Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis.

Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer1-3. However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.

Age-related remodelling of oesophageal epithelia by mutated cancer drivers.

Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which-depending on lifestyle risks-may affect cancer development.

Synergistic antitumor activity by dual blockade of CCR1 and CXCR2 expressed on myeloid cells within the tumor microenvironment.

BACKGROUND: Chemokine signaling within the tumor microenvironment can promote tumor progression. Although CCR1 and CXCR2 on myeloid cells could be involved in tumor progression, it remains elusive what effect would be observed if both of those are blocked. METHODS: We employed two syngeneic colorectal cancer mouse models: a transplanted tumor model and a liver metastasis model. We generated double-knockout mice for CCR1 and CXCR2, and performed bone marrow (BM) transfer experiments in which sub-lethally irradiated wild-type mice were reconstituted with BM from either wild-type, Ccr1-/-, Cxcr2-/- or Ccr1-/-Cxcr2-/- mice. RESULTS: Myeloid cells that express MMP2, MMP9 and VEGF were accumulated around both types of tumors through CCR1- and CXCR2-mediated pathways. Mice reconstituted with Ccr1-/-Cxcr2-/- BM exhibited the strongest suppression of tumor growth and liver metastasis compared with other three groups. Depletion of CCR1+CXCR2+ myeloid cells led to a higher frequency of CD8+ T cells, whereas the numbers of Ly6G+ neutrophils, FOXP3+ Treg cells and CD31+ endothelial cells were significantly decreased. Furthermore, treatment with a neutralizing anti-CCR1 mAb to mice reconstituted with Cxcr2-/- BM significantly suppressed tumor growth and liver metastasis. CONCLUSION: Dual blockade of CCR1 and CXCR2 pathways in myeloid cells could be an effective therapy against colorectal cancer.

FBXW7 regulates the sensitivity of imatinib in gastrointestinal stromal tumors by targeting MCL1.

BACKGROUND: Imatinib contributes to improving prognosis of high-risk or unresectable gastrointestinal stromal tumors (GISTs). As therapeutic efficacy is limited by imatinib resistance and toxicity, the exploration of predictive markers of imatinib therapeutic efficacy that enables patients to utilize more effective therapeutic strategies remains urgent. METHODS: The correlation between FBXW7 and imatinib resistance via FBXW7-MCL1 axis was evaluated in vitro and in vivo experiments. The significance of FBXW7 as a predictor of imatinib treatment efficacy was examined in 140 high-risk patients with GISTs. RESULTS: The ability of FBXW7 to predict therapeutic efficacy of adjuvant imatinib in high-risk GIST patients was determined through 5-year recurrence-free survival (RFS) rates analysis and multivariate analysis. FBXW7 affects imatinib sensitivity by regulating apoptosis in GIST-T1 cells. FBXW7 targets MCL1 to regulate apoptosis. MCL1 involves in the regulation of imatinib sensitivity through inhibiting apoptosis in GIST-T1 cells. FBXW7 regulates imatinib sensitivity by down-regulating MCL1 to enhance imatinib-induced apoptosis in vitro. FBXW7 regulates imatinib sensitivity of GIST cells by targeting MCL1 to predict efficacy of imatinib treatment in vivo. CONCLUSIONS: FBXW7 regulates imatinib sensitivity by inhibiting MCL1 to enhance imatinib-induced apoptosis in GIST, and predicts efficacy of imatinib treatment in high-risk GIST patients treated with imatinib.

Risk factors for anastomotic leakage after low anterior resection for obese patients with rectal cancer.

PURPOSE: We aimed to analyze the risk factors for anastomotic leakage (AL) after low anterior resection (LAR) in obese patients (body mass index [BMI] ≥ 25 kg/m2) with rectal cancer. METHODS: Data were collected from four hundred two obese patients who underwent LAR for rectal cancer in 51 institutions. RESULTS: Forty-six (11.4%) patients had clinical AL. The median BMI (27 kg/m2) did not differ between the AL and non-AL groups. In the AL group, comorbid respiratory disease was more common (p = 0.025), and the median tumor size was larger (p = 0.002). The incidence of AL was 11.5% in the open surgery subgroup and 11.4% in the laparoscopic surgery subgroup. Among the patients who underwent open surgery, the AL group showed a male predominance (p = 0.04) in the univariate analysis, but it was not statistically significant in the multivariate analysis. Among the patients who underwent laparoscopic surgery, the AL group included a higher proportion of patients with comorbid respiratory disease (p = 0.003) and larger tumors (p = 0.007). CONCLUSION: Comorbid respiratory disease and tumor size were risk factors for AL in obese patients with rectal cancer. Careful perioperative respiratory management and appropriate selection of surgical procedures are required for obese rectal cancer patients with respiratory diseases.

Novel and efficient method for culturing patient-derived gastric cancer stem cells.

Experimental techniques for patient-derived cancer stem-cell organoids/spheroids can be powerful diagnostic tools for personalized chemotherapy. However, establishing their cultures from gastric cancer remains challenging due to low culture efficiency and cumbersome methods. To propagate gastric cancer cells as highly proliferative stem-cell spheroids in vitro, we initially used a similar method to that for colorectal cancer stem cells, which, unfortunately, resulted in a low success rate (25%, 18 of 71 cases). We scrutinized the protocol and found that the unsuccessful cases were largely caused by the paucity of cancer stem cells in the sampled tissues as well as insufficient culture media. To overcome these obstacles, we extensively revised our sample collection protocol and culture conditions. We then investigated the following second cohort and, consequently, achieved a significantly higher success rate (88%, 29 of 33 cases). One of the key improvements included new sampling procedures for tumor tissues from wider and deeper areas of gastric cancer specimens, which allowed securing cancer stem cells more reproducibly. Additionally, we embedded tumor epithelial pieces separately in both Matrigel and collagen type-I as their preference to the extracellular matrix was different depending on the tumors. We also added a low concentration of Wnt ligands to the culture, which helped the growth of occasional Wnt-responsive gastric cancer stem-cell spheroids without allowing proliferation of the normal gastric epithelial stem cells. This newly improved spheroid culture method may facilitate further studies, including personalized drug-sensitivity tests prior to drug therapy.

Specialty-Certified Colorectal Surgeons Demonstrate Favorable Short-term Surgical Outcomes for Laparoscopic Low Anterior Resection: Assessment of a Japanese Nationwide Database.

BACKGROUND: There are few studies on the impact of a colorectal-specific technically certified surgeon on good surgical outcomes for laparoscopic low anterior resection in the real world. OBJECTIVE: To evaluate the short-term outcomes of laparoscopic low anterior resection with the participation of a certified colorectal surgeon. DESIGN: This was a retrospective cohort study using a Japanese nationwide database. SETTING: This study was conducted as a project for the Japan Society of Endoscopic Surgery and the Japanese Society of Gastroenterological Surgery. PATIENTS: This study included 41,741 patients listed in the National Clinical Database who underwent laparoscopic low anterior resection performed by certified, noncertified, and colorectal-specific certified surgeons, according to the Endoscopic Surgical Skill Qualification System, from 2016 to 2018. MAIN OUTCOME MEASURES: Operative mortality rate and anastomotic leak rate were the primary outcome measures. RESULTS: Overall 30-day mortality and operative mortality were 0.2% and 0.3%, respectively, without significant differences between all kinds of certified and noncertified surgeon groups. Overall anastomotic leak rate was 9.3%, with a significant difference between the 2 groups. Colorectal- and stomach-certified groups had lower 30-day mortality and operative mortality than the biliary-certified and noncertified groups. The anastomotic leak rate was the lowest in the colorectal-certified group. Based on a logistic regression analysis using the risk-adjusted model, operative mortality was significantly higher in the biliary-certified group than in the colorectal-certified group. Moreover, anastomotic leak rate was significantly lower in the colorectal-certified group than in the stomach-certified and noncertified groups. LIMITATIONS: This study was a retrospective study, and there was a possibility of different definitions of anastomotic leak due to the use of a nationwide database. CONCLUSIONS: The participation of a colorectal-specific certified surgeon may decrease the risk of operative mortality and anastomotic leak for laparoscopic low anterior resection. CIRUJANO COLORRECTAL ALTAMENTE CALIFICADO PROVOCA RESULTADOS QUIRRGICOS FAVORABLES A CORTO PLAZO PARA LA RESECCIN ANTERIOR BAJA LAPAROSCPICA EVALUACIN DE LA BASE DE DATOS NACIONAL JAPONESA: ANTECEDENTES:Hay pocos estudios sobre el impacto de un cirujano certificado técnicamente especializado en cáncer colorrectal con un buen resultado quirúrgico para la resección anterior baja laparoscópica en el mundo real.OBJETIVO:Evaluar los resultados a corto plazo de la resección anterior baja laparoscópica con la participación de un cirujano colorrectal certificado.DISEÑO:Este fue un estudio de cohorte retrospectivo que utilizó una base de datos nacional japonesa.AJUSTE:Este estudio se realizó como un proyecto para la Sociedad Japonesa de Cirugía Endoscópica y la Sociedad Japonesa de Cirugía Gastroenterológica.PACIENTES:este estudio incluyó a 41 741 pacientes incluidos en la base de datos clínica nacional que se sometieron a una resección anterior baja laparoscópica realizada por cirujanos certificados, no certificados y certificados específicamente colorrectales, según el Sistema de calificación de habilidades quirúrgicas endoscópicas de 2016 a 2018.PRINCIPALES MEDIDAS DE RESULTADO:La tasa de mortalidad operatoria y la tasa de fuga anastomótica fueron los resultados primarios.RESULTADOS:La mortalidad general a los 30 días y la mortalidad operatoria fueron del 0,2 % y el 0,3 %, respectivamente, sin diferencias significativas entre los grupos de todos los tipos de cirujanos certificados y no certificados. La tasa global de fuga anastomótica fue del 9,3 %, con una diferencia significativa entre los dos grupos. Los grupos con certificación colorrectal y estomacal tuvieron una mortalidad a los 30 días y una mortalidad operatoria más bajas que los grupos con certificación biliar y sin certificación. La tasa de fuga anastomótica fue la más baja en el grupo certificado colorrectal. Con base en un análisis de regresión logística utilizando el modelo ajustado por riesgo, la mortalidad operatoria fue significativamente más alta en el grupo con certificación biliar que en el grupo con certificación colorrectal. Además, la tasa de fuga anastomótica fue significativamente más baja en el grupo con certificación colorrectal que en los grupos con certificación estomacal y sin certificación.LIMITACIONES:Este estudio fue retrospectivo y existía la posibilidad de diferentes definiciones de fuga anastomótica debido al uso de una base de datos nacional.CONCLUSIONES:La participación de un cirujano certificado en video específico colorrectal puede disminuir el riesgo de mortalidad operatoria y fuga anastomótica para la resección anterior baja laparoscópica. (Traducción-Dr. Mauricio Santamaria ).

Skill-qualified surgeons positively affect short-term outcomes after laparoscopic gastrectomy for gastric cancer: a survey of the National Clinical Database of Japan.

BACKGROUND: Proficiency of the operating surgeon is one of the most critical factors potentially associated with reductions in complications and surgery-related mortality. With video-rating systems having shown potential for assessing laparoscopic surgeons' proficiency, the Endoscopic Surgical Skill Qualification System (ESSQS) was developed by the Japan Society for Endoscopic Surgery to subjectively assess the proficiency of laparoscopic surgeons by rating applicants' non-edited case videos. We conducted a study to evaluate how ESSQS skill-qualified (SQ) surgeon involvement influences short-term outcomes of laparoscopic gastrectomy performed for gastric cancer. METHODS: Data from the National Clinical Database regarding laparoscopic distal and total gastrectomy performed for gastric cancer between January 2016 and December 2018 were analyzed. Operative mortality, defined as 30-day mortality or 90-day in-hospital mortality, and anastomotic leakage rates were compared per involvement vs. non-involvement of an SQ surgeon. Outcomes were also compared per involvement of a gastrectomy-, colectomy-, or cholecystectomy-qualified surgeon. The association between the area of qualification and operative mortality/anastomotic leakage was also analyzed with a generalized estimating equation logistic regression model used to account for patient-level risk factors and institutional differences. RESULTS: Of 104,093 laparoscopic distal gastrectomies, 52,143 were suitable for inclusion in the study; 30,366 (58.2%) were performed by an SQ surgeon. Of 43,978 laparoscopic total gastrectomies, 10,326 were suitable for inclusion; 6501 (63.0%) were performed by an SQ surgeon. Gastrectomy-qualified surgeons outperformed non-SQ surgeons in terms of both operative mortality and anastomotic leakage. They also outperformed cholecystectomy- and colectomy-qualified surgeons in terms of operative mortality or anastomotic leakage in distal and total gastrectomy, respectively. CONCLUSION: The ESSQS appears to discriminate laparoscopic surgeons who can be expected to achieve significantly improved gastrectomy outcomes.

Long-term results of a phase 2 study of neoadjuvant chemotherapy with molecularly targeted agents for locally advanced rectal cancer.

BACKGROUND: We previously reported the feasibility and efficacy of neoadjuvant chemotherapy without radiotherapy for locally advanced rectal cancer. Here, we report the results of a long-term follow-up study. METHODS: This was a multi-institutional, prospective phase 2 study of patients with locally advanced rectal cancer. Patients received neoadjuvant chemotherapy with molecularly targeted agents before undergoing total mesorectal excision. Six cycles of modified FOLFOX (mFOLFOX6) with bevacizumab were administered to KRAS-mutant patients, and mFOLFOX6 with cetuximab was administered to KRAS-wild-type patients. Here, we report the secondary end points of overall survival, relapse-free survival, and local recurrence rate. RESULTS: Sixty patients were enrolled in this study. R0 resection was achieved in 98.3% (59/60) patients, and pathological complete response was achieved in 16.7% (10/60) patients. After a median follow-up of 5.4 years, the 5 year overall survival was 81.6%, the 5 year relapse-free survival was 71.7%, and the 5 year local recurrence rate was 12.6%. None of the patients who achieved pathological complete response developed recurrence within 5 years. CONCLUSIONS: The use of molecularly targeted agents in the neoadjuvant setting for locally advanced rectal cancer has an acceptable prognosis.

Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase.

Neutrophil extracellular traps (NETs) play important roles in host immunity, as there is increasing evidence of their contribution to the progression of several types of cancers even though their role in colorectal cancers (CRCs) remains unclear. To investigate the clinical relevance of NETs in CRCs, we examined the expression of citrullinated histone H3 using immunohistochemistry and preoperative serum myeloperoxidase-DNA complexes in CRC patients using an enzyme-linked immunosorbent assay. High expression of intratumoral or systemic NETs was found to correlate with poor relapse-free survival (RFS), for which it is an independent prognostic factor. In vitro investigations of CRC cells (HCT116, HT29) revealed that NETs did not affect their proliferation but did promote the migration of CRC cells mediated by neutrophil elastase (NE) released during NETosis to increase extracellular signal-regulated kinase (ERK) activity. In vivo experiments using nude mice (KSN/slc) revealed that NE inhibition suppressed liver metastases in CRC cells, although it did not affect the growth of subcutaneously implanted tumors. Taken together, these results suggest that NET formation correlates with poor prognoses of patients with CRC and that the inhibition of NE could be a potential therapy for CRC metastases.

Laparoscopic Versus Open Surgery for Locally Advanced Rectal Cancer: Five-Year Survival Outcomes in a Large, Multicenter, Propensity Score-Matched Cohort Study.

BACKGROUND: There is a paucity of evidence pertaining to long-term survival outcomes of laparoscopic versus open surgery for locally advanced rectal cancer. OBJECTIVE: This study aimed to evaluate the long-term survival outcomes of laparoscopic surgery for locally advanced rectal cancer and to investigate the recurrence pattern. DESIGN: This was a prospective analysis of a registered cohort. SETTINGS: This study was conducted at 69 institutions across Japan. PATIENTS: A total of 1500 patients with clinical stage II-III rectal cancer located below the peritoneal reflection between January 2010 and December 2011 were included. After propensity score matching, all eligible patients, including the matched patients registered in 2014, were prospectively followed up. MAIN OUTCOME MEASURES: Five-year relapse-free survival was the primary outcome. RESULTS: The median follow-up period was 5.6 years. Among the 964 matched patients, the 5-year relapse-free survival was 65.1% in the open group versus 63.5% in the laparoscopic group (HR 1.04; p = 0.71). Distant recurrences at rare sites, which were more frequently observed in the laparoscopic group, were significantly less salvaged (adjusted OR 0.74; p = 0.045). Postrecurrence 5-year overall survival was significantly better for patients who underwent salvage surgery than for those who did not; 55.3% vs 29.5% for patients with initial local recurrence ( p = 0.03) and 64.4% vs 30.7% for patients with distant recurrence alone ( p < 0.001). LIMITATIONS: Potential heterogeneity and influence of unknown confounding. CONCLUSIONS: Five-year follow-up data demonstrated that laparoscopic surgery for locally advanced rectal cancer was safely performed in terms of long-term prognosis. In addition, salvage surgery for recurrent lesions was associated with prolonged postrecurrence survival, both in patients with local and distant recurrence. However, recurrence at rare sites may require further investigation. See Video Abstract at http://links.lww.com/DCR/B793 . CIRUGA LAPAROSCPICA VERSUS CIRUGA ABIERTA EN CNCER DE RECTO LOCALMENTE AVANZADO RESULTADOS DE SUPERVIVENCIA A CINCO AOS EN UN ESTUDIO DE COHORTE DE GRAN MAGNITUD, MULTICNTRICO Y DE PAREAMIENTO POR PUNTAJE DE PROPENSIN: ANTECEDENTES:Existe una escasez de pruebas relacionadas con los resultados de supervivencia a largo plazo de la cirugía laparoscópica versus abierta para el cáncer de recto localmente avanzado.OBJETIVO:Este estudio tuvo como objetivo evaluar los resultados de supervivencia a largo plazo de la cirugía laparoscópica para el cáncer de recto localmente avanzado e investigar el patrón de recurrencia.DISEÑO:Fue un análisis prospectivo de una cohorte registrada.ENTORNO CLÍNICO:El estudio se llevó a cabo en 69 instituciones en todo Japón.PACIENTES:Se incluyó un total de 1500 pacientes con cáncer de recto en estadio clínico II-III ubicados por debajo de la reflección peritoneal, entre enero del 2010 y diciembre del 2011. Después del pareamiento por puntaje de propensión, se realizó un seguimiento prospectivo de todos los pacientes elegibles, incluidos los pacientes emparejados registrados en 2014.PRINCIPALES MEDIDAS DE VALORACIÓN:La supervivencia sin recaídas a cinco años fue el resultado primario.RESULTADOS:El período de seguimiento medio fue de 5,6 años. Entre los 964 pacientes emparejados, la supervivencia libre de recaída a 5 años fue del 65,1% en el grupo abierto frente al 63,5% en el grupo laparoscópico (cociente de riesgo 1,04; p = 0,71). Las recurrencias a distancia en sitios raros, que se observaron con mayor frecuencia en el grupo laparoscópico, tuvieron menor sobrevida (razón de posibilidades ajustada 0,74; p = 0,045). La supervivencia general a los 5 años después de la recidiva fue significativamente menor en los pacientes sometidos a una cirugía de rescate; 55,3% frente al 29,5% para los pacientes con recidiva local inicial ( p = 0,03) y 64,4% frente al 30,7% para los pacientes con recidiva a distancia sola ( p < 0,001).LIMITACIONES:Potencial heterogeneidad e influencia de factores de confusión desconocidos.CONCLUSIONES:El seguimiento a cinco años demostró que la cirugía laparoscópica para el cáncer de recto localmente avanzado es segura en términos de pronóstico a largo plazo. Además, la cirugía de rescate de las lesiones recurrentes se asoció con una mayor supervivencia posrecurrencia, tanto en pacientes con recurrencia local como a distancia. Sin embargo, la recurrencia en sitios raros puede requerir una mayor investigación. Consulte Video Resumen en http://links.lww.com/DCR/B793 . (Traducción- Dr. Ingrid Melo ).

Identification of high-risk stage I colon and rectal cancer patients: a retrospective analysis of a large Japanese cohort.

PURPOSE: Data regarding risk factors for recurrence in stage I colorectal cancer patients are limited. The aim of this study was to clarify the existence of a high-recurrence-risk population among stage I colorectal cancer patients. METHODS: This analysis included 7,539 stage I colorectal cancer patients treated between 1997 and 2012 at 24 leading hospitals in Japan. Risk factors for time to recurrence were evaluated using a Cox proportional hazards model, and a high-risk group for recurrence was identified. Prognostic outcomes of high-risk stage I colorectal cancer patients were compared with those of low-risk stage I and stage II patients. RESULTS: Multivariable analyses identified left-sided location (hazard ratio [HR]: 1.65, 95% confidence interval [CI]: 1.09-2.58), T2 tumors (HR: 1.80, 95% CI: 1.21-2.66), and lymphatic invasion (HR: 1.55, 95% CI: 1.05-2.28) as risk factors for recurrence in stage I colon cancer, and patients with these three risk factors were classified as high risk. For stage I rectal cancer, patients with poor differentiation (HR: 2.86, 95% CI: 1.21-5.69), T2 tumors (HR: 1.53, 95% CI: 1.07-2.23), and venous invasion (HR: 1.51, 95% CI: 1.08-2.13) were identified as high risk. The Kaplan-Meier analysis of cumulative recurrence rate and recurrence-free survival revealed that the high-risk stage I colorectal cancer patients have poorer clinical outcomes than the low-risk patients. CONCLUSION: Although stage I colorectal cancer patients generally have a favorable prognosis after curative surgery, poorer prognosis was observed in high-risk stage I colorectal cancer patients than in low-risk patients.

Involvement of a skill-qualified surgeon favorably influences outcomes of laparoscopic cholecystectomy performed for acute cholecystitis.

OBJECTIVE: The Endoscopic Surgical Skill Qualification System (ESSQS) was developed by the Japan Society for Endoscopic Surgery as a means of subjectively assessing the proficiency of laparoscopic surgeons. We conducted a study to evaluate how involvement of an ESSQS skill-qualified (SQ) surgeon influences short-term outcomes of laparoscopic cholecystectomy performed for acute cholecystitis. Previous reports suggest that assessment of the video-rating system is a potential tool to discriminate laparoscopic surgeons' proficiency and top-rated surgeons face less surgical mortality and morbidity in bariatric surgery. METHODS: Data from the National Clinical Database regarding laparoscopic cholecystectomy performed for acute cholecystitis between January 2016 and December 2018 were analyzed. Outcomes were compared between patients grouped according to involvement vs. non-involvement of an SQ surgeon. Outcomes were also compared between patients grouped according to whether their operation was performed by biliary tract-, stomach-, or colon-qualified surgeon. RESULTS: Of the 309,998 laparoscopic cholecystectomies during the study period, 65,295 were suitable for inclusion in the study and 13,670 (20.9%) were performed by an SQ surgeon. Patients' clinical characteristics did not differ between groups. Thirty-day mortality was significantly lower in the SQ group (0.1%) 16/13,670 than in the non-SQ group (0.2%) 140/51,625 (P = 0.001). Thirty-day mortality was [0.1% (9/7173)] in the biliary tract-qualified group, [0.2% (5/3527)] in the stomach-qualified group, and [0.1% (2/3240)] in the colon-qualified group. CONCLUSION: Surgeons with ESSQS certification outperform the non-skilled surgeons in terms of surgical mortality in 30 and 90 days. Further verification of the value of the ESSQS is warranted and similar systems may be needed in countries across the world to ensure patient safety and control the quality of surgical treatments.

Chronological Changes in Skeletal Muscle Mass Two Years after Minimally Invasive Esophagectomy: A Prospective Cohort Study.

BACKGROUND: Preoperative loss of skeletal muscle mass, defined as sarcopenia, has been reported to be associated with higher incidence of complications following esophagectomy in patients with esophageal cancer. Although skeletal muscle loss promotes disability and reduced quality of life (QOL), only a few studies have focused on changes in skeletal muscle mass after surgery. This prospective cohort study aimed to evaluate the chronological changes in skeletal muscle mass after minimally invasive esophagectomy (MIE). METHODS: Patients with esophageal cancer scheduled to undergo MIE at our institution were prospectively registered. Skeletal muscle mass was evaluated before and 2, 6, 12, and 24 months after surgery. The effects of preoperative sarcopenia on surgical outcomes and chronological changes in skeletal muscle mass were evaluated. RESULTS: Among the 71 eligible preoperative patients, 29 (40.8%) were diagnosed with sarcopenia. Patients with sarcopenia had significantly higher incidences of total (79.3% vs 52.4%, p = 0.026) and gastrointestinal (37.9% vs 11.9%, p = 0.019) complications and a significantly longer length of hospital stay (31 vs 23 days, p = 0.005) than those without sarcopenia. The median skeletal muscle mass index (kg/m2) was 7.09 before surgery, which decreased to 6.46 two months after surgery (- 7.2%, P < 0.01). Thereafter, values of 6.90, 6.86, and 7.06 were reported at 6, 12, and 24 months after surgery, respectively. CONCLUSION: Patients with preoperative sarcopenia developed more postoperative complications than those without it. Additionally, patients experienced a decrease in skeletal muscle mass during the early postoperative period following MIE. Further research on perioperative countermeasures to prevent skeletal muscle loss during the early postoperative period and to prevent postoperative complications is necessary for patients undergoing MIE.

Mesenteric closure after laparoscopic total gastrectomy with Roux-en-Y reconstruction is effective for prevention of internal hernia: a multicenter retrospective study.

BACKGROUND: Internal hernia (IH) is one of the critical complications after gastrectomy with Roux-en-Y reconstruction, which can be prevented by closing mesenteric defects. However, only few studies have investigated the incidence of IH after laparoscopic total gastrectomy (LTG) with Roux-en-Y reconstruction for gastric cancer till date. This study aimed to assess the efficacy of defect closure for the prevention of IH after LTG. METHODS: This multicenter, retrospective cohort study collected data from 714 gastric cancer patients who underwent LTG with Rou-en-Y reconstruction between 2010 and 2016 in 13 hospitals. We evaluated the incidence of postoperative IH by comparing closure and non-closure groups of Petersen's defect, jejunojejunostomy mesenteric defect, and transverse mesenteric defect. RESULTS: The closure group for Petersen's defect included 609 cases, while the non-closure group included 105 cases. The incidence of postoperative IH in the closure group for Petersen's defect was significantly lower than it was in the non-closure group (0.5% vs. 4.8%, p < 0.001). The closure group for jejunojejunostomy mesenteric defect included 641 cases, while the non-closure group included 73 cases. The incidence of postoperative IH in the closure group of jejunojejunostomy mesenteric defect was significantly lower than that in the non-closure group (0.8% vs. 4.1%, p = 0.004). Out of 714 patients, 41 underwent retro-colic reconstruction. No patients in the transverse mesenteric defect group developed IH. CONCLUSION: Mesenteric defect closure after LTG with Roux-en-Y reconstruction may reduce postoperative IH incidence. Endoscopic surgeons should take great care to prevent IH by closing mesenteric defects.

Side-overlap esophagogastric tube (SO-EG) reconstruction after minimally invasive Ivor Lewis esophagectomy or laparoscopic proximal gastrectomy for cancer of the esophagogastric junction.

PURPOSE: Both laparoscopic proximal gastrectomy with lower esophagectomy (extended LPG) and minimally invasive Ivor Lewis esophagectomy (MIILE) are acceptable treatments for adenocarcinoma of the esophagogastric junction (AEG), but the optimal reconstruction technique for mediastinal esophagogastrostomy (one that provides adequate reflux prevention) has not been established. We devised a novel side-overlap esophagogastric-tube (SO-EG) reconstruction. METHODS: We performed a retrospective review of patient records after LPG or MIILE. In each patient, we created a 3-cm wide gastric tube, overlapping the esophagus by 5 cm. A linear stapler was inserted into the left side of the esophageal stump and the anterior gastric wall along the greater curvature. The entry hole was closed to make a slit-like anastomosis, and the right side of the esophageal wall was fixed to the anterior gastric wall. RESULTS: Ten consecutive patients underwent this procedure between June 2020 and July 2021. Five patients had Siewert type II AEG: 4 with lower thoracic esophageal cancer and 1 with benign lower esophageal stenosis. A total of 3 patients underwent extended LPG, and 7 underwent MIILE. The median operative time was 352 min (range, 221-556 min). The postoperative course was uneventful in 9 patients; a single patient developed pneumonia. Seven patients underwent follow-up endoscopy at 6 months. One patient with anastomotic stenosis and 2 with mild reflux esophagitis were treated conservatively. CONCLUSION: Our novel SO-EG reconstruction is simple and feasible, with acceptable results for preventing reflux esophagitis. This technique can be performed with either extended LPG or MIILE.

Establishment and validation of a nomogram for predicting potential lateral pelvic lymph node metastasis in low rectal cancer.

BACKGROUND: Identifying lateral pelvic lymph node (LPN) metastasis in low rectal cancer is crucial before treatment. Several risk factors and prediction models for LPN metastasis have been reported. However, there is no useful tool to accurately predict LPN metastasis. Therefore, we aimed to construct a nomogram for predicting LPN metastasis in rectal cancer. METHODS: We analyzed the risk factors for potential LPN metastasis by logistic regression analysis in 705 patients who underwent primary resection of low rectal cancer. We included patients at 49 institutes of the Japan Society of Laparoscopic Colorectal Surgery between June 2010 and February 2012. Clinicopathological factors and magnetic resonance imaging findings were evaluated. The nomogram performance was assessed using the c-index and calibration plots, and the nomogram was validated using an external cohort. RESULTS: In the univariable logistic regression analysis, age, sex, carcinoembryonic antigen, tumor location, clinical T stage, tumor size, circumferential resection margin (CRM), extramural vascular invasion (EMVI), and the short and long axes of LPN and perirectal lymph node (PRLN) were nominated as risk factors for potential LPN metastasis. We identified a combination of the short axis of LPN, tumor location, EMVI, and short axis of PRLN as optimal for predicting potential LPN metastasis and developed a nomogram using these factors. This model had a c-index of 0.74 and was moderately calibrated and well-validated. CONCLUSIONS: This is the first study to construct a well-validated nomogram for predicting potential LPN metastasis in rectal cancer, and its performance was high.

Lineage tracing and targeting of IL17RB+ tuft cell-like human colorectal cancer stem cells.

Cancer stem cell (CSC)-specific markers may be potential therapeutic targets. We previously identified that Dclk1, a tuft cell marker, marks tumor stem cells (TSCs) in mouse intestinal adenomas. Based on the analysis of mouse Dclk1+ tumor cells, we aimed to identify a CSC-specific cell surface marker in human colorectal cancers (hCRCs) and validate the therapeutic effect of targeting it. IL17RB was distinctively expressed by Dclk1+ mouse intestinal tumor cells. Using Il17rb-CreERT2-IRES-EGFP mice, we show that IL17RB marked intestinal TSCs in an IL13-dependent manner. Tuft cell-like cancer cells were detected in a subset of hCRCs. In these hCRCs, lineage-tracing experiments in CRISPR-Cas9-mediated IL17RB-CreERT2 knockin organoids and xenograft tumors revealed that IL17RB marks CSCs that expand independently of IL-13. We observed up-regulation of POU2F3, a master regulator of tuft cell differentiation, and autonomous tuft cell-like cancer cell differentiation in the hCRCs. Furthermore, long-term ablation of IL17RB-expressing CSCs strongly suppressed the tumor growth in vivo. These findings reveal insights into a CSC-specific marker IL17RB in a subset of hCRCs, and preclinically validate IL17RB+ CSCs as a cancer therapeutic target.

Feasibility of the semi-opened method of specimen resection for a circumferential resection margin in rectal cancer surgery: a multicenter study.

PURPOSE: A circumferential resection margin (CRM) > 1 mm is a surrogate marker of oncologic outcomes in rectal cancer patients. In Japan, because the mesentery is removed from the rectum, the CRM cannot be measured. This multicenter prospective study evaluates the feasibility of a resected specimen processing method that allows CRM measurement. METHODS: Fifty patients with rectal cancer were enrolled. Resected specimens were processed as previously reported. The primary outcomes were CRM measurement and the rate of CRM positivity. The secondary outcomes were the quality of total mesorectal excision, the possibility to visualize and sample the tumor, the number of harvested lymph nodes, and comparison between the pathological CRM and preoperative mesorectal fascia (MRF) involvement. This study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry under identification number UMIN000031735. RESULTS: The CRM was measurable in all patients and found to be positive in three (6%). We confirmed tumor localization, sampled the tumor, and measured the distal margin in all patients. A median of 20 lymph nodes were harvested. The concordance rate between preoperative MRF involvement and pathological CRM status was 90%. CONCLUSION: A semi-opened rectal specimen with transverse slicing is a feasible method for measuring the CRM.

Lower Incidence of Postoperative Pulmonary Complications Following Robot-Assisted Minimally Invasive Esophagectomy for Esophageal Cancer: Propensity Score-Matched Comparison to Conventional Minimally Invasive Esophagectomy.

BACKGROUND: Whether robot-assisted minimally invasive surgery (RAMIE) is more beneficial than conventional minimally invasive surgery (MIE) remains unclear. METHODS: In total, 165 consecutive patients with esophageal carcinoma who underwent esophagectomy between January 2015 and April 2020 were retrospectively assessed. A 1:1 propensity score matching analysis was performed to compare the short-term outcomes between RAMIE and conventional MIE. RESULTS: After matching, 45 patients were included in the RAMIE and conventional MIE groups. RAMIE had a significantly longer total operative time (708 vs. 612 min, P < 0.001) and thoracic operative time (348 vs. 285 min, P < 0.001) than conventional MIE. However, there were no significant differences in terms of oncological outcomes, such as R0 resection rate and number of resected lymph nodes. The overall postoperative morbidity (Clavien-Dindo [C-D] grade II or higher) rate of RAMIE and conventional MIE were 51% and 73% (P = 0.03), respectively, and the severe postoperative morbidity (C-D grade III or higher) rates were 11% and 29% (P = 0.04), respectively. The incidence rate of recurrent laryngeal nerve palsy was halved in RAMIE (7%) compared with conventional MIE (20%) (P = 0.06). Finally, the pulmonary complication rate (18%) was significantly lower in patients who underwent RAMIE than in those who underwent conventional MIE (44%) (P = 0.006). CONCLUSIONS: RAMIE was safe and feasible, even during the early period of its application at a specialized center. Moreover, it may be a promising alternative to conventional MIE, with better short-term outcomes, including significantly lower incidence of pulmonary complications.