-19 infection itself”, and “trust in the efficacy and safety of the vaccines in general” were significantly correlated with willingness to receive paid vaccinations. The severity of AEs and source of information were not related to participants’ willingness to receive booster vaccinations. Participants with positive reasons for vaccination were more likely to accept a third dose.

Abstract Aim We explored institutional factors in Japan associated with lower operative mortality and failure‐to‐rescue (FTR) rates for eight major gastrointestinal procedures. Methods A 22‐item online questionnaire was sent to 2119 institutional departments (IDs) to examine the association between institutional factors and operative mortality and FTR rates. IDs were classified according to the number of annual surgeries, board certification status, and locality. In addition, the top 20% and bottom 20% of IDs were identified based on FTR rates and matched with the results of the questionnaire survey. Factors associated with operative mortality were selected by multivariate analysis. Results Of the 1083 IDs that responded to the questionnaire, 568 (213 382 patients) were included in the analysis. Operative morbidity, operative mortality, and FTR rates in the top 20% and bottom 20% of IDs were 13.1% and 8.4% (p

Abstract Aim The aim of this study was to verify the clinical feasibility of tele‐proctoring using our ultra‐low latency communication system with shared internet access. Methods Connections between two multiple remote locations at various distances were established through the TELEPRO® tele‐proctoring system. The server records the latency between the two locations for tele‐proctoring using the annotations. Questionnaires were administered to the surgeons, assistants, and medical staff. Respondents rated the quickness and quality of communication in terms of latency and disturbances in the audio, video, and usefulness of the live telestrations with annotation. Results Seven hospitals tele‐proctored with Sapporo Medical University between January 2021 and September 2022. The median latency of annotation between the two locations ranged from 24.5 to 48.5 ms. No major technological problems occurred, such as streaming interruption, loss of video or audio, poor resolution. The video encoding time was 10 ms, and its decoding time was 0.8 ms. The total latency positively correlated with the distance between two locations (R = 0.55, p

Abstract Background Although adjuvant gemcitabine (GEM) monotherapy improves the overall survival (OS) of patients with resected pancreatic cancer, its efficacy requires further improvement. This multicenter, phase II study investigated the efficacy of adjuvant portal vein infusion (PVI) chemotherapy followed by GEM therapy in patients with resected pancreatic cancer. Methods 5‐fluorouracil (250 mg/day) and heparin (2000 IU/day) PVI chemotherapy were combined with systemic administration of mitomycin C (4 mg; days 6, 13, 20, and 27) and cisplatin (10 mg; days 7, 14, 21, and 28) for 4 weeks (PI4W), followed by GEM (1000 mg/m2; days 1, 8, and 15 every 4 weeks for 6 months). The primary endpoint was relapse‐free survival (RFS) and the secondary endpoints were OS and treatment completion. Results Between November 2010 and August 2013, 53 patients who underwent complete resection were enrolled, including 30, 20, and 3 patients who underwent pancreaticoduodenectomies and distal and total pancreatectomies, respectively. In total, 51 (96.2%) patients underwent R0 resection, of whom 3, 2, 12, 35, 0, and 1 had stages IA, IB, IIA, IIB, III, and IV cancer, respectively, and 47 (88.7%) patients completed PI4W. The median RFS was 22.0 months (1‐, 3‐, 5, and 10 years RFS: 64.9%, 38.1%, 38.1%, and 38.1%, respectively), whereas the median OS was 32.0 months (1‐, 3‐, 5, and 10 years OS:86.6%, 47.2%, 44.4%, and 44.4%, respectively). Conclusion Treatment with PI4W followed by GEM for 6 months after surgery may be beneficial in patients undergoing curative resection of pancreatic cancer.

Abstract Aim The Coronavirus Disease 2019 (COVID‐19) pandemic affected the allocation of various medical resources to several areas, including intensive care units (ICUs). However, currently, its impact on the short‐term postoperative outcomes of gastrointestinal cancer surgeries remains unclear. We aimed to evaluate the impact of the pandemic on the incidence of complications occurring after low anterior resection in patients with rectal cancer in Japan. Methods Data from the Japanese National Clinical Database between 2018 and 2021 were retrospectively examined. The primary outcome of the study was the postoperative morbidity and mortality rates before and after COVID‐19 pandemic. Moreover, the postoperative ICU admission rate was assessed. Morbidity and mortality rates were also assessed using a standardized morbidity/mortality ratio (SMR, the ratio of the actual number of incidences to the expected number of incidences calculated by the risk calculator). Results This study included 74 181 patients, including 43 663 (58.9%) from COVID‐19 epidemic areas. The mean actual incidences of anastomotic leakage (AL) and pneumonia during the study period were 9.2% and 0.9%, respectively. The SMRs of these complications did not increase during the pandemic but those of AL declined gradually. The mean 30‐day mortality and operative mortality rates were 0.3% and 0.5%, respectively. Moreover, SMRs did not change significantly in the pandemic or regional epidemic status. The ICU admission rate temporarily decreased, especially in the epidemic areas. Conclusion Although the pandemic temporarily decreased the ICU admission rate, its impact on short‐term outcomes following low anterior resection in patients with rectal cancer was insignificant in Japan.

Abstract The severity of chest X-ray (CXR) findings is a prognostic factor in patients with coronavirus disease 2019 (COVID-19). We investigated the clinical and genetic characteristics and prognosis of patients with worsening CXR findings during early hospitalization. We retrospectively included 1656 consecutive Japanese patients with COVID-19 recruited through the Japan COVID-19 Task Force. Rapid deterioration of CXR findings was defined as increased pulmonary infiltrates in ≥ 50% of the lung fields within 48 h of admission. Rapid deterioration of CXR findings was an independent risk factor for death, most severe illness, tracheal intubation, and intensive care unit admission. The presence of consolidation on CXR, comorbid cardiovascular and chronic obstructive pulmonary diseases, high body temperature, and increased serum aspartate aminotransferase, potassium, and C-reactive protein levels were independent risk factors for rapid deterioration of CXR findings. Risk variant at the ABO locus (rs529565-C) was associated with rapid deterioration of CXR findings in all patients. This study revealed the clinical features, genetic features, and risk factors associated with rapid deterioration of CXR findings, a poor prognostic factor in patients with COVID-19.

Hepatocyte transplantation (HCT) is a potential bridging therapy or an alternative to liver transplantation. Conventionally, single-cell hepatocytes are injected via the portal vein. This strategy, however, has yet to overcome poor cell engraftment and function. Therefore, we developed an orthotopic HCT method using a liver-derived extracellular matrix (L-ECM) gel. PXB cells (flesh mature human hepatocytes) were dispersed into the hydrogel solution in vitro, and the gel solution was immediately gelated in 37°C incubators to investigate the affinity between mature human hepatocyte and the L-ECM gel. During the 3-day cultivation in hepatocyte medium, PXB cells formed cell aggregates via cell–cell interactions. Quantitative analysis revealed human albumin production in culture supernatants. For the in vivo assay, PXB cells were encapsulated in the L-ECM gel and transplanted between the liver lobes of normal rats. Pathologically, the L-ECM gel was localized at the transplant site and retained PXB cells. Cell survival and hepatic function marker expression were verified in another rat model wherein thioacetamide was administered to induce liver fibrosis. Moreover, cell–cell interactions and angiogenesis were enhanced in the L-ECM gel compared with that in the collagen gel. Our results indicate that L-ECM gels can help engraft transplanted hepatocytes and express hepatic function as a scaffold for cell transplantation.

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

Abstract Aim Tumor rupture has been indicated as a risk factor for recurrence of gastrointestinal stromal tumors (GISTs). The universal definition of tumor rupture was proposed. This study evaluated whether the universal definition was more accurate in identification of GISTs with high recurrent risk than subjective judgment. Methods The study included 507 patients with high‐risk GISTs who underwent complete resection between December 2012 and December 2015. We conducted a questionnaire survey in participating institutes to re‐diagnose tumor rupture based on the universal definition according to their surgical and pathological findings. We compared the clinical outcomes of tumor rupture based on the definition to those based on the surgeon's judgment and clarified the clinical importance of the rupture. Results Sixty‐four patients were initially registered to have tumor rupture by surgeon's judgment, and it became 90 patients who had tumor rupture after reevaluation. Although there were significant differences in recurrence‐free survival (RFS) between no rupture and rupture for both initial registration and reevaluation (p = 0.002,

Abstract Background The coronavirus disease 2019 (COVID‐19) pandemic had resulted in either failure to provide required medical resources or delayed treatment for gastric cancer patients. This study aimed to investigate the impact of COVID‐19 on the incidence of postoperative complications using a nationwide Japanese database of patients undergoing distal gastrectomy for gastric cancer. Methods We collected the data of patients who underwent distal gastrectomy from January 2018 to December 2021 from the National Clinical Database (NCD), a web‐based surgical registration system in Japan. The number of surgical cases, the use of intensive care units, and the incidence of morbidity per month were analyzed. We also calculated the standardized mortality ratio (SMR), defined as the ratio of the number of observed patients to the expected number of patients calculated using the risk calculator established in the NCD, for several morbidities, including pneumonia, sepsis, 30‐day mortality, and surgical mortality. Results A decrease of 568 gastrectomies was observed from April 2020 to May 2020. Although the absolute number of patients admitted to intensive care units had declined since 2020, the proportion of patients admitted to the ICU did not change before and after the pandemic. Mortality and critical morbidity (such as pneumonia and sepsis) rates were not worse during the pandemic compared to pre‐pandemic periods per the SMR. Conclusions Surgical management was conducted adequately through the organized efforts of the entire surgery department in our country even in a pandemic during which medical resources and staff may have been limited.

Abstract Drug-induced liver fibrosis models are used in normal and immunosuppressed small animals for transplantation and regenerative medicine to improve liver fibrosis. Although large animal models are needed for pre-clinical studies, they are yet to be established owing to drug sensitivity in animal species and difficulty in setting doses. In this study, we evaluated liver fibrosis by administering thioacetamide (TA) to normal microminipig and thymectomized microminipig; 3 times for 1 week (total duration: 8 weeks). The pigs treated with TA showed elevated blood cytokine levels and a continuous liver injury at 8 weeks. RNA-seq of the liver showed increased expression of fibrosis-related genes after TA treatment. Histopathological examination showed degenerative necrosis of hepatocytes around the central vein, and revealed fibrogenesis and hepatocyte proliferation. TA treatment caused CD3-positive T cells and macrophages scattered within the hepatic lobule to congregate near the center of the lobule and increased αSMA-positive cells. Thymectomized pigs showed liver fibrosis similar to that of normal pigs, although the clinical signs tended to be milder. This model is similar to pathogenesis of liver fibrosis reported in other animal models. Therefore, it is expected to contribute to research as a drug discovery and pre-clinical transplantation models.

Abstract Aim Neoadjuvant chemoradiotherapy may improve survival in patients with advanced cholangiocarcinoma. This Phase I study aimed to determine the recommended dose of neoadjuvant chemoradiotherapy and decide whether to move to a Phase II study. Methods Patients diagnosed with resectable stage II–IVa cholangiocarcinoma were administered cisplatin (40 [level 0], 50 [level 1 as starting dose], or 60 [level 2] mg/m2), 80 mg/m2 of S‐1, and 50.4 Gy of external beam radiation. The recommended dose was defined as a dose one‐step lower than the maximum‐tolerated dose, which was defined when dose‐limiting toxicity was observed in three or more of the six patients. Results Twelve patients were eligible from November 2012 to May 2016. Ten patients had perihilar cholangiocarcinoma and two patients had distal cholangiocarcinoma. Dose‐limiting toxicity was observed in one of the first six patients at level 1 and two of the next six patients at level 2; thus, the maximum‐tolerated dose was not determined even at level 2 and the recommended dose was determined as level 2. Four patients had partial response, four patients had stable disease, and two patients had progression of disease because of liver metastases. Finally, nine patients underwent radical surgery and seven cases achieved R0 resection. However, five cases suffered biliary leakage and one suffered intrahospital death due to rupture of the hepatic artery. Conclusion We determined the recommended dose of neoadjuvant chemoradiotherapy for resectable cholangiocarcinoma. However, we terminated the trial due to a high incidence of morbidity and unexpected mortality.

Abstract Background The current standard operation for proximal gastric and gastroesophageal junction (P/GEJ) cancers with limited esophageal extension is total gastrectomy (TG). TG is associated with impaired appetite and weight loss due to the loss of gastric functions such as production of ghrelin and with anemia due to intrinsic factor loss and vitamin B12 malabsorption. Theoretically, proximal gastrectomy (PG) can mitigate these problems by preserving gastric function. However, PG with direct esophagogastric reconstruction is associated with severe postoperative reflux, delayed gastric emptying, and poor quality of life (QoL). Minimally invasive PG (MIPG) with antireflux techniques has been increasingly performed by experts but is technically demanding owing to its complexity. Moreover, the actual advantages of MIPG over minimally invasive TG (MITG) with regards to postoperative QoL are unknown. Our overall objective of this study is to determine the short-term QoL benefits of MIPG. Our central hypotheses are that MIPG is safe and that patients have improved appetite after MIPG with effective antireflux techniques, which leads to an overall QoL improvement when compared with MITG. Methods Enrollment of a total of 60 patients in this prospective survey-collection study is expected. Procedures (MITG versus MIPG, antireflux techniques for MIPG [double-tract reconstruction versus the double-flap technique]) will be chosen based on surgeon and/or patient preference. Randomization is not considered feasible because patients often have strong preferences regarding MITG and MIPG. The primary outcome is appetite level (reported on a 0-10 scale) at 3 months after surgery. With an expected 30 patients per cohort (MITG versus MIPG), this study will have 80% power to detect a one-point difference in appetite level. Patient-reported outcomes will be longitudinally collected (including questions about appetite and reflux), and specific QoL items, body weight, body mass index and ghrelin, albumin, and hemoglobin levels will be compared. Discussion Surgeons from the US, Japan, and South Korea formed this collaboration with the agreement that the surgical approach to P/GEJ cancers is an internationally important but controversial topic that requires immediate action. At the completion of the proposed research, our expected outcome is the establishment of the benefit and safety of MIPG. Trial registration This trial was registered with Clinical Trials Reporting Program Registration under the registration number NCI-2022–00267 on January 11, 2022, as well as with ClinicalTrials.gov under the registration number NCT05205343 on January 11, 2022.

Patients with pancreatic neuroendocrine tumors (pNETs) have limited access to effective targeted agents and invariably succumb to progressive disease. MUC1-C is a druggable oncogenic protein linked to driving pan-cancers. There is no known involvement of MUC1-C in pNET progression. The present work was performed to determine if MUC1-C represents a potential target for advancing pNET treatment. We demonstrate that the MUC1 gene is upregulated in primary pNETs that progress with metastatic disease. In pNET cells, MUC1-C drives E2F- and MYC-signaling pathways necessary for survival. Targeting MUC1-C genetically and pharmacologically also inhibits self-renewal capacity and tumorigenicity. Studies of primary pNET tissues further demonstrate that MUC1-C expression is associated with (i) an advanced NET grade and pathological stage, (ii) metastatic disease, and (iii) decreased disease-free survival. These findings demonstrate that MUC1-C is necessary for pNET progression and is a novel target for treating these rare cancers with anti-MUC1-C agents under clinical development.

Abstract Aim This study was performed to evaluate the oncological impact of surgical site infection (SSI) and pneumonia on long‐term outcomes after esophagectomy. Methods The Japan Society for Surgical Infection conducted a multicenter retrospective cohort study involving 407 patients with curative stage I/II/III esophageal cancer at 11 centers from April 2013 to March 2015. We investigated the association of SSI and postoperative pneumonia with oncological outcomes in terms of relapse‐free survival (RFS) and overall survival (OS). Results Ninety (22.1%), 65 (16.0%), and 22 (5.4%) patients had SSI, pneumonia, and both SSI and pneumonia, respectively. The univariate analysis demonstrated that SSI and pneumonia were associated with worse RFS and OS. In the multivariate analysis, however, only SSI had a significant negative impact on RFS (HR, 1.63; 95% confidence interval, 1.12–2.36; P = 0.010) and OS (HR, 2.06; 95% confidence interval, 1.41–3.01; P

Abstract Aim Liver allografts from brain‐dead donors, which were declined and were eventually not transplanted due to accompanying marginal factors, have never been surveyed in Japan. We surveyed the declined allografts and discussed the graft potential focusing on various marginal factors. Methods We collected data on brain‐dead donors between 1999 and 2019 from the Japan Organ Transplant Network. We divided their liver allografts into declined (nontransplanted) and transplanted ones, and then characterized declined ones focusing on their timepoints of decline and accompanying marginal factors. For each marginal factor, we calculated the decline rate from the number of declined and transplanted allografts, and assessed the 1‐year graft survival rate from transplanted allografts. Results A total of 571 liver allografts were divided into 84 (14.7%) declined and 487 (85.3%) transplanted ones. In the declined allografts, a majority was declined after laparotomy (n = 55, 65.5%), most of which had steatosis and/or fibrosis (n = 52). Out of the moderate steatotic (without F ≥ 2 fibrosis) allografts (n = 33), 21 were declined and 12 were transplanted, leading to a 63.6% decline rate. The latter 12 achieved a 92.9% 1‐year graft survival rate after transplantation. Comparison of donor background showed no significant difference between the declined and transplanted allografts. Conclusion Pathological abnormalities of steatosis/fibrosis seem to be the most common donor factor leading to graft decline in Japan. Allografts with moderate steatosis were highly declined; however, transplanted ones achieved promising outcomes. This national survey highlights the potential utility of liver allografts with moderate steatosis.

Abstract Aim This study aimed to evaluate the impact of the coronavirus disease (COVID‐19) pandemic on elective endoscopic surgeries in Japan using the National Clinical Database. Methods We retrospectively analyzed the clinicopathological factors and surgical outcomes of laparoscopic cholecystectomy (LC), laparoscopic distal gastrectomy (LDG), and laparoscopic low anterior resection (LLAR) and compared the monthly numbers of each procedure performed in 2020 with those in 2018 and 2019. The degree of infection in prefectures was classified into low and high groups. Results In 2020, the number of LCs (except for acute cholecystitis) was 76 079 (93.0% of that in 2019), the number of LDGs was 14 271 (85.9% of that in 2019), and the number of LLARs was 19 570 (88.1% of that in 2019). Although the number of robot‐assisted LDG and LLAR cases increased in 2020, the growth rate was mild compared with that in 2019. There was little difference in the number of cases in the degree of infection in the prefectures. The numbers of LC, LDG, and LLAR cases decreased from May to June and recovered gradually. In late 2020, the proportion of T4 and N2 cases of gastric cancer and the number of T4 cases of rectal cancer increased compared with those in 2019. There was little difference between the proportions of postoperative complications and mortality in the three procedures between 2019 and 2020. Conclusion The number of endoscopic surgeries decreased in 2020 as a result of the COVID‐19 pandemic. However, the procedures were performed safely in Japan.

Objectives: COVID-19 was severe in the Delta variant-dominated epidemic wave (fifth wave) in Japan. The clinical characteristics and effectiveness of COVID-19 vaccination are not fully understood in the Omicron variant-dominated wave (sixth and seventh waves), especially in hospitalized patients. We investigated the relationship between vaccination and disease severity in the Omicron-dominated wave and compared these variant-dominated waves. Methods: The nationwide COVID-19 database (Japan COVID-19 Task Force) was used to compare clinical characteristics and critical outcomes in patients hospitalized with Delta (fifth, N = 735) vs Omicron-dominated waves (sixth, N = 495; seventh, N = 128). Results: Patients in the sixth and seventh waves had a lower incidence of critical outcomes and respiratory outcomes, and a higher incidence of bacterial infection, although the mortality rate did not differ significantly between waves. In the sixth and seventh waves, 138 (27.9%) and 29 (22.7%) patients with COVID-19 were unvaccinated, respectively. Multivariable analysis adjusted with previously reported factors revealed that the proportion of (1) critical outcomes and (2) respiratory outcomes decreased in a frequency-dependent manner. Thus, (1) (the number of vaccinations): 1-2 times: adjusted odds ratio (aOR) 0.37 (95% confidence interval [CI]; 0.20-0.69); 3-4 times: aOR 0.25 (95% CI; 0.11-0.58); and (2) 1-2 times: aOR 0.43 (95% CI; 0.27-0.66); 3-4 times: aOR 0.36 (95% CI; 0.21-0.60). Conclusions: Patients hospitalized with COVID-19 with Omicron infections showed a lower incidence of critical outcomes than those with Delta infections, and COVID-19 vaccination may contribute to preventing respiratory failure.

Reconstruction of the biliary system is indispensable for the regeneration of transplantable liver grafts. Here, we report the establishment of the first continuous three-dimensional biliary system scaffold for bile acid excretion using a novel method. We confirmed the preservation of the liver-derived extracellular matrix distribution in the scaffold. In addition, hepatocyte progenitors decellularized via the bile duct by slow-speed perfusion differentiated into hepatocyte- and cholangiocyte-like cells, mimicking hepatic cords and bile ducts, respectively. Furthermore, qRT-PCR demonstrated increased ALB, BSEP, and AQP8 expression, revealing bile canaliculi- and bile duct-specific genetic patterns. Therefore, we concluded that locally preserved extracellular matrices in the scaffold stimulated hepatic progenitors and provided efficient differentiation, as well as regeneration of a three-dimensional continuous biliary system from hepatic cords through bile ducts. These findings suggest that organ-derived scaffolds can be utilized for the efficient reconstruction of functional biliary systems.

We conducted a subgroup analysis of a study on the long-term effects of COVID-19 (long COVID) in Japan to assess the effect of vaccination on long COVID symptoms. We assessed the clinical course of 111 patients with long COVID at the time of vaccination. The follow-up period was one year from the onset of COVID-19 or until the administration of the third vaccine dose. Of the 111 patients, 15 (13.5%) reported improvement, four (3.6%) reported deterioration, and 92 (82.9%) reported no change in their long COVID symptoms after vaccination. The most common long COVID symptoms before vaccination were alopecia, dyspnea, muscle weakness, fatigue, and headache among participants whose symptoms improved. Reduced dyspnea and alopecia were the most frequently reported improvements in symptoms after vaccination. Some symptoms persisted, including sleep disturbance, myalgia, and hypersensitivity. Vaccination did not appear to have a clinically important effect on patients with long COVID symptoms.

Background Krebs von den Lungen-6 (KL-6) is a known biomarker for diagnosis and monitoring of interstitial lung diseases. However, the role of serum KL-6 and the mucin 1 (MUC1) variant (rs4072037) in COVID-19 outcomes remains to be elucidated. We aimed to evaluate the relationships among serum KL-6 levels, critical outcomes and the MUC1 variant in Japanese patients with COVID-19.Methods This is a secondary analysis of a multicentre retrospective study using data from the Japan COVID-19 Task Force collected from February 2020 to November 2021, including 2226 patients with COVID-19 whose serum KL-6 levels were measured. An optimal serum KL-6 level cut-off to predict critical outcomes was determined and used for multivariable logistic regression analysis. Furthermore, the relationship among the allele dosage of the MUC1 variant, calculated from single nucleotide polymorphism typing data of genome-wide association studies using the imputation method, serum KL-6 levels and COVID-19 critical outcomes was evaluated.Results Serum KL-6 levels were significantly higher in patients with COVID-19 with critical outcomes (511±442 U/mL) than those without (279±204 U/mL) (p

Abstract Aim This study aimed to investigate the effect of the coronavirus disease pandemic on the number of surgeries for gastroenterological cancer cases in Japan. Methods The data recorded in the National Clinical Database of Japan between 2018 and 2020 were utilized for this study. Five specific surgeries for primary cancers and surgery for acute diffuse peritonitis were considered the primary endpoints. We divided the study period into the prepandemic and postpandemic (after April 2020) periods and examined the number of surgeries in relation to clinical factors. Results Overall, 228 860 surgeries were analyzed. Among the five primary cancer surgeries, the number of distal gastrectomies for gastric cancer decreased the most (to 81.0% of the monthly number in the prepandemic period), followed by that of low anterior resections for rectal cancer (91.4%). In contrast, the number of pancreaticoduodenectomies for pancreatic cancer increased by 7.1%, while that of surgeries for peritonitis remained stable. This trend was observed nationwide. We also noted a marked reduction in the number of distal gastrectomy (to 72.5%), low anterior resection (84.0%), and esophagectomy (88.8%) procedures for T1 tumors. The noncurative resection rate and mortalities were low despite the increased proportion of T4 tumors and older patients. Conclusion A marked reduction in surgeries for gastric and rectal cancers with early T factors may reflect prioritization of surgeries and reduction in cancer screenings. Although the quality of the surgery was maintained in terms of reduced mortalities and morbidities, the long‐term effects of this pandemic should be monitored.

Abstract Background Loss of skeletal muscle mass is a prognostic factor after surgery for gastrointestinal cancers. The treatment for perihilar cholangiocarcinoma (PHC) is a highly invasive surgery. Biliary drainage and portal vein embolization, which can prolong the preoperative waiting time (PWT), are often required before surgery. Assuming that the skeletal muscle mass can change during PWT, we investigated the clinical effect of skeletal muscle change on surgical outcomes of PHC. Methods We retrospectively reviewed the medical records of 89 patients who underwent curative surgery for PHC from January 2013 to December 2019. We defined the psoas muscle area (PMA) at the third lumbar vertebra as the skeletal muscle mass. The PMA just before surgery was divided by that at the time of diagnosis, and we defined it as the rate of change of PMA (CPMA). Patients were divided into two groups according to CPMA: wasting (n = 44, below the median CPMA) and no‐change (n = 45, above the median CPMA). Results The median PWT was 63 d, and CPMA was 96.1%. The median recurrence‐free survival and overall survival were significantly shorter in the wasting group than in the no‐change group (8.0 vs 33.2 mo, P = 0.001 and 14.2 vs 48.7 mo, P

Abstract Aim The National Clinical Database (NCD) of Japan is a nationwide data entry system for surgery, and it marked its 10th anniversary in 2020. The aim was to present the 2020 annual report of gastroenterological surgery of the NCD. Methods The data of the surgical procedures stipulated by the training curriculum for board‐certified surgeons of the Japanese Society of Gastroenterological Surgery in the NCD from 2011 to 2020 were summarized. Results In total, 5 622 845 cases, including 593 088 cases in 2020, were extracted from the NCD. The total number of gastroenterological surgeries increased gradually in these 10 years, except for the year 2020 due to the COVID‐19 pandemic. The annual number of surgeries of each organ, except the pancreas and liver, decreased by 0.4%–13.1% in 2020 compared to 2019. The surgical patients were consistently aging, with more than 20% of all gastroenterological surgeries in 2020 involving patients aged 80 years or older. The participation of board‐certified surgeons increased for each organ (75.9%–95.7% in 2020). The rates of endoscopic surgery also increased constantly. Although the incidences of postoperative complications of each organ increased by 0.7%–7.9% in these 10 years, postoperative mortality rates decreased by 0.2%–1.5%. Conclusions We present here the short‐term outcomes of each gastroenterological operative procedure in 2020. This review of the 10‐years of NCD data of gastroenterological surgery revealed a consistent increase of the number of surgeries (except for in 2020), especially endoscopic procedures, and aging of the Japanese population. The good safety of Japanese gastroenterological surgeries was also indicated.

Abstract Background Although cases of respiratory bacterial infections associated with coronavirus disease 2019 (COVID-19) have often been reported, their impact on the clinical course remains unclear. Herein, we evaluated and analyzed the complication rates of bacterial infections, causative organisms, patient backgrounds, and clinical outcome in Japanese patients with COVID-19. Methods We performed a retrospective cohort study that included inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021) and obtained demographic, epidemiological, and microbiological results and the clinical course and analyzed the cases of COVID-19 complicated by respiratory bacterial infections. Results Of the 1,863 patients with COVID-19 included in the analysis, 140 (7.5%) had respiratory bacterial infections. Community-acquired co-infection at COVID-19 diagnosis was uncommon (55/1,863, 3.0%) and was mainly caused by Staphylococcus aureus, Klebsiella pneumoniae and Streptococcus pneumoniae. Hospital-acquired bacterial secondary infections, mostly caused by Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia, were diagnosed in 86 patients (4.6%). Severity-associated comorbidities were frequently observed in hospital-acquired secondary infection cases, including hypertension, diabetes, and chronic kidney disease. The study results suggest that the neutrophil–lymphocyte ratio (> 5.28) may be useful in diagnosing complications of respiratory bacterial infections. COVID-19 patients with community-acquired or hospital-acquired secondary infections had significantly increased mortality. Conclusions Respiratory bacterial co-infections and secondary infections are uncommon in patients with COVID-19 but may worsen outcomes. Assessment of bacterial complications is important in hospitalized patients with COVID-19, and the study findings are meaningful for the appropriate use of antimicrobial agents and management strategies.

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

Objectives: Smoking and chronic obstructive pulmonary disease (COPD) are risk factors for severe COVID-19. However, limited literature exists on the effect of COPD and smoking on COVID-19 outcomes. This study examined the impact of smoking exposure in pack-years (PY) and COPD on COVID-19 outcomes among smokers in Japan. Methods: The study included 1266 smokers enrolled by the Japan COVID-19 task force between February 2020 and December 2021. PY and COPD status was self-reported by patients. Patients were classified into the non-COPD (n = 1151) and COPD (n = 115) groups; the non-COPD group was further classified into 30 PY (n = 361). The study outcome was the need for invasive mechanical ventilation (IMV). Results: The incidence of IMV increased with increasing PY and was highest in the COPD group (30 PY = 15.2%, COPD = 26.1%; P 30 PY and COPD groups through univariate (odds ratio [OR]: >30 PY = 2.11, COPD = 4.14) and multivariate (OR: >30 PY = 2.38; COPD = 7.94) analyses. Increasing PY number was also associated with increased IMV requirement in patients aged

Abstract Aim To investigate the impact of postoperative infection (PI), surgical site infection, and remote infection (RI), on long‐term outcomes in patients with colorectal cancer (CRC). Methods The Japan Society for Surgical Infection conducted a multicenter retrospective cohort study involving 1817 curative stage I/II/III CRC patients from April 2013 to March 2015. Patients were divided into the No‐PI group and the PI group. We examined the association between PI and oncological outcomes for cancer‐specific survival (CSS) and overall survival (OS) using Cox proportional hazards models and propensity score matching. Results Two hundred and ninety‐nine patients (16.5%) had PIs. The 5‐year CSS and OS rates in the No‐PI and PI groups were 92.8% and 87.6%, and 87.4% and 83.8%, respectively. Both the Cox proportional hazards models and propensity score matching demonstrated a significantly worse prognosis in the PI group than that in the No‐PI group for CSS (hazard ratio: 1.60; 95% confidence interval: 1.10‐2.34; P = .015 and P = .031, respectively) but not for OS. RI and the PI severity were not associated with oncological outcomes. The presence of PI abolished the survival benefit of adjuvant chemotherapy. Conclusions These results suggest that PI after curative CRC surgery is associated with impaired oncological outcomes. This survival disadvantage of PI was primarily derived from surgical site infection, not RI, and PI induced lower efficacy of adjuvant chemotherapy. Strategies to prevent PI and implement appropriate postoperative treatment may improve the quality of care and oncological outcomes in patients undergoing curative CRC surgery.

Abstract Aim This study aimed to predict cases of acute superior mesenteric artery (SMA) occlusion requiring bowel resection using occlusion site and time from symptom onset to diagnosis at five Japanese institutions. Advances in imaging, endovascular treatment, and perioperative management have improved the clinical outcomes of patients with acute SMA occlusion; however, in clinical practice it remains difficult to effectively determine patients requiring bowel resection. Methods We retrospectively analyzed the data of 48 patients (mean age: 82.5 y; male: 37.5%) diagnosed with acute SMA occlusion between June 2009 and August 2018. Background data of patients who required and did not require bowel resection were compared. A multivariable predictive model was developed using the time from symptom onset to diagnosis and whether SMA occlusion was proximal, including the origin of the middle colic artery. Results Fifteen patients (31.3%) died during the hospital stay. Atrial fibrillation (83.3%) was the most common comorbidity. The median time from symptom onset to diagnosis was 13.0 (interquartile range, 4.75–24.0) h. Laparotomy, bowel resection, and thrombus embolectomy were performed in 41 (85.4%), 26 (54.2%), and 21 (43.8%) patients, respectively. A logistic regression model achieved 78.6% sensitivity in predicting cases not requiring bowel resection. Proximal occlusion was significantly associated with the requirement for bowel resection (P = .039). Conclusion The time from symptom onset to diagnosis and occlusion site contributed to high sensitivity in determining the need for bowel resection in patients with acute SMA occlusion. Further prospective studies are warranted to investigate the clinical impact of this model.

Abstract Background We aimed to elucidate differences in the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan, by COVID-19 waves, from conventional strains to the Delta variant. Methods We used secondary data from a database and performed a retrospective cohort study that included 3261 patients aged ≥ 18 years enrolled from 78 hospitals that participated in the Japan COVID-19 Task Force between February 2020 and September 2021. Results Patients hospitalized during the second (mean age, 53.2 years [standard deviation {SD}, ± 18.9]) and fifth (mean age, 50.7 years [SD ± 13.9]) COVID-19 waves had a lower mean age than those hospitalized during the other COVID-19 waves. Patients hospitalized during the first COVID-19 wave had a longer hospital stay (mean, 30.3 days [SD ± 21.5], p

Abstract Aim The National Health Insurance system has reimbursed robotic gastrointestinal surgery since April 2018 in Japan. Additionally, strict facility and surgeon standards were established by the government and the academic society. This study aimed to evaluate the prevalence and safety of robotic surgery using a Japanese nationwide web‐based database. Methods Patients who underwent the following robotic surgeries for malignant tumors in 2018 were included: esophagectomy (RE), total gastrectomy (RTG), distal gastrectomy (RDG), proximal gastrectomy (RPG), low anterior resection (RLAR), and rectal resections other than RLAR (RRR). The number of cases and surgical mortality rates each month were calculated to evaluate the prevalence and safety of robotic procedures. Results A total of 3281 patients underwent robotic gastrointestinal surgery. The monthly number of robotic surgeries nearly doubled in April 2018 when they were initially reimbursed by the National Health Insurance system. Operative mortality rates were 0.9%, 0.4%, 0.2%, and 2.8% for RE (n = 330), RTG (n = 239), RDG (n = 1167), and RPG (n = 109), respectively. No mortality was observed in RLAR (n = 1062) or RRR (n = 374). Conclusion Robotic surgery for gastrointestinal malignant tumors was safely introduced into daily clinical practice along with rigorous surgeon and facility standards in Japan.

Abstract Background The incidence of pancreatic neuroendocrine neoplasm (PNEN) has been increasing. Resection is typically indicated for PNEN, regardless of its size; however, the indications for its resection are controversial. This study aimed to evaluate the treatment results of surgical resection of PNEN at our institute. Methods In this single-center, retrospective, case-control study, 87 patients who underwent PNEN resection and 17 patients with PNEN who did not undergo surgical resection between 1993 and 2020 were included in this study. Clinical characteristics and outcomes were reviewed and statistically compared. Survival was also estimated for the patients in each cohort. Results Seventeen patients who underwent resection (20%) had lymph node metastasis. Tumors measuring ≥ 2.0 cm and multiple lesions were identified as independent predictors for lymph node metastasis (odds ratio [OR] 17.3, 95% confidence interval [CI] 3.0–100.0, p = 0.001 and OR 8.7, 95% CI 1.5–52.0, p = 0.018, respectively). There was a significant difference in the survival curves depending on the presence or absence of lymph node metastasis (5-year overall survival 74.7% vs. 94.3%, p < 0.001; 5-year recurrence-free survival: 66.3% vs. 93.6%, p < 0.001). All 17 PNEN cases under observation with a median 8 mm (range 5–23) tumor size for a median of 34 (range 2.4–114) months showed slight morphological change with a median tumor growth rate of 0.15 mm (range 0–3.33) per year. Conclusion Patients with tumors measuring ≥ 2.0 cm have a high probability of lymph node metastasis or recurrence, thereby requiring resection. PNEN measuring < 1.0 cm may be acceptable for observation.

Abstract Background Respiratory symptoms are associated with coronavirus disease 2019 (COVID-19) outcomes. However, the impacts of upper and lower respiratory symptoms on COVID-19 outcomes in the same population have not been compared. The objective of this study was to characterize upper and lower respiratory symptoms and compare their impacts on outcomes of hospitalized COVID-19 patients. Methods This was a multicenter, retrospective cohort study; the database from the Japan COVID-19 Task Force was used. A total of 3314 COVID-19 patients were included in the study, and the data on respiratory symptoms were collected. The participants were classified according to their respiratory symptoms (Group 1: no respiratory symptoms, Group 2: only upper respiratory symptoms, Group 3: only lower respiratory symptoms, and Group 4: both upper and lower respiratory symptoms). The impacts of upper and lower respiratory symptoms on the clinical outcomes were compared. The primary outcome was the percentage of patients with poor clinical outcomes, including the need for oxygen supplementation via high-flow oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation or death. Results Of the 3314 COVID-19 patients, 605, 1331, 1229, and 1149 were classified as Group 1, Group 2, Group 3, and Group 4, respectively. In univariate analysis, patients in Group 2 had the best clinical outcomes among all groups (odds ratio [OR]: 0.21, 95% confidence interval [CI]: 0.11–0.39), while patients in Group 3 had the worst outcomes (OR: 3.27, 95% CI: 2.43–4.40). Group 3 patients had the highest incidence of pneumonia, other complications due to secondary infections, and thrombosis during the clinical course. Conclusions Upper and lower respiratory tract symptoms had vastly different impacts on the clinical outcomes of COVID-19.

Abstract Background C–C chemokine receptor type 7 (CCR7) participates in chemotactic and metastatic responses in various cancers, including in esophageal squamous cell carcinoma (ESCC). The microRNA (miRNA) let-7a suppresses migration and invasion of various types of cancer cells by downregulating CCR7 expression. Methods The expression levels of CCR7 and let-7a were measured in the cell lines, tumor, and peritumoral tissues of ESCC patients. KYSE cell lines were transfected with synthetic let-7a miRNA and a let-7a miRNA inhibitor, and their CCR7 expression levels as well as invasive ability were evaluated. A highly invasive cell line was established via an invasion assay, and CCR7 expression level along with let-7a level was subsequently evaluated. Cancer cells overexpressing CCR7 were injected subcutaneously into mice, and the animals were monitored for tumor growth along with lymph node metastasis. Results A negative correlation between CCR7 and let-7a expression was observed in the ESCC cell lines as well as in tissue samples from patients. Synthetic let-7a decreased CCR7 expression level, while the let-7a inhibitor increased it. In vitro, the established highly invasive cancer cells with high and low levels of CCR7 and let-7a expression, respectively, exhibited a greater invasive ability than the wild-type cell line. The cells were associated with tumor growth and lymph node metastasis in mice. Patients in the high-CCR7/low-let-7a group had the worst prognosis, with a five-year recurrence free survival (5-RFS) rate of 37.5%, followed by the high-CCR7/high-let-7a (5-RFS: 60.0%) and low-CCR7 (5-RFS: 85.7%; p = 0.038) groups. Conclusions The expression of CCR7 was downregulated by let-7a miRNA in esophageal cancer cells. The decrease in let-7a expression level led to the increased expression level of CCR7 in ESCC cells, consequently increasing their invasive ability and malignancy and resulting in a worse prognosis for ESCC patients. Trial registration. Retrospectively registered.