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Background: The COVID-19 pandemic had a profound impact on cancer screening, diagnosis, and treatment procedures. We speculated that during the COVID-19 pandemic, sufficient medical resources were maintained in board-certified hospitals, resulting in favorable short-term outcomes, whereas hospital functions in non-board-certified hospitals declined, leading to mortality increase. The aim of this study is to investigate the impact of COVID-19 pandemic on short-term outcomes after esophagectomy, based on the scale of the facilities., Methods: Data of patients who underwent esophagectomy for esophageal cancer between January 2018 and December 2022 were analyzed using the National Clinical Database (NCD) of Japan. We selected the Authorized Institutes for Board-certified Esophageal Surgeons (AIBCESs) certified by the Japan Esophageal Society (JES) at the hospital level for evaluating the difference in outcomes between institutions. Operative mortality rates and other morbidities were evaluated using the standardized mortality and morbidity ratio (SMR, the ratio of the number of observed patients to the expected number of patients)., Results: Within the study period, the annual mean operative mortality rate was higher in non-AIBCESs than in AIBCESs. The SMR showed no significant difference after the COVID-19 pandemic in non-AIBCES for mortality, as well as that in AIBCES., Conclusions: In non-AIBCESs, no worsening of results caused by the COVID-19 pandemic was observed despite the shortage of medical resources. Our findings highlighted the high quality of esophageal surgery in Japan during the COVID-19 pandemic, a critical situation with limited medical resources., Competing Interests: Declarations. Conflict of interest: Yuko Kitagawa reports grants and personal fees from ASAHI KASEI PHARMA CORPORATION, grants, personal fees, and others from ONO PHARMACEUTICAL CO., LTD., grants and personal fees from Otsuka Pharmaceutical Factory, Inc., grants and personal fees from Nippon Covidien Inc., grants, personal fees, and others from TAIHO PHARMACEUTICAL CO., LTD, grants, personal fees, and others from CHUGAI PHARMACEUTICAL CO., LTD., grants and personal fees from KAKEN PHARMACEUTICAL CO., LTD., personal fees from AstraZeneca K.K., personal fees from Ethicon Inc., personal fees from Olympus Corporation, personal fees from SHIONOGI & CO., LTD., personal fees from Bristol-Myers Squibb K.K., personal fees from MSD K.K., personal fees from Smith & Nephew KK, personal fees from ASKA Pharmaceutical Co., Ltd., personal fees from MIYARISAN PHARMACEUTICAL CO., LTD., personal fees from Toray Industries, Inc., personal fees from DAIICHI SANKYO COMPANY, LIMITED, personal fees from Chugai Foundation for Innovative Drug Discovery Science, personal fees from Nippon Kayaku Co., Ltd., grants from Yakult Honsha Co., Ltd., grants from TSUMURA & CO., grants from Sumitomo Pharma Co., Ltd., grants and personal fees from EA Pharma Co., Ltd., grants from Eisai Co., Ltd., grants from Kyowa Kirin Co., Ltd., grants from MEDICON INC., grants from Takeda Pharmaceutical Co., Ltd., grants from TEIJIN PHARMA LIMITED, and personal fees from Intuitive Surgical G.K., outside the submitted work. Hideki Endo and Hiroyuki Yamamoto are affiliated with the Department of Healthcare Quality Assessment at the University of Tokyo. The department is a social collaboration department supported by the National Clinical Database, Johnson & Johnson K.K., Nipro Corporation, and Intuitive Surgical Sàrl., (© 2024. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Objectives: Lockdowns and outing restrictions during the COVID-19 pandemic may have altered attitudes towards hospital visits. This study aimed to investigate changes in long-distance visits outside of secondary healthcare service areas (SHSA) among cancer patients in Japan., Design: Retrospective observational study., Setting: Inpatient data from the Japanese Diagnosis Procedure Combination database., Primary and Secondary Outcome Measures: We retrospectively analysed inpatient data from January 2018 to December 2021, extracted from the Japanese Diagnosis Procedure Combination database. The study examined whether the patient's hospital was within their residence's SHSA and compared the admission rates before and after the pandemic., Results: The data of a total of 2 394 760 patients were analysed. Admission rates outside the SHSA significantly decreased after the pandemic compared with prepandemic years (26.67% and 27.58%, respectively, p<0.001). Significant reductions were observed in nearly all age groups over 30 years old, but not in younger ones. Characteristics of patients' residences, including COVID-19 infection rates, population density and the number of regional cancer hospitals, were also influential factors. The cancer site was a significant factor, with the respiratory system showing a 3.77% decrease, particularly a 5.29% decrease in those who needed surgeries that are not highly specialised (p<0.001)., Conclusions: Admission to distant hospitals among cancer patients decreased following the COVID-19 pandemic, indicating a restraint in their behaviour of visiting distant hospitals. The appropriate allocation of specialised hospitals will serve as a measure for the next pandemic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Previous studies reported that there is an association between abnormal body fluid balance and prognosis in colitis patients. However, it remains to be clarified the effects of colitis on characteristics of body electrolytes or water content, including alternation in blood pressure. In this study, we examined the effects of colon injury on body water balance and blood pressure in the dextran sodium sulfate (DSS)-induced colitis mouse model. We evaluated body electrolytes and water content, blood pressure, and urea-associated water conservation in DSS mice. By 5 days after the treatment, DSS mice exhibited diarrhea but relatively maintained body weight and total body sodium, potassium, and water content by increases in water intake and hepatic ureagenesis. On 7 days after DSS treatment, when colitis becomes severe, DSS mice significantly decreased food and water intake, and body weight but significantly increased relative total body sodium, potassium, and water content per dry mass. Notably, DSS induced more total body dry mass loss relative to water loss. These body electrolytes and water accumulation on day 7 were associated with a reduction in urinary osmole excretion and urine volume accompanied by renal urea accumulation. DSS mice significantly increased blood pressure by day 5 and then decreased on day 7. These findings suggest that body electrolyte and fluid imbalance and alternations in blood pressure in colitis vary with the stage and severity of the condition. Assessment and correction of electrolyte and water content at the tissue level would be important to improve the prognosis of colitis., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: In patients with colorectal cancer, both the C-reactive protein-to-albumin ratio and comprehensive risk score of the estimation of physiologic ability and surgical stress have demonstrated prognostic significance., Objective: To assess the clinical value of the combined use of C-reactive protein-to-albumin ratio and comprehensive risk score for predicting prognosis in patients with colorectal cancer., Design: Multicenter retrospective study., Settings: The cohort was divided into 3 groups based on a combined score derived from the value of C-reactive protein-to-albumin ratio and comprehensive risk score (low/mid/high)., Patients: Patients who underwent curative resection between 2010 and 2019 at multiple institutions were enrolled in this study., Main Outcome Measures: Overall and recurrence-free survival., Results: A total of 2207 patients (801 in the low cohort, 817 in the mid cohort, and 589 in the high cohort) were included in this study. Multivariate analysis revealed that combined score was an independent prognostic factor for both overall and recurrence-free survival, irrespective of disease stage ( p < 0.05). Furthermore, Harrell's C-index indicated that the predictive power of the combined score was significantly superior to that of the C-reactive protein-to-albumin ratio or comprehensive risk score ( p < 0.001)., Limitations: This study had a retrospective design, and data on genetic markers were not included., Conclusions: The synergistic combination of C-reactive protein-to-albumin ratio and comprehensive risk score contributes to the robust definition of combined score, a potent prognostic factor, regardless of disease stage. This finding has the potential to provide novel insights into the management of patients with colorectal cancer who have undergone curative resection. See the Video Abstract ., La Puntuacin Combinada De Riesgo Integral De La Estimacin De La Capacidad Fisiolgica Y El Estrs Quirrgico Y La Relacin Protena C Reactiva/albmina Es Un Fuerte Indicador Pronstico De Los Resultados a Largo Plazo En El Cncer Colorrectal: ANTECEDENTES:En pacientes con cáncer colorrectal, tanto la relación proteína C reactiva/albúmina como la puntuación de riesgo integral de la Estimación de la capacidad fisiológica y el estrés quirúrgico han demostrado importancia pronóstica.OBJETIVO:Evaluar el valor clínico del uso combinado de la relación proteína C reactiva/albúmina y la puntuación de riesgo integral para predecir el pronóstico en pacientes con cáncer colorrectal.DISEÑO:Estudio retrospectivo multicéntrico.AJUSTES:La cohorte se dividió en tres grupos según una puntuación combinada derivada del valor de la relación proteína C reactiva/albúmina y la puntuación de riesgo integral (bajo/medio/alto).PACIENTES:En este estudio se inscribieron pacientes que se sometieron a resección curativa entre 2010 y 2019 en múltiples instituciones.PRINCIPALES MEDIDAS DE VALORACIÓN:Supervivencia general y libre de recurrencia.RESULTADOS:En este estudio se incluyeron un total de 2207 pacientes (801 en la cohorte baja, 817 en la cohorte media y 589 en la cohorte alta). El análisis multivariado reveló que la puntuación combinada fue un factor pronóstico independiente tanto para la supervivencia general como para la supervivencia libre de recurrencia, independientemente del estadio de la enfermedad (p <0,05). Además, el índice C de Harrell indicó que el poder predictivo de la puntuación combinada era significativamente superior al de la relación proteína C reactiva-albúmina o a la puntuación de riesgo integral (p <0,001).LIMITACIONES:Este estudio tuvo un diseño retrospectivo y no se incluyeron datos sobre marcadores genéticos.CONCLUSIÓN:La combinación sinérgica de la relación proteína C reactiva/albúmina y la puntuación de riesgo integral contribuye a la definición sólida de la puntuación combinada, un potente factor pronóstico, independientemente del estadio de la enfermedad. Este hallazgo tiene el potencial de proporcionar conocimientos novedosos sobre el tratamiento de pacientes con CCR sometidos a resección curativa. (Traducción- Dr. Ingrid Melo )., (Copyright © The ASCRS 2024.)

Objective: To create a recurrence prediction value (RPV) of high-risk factor and identify the patients with high risk of cancer recurrence., Background: There are several high-risk factors known to lead to poor outcomes. Weighting each high-risk factor based on their association with increased risk of cancer recurrence can provide a more precise understanding of risk of recurrence., Methods: We performed a multi-institutional international retrospective analysis of patients with stage II colon cancer patients who underwent surgery from 2010 to 2020. Patient data from a multi-institutional database were used as the Training data, and data from a completely separate international database from 2 countries were used as the Validation data. The primary endpoint was recurrence-free survival., Results: A total of 739 patients were included from Training data. To validate the feasibility of RPV, 467 patients were included from Validation data. Training data patients were divided into RPV low (n=564) and RPV high (n=175). Multivariate analysis revealed that risk of recurrence was significantly higher in the RPV high than the RPV low [hazard ratio (HR) 2.628; 95% confidence interval (CI) 1.887-3.660; P <0.001). Validation data patients were divided into 2 groups (RPV low, n=420) and RPV high (n=47). Multivariate analysis revealed that risk of recurrence was significantly higher in the RPV high than the RPV low (HR 3.053; 95% CI 1.962-4.750; P <0.001)., Conclusions: RPV can identify stage II colon cancer patients with high risk of cancer recurrence worldwide., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted the allocation of medical resources, including cancer screening, diagnosis, and treatment. We aimed to investigate the effects of the pandemic on morbidity and mortality following hepatectomy for hepatocellular carcinoma (HCC)., Methods: We identified patients who underwent hepatectomy for HCC between 2018 and 2021 from the Japanese National Clinical Database (NCD). The number of surgical cases, the use of intensive care units, and the incidence of morbidity were assessed. The standardized morbidity / mortality ratio (SMR) was used to evaluate the rates of morbidity (bile leakage and pneumonia) and mortality in each month, which compares the observed incidence to the expected incidence calculated by the NCD's risk calculator., Results: The study included a total of 10 647 cases. The number of patients undergoing hepatectomy for HCC gradually decreased. The proportion of patients aged 80 years or older increased and that of cases with T1 stage decreased. The proportion of patients who were admitted to the intensive care unit did not change between the pre- and postpandemic period. The mean actual incidence rates of bile leakage, pneumonia, 30-day mortality, and surgical mortality were 9.2%, 2.3%, 1.4%, and 2.1%, respectively. The SMR for the mortalities and morbidities in each month did not increase mostly throughout the COVID-19 pandemic., Conclusions: The present study showed the decreasing number of resected cases for HCC, while the surgical safety for hepatectomy was enough to be maintained by managing medical resources in Japan., (© 2024 Japan Society of Hepatology.)

Mechanoresponsive materials have been studied to visualize and measure stresses in various fields. However, the high-sensitive and spatiotemporal imaging remain a challenging issue. In particular, the time evolutional responsiveness is not easily integrated in mechanoresponsive materials. In the present study, high-sensitive spatiotemporal imaging of weak compression stresses is achieved by time-evolutional controlled diffusion processes using conjugated polymer, capsule, and sponge. Stimuli-responsive polydiacetylene (PDA) is coated inside a sponge. A mechanoresponsive capsule is set on the top face of the sponge. When compression stresses in the range of 6.67-533 kPa are applied to the device, the blue color of PDA is changed to red by the diffusion of the interior liquid containing a guest polymer flowed out of the disrupted capsule. The applied strength (F/N), time (t/s), and impulse (F·t/N s) are visualized and quantified by the red-color intensity. When a guest metal ion is intercalated in the layered structure of PDA to tune the responsivity, the device visualizes the elapsed time (τ/min) after unloading the stresses. PDA, capsule, and sponge play the important roles to achieve the time evolutional responsiveness for the high-sensitive spatiotemporal distribution imaging through the controlled diffusion processes., (© 2024 The Authors. Small published by Wiley‐VCH GmbH.)

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 vs. >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 <4 weeks before surgery., Conclusions: Patients with a history of SARS-CoV-2 infection had a significantly higher incidence of pneumonia. This finding can be particularly valuable for countries that have implemented strict regulations in response to the COVID-19 pandemic and have lower SARS-CoV-2 infection-related mortality rates., Competing Interests: Dr. Kitagawa received grants and personal fees from Asahi Kasei Pharma Corporation; grants, personal fees, and others from Ono Pharmaceutical Co., Ltd.; grants and personal fees from Otsuka Pharmaceutical Factory, Inc.; grants and personal fees from Nippon Covidien Inc.; grants, personal fees, and others from Taiho Pharmaceutical Co., Ltd.; grants, personal fees, and others from Chugai Pharmaceutical Co., Ltd.; grants and personal fees from Kaken Pharmaceutical Co., Ltd.; personal fees from AstraZeneca K.K.; personal fees from Ethicon Inc.; personal fees from Olympus Corporation; personal fees from Shionogi & Co., Ltd.; personal fees and others from Bristol‐Myers Squibb K.K.; personal fees from MSD K.K.; personal fees from Smith & Nephew K.K.; personal fees from ASKA Pharmaceutical Co., Ltd.; personal fees from Miyarisan Pharmaceutical Co., Ltd.; personal fees from Toray Industries, Inc.; personal fees from Daiichi Sankyo Company, Limited; personal fees from Chugai Foundation for Innovative Drug Discovery Science; personal fees from Nippon Kayaku Co., Ltd.; grants from Yakult Honsha Co. Ltd.; grants from Otsuka Pharmaceutical Co., Ltd.; grants from Tsumura & Co.; grants from Sumitomo Pharma Co., Ltd.; grants and personal fees from EA Pharma Co., Ltd.; grants from Eisai Co., Ltd.; grants from Kyowa Kirin Co., Ltd.; grants from Medicon Inc.; grants from Takeda Pharmaceutical Co., Ltd.; grants from Teijin Pharma Limited; and personal fees from Intuitive Surgical G.K., outside the submitted work. Yuko Kitagawa is a Chief Editor of Annals of Gastroenterological Surgery. Masaki Mori is Emeritus Editor‐in‐Chief of Annals of Gastroenterological Surgery. Yasuyuki Seto, Yoshihiro Kakeji and Hideki Ueno are Associate Editors of Annals of Gastroenterological Surgery., (© 2024 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

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., Competing Interests: Y. Kitagawa is Editor in Chief of Annals of Gastroenterological Surgery. M. Mori is Emeritus Editor in Chief of Annals of Gastroenterological Surgery. H. Ueno is currently Associate Editor of Annals of Gastroenterological Surgery. Y. Kakeji is an editorial board member of Annals of Gastroenterological Surgery. Y. Kitagawa reports Honoraria from Asahi Kasei Pharma Corporation, AstraZeneca K.K., Ethicon Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Factory, Inc., Olympus Corporation, Cardinal Health K.K., Shionogi & Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Bristol‐Myers Squibb K.K., MSD K.K., Smith & Nephew KK, Kaken Pharmaceutical Co., Ltd., ASKA Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Toray Industries, Inc., Daiichi Sankyo Company Ltd., Chugai Foundation for Innovative Drug Discovery Science, Nippon Kayaku Co., Ltd. EA Pharma Co., Ltd., Intuitive Surgical G.K., Takeda Pharmaceutical Company Limited, Sysmex Corporation, and Tsumura & Co. Y. Kitagawa also receive research funding from Asahi Kasei Pharma Corporation, Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Factory Inc., Nippon Covidien Inc., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Kaken Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., Yakult Honsha Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Tsumura & Co. Sumitomo Pharma Co., Ltd., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Cardinal Health., and Kowa Company, Ltd. Y. Kitagawa received the other fees from Sysmex Corporation and Medicaroid Corporation outside the submitted work. E. Hideki and Y. Hiroyuki are affiliated with the Department of Healthcare Quality Assessment at the University of Tokyo. The department is a social collaboration department supported by grants from the National Clinical Database, Intuitive Surgical Sarl, Johnson & Johnson K.K., and Nipro Co., (© 2024 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

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  < 0.001) and CSS (5-year CSS for low ChE and high ChE: 84.8% and 95.6%, respectively; p  < 0.001)., Conclusions: Lower preoperative serum ChE levels are a predictive factor of poor prognosis for CRC patients. As serum ChE levels can be measured quickly and evaluated easily, ChE could become a useful marker for predicting the postoperative long-term outcomes of CRC patients., Competing Interests: Author Y.K. is Editor in Chief of Annals of Gastroenterological Surgery. Y.K. received grants from Taiho Pharmaceutical Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; Yakult Honsha Co. Ltd.; Daiichi Sankyo Company; Merck Serono Co., Ltd.; AsahiKASEI Co., Ltd.; EA Pharma Co., Ltd.; Otsuka Pharmaceutical Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; Otsuka Pharmaceutical Factory Inc.; Shionogi & Co., Ltd.; Kaken Pharmaceutical Co., Ltd.; Kowa Pharmaceutical Co., Ltd.; Astellas Pharma Inc.; Medicon Inc., Dainippon Sumitomo Pharma Co., Ltd.; Taisho Toyama Pharmaceutical Co., Ltd.; Kyouwa Hakkou Kirin Co., Ltd.; Pfizer Japan Inc.; Ono Pharmaceutical Co., Ltd.; Nihon Pharmaceutical Co., Ltd.; Japan Blood Products Organization; Medtronic Japan Co., Ltd.; Sanofi K.K.; Eisai Co., Ltd.; TSUMURA & CO.; KCI Licensing, Inc.; Abbott Japan Co., Ltd; and Fujifilm Toyama Chemical Co., Ltd., outside the submitted work., (© 2024 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

Colorectal mucinous adenocarcinoma (MAC) is one of the most lethal histological types of colorectal cancer, and its mechanism of development is not well understood. In this study, we aimed to clarify the molecular characteristics of MAC via in silico analysis using The Cancer Genome Atlas database. The expression of genes on chromosome 20q (Chr20q) was negatively associated with the expression of MUC2, which is a key molecule that can be used to distinguish between MAC and nonmucinous adenocarcinoma (NMAC). This was consistent with a significant difference in copy number alteration of Chr20q between the two histological types. We further identified 475 differentially expressed genes (DEGs) between MAC and NMAC, and some of the Chr20q genes among the DEGs are considered to be pivotal genes used to define MAC. Both in vitro and in vivo analysis showed that simultaneous knockdown of POFUT1 and PLAGL2, both of which are located on Chr20q, promoted MUC2 expression. Moreover, these genes were highly expressed in NMAC but not in MAC according to the results of immunohistological studies using human samples. In conclusion, POFUT1 and PLAGL2 are considered to be important for defining MAC, and these genes are associated with MUC2 expression., (© 2024 The Authors. Cell Biochemistry and Function published by John Wiley & Sons Ltd.)

Background: Transanal drainage tube (TDT) is used to prevent anastomotic leakage after surgery for rectal cancer. However, it remains unclear whether intraoperative TDT placement is also useful in preventing anastomotic leakage after ileal pouch-anal or ileal pouch-anal canal anastomosis (IPAA) in patients with ulcerative colitis (UC). This study aimed to evaluate the efficacy of intraoperative TDT placement in preventing anastomotic leakage after IPAA in patients with UC., Methods: Patients with UC who underwent proctectomy with IPAA in the study institution between January 2000 and December 2021 were enrolled in this retrospective cohort study. The relationship between TDT placement and anastomotic leakage was evaluated by logistic regression analysis., Results: The study population included 168 patients. TDT was placed intraoperatively in 103 of the 168 patients (61.3%). The rate of anastomotic leakage was significantly lower in the TDT group than in the non-TDT group (7.8% vs 18.5%, p = 0.037). Reoperation was not needed in any patient in the TDT group whereas two reoperations were necessary in the non-TDT group (3.1%). By logistic regression analysis, intraoperative TDT placement was an independent protective factor for anastomotic leakage., Conclusions: TDT placement was significantly associated with anastomotic leakage of IPAA in patients with UC undergoing surgery. Although two-stage surgery with ileostomy is usually preferred in UC surgery, our findings suggest that TDT placement might contribute to the improvement of postoperative outcomes after UC surgery., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Osteopenia, a condition in which bone mineral density is lower than normal, is a noted risk factor that leads to a shortened healthy life expectancy., Objective: To investigate the prognostic impact of preoperative osteopenia in patients with colorectal cancer., Design: This was a retrospective study., Setting: This study was conducted at a university hospital., Patients: A total of 1086 patients with stage I to III colorectal cancer who underwent curative resection., Main Outcome Measures: Osteopenia was evaluated with CT. Overall survival, disease-specific survival, and recurrence-free survival were the primary end points., Results: Osteopenia was identified in 300 patients (27.6%). Compared with the no osteopenia group, the 5-year overall survival (74.0% vs 93.4%, p < 0.001), disease-specific survival (81.6% vs 97.2%, p < 0.001), and recurrence-free survival rates (57.1% vs 88.3%, p < 0.001) were significantly lower in the osteopenia group. Multivariate analyses showed that preoperative osteopenia was significantly associated with worse overall survival (HR: 4.135; 95% CI, 2.963-5.770; p < 0.001), disease-specific survival (HR: 7.673; 95% CI, 4.646-12.675; p < 0.001), and recurrence-free survival (HR: 5.039; 95% CI, 3.811-6.662; p < 0.001). The prognosis of the osteopenia group was poorer than that of the no osteopenia group in every stage: 5-year overall survival (stage I: 89.4% vs 96.9%, p = 0.028; stage II: 76.5% vs 91.9%, p < 0.001; stage III: 56.4% vs 90.8%, p < 0.001) and 5-year recurrence-free survival (stage I: 85.4% vs 96.6%, p = 0.002; stage II: 62.0% vs 86.5%, p < 0.001; stage III: 26.4% vs 80.0%, p < 0.001)., Limitations: The main limitations are retrospective single-institutional features and races of the study population., Conclusions: Preoperative osteopenia could be a strong predictive marker for long-term prognosis in colorectal cancer regardless of stage., El Impacto Pronstico De La Osteopenia Preoperatoria En Pacientes Con Cncer Colorrectal: ANTECEDENTES:La osteopenia, una afección en la que la densidad mineral ósea es más baja de lo normal, es un relevante factor de riesgo que conduce a una expectativa menor de vida saludable.OBJETIVO:Investigar el impacto pronóstico de la osteopenia preoperatoria en pacientes con cáncer colorrectal (CCR).DISEÑO:Un estudio retrospectivo.AJUSTE:Estudio realizado en un hospital universitario.PACIENTES:Un total de 1.086 pacientes con CCR en estadio I-III sometidos a una resección curativa.PRINCIPALES MEDIDAS DE RESULTADO:La osteopenia se evaluó con imágenes de tomografía computarizada. La supervivencia global la supervivencia específica de la enfermedad y la supervivencia libre de recurrencia fueron los criterios de valoración primaria.RESULTADOS:Se identificó osteopenia en 300 pacientes (27,6%). En comparación con el grupo sin osteopenia, las tasas de supervivencia global a 5 años (74,0% frente a 93,4%, p < 0,001), supervivencia especifica de la enfermedad (81,6 % frente a 97,2%, p < 0,001) tasas de supervivencia libre de recurrencia (57,1% frente a 88,3%, p < 0,001) fueron significativamente más bajas en el grupo de osteopenia. Los análisis multivariados mostraron que la osteopenia preoperatoria se asoció significativamente con una peor supervivencia global (HR 4,135; IC 95% 2,963-5,770; p < 0,001), supervivencia especifica de la enfermedad (HR 7,673; IC 95% 4,646-12,675; p < 0,001) y tasas de supervivencia libre de recurrencia (HR 5,039; IC 95% 3,811-6,662; p < 0,001). El pronóstico del grupo con osteopenia fue peor que el del grupo sin osteopenia en todos los estadios: supervivencia global a 5 años (estadio I: 89,4% frente a 96,9%, p = 0,028; estadio II: 76,5% frente a 91,9%, p < 0,001; estadio III: 56,4% frente a 90,8%, p < 0,001) y tasas de supervivencia libre de recurrencia a 5 años (estadio I: 85,4% frente a 96,6%, p < 0,002; estadio II: 62,0% frente a 86,5%, p < 0,001; estadio III: 26,4% frente a 80,0%, p < 0,001).LIMITACIONES:Las principales limitaciones son las características retrospectivas de una sola institución y las razas de la población de estudio.CONCLUSIONES:La osteopenia preoperatoria puede ser un fuerte marcador predictivo para el pronóstico a largo plazo en CCR independientemente de la etapa. (Traducción-Dr. Fidel Ruiz Healy )., (Copyright © The ASCRS 2023.)

Purpose: The number of patients with late-onset ulcerative colitis (UC) requiring surgery has increased in recent years. The risk of postoperative complications is higher in the elderly, so preoperative assessment is important. We aimed to explore the performance of preoperative assessment of nutritional markers for predicting postoperative complications in patients with late-onset UC., Methods: We retrospectively analysed 140 medically refractory UC patients who underwent surgery. The association between age at UC onset and risk of postoperative complications was explored using a fractional polynomial model. Uni- and multi-variate logistic regression analyses were performed to identify nutritional markers associated with postoperative complications., Results: The polynomial model showed patients with UC onset after 50 years of age had an increased risk of postoperative complications. Late-onset (LO) UC, an onset occurring after 50 years old, was associated with a higher risk of incisional surgical site infection (SSI) and intra-abdominal abscess than early-onset (EO) UC. Compared with the EO group, the LO group had fewer nutritional markers that were significantly associated with postoperative complications. The prognostic nutritional index (PNI) was calculated using the albumin level and the total lymphocyte count, and it was the only index that was significant in the LO group (odds ratio 0.872 95% CI 0.77-0.99, P = 0.03)., Conclusions: It was more difficult to use nutritional status to predict the risk of postoperative complications in patients with late-onset UC than in patients with early-onset ulcerative colitis. PNI may be a useful nutritional marker for patients with both late- and early-onset UC., (© 2023. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background: It is unclear how early- and delayed-onset organ/space surgical site infections (SSIs) affect the long-term prognosis of patients with colorectal cancer, who are potential candidates for adjuvant chemotherapy. This study aimed to investigate the association between the timing of SSI onset and clinical outcome., Methods: This retrospective, multicenter cohort study evaluated patients who were diagnosed with high-risk stage II or III colorectal cancer and underwent elective surgery between 2010 and 2020. Five-year recurrence-free survival (RFS) was the primary endpoint and was compared between early SSI, delayed SSI (divided based on the median date of SSI onset), and non-SSI groups., Results: A total of 2,065 patients were included. Organ/space SSI was diagnosed in 91 patients (4.4%), with a median onset of 6 days after surgery. The early-onset SSI group had a higher proportion of patients with Clavien-Dindo grade ≥IIIb SSI than the delayed-onset SSI. Patients who received adjuvant chemotherapy (AC) had earlier organ/space SSI onset than those who did not. The adjusted hazard ratio of 5-year RFS in the delayed-onset SSI was 2.58 (95% confidence interval: 1.43-4.65; p = 0.002): higher than that in the early-onset SSI, with the non-SSI as the reference., Conclusions: Delayed-onset organ/space SSI worsened long-term prognosis compared to early-onset, and this may be due to delayed initiation of AC. Patients who are clinically suspected of having lymph node metastasis might need additional intervention to prevent delays in commencing AC due to the delayed SSI., (© 2023. The Society for Surgery of the Alimentary Tract.)

Background: The coronavirus disease 2019 (COVID-19) pandemic had adversely impacted cancer screening, diagnosis, and treatment. We investigated the change in medical resource, such as the intensive care unit use, and short-term outcomes after esophagectomy during the pandemic., Methods: Data of patients who underwent esophagectomy for esophageal cancer registered in the National Clinical Database (NCD) in Japan from January 2018 to December 2021 were analyzed. The time series change in the number of surgical cases; usage of intensive care unit; incidence of morbidity and mortality; standardized mortality and morbidity ratio (SMR) for 30-days mortality; surgical mortality; and morbidities for pneumonia, sepsis, unplanned intubation, and anastomotic leakage were evaluated., Results: The annual number of patients undergoing esophagectomy remained similar from 2018 to 2021. The negative impact of the pandemic on medical resources was strongly identified in the patients from an epidemic area where there is a higher cumulative number of infections per population as compared to all prefectures. The proportions of patients admitted to the intensive care unit were 91.4%, 93.0%, 91.6%, and 90.5% in 2018, 2019, 2020, and 2021, respectively. Moreover, 93.3%, 94.0%, 92.0%, and 90.9% patients who underwent surgery in an epidemic area were admitted to the intensive care unit in 2018, 2019, 2020, and 2021, respectively. However, the morbidity and mortality rates during the pandemic did not worsen according to the SMR values., Conclusions: Esophagectomy was performed during the pandemic despite limited medical resources by a systematic endeavor of the entire surgical department in Japan, without increasing the incidence rate of worse outcome., (© 2023. The Author(s) under exclusive licence to The Japan Esophageal Society.)

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., Competing Interests: Yuko Kitagawa received grants from TAIHO PHARMACEUTICAL CO., LTD.; CHUGAI PHARMACEUTICAL CO., LTD.; Yakult Honsha Co. Ltd.; DAIICHI SANKYO COMPANY; Merck Serono Co., Ltd; AsahiKASEI Co., Ltd; EA Pharma Co., Ltd.; Otsuka Pharmaceutical Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; Otsuka Pharmaceutical Factory Inc.; SHIONOGI & CO., LTD.; KAKEN PHARMACEUTICAL CO., LTD.; Kowa Pharmaceutical Co., Ltd.; Astellas Pharma Inc.; MEDICON INC., DAINIPPON SUMITOMO PHARMA Co., Ltd.; Taisho Toyama Pharmaceutical Co., Ltd.; Kyouwa Hakkou Kirin Co., Ltd.; Pfizer Japan Inc.; ONO PHARMACEUTICAL CO., LTD.; NIHON PHARMACEUTICAL CO., LTD.; Japan Blood Products Organization; Medtronic Japan Co., Ltd.; Sanofi K.K.; Eisai Co., Ltd; TSUMURA & CO.; KCI Licensing, Inc.; ABBOTT JAPAN CO., LTD; and FUJIFILM Toyama Chemical Co., Ltd., outside the submitted work. Hideki Endo, Hiroyuki Yamamoto, and Hiroaki Miyata are affiliated with the Department of Healthcare Quality Assessment at the University of Tokyo. The department is a social collaboration center supported by the National Clinical Database, Johnson & Johnson K.K., Nipro Corporation, and Intuitive Surgical Sàrl. Yuko Kitagawa is a Chief Editor of Annals of Gastroenterological Surgery. Masaki Mori is Emeritus Editor‐in‐Chief of Annals of Gastroenterological Surgery. Yasuyuki Seto, Yoshihiro Kakeji, and Hideki Ueno are Associate Editors of Annals of Gastroenterological Surgery., (© 2023 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

Aim: The splenic flexure has variable vascular anatomy, and the details of the venous forms are not known. In this study, we report the flow pattern of the splenic flexure vein (SFV) and the positional relationship between the SFV and arteries such as the accessory middle colic artery (AMCA)., Methods: This was a single-centre study using preoperative enhanced CT colonography images of 600 colorectal surgery patients. CT images were reconstructed into 3D angiography. SFV was defined as a vein flowing centrally from the marginal vein of the splenic flexure visible on CT. AMCA was defined as the artery feeding the left side of the transverse colon, separate from the left branch of the middle colic artery., Results: The SFV returned to the inferior mesenteric vein (IMV) in 494 cases (82.3%), the superior mesenteric vein in 51 cases (8.5%) and the splenic vein in seven cases (1.2%). The AMCA was present in 244 cases (40.7%). The AMCA branched from the superior mesenteric artery or its branches in 227 cases (93.0% of cases with existing AMCA). In the 552 cases in which the SFV returned to the IMV, superior mesenteric vein or splenic vein, the left colic artery was the most frequent artery accompanying the SFV (42.2%), followed by the AMCA (38.1%) and the left branch of the middle colic artery (14.3%)., Conclusions: The most common flow pattern of the vein in the splenic flexure is from the SFV to IMV. The SFV is frequently accompanied by the left colic artery or AMCA., (© 2023 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Introduction: The aim of this study was to evaluate the effect of biologics on the risk of advanced-stage inflammatory bowel disease (IBD)-associated intestinal cancer from a nationwide multicenter data set., Methods: The medical records of patients with Crohn's disease (CD) and ulcerative colitis (UC) diagnosed with IBD-associated intestinal neoplasia (dysplasia or cancer) from 1983 to 2020 were included in this study. Therapeutic agents were classified into 3 types: biologics, 5-aminosalicylic acid, and immunomodulators. The pathological cancer stage was compared based on the drug used in both patients with CD and UC., Results: In total, 1,042 patients (214 CD and 828 UC patients) were included. None of the drugs were significantly associated with cancer stage in the patients with CD. In the patients with UC, an advanced cancer stage was significantly associated with less use of biologics (early stage: 7.7% vs advanced stage: 2.0%, P < 0.001), 5-aminosalicylic acid, and immunomodulators. Biologic use was associated with a lower incidence of advanced-stage cancer in patients diagnosed by regular surveillance (biologics [-] 24.5% vs [+] 9.1%, P = 0.043), but this was not the case for the other drugs. Multivariate analysis showed that biologic use was significantly associated with a lower risk of advanced-stage disease (odds ratio = 0.111 [95% confidence interval, 0.034-0.356], P < 0.001)., Discussion: Biologic use was associated with a lower risk of advanced IBD-associated cancer in patients with UC but not with CD. The mechanism of cancer progression between UC and CD may be different and needs to be further investigated., (Copyright © 2023 by The American College of Gastroenterology.)

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., Competing Interests: Dr. Kitagawa reports grants and personal fees from Asahi Kasei Pharma Corporation; grants, personal fees, and other from Ono Pharmaceutical Co., Ltd.; grants and personal fees from Otsuka Pharmaceutical Factory, Inc.; grants and personal fees from Nippon Covidien Inc.; grants, personal fees, and other from Taiho Pharmaceutical Co., Ltd.; grants, personal fees, and other from Chugai Pharmaceutical Co., Ltd.; grants and personal fees from Kaken Pharmaceutical Co., Ltd.; personal fees from AstraZeneca K.K.; personal fees from Ethicon Inc.; personal fees from Olympus Corporation; personal fees from Shionogi & Co., Ltd.; personal fees and other from Bristol‐Myers Squibb K.K.; personal fees from MSD K.K.; personal fees from Smith & Nephew K.K.; personal fees from Aska Pharmaceutical Co., Ltd.; personal fees from Miyarisan Pharmaceutical Co. Ltd.; personal fees from Toray Industries, Inc.; personal fees from Daiichi Sankyo Company, Limited; personal fees from Chugai Foundation for Innovative Drug Discovery Science; personal fees from Nippon Kayaku Co., Ltd.; grants from Yakult Honsha Co. Ltd.; grants from Otsuka Pharmaceutical Co., Ltd.; grants from Tsumura & Co.; grants from Sumitomo Pharma Co., Ltd.; grants and personal fees from EA Pharma Co., Ltd.; grants from Eisai Co., Ltd.; grants from Kyowa Kirin Co., Ltd.; grants from Medicon Inc.; grants from Takeda Pharmaceutical Co., Ltd.; grants from Teijin Pharma Limited.; and personal fees from Intuitive Surgical G.K., outside the submitted work. Hideki Endo, Hiroyuki Yamamoto, and Hiroaki Miyata are affiliated with the Department of Healthcare Quality Assessment at the University of Tokyo. The department is a social collaboration department supported by the National Clinical Database, Johnson & Johnson K.K., Nipro Corporation, and Intuitive Surgical Sàrl. Yuko Kitagawa is a Chief Editor of Annals of Gastroenterological Surgery. Masaki Mori is Emeritus Editor‐in‐Chief of Annals of Gastroenterological Surgery. Yasuyuki Seto, Yoshihiro Kakeji, and Hideki Ueno are Associate Editors of Annals of Gastroenterological Surgery., (© 2023 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

Background: Although extended lymph node dissection during colon cancer surgery is recommended in both Western and Eastern countries, the perception and clinical significance of main lymph node metastasis (MLNM) remains controversial., Methods: In total, 1557 patients with colon cancer who underwent curative resection with D3 dissection were retrospectively analyzed. Clinicopathological factors associated with MLNM were analyzed. Kaplan-Meier survival analysis and log-rank tests were used to compare the prognosis between the MLNM and non-MLNM groups., Results: Multivariate analysis showed that overall survival (OS) [hazard ratio, 2.117 (0.939-4.774), p = 0.071] and recurrence-free survival (RFS) [hazard ratio, 2.183 (1.182-4.031), p = 0.013] were affected by the MLNM status independent of the TNM stage. Survival analysis demonstrated that among patients with stage III disease, the OS and RFS rates were significantly different between patients with and without MLNM (OS: p = 0.0147, RFS: p = 0.0001). However, the OS and RFS rates were not significantly different between patients who had stage III disease with MLNM and patients who had stage IV disease (OS: p = 0.5901, RFS: p = 0.9610)., Conclusions: MLNM is an independent prognostic factor for patients with colon cancer. The addition of the MLNM status to the current TNM classification may enhance the prognostic value of the TNM staging system and the clinical efficacy of adjuvant therapy in patients with colon cancer., (© 2023. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background: The number of lymph node metastasis (LNM) is a strong prognostic factor in the treatment of colorectal cancer (CRC). However, the impact of the mesentery location on LNM remains unclear. We assessed the impact LNM location on the recurrence of stage III CRC., Methods: Subjects with CRC and pathologically positive LNM were enrolled retrospectively. We defined three groups: LNM adjacent to the tumour (group A), metastases with horizontal or vertical spread (group B), and metastases with both horizontal and vertical spread (group C). Recurrence-free survival (RFS) was the primary outcome measure used for the study., Results: A total of 241 (Group A: 121, B: 90, and C: 30) patients were recruited for the study. Multivariate analysis by Cox regression model indicated LNM location to be an independent predisposing risk factor for recurrence [group B: Hazard ratio (HR) 2.01, 95% Confidential interval (CI) 1.12-3.60, P = 0.019; group C: HR 3.00, 95% CI 1.34-6.72, P = 0.008]. Addition of mesentery spread to the N classification was significant risk factor for recurrence (mN2a: HR 2.01, 95% CI 1.07-3.78, P = 0.029; mN2b: HR 3.96, 95% CI 2.12-7.40, P < 0.01). Comparison of Harrell's C-index values was conducted, and the modified N staging risk was 0.6377, whereas the TNM N stage classification was 0.5869., Conclusion: Mesentery location of LNM was a risk factor and consideration of it might be beneficial for accurate prediction of CRC prognosis., (© 2023 Royal Australasian College of Surgeons.)

Imaging and measuring compression stresses secure a safe and healthy life. Compression stresses in kPa range are not easily detected by conventional mechanoresponsive materials because microscopic molecular motion of the chromophores is not induced by such weak stresses. Moreover, imaging of the stress distribution is not achieved so far. The present study shows a sponge device combining two stimuli-responsive materials, a capsule releasing interior liquid and color-changing polymer in responses to compression stress and chemical stimulus, respectively. The stimuli-responsive capsule is dispersed on a melamine sponge comprised of the fibers with coating the layered polydiacetylene (PDA). The application of weak compression stresses induces collapse of the capsules, outflow of the interior liquid, and subsequent irreversible color change of PDA. The cascading response in the sponge device colorimetrically enables imaging of the distribution and measuring the strength of the compression stresses in kPa range. Furthermore, the device demonstrates imaging and measuring unknown weak compression stresses applied by the irregular-shaped objects. A couple of clinical issues in surgical operation of intestine are studied using the stress-imaging sponge device. The device and its design strategy can be applied to stress imaging in a variety of fields., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background/aim: STAT3 is involved in the progression of several cancers, and has been proposed as target for therapy. Indeed, the multitargeted tyrosine kinase inhibitor drug regorafenib, which indirectly inhibits STAT3, can significantly enhance the effects of anti-programmed death receptor (PD)-1 therapy in hepatocellular carcinoma (HCC) models. Here, we studied the impact of a direct STAT3 inhibitor on the tumor microenvironment and PD-1 blockade efficacy in HCC models., Materials and Methods: Orthotopic mouse models of HCC (RIL-175 and HCA-1 grafts in syngeneic mice) were used to test the efficacy of the selective STAT3 inhibitor STX-0119 alone or combined with anti-PD-1 antibodies. We evaluated the effects of therapy on tumor vasculature and the immune microenvironment using immunofluorescence (IF), cell viability assay and quantitative real-time (qRT)-PCR in tumor tissues., Results: Combining anti-PD-1 antibodies with a STX-0119 failed to show a growth delay or survival benefit compared to each agent alone or control in any of the HCC models. Interestingly, evaluation of intratumoral CD8+ T cell infiltration by IF showed a significant increase after one-week treatment with STX-0119 (p=0.034). However, STX-0119 treatment simultaneously promoted increased immunosuppression in the tumor microenvironment by increasing the proportion of Tregs, tissue hypoxia and α-SMA activated cancer-associated fibroblasts (CAFs) measured by IF. Consistent with these findings, we found increased immature tumor vessels by IF and VEGF, Tgf-β and Vash2 expression by qPCR., Conclusion: Pharmacologic STAT3 inhibition could significantly enhance CD8 + T cell infiltration in HCC but also significantly alter the immunosuppression and vascular abnormalization in the tumor microenvironment., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Metformin has been reported to be associated with improved cancer prognosis when used in combination with chemotherapy and/or radiotherapy. In this study, we present a systematic review and meta-analyses of studies evaluating the association of tumor pathological response with the use of metformin during neoadjuvant chemoradiotherapy (NACRT) in rectal and esophageal/gastroesophageal cancer patients., Methods: We systematically searched databases for articles that compared concurrent metformin use with no metformin use in cancer patients treated with NACRT following the PRISMA 2020. The design and quality of the collected studies were reviewed, and meta-analyses were performed on the pathologic complete response (pCR) rate, tumor regression grade (TRG), T factor downstaging, and N factor downstaging., Results: Three databases were searched, and 220 papers were screened. Five retrospective cohort study papers were eligible for the meta-analysis, with a total of 2041 patients. The included papers contained only rectal and esophageal/gastroesophageal cancers. In the metformin group, the pCR rate was 26% [20-32%], and metformin was associated with the pCR rate (odds ratio [OR] = 0.51 [0.34-0.76], p < 0.01). Meta-regression analysis of the pCR rate showed a positive correlation with adenocarcinoma (coefficient = 0.13 [0.02-0.25], p = 0.03) and fluoropyrimidine anticancer drug use (coefficient = 0.01 [0.001-0.02], p = 0.03)., Conclusions: The results suggest that metformin is associated with pCR rate when used in combination with NACRT. The association of metformin and pCR rate in combination with fluoropyrimidine anticancer drugs was observed mostly for adenocarcinoma patients., (© 2022. The Society for Surgery of the Alimentary Tract.)

Obesity is a major problem worldwide and has been associated with colorectal cancer development, among other diseases. Ephrin receptors and ligands play an important role in the turnover of the intestinal mucosa and intestinal crypt compartmentalization. It has been hypothesised that obesity-induced inflammation affects ephrin signals, leading to carcinogenesis. Therefore, the aim of the present study was to assess the relationship between Eph-ephrin B signalling, obesity and obesity-associated colorectal cancer. An azoxymethane-induced obesity-associated cancer KKAy mouse model developed in our prior study was used. A total of 46 patients with consecutive colorectal cancer and 48 tumours were analysed. Immunohistological analyses were performed in mouse and human samples, and immunoreactive scores (IRS) were determined. KKAy mice were significantly more prone to cancer development compared with control C57/BL mice (2/15 in C57/BL vs. 10/10 in KKAy; P<0.001). TUNEL assay revealed a lower number of apoptotic cells in normal mucosa of KKAy mice (8.8% in C57/BL vs. 3.2% in KKAy; P<0.001) and obese patients (9.2% with BMI <25 vs. 3.6% with BMI ≥25; P=0.021). Immunohistological analysis revealed that ephrin-B1 was downregulated in normal mucosa from KKAy mice and obese patients (IRS, 2.86 with BMI <25 vs. 6.00 with BMI ≥25; P=0.002). Moreover, EphB2 was downregulated in tumours from KKAy mice and obese patients (IRS, 6.58 with BMI <25 vs. 3.83 with BMI ≥25; P<0.001). The distribution of infiltrated macrophages corresponded to the MCP-1 expression pattern in KKAy mice, and the number of macrophages was also significantly higher in those mice (36.3 in C57/BL vs. 120.0 in KKAy; P=0.029). The findings suggested that obesity results in disruption of EphB2/ephrin-B1 signalling, promoting colorectal cancer development and progression., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Suzuki et al.)

Aim: To evaluate the significance of next-generation sequencing-based gene panel testing in surgically resectable colorectal cancer by analyzing real-world data. Materials & methods: A total of 107 colorectal cancer patients who underwent curative surgery were included, and correlations between next-generation sequencing data and clinicopathological findings were evaluated. Results: More combination patterns in gene alteration were identified in advanced-stage tumors than in early-stage tumors. The copy number alteration count was significantly lower in right-sided colon tumors and early-stage tumors. Homologous recombination deficiency was more often identified in advanced-stage tumors, and high homologous recombination deficiency status was useful for identifying high-risk stage II tumors. Conclusion: Homologous recombination deficiency was identified as a useful result of gene panel testing with novel utility in clinical practice.

Metformin is a commonly used drug for the treatment of diabetes. Accumulating evidence suggests that it exerts anti-cancer effects in many cancers, including colorectal cancer. However, the underlying molecular mechanisms of colorectal cancer metastasis remain unclear. Colorectal cancer cell lines were treated with metformin, and cell proliferation, invasion, and migration were analyzed in vitro. The relationship between metformin and the AMPK-mTOR axis was assessed by Western blot analysis and transfection with small interfering RNA. A colorectal cancer xenograft mouse model was used to observe the effects of metformin on liver metastasis. Immunohistochemical analysis was performed on liver metastatic tumors. In in vitro experiments, metformin significantly inhibited the proliferation, migration, and invasion only in HCT116 and SW837 cells, but not in HCT8 and Lovo cells. Only in HCT116 and SW837, a change in AMPK-mTOR expression was observed in a dose-dependent manner. In colorectal cancer xenograft mice, the liver metastatic rate (10% vs. 50%, p = 0.05) and the number of liver metastatic nodules (0.1/body vs. 1.2/body, p = 0.04) were significantly lower in the metformin group. Tumor proliferation and EMT were decreased and apoptosis was promoted only in metastatic liver tumors of mice treated with metformin. The molecular mechanism of the anti-cancer effects of metformin involves repression of mTOR pathways via AMPK activation. Moreover, the differences in metformin sensitivity depend on the response of the AMPK-mTOR pathway to metformin. Our study provides a theoretical basis for the anti-metastatic treatment of colorectal cancer using metformin., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Angiopoietin-like 4 (ANGPTL4) was recently shown to be associated with cancer progression but little is known about its contribution to cancer metabolism. The purpose of this study was to elucidate the role of ANGPTL4 in glucose metabolism in colorectal cancer (CRC)., Methods: Immunohistochemical staining of CRC specimens classified 84 patients into two groups according to ANGPTL4 expression. Clinicopathological characteristics, gene mutation status obtained by next-generation sequencing, and fluorodeoxyglucose (FDG) uptake measured by positron emission tomography/computed tomography (PET/CT) were compared between the two groups. Furthermore, the impact of ANGPTL4 expression on cancer metabolism was investigated by a subcutaneous xenograft mouse model using the ANGPTL4 knockout CRC cell line, and glucose transporter (GLUT) expression was evaluated., Results: There were significantly more cases of T3/4 tumours (94.3% vs. 57.1%, P < 0.001) and perineural invasion (42.9% vs. 22.4%, P = 0.046) in the ANGPTL4-high group than in the low group. Genetic exploration revealed a higher frequency of KRAS mutation (54.3% vs. 22.4%, P = 0.003) in the ANGPTL4-high tumours. All the FDG uptake parameters were significantly higher in ANGPTL4-high tumours. In vivo analysis showed a significant reduction in tumour size due to ANGPTL4 knockout with lower expression of GLUT1 and GLUT3, and suppression of AKT phosphorylation., Conclusion: ANGPTL4 regulates the expression of GLUTs by activating the PI3K-AKT pathway and thereby promoting glucose metabolism in CRC. These findings establish a new functional role of ANGPTL4 in cancer progression and lay the foundation for developing a novel therapeutic target., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The relationship between preoperative mean corpuscular volume and postoperative prognosis has been reported in some cancers recently, but no certain consensus has been reached, especially for colorectal cancer. We evaluated the usefulness of mean corpuscular volume as a prognostic factor in colorectal cancer patients., Methods: This study included 1003 patients with colorectal cancer who underwent curative surgery in a single institution. The relationship between mean corpuscular volume values and postoperative recurrence was evaluated by fractional polynomial model. Based on the result, patients were divided into groups according to mean corpuscular volume values. Clinicopathological factors and long-term outcomes were compared between the groups., Results: The risk of postoperative recurrence according to mean corpuscular volume value showed a J-shaped curve, suggesting that both low and high mean corpuscular volume have high risk. Low mean corpuscular volume (≤84 fl) group was oncologically advanced in terms of pathological tumor stage, histological grade and lymphatic invasion with higher inflammation markers. High mean corpuscular volume (>95 fl) group had higher frequency of drinking habit with higher values of aspartate aminotransferase, alanine aminotransferase and γ-glutamyl transpeptidase. Abnormal mean corpuscular volume group including these two groups showed significantly worse disease-free survival than the other (P < 0.001). Multivariate analysis suggested that abnormal mean corpuscular volume was an independent risk factor for postoperative recurrence (hazard ratio, 1.344; 95% confidence interval, 1.005-1.796; P = 0.046). Furthermore, its prognostic impact was more significant in pStage III than in other stages., Conclusion: Preoperative low and high mean corpuscular volume is a poor prognostic factor in colorectal cancer patients. It could be a predictive marker to estimate worse survival outcome after surgery., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To evaluate the prognostic value of the comprehensive risk score (CRS) of the Estimation of Physiologic Ability and Surgical Stress for managing patients with colorectal cancer (CRC) who underwent elective and emergency colorectal cancer surgery with curative intent., Summary Background Data: CRS, which is calculated based on both clinical and surgical factors, is a good predictor of postoperative complications and mortality. However, the impact of CRS in CRC prognosis remains unclear., Methods: Patients with CRC who underwent curative resection between 2010 and 2019 were retrospectively enrolled in this study. The cohort was divided into the low and high CRS groups. The prognostic value of CRS was evaluated via Cox regression and Kaplan-Meier analyses. The CRS cutoff value was obtained using the Youden index applied to OS curves and have not been validated by any validation cohorts., Results: In total, 2407 patients, including 1359 and 1048 patients with low and high CRS, respectively, were enrolled in this study. Multivariate analysis revealed that a CRS was an independent prognostic factor of overall and recurrence-free survival regardless of disease stage. Furthermore, adjuvant chemotherapy was beneficial for the survival of patients with stage III CRC in both high and low CRS groups; however, the survival benefit was limited in elderly high CRS patients., Conclusions: CRS was a strong prognostic factor for CRC regardless of disease stage and might be considered as a biomarker for selecting elderly patients who are eligible for adjuvant chemotherapy., (Copyright © 2022 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: It has been reported that in conventional open surgery, approximately 10% of surgical gloves are perforated during surgery without being noticed. To protect both the patient and medical staff from harm, double gloving or changing gloves routinely at certain intervals during surgery is recommended. However, whether these protective measures are also necessary for laparoscopic colorectal surgery is unknown because the actual perforation rate during laparoscopic procedures is unclear., Methods: Seventy-seven laparoscopic colorectal surgeries were evaluated, and a total of 616 surgical gloves used in the surgeries were collected for analysis. The presence of glove perforation was tested by the standard water-leak test method (EN455-1)., Results: Seven perforations were detected (1.1%). The duration of the laparoscopic procedure was not a statistically significant risk factor for glove perforation (p = 0.41). Postoperative surgical site infections (SSIs) were observed in 12 cases (15.6%), but there was no significant correlation between the presence of glove perforation and SSI (p = 0.92). According to the bacterial cultivation results, the majority of causative agents of SSI were enterobacteria, which belong to the major gut flora., Conclusion: Although the perforation rate was considerably lower than that in open surgery, surgical glove perforation occurred during laparoscopic procedures. Double gloving in laparoscopic colorectal surgery is recommended not to prevent SSI but to protect medical workers from harmful infections after direct contact with the patient., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Risk stratification is required to improve the management of pouchitis with ulcerative colitis (UC) patients who undergo ileal pouch-anal anastomosis (IPAA). Recently, the colectomy risk score (CRS) has been used to assess UC severity and predict the need for surgery. We explored whether the CRS predicted pouchitis in patients with UC who underwent IPAA. This retrospective study included 168 UC patients who underwent IPAA. Pouchitis was diagnosed according to the pouchitis disease activity index. The primary endpoint was the cumulative incidence of pouchitis. The risk factors for pouchitis using preoperatively obtained data, including the CRS, were investigated. Based on their CRS, patients were assigned to low- (scores 0-3), intermediate- (scores 4-6), and high-risk (scores 7-9) groups. The incidence of pouchitis was estimated using the Kaplan-Meier curve. CRS validity was assessed using the Cox proportional hazards model. During the median 7.2 (interquartile range [IQR] 2.8-11.1) years' follow-up, 37 (28.5%) patients were diagnosed with pouchitis. Patients with pouchitis had significantly higher CRS than patients without pouchitis (median 7.0; IQR, 4.0-7.0 vs median 5.0; IQR, 3.0-7.0). The cumulative incidences of pouchitis in the low-, intermediate-, and high-risk groups were 10.3%, 18.3%, and 36.1% at 5 years, respectively. Thus, the incidence trended to increase significantly as CRS increased. Multivariate analysis revealed high-risk CRS status was an independent predictor of pouchitis (hazard ratio: 18.03; 95% confidence interval 1.55-210.05). CRS is useful in risk stratification for the development of subsequent pouchitis in patients with UC undergoing IPAA., (© 2021. Italian Society of Surgery (SIC).)

Background: Anastomotic leakage is one of the most severe and critical complications of laparoscopic surgery for colorectal cancer. However, definitive preoperative predictors of anastomotic leakage remain elusive. With the ageing of society, the number of colorectal cancer patients with arteriosclerotic disease in Japan is increasing. This study was performed to evaluate the correlation between preoperative arteriosclerosis and anastomotic leakage., Methods: In total, 98 patients undergoing laparoscopic surgery for colorectal cancer with reconstruction using the double-stapling technique without diversion of the stoma were enrolled in the study. Preoperative assessment of arteriosclerotic disease was performed by abdominal computed tomography. The calcification volume percentage of the aorta between the level of the celiac artery root and aortic bifurcation was calculated using ZIOstation2 software, and the relationship between arteriosclerosis and anastomotic leakage was analysed., Results: Among 98 cases, anastomotic leakage was observed in 16 (16.3%). The median calcification volume percentage (range) was 2.35% (0-40.3%). Age, male sex, hypertension, dissection number, estimated glomerular filtration rate and tumour location were correlated with anastomotic leakage on statistical analysis. Statistical analysis showed that calcification volume percentage was one of the robust risk factors for anastomotic leakage (odds ratio: 1.09, 95% confidence interval: 1.03-1.17, P < 0.01)., Conclusions: Calcification of the abdominal aorta may be a promising predictor of AL after laparoscopic surgery for colorectal cancer reconstruction using the double-stapling technique., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: In laparoscopic surgery (LS) for colorectal cancer (CRC), the relationship between intraoperative end-tidal carbon dioxide concentration (EtCO 2 ) and surgery-related complications remains unexplored. This study assessed the impact of intraoperative EtCO 2 on postoperative complications in LS for CRC., Methods: In total, 909 patients who underwent LS for CRC were enrolled. Hypocapnia and hypercapnia were defined as EtCO 2  < 35 mmHg and > 40 mmHg, respectively, and the relationships between hypocapnia or hypercapnia duration and postoperative complications were analyzed., Results: The median (range) durations of hypocapnia and hypercapnia were 2.0 (0-8.3) h and 0.3 (0-5.8) h, respectively. Complications were observed in 208 cases (23.0%), which included 37 (4.1%) instances of anastomotic leakage and 86 (9.5%) of superficial surgical site infection (SSI). While the hypercapnia duration was not associated with the short-term outcomes, prolonged hypocapnia was significantly correlated with complications (p = 0.02), specifically superficial SSI (p = 0.005). Multivariate analyses adjusted for confounding factors confirmed that hypocapnia prolongation was an independent risk factor for postoperative superficial SSI [OR 1.19; 95% confidence interval (Cl) 1.03-1.36, p = 0.01]., Conclusion: Intraoperative hypocapnia may be a risk factor for postoperative complications, in particular superficial SSI, in LS for CRC., (© 2021. Springer Nature Singapore Pte Ltd.)

Background/aim: The role of brahma-related gene 1 (BRG1)-associated factor 57 (BAF57), a transcription factor, has been determined in prostate, breast, and ovarian cancer. However, the relationship between BAF57 and colorectal cancer (CRC) is obscure. Thus, we examined the functional correlation between BAF57 expression and oncological malignancy in CRC in vitro., Materials and Methods: BAF57 expression in WiDr and HT29 CRC cell lines and clinical specimens from CRC patients was analysed by western blotting and/or RT-PCR. BAF57 expression was down-regulated in WiDr cells through siRNA transfection. An invasion assay was also performed to assess malignancy., Results: BAF57 was expressed in both human CRC cell lines. Overall survival and recurrence-free survival rates were significantly reduced in high BAF57-expressing specimens. BAF57 expression was an independent predictive factor for long-term survival., Conclusion: BAF57 correlates with oncological malignancy and may be a novel therapeutic target in CRC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The lymphatic system is known to be the primary pathway of metastasis for colorectal cancer. However, beyond regional lymph node metastases, little is known about the pathway of lymphatic metastases and the differences in the recurrence site risk. The aim of this study was to clarify the relationship between lymph node metastasis and the first recurrence site in colorectal cancer., Methods: Patients with colorectal cancer who underwent curative resection in our institution between January 2003 and December 2016 were included in this analysis. The relationship between the first recurrence site and clinicopathological factors was analyzed by the Cox regression model and competing risk regression model., Results: In total, 1,249 patients with colorectal cancer were included in this analysis. We found that the stages of lymph node metastases (N0 vs N1: P = .008, N0 vs N2a: P < .001, N0 vs N2b: P < .001) were significantly associated with lung metastasis in the multivariate analysis. Furthermore, in the competing risk analysis, the stages of lymph node metastases were significantly correlated with lung metastasis (N0 vs N1: P = .002, N0 vs N2a: P < .001, N0 vs N2b: P < .001) but were not correlated with other recurrence sites., Conclusion: The severity of lymph node involvement had a strong correlation with lung metastases in patients with colorectal cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Importance: The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer., Observations: Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts., Conclusions and Relevance: The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.

Aim: Main lymph node (LN) metastasis dissected with a high vascular tie at the root of the feeding artery is a poor prognostic factor in colorectal cancer (CRC). However, the effects of horizontal spread on recurrence after curative resection remain unclear. The purpose of this study is to evaluate the relationship between the horizontal spread of LN metastasis and recurrence in CRC., Method: In this retrospective study, 189 CRC patients (98 men, 91 women) who underwent curative resection at our hospital from 2003 to 2018 and had only pericolic LN metastasis were divided into two groups: patients with LN metastasis beside the tumour only (T group, n = 121) and those with LN metastasis with horizontal spread (S group, n = 68) (mean follow-up period 50.9 ± 34.1 months). The primary outcome was recurrence-free survival (RFS). We investigated the correlation between clinicopathological background factors and recurrence using Cox regression analysis., Results: Fewer than three LN metastases (N1) were found in 157 patients (107 T group, 50 S group), and four or more metastases (N2a) were found in 32 patients (14 T group, 18 S group). Univariate analyses revealed significantly shorter RFS in the S group [hazard ratio (HR) 1.95, 95% CI 1.07-3.55; p = 0.03). Multivariate analyses revealed that horizontal spread is an independent risk factor for recurrence (HR 1.95, 95% CI 1.05-3.68; p = 0.03)., Conclusion: Although further investigation is needed, horizontal spread of LN metastasis is a prognostic factor for recurrence in Stage III CRC., (© 2021 The Association of Coloproctology of Great Britain and Ireland.)

Introduction: Recently, clinical studies have revealed that smoking can contribute to the poor prognosis of colorectal cancer (CRC) and, additionally, can be a risk factor for pulmonary metastasis of CRC. However, there has been no basic research regarding the underlying molecular mechanism. The purpose of this study was to clarify the mechanism by which smoking causes pulmonary metastasis of CRC., Methods: First, pulmonary metastasis model mice inhaled cigarette smoke or air (control) for 1 h once a day for 3 weeks. We attempted to clarify the effect of smoking on the incidence of pulmonary metastasis. On the 15th day, CMT-93 cells were injected into the tail vein. At 6 and 8 weeks following injection, the extent of pulmonary metastasis was evaluated using in vivo micro CT. After the last CT examination, the mice were sacrificed, and the lungs were extracted for pathological examination., Results: The number of mice with pulmonary metastases in the smoking group was significantly higher than in the control group. Three weeks of smoking induced mild inflammation in the lungs, as evidenced by increases in the levels of IL-6 and TNF-α in bronchoalveolar lavage. Moreover, the adhesion-related molecule ICAM-1 was overexpressed in pulmonary tissue, which allowed drained cancer cells to remain in the lung and contribute to the formation of pulmonary metastasis., Conclusion: Collectively, cigarette smoking may contribute to the pathogenesis and development of pulmonary metastasis in CRC through enhancement of adhesion and inflammation., Competing Interests: Prof. Dr. Yuko Kitagawa reports grants and/or personal fees from ASAHI KASEI PHARMA CO., LTD., TAIHO PHARMACEUTICAL CO., LTD, CHUGAI PHARMACEUTICAL CO., LTD., DAIICHI SANKYO COMPANY, LIMITED, Merck Serono Co., Ltd., EA Pharma Co., Ltd., Yakult Honsha Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Factory Inc., SHIONOGI & CO., LTD., KAKEN PHARMACEUTICAL CO., LTD., Kowa Pharmaceutical Co., Ltd., Astellas Pharma Inc., MEDICON INC., DAINIPPON SUMITOMO PHARMA Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Pfizer Japan Inc., ONO PHARMACEUTICAL CO., LTD., NIHON PHARMACEUTICAL CO., LTD., Japan Blood Products Organization, Medtronic Japan Co., Ltd., Sanofi K.K., Eisai Co., Ltd., TSUMURA & CO., KCI Licensing, Inc., ABBOTT JAPAN CO., LTD., FUJIFILM Toyama Chemical Co., Ltd., outside the submitted work. The authors report no other conflicts of interest in this work., (© 2020 Makino et al.)

LGR5 marks resident adult epithelial stem cells at the gland base in the mouse pyloric stomach 1 , but the identity of the equivalent human stem cell population remains unknown owing to a lack of surface markers that facilitate its prospective isolation and validation. In mouse models of intestinal cancer, LGR5 + intestinal stem cells are major sources of cancer following hyperactivation of the WNT pathway 2 . However, the contribution of pyloric LGR5 + stem cells to gastric cancer following dysregulation of the WNT pathway-a frequent event in gastric cancer in humans 3 -is unknown. Here we use comparative profiling of LGR5 + stem cell populations along the mouse gastrointestinal tract to identify, and then functionally validate, the membrane protein AQP5 as a marker that enriches for mouse and human adult pyloric stem cells. We show that stem cells within the AQP5 + compartment are a source of WNT-driven, invasive gastric cancer in vivo, using newly generated Aqp5-creERT2 mouse models. Additionally, tumour-resident AQP5 + cells can selectively initiate organoid growth in vitro, which indicates that this population contains potential cancer stem cells. In humans, AQP5 is frequently expressed in primary intestinal and diffuse subtypes of gastric cancer (and in metastases of these subtypes), and often displays altered cellular localization compared with healthy tissue. These newly identified markers and mouse models will be an invaluable resource for deciphering the early formation of gastric cancer, and for isolating and characterizing human-stomach stem cells as a prerequisite for harnessing the regenerative-medicine potential of these cells in the clinic.

Wnt signaling is critical for directing epithelial gland development within the uterine lining to ensure successful gestation in adults. Wnt-dependent, Lgr5-expressing stem/progenitor cells are essential for the development of glandular epithelia in the intestine and stomach, but their existence in the developing reproductive tract has not been investigated. Here, we employ Lgr5-2A-EGFP/CreERT2/DTR mouse models to identify Lgr5-expressing cells in the developing uterus and to evaluate their stem cell identity and function. Lgr5 is broadly expressed in the uterine epithelium during embryogenesis, but becomes largely restricted to the tips of developing glands after birth. In-vivo lineage tracing/ablation/organoid culture assays identify these gland-resident Lgr5 high cells as Wnt-dependent stem cells responsible for uterine gland development. Adjacent Lgr5 neg epithelial cells within the neonatal glands function as essential niche components to support the function of Lgr5 high stem cells ex-vivo. These findings constitute a major advance in our understanding of uterine development and lay the foundations for investigating potential contributions of Lgr5 + stem/progenitor cells to uterine disorders.

The incidence of colorectal cancer (CRC) has been on the rise, which is linked to the increasing prevalence of obesity, based on global epidemiological evidence. Although chronic inflammation is implicated in tumor development, the mechanisms underlying obesity-associated CRC remain unknown. Here, we sought to identify the inflammatory cytokines and their roles in obesity-related colorectal tumorigenesis using cytokine array analyses in a mouse model. Colorectal tumorigenesis was induced through i.p. injection of azoxymethane once a week for 6 weeks in 6-week-old female WT C57Black/6J mice and the obesity diabetes model mouse KK/TaJcl, KK-Ay/TaJcl. The formation of aberrant crypt foci and colorectal tumors were more frequent in obese mice compared with WT mice, and both serum interleukin (IL)-13 and IL-13 receptor (R) expression in the normal intestinal mucosal epithelium were significantly increased in the obese mice. Furthermore, addition of IL-13 to a human CRC cell line and a human colon organoid culture altered the phenotype of intestinal epithelial cells. Knockdown experiments further revealed that IL-13Rα1 dominantly induced mucosal proliferation. Collectively, These results suggest an association between anti-inflammatory cytokines and colorectal carcinogenesis, and provide new research directions for cancer prevention strategies. In particular, inflammation provoked by obesity, notably by increased expression of the cytokine IL-13, could play an important role in the carcinogenesis of obesity-related CRC., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Intestinal stem cells (ISCs) marked by Lgr5 are located at the bottom of the epithelial crypt compartment. Canonical Wnt signaling, activated by Wnt/Rspo ligands, determines the stem cell identity of Lgr5 + ISCs and is strictly regulated by the ISC niche. Emerging evidence indicates that both epithelial and stromal compartments provide the requisite Wnt/Rspo ligands, confining the ISC niche to the lower crypt regions of the intestine. Recent studies have also shown that the ISC niche can reprogram differentiated cells to replenish lost ISCs following tissue injury, accounting for the epithelial cell plasticity within the crypt compartment. Here we review these recent advances and discuss the role of canonical Wnt signaling in maintaining homeostasis and effecting cell plasticity following tissue injury in the intestine, which could reveal potential novel therapeutic opportunities in the clinic., (Copyright © 2019 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)