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.

Differential involvement of LUBAC-mediated linear ubiquitination in intestinal epithelial cells and macrophages during intestinal inflammation.

Disruption of the intestinal epithelial barrier and dysregulation of macrophages are major factors contributing to the pathogenesis of inflammatory bowel diseases (IBDs). Activation of NF-κB and cell death are involved in maintaining intestinal homeostasis in a cell type-dependent manner. Although both are regulated by linear ubiquitin chain assembly complex (LUBAC)-mediated linear ubiquitination, the physiological relevance of linear ubiquitination to intestinal inflammation remains unexplored. Here, we used two experimental mouse models of IBD (intraperitoneal LPS and oral dextran sodium sulfate [DSS] administration) to examine the role of linear ubiquitination in intestinal epithelial cells (IECs) and macrophages during intestinal inflammation. We did this by deleting the linear ubiquitination activity of LUBAC specifically from IECs or macrophages. Upon LPS administration, loss of ligase activity in IECs induced mucosal inflammation and augmented IEC death. LPS-mediated death of LUBAC-defective IECs was triggered by TNF. IEC death was rescued by an anti-TNF antibody, and TNF (but not LPS) induced apoptosis of organoids derived from LUBAC-defective IECs. However, augmented TNF-mediated IEC death did not overtly affect the severity of colitis after DSS administration. By contrast, defective LUBAC ligase activity in macrophages ameliorated DSS-induced colitis by attenuating both infiltration of macrophages and expression of inflammatory cytokines. Decreased production of macrophage chemoattractant MCP-1/CCL2, as well as pro-inflammatory IL-6 and TNF, occurred through impaired activation of NF-κB and ERK via loss of ligase activity in macrophages. Taken together, these results indicate that both intraperitoneal LPS and oral DSS administrations are beneficial for evaluating epithelial integrity under inflammatory conditions, as well as macrophage functions in the event of an epithelial barrier breach. The data clarify the cell-specific roles of linear ubiquitination as a critical regulator of TNF-mediated epithelial integrity and macrophage pro-inflammatory responses during intestinal inflammation. © 2022 The Pathological Society of Great Britain and Ireland.

Real-time detection of active bleeding in laparoscopic colectomy using artificial intelligence.

BACKGROUND: Most intraoperative adverse events (iAEs) result from surgeons' errors, and bleeding is the majority of iAEs. Recognizing active bleeding timely is important to ensure safe surgery, and artificial intelligence (AI) has great potential for detecting active bleeding and providing real-time surgical support. This study aimed to develop a real-time AI model to detect active intraoperative bleeding. METHODS: We extracted 27 surgical videos from a nationwide multi-institutional surgical video database in Japan and divided them at the patient level into three sets: training (n = 21), validation (n = 3), and testing (n = 3). We subsequently extracted the bleeding scenes and labeled distinctively active bleeding and blood pooling frame by frame. We used pre-trained YOLOv7_6w and developed a model to learn both active bleeding and blood pooling. The Average Precision at an Intersection over Union threshold of 0.5 (AP.50) for active bleeding and frames per second (FPS) were quantified. In addition, we conducted two 5-point Likert scales (5 = Excellent, 4 = Good, 3 = Fair, 2 = Poor, and 1 = Fail) questionnaires about sensitivity (the sensitivity score) and number of overdetection areas (the overdetection score) to investigate the surgeons' assessment. RESULTS: We annotated 34,117 images of 254 bleeding events. The AP.50 for active bleeding in the developed model was 0.574 and the FPS was 48.5. Twenty surgeons answered two questionnaires, indicating a sensitivity score of 4.92 and an overdetection score of 4.62 for the model. CONCLUSIONS: We developed an AI model to detect active bleeding, achieving real-time processing speed. Our AI model can be used to provide real-time surgical support.

Anterior versus posterior mediastinal reconstruction after esophagectomy in esophageal cancer patients: a systematic review and meta-analysis.

PURPOSE: Esophagectomy is the primary surgical treatment for esophageal cancer, although other treatment approaches are often incorporated, including preoperative chemotherapy and chemoradiotherapy. The two major routes of esophageal reconstruction after esophagectomy are the anterior mediastinal (retrosternal, heterotopic) and posterior mediastinal (prevertebral, orthotopic) routes. However, which of these two routes of reconstruction is the most appropriate remains controversial. This systematic review aimed to compare the efficacy and safety of anterior mediastinal reconstruction with those of posterior mediastinal reconstruction after esophagectomy in esophageal cancer. METHODS: In January 2022, a literature search of the CENTRAL, MEDLINE, and EMBASE databases was conducted to identify all published and unpublished randomized controlled trials, regardless of language. Eight studies were included for quantitative synthesis. RESULTS: Postoperative death (9/129 and 4/125, risk ratio [RR]: 2.07, 95% confidence interval [CI]: 0.65-6.64) and incidence of anastomotic leak (24/208 and 26/208, RR: 0.95, 95% CI: 0.56-1.62) were not significantly different between the two mediastinal reconstructions. We could not perform a meta-analysis for quality of life, loss of body weight, or postoperative hospital stay due to data limitations. CONCLUSION: Overall, there was low-quality evidence to suggest that the outcomes of the anterior and posterior mediastinal routes of reconstruction are not significantly different in patients with esophageal cancer.

Impact of the coronavirus disease 2019 pandemic on gastric and colorectal cancer surgeries: a multicenter epidemiologic study from the Kinki region of Japan.

The coronavirus disease 2019 pandemic affected cancer surgeries and advanced cancer diagnoses; however, the trends in patient characteristics in medical institutions during this time, and the surgical approaches used are unclear. We investigated the impact of the pandemic on gastric and colorectal cancer surgeries in the Kinki region of Japan. We grouped 1688 gastric and 3493 colorectal cancer surgeries into three periods: "pre-pandemic" (April 2019-March 2020), "pandemic 1" (April 2020-March 2021), and "pandemic 2" (April 2021-September 2021), to investigate changes in the number of surgeries, patient characteristics, surgical approaches, and cancer progression after surgery. Gastric and colorectal cancer surgeries decreased from the pre-pandemic levels, by 20% and 4%, respectively, in pandemic 1, and by 31% and 19%, respectively, in pandemic 2. This decrease had not recovered to pre-pandemic levels by September, 2021. Patient characteristics, surgical approaches, and cancer progression of gastric and colorectal surgeries did not change remarkably as a result of the coronavirus disease 2019 pandemic.

Inhibition of the bone morphogenetic protein pathway suppresses tumor growth through downregulation of epidermal growth factor receptor in MEK/ERK-dependent colorectal cancer.

The bone morphogenetic protein (BMP) pathway promotes differentiation and induces apoptosis in normal colorectal epithelial cells. However, its role in colorectal cancer (CRC) is controversial, where it can act as context-dependent tumor promoter or tumor suppressor. Here we have found that CRC cells reside in a BMP-rich environment based on curation of two publicly available RNA-sequencing databases. Suppression of BMP using a specific BMP inhibitor, LDN193189, suppresses the growth of select CRC organoids. Colorectal cancer organoids treated with LDN193189 showed a decrease in epidermal growth factor receptor, which was mediated by protein degradation induced by leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) expression. Among 18 molecularly characterized CRC organoids, suppression of growth by BMP inhibition correlated with induction of LRIG1 gene expression. Notably, knockdown of LRIG1 in organoids diminished the growth-suppressive effect of LDN193189. Furthermore, in CRC organoids, which are susceptible to growth suppression by LDN193189, simultaneous treatment with LDN193189 and trametinib, an FDA-approved MEK inhibitor, resulted in cooperative growth inhibition both in vitro and in vivo. Taken together, the simultaneous inhibition of BMP and MEK could be a novel treatment option in CRC cases, and evaluating in vitro growth suppression and LRIG1 induction by BMP inhibition using patient-derived organoids could offer functional biomarkers for predicting potential responders to this regimen.

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.

Management of Patients Receiving Antiplatelet Therapy During Gastroenterological Surgery: A Multicenter Prospective Cohort Study (GSATT).

OBJECTIVE: This study aimed to evaluate the effect of continuing preoperative aspirin monotherapy on surgical outcomes in patients receiving antiplatelet therapy (APT). SUMMARY BACKGROUND DATA: The effectiveness of continuing preoperative aspirin monotherapy in patients undergoing APT in preventing thromboembolic consequences is mostly unknown. METHODS: This prospective multicenter cohort study on the Safety and Feasibility of Gastroenterological Surgery in Patients Undergoing Antithrombotic Therapy (GSATT study) conducted at 14 clinical centers enrolled and screened patients between October 2019 and December 2021. The participants (n=1,170) were assigned to the continued APT group, discontinued APT group, or non-APT group, and the surgical outcomes of each group were compared. Propensity score matching was performed between the continued and discontinued APT groups to investigate the effect of continuing preoperative aspirin therapy on thromboembolic complications. RESULTS: The rate of thromboembolic complications in the continued APT group was substantially lower than that in the non-APT or discontinued APT groups (0.5% vs. 2.6% vs. 2.9%; P=0.027). Multivariate investigation of the entire cohort revealed that discontinuation of APT (P<0.001) and chronic anticoagulant use (P<0.001) were independent risk factors for postoperative thromboembolism. The post-matching evaluation demonstrated that the rates of thromboembolic complications were significantly different between the continued and discontinued APT groups (0.6% vs. 3.3%; P=0.012). CONCLUSIONS: APT discontinuation following elective gastroenterological surgery increases the risk of thromboembolic consequences, whereas continuing preoperative aspirin greatly reduces this risk. The continuation of preoperative aspirin therapy in APT-received patients is considered one of the best alternatives for preventing thromboembolism during elective gastroenterological surgery.

Comparison of Minimally Invasive Surgery with Open Surgery for Remnant Gastric Cancer: A Multi-institutional Cohort Study.

BACKGROUND: Despite growing evidence of the effectiveness of minimally invasive surgery (MIS) for primary gastric cancer, MIS for remnant gastric cancer (RGC) remains controversial due to the rarity of the disease. This study aimed to evaluate the surgical and oncological outcomes of MIS for radical resection of RGC. PATIENTS AND METHODS: Patients with RGC who underwent surgery between 2005 and 2020 at 17 institutions were included, and a propensity score matching analysis was performed to compare the short- and long-term outcomes of MIS with open surgery. RESULTS: A total of 327 patients were included in this study and 186 patients were analyzed after matching. The risk ratios for overall and severe complications were 0.76 [95% confidence interval (CI): 0.45, 1.27] and 0.65 (95% CI: 0.32, 1.29), respectively. The MIS group had significantly less blood loss [mean difference (MD), -409 mL; 95% CI: -538, -281] and a shorter hospital stay (MD, -6.5 days; 95% CI: -13.1, 0.1) than the open surgery group. The median follow-up duration of this cohort was 4.6 years, and the 3-year overall survival were 77.9% and 76.2% in the MIS and open surgery groups, respectively [hazard ratio (HR), 0.78; 95% CI: 0.45, 1.36]. The 3-year relapse-free survival were 71.9% and 62.2% in the MIS and open surgery groups, respectively (HR, 0.71; 95% CI: 0.44, 1.16). CONCLUSIONS: MIS for RGC showed favorable short- and long-term outcomes compared to open surgery. MIS is a promising option for radical surgery for RGC.

Employment Status of Patients With Colorectal Cancer After Surgery: A Multicenter Prospective Cohort Study in Japan.

BACKGROUND: Because of improved survival rates, patients with colorectal cancer may try to return to work. Many countries, however, have limited knowledge of the employment status of these patients. OBJECTIVE: To explore the employment status of patients with colorectal cancer after surgery in Japan and the risk factors affecting the same. DESIGN: This is a prospective multicenter cohort study that used self-administered questionnaires. Patients were recruited from June 2019 to August 2020 and were followed up for 12 months after surgery. SETTING: Six community hospitals and 1 university hospital in Japan. PATIENTS: Patients with clinical stages I to III colorectal cancer, employed at the time of diagnosis. INTERVENTIONS: Patients who underwent surgical resection between June 2019 and August 2020. MAIN OUTCOME MEASUREMENTS: The time it takes patients to return to work after surgery and the proportion of working patients 12 months after surgery were collected using self-administered questionnaires. RESULTS: A total of 129 patients were included in the analyses. The median time to return-to-work was 1.1 months, and the proportion of working patients at 12 months after surgery was 79%. Risk factors for delayed return-to-work after surgery were an advanced tumor stage, stoma, severe postoperative complications, shorter years of service at the workplace, and lower willingness to return-to-work. Risk factors for not working 12 months after surgery were stoma, lower willingness to return-to-work, nonregular employee status, lower income, national health insurance, and no private medical insurance. LIMITATIONS: This study is limited by its short-term follow-up and small sample size. CONCLUSIONS: This study revealed that Japanese patients with stages I to III colorectal cancer found favorable employment outcomes in the 12 months after surgery. These results may help health care providers better understand the employment status of patients with colorectal cancer and encourage them to consider returning to work after surgery. SITUACIN LABORAL DE LOS PACIENTES CON CNCER COLORRECTAL DESPUS DE LA CIRUGA UN ESTUDIO DE COHORTE PROSPECTIVO MULTICNTRICO EN JAPN: ANTECEDENTES:Debido a las mejores tasas de supervivencia, los pacientes con cáncer colorrectal pueden intentar volver al trabajo. Muchos países, sin embargo, tienen un conocimiento limitado de su situación laboral.OBJETIVO:Explorar la situación laboral de los pacientes con cáncer colorrectal después de la cirugía en Japón y los factores de riesgo que afectan a la misma.DISEÑO:Este es un estudio prospectivo de cohortes multicéntrico que utiliza cuestionarios autoadministrados. Los pacientes fueron reclutados desde junio de 2019 hasta agosto de 2020 y fueron seguidos durante 12 meses después de la cirugía.ENTORNO CLINICO:Seis hospitales comunitarios y un hospital universitario en Japón.PACIENTES:Pacientes con estadios clínicos I-III de cáncer colorrectal, trabajando en el momento del diagnóstico.INTERVENCIONES:Pacientes que recibieron resección quirúrgica desde junio de 2019 hasta agosto de 2020.PRINCIPALES MEDIDAS DE RESULTADO:El tiempo que tardan los pacientes en volver al trabajo después de la cirugía y la proporción de pacientes que trabajan 12 meses después de la cirugía se recogieron mediante cuestionarios autoadministrados.RESULTADOS:Un total de 129 pacientes fueron incluidos en los análisis. La mediana de tiempo de reincorporación al trabajo fue de 1,1 meses y la proporción de pacientes que trabajaban a los 12 meses de la cirugía fue del 79%. Los factores de riesgo para el retraso en el regreso al trabajo después de la cirugía fueron un estadio avanzado del tumor, estoma, complicaciones postoperatorias graves, menos años de servicio en el lugar de trabajo y menor disposición para volver al trabajo. Los factores de riesgo para no trabajar 12 meses después de la cirugía fueron estoma, menor voluntad de volver al trabajo, condición de empleado no regular, ingresos más bajos, seguro nacional de salud y la falta de seguro médico privado.LIMITACIONES:Este estudio está limitado por su seguimiento a corto plazo y tamaño de muestra pequeño.CONCLUSIONES:Este estudio reveló que los pacientes japoneses con cáncer colorrectal en estadios I-III obtuvieron resultados laborales favorables en los 12 meses posteriores a la cirugía. Estos resultados pueden ayudar a los proveedores de atención médica a comprender mejor la situación laboral de los pacientes con cáncer colorrectal y alentarlos a considerar regresar al trabajo después de la cirugía. (Traducción- Dr. Francisco M. Abarca-Rendon ).

Robotic gastrectomy for gastric cancer: systematic review and future directions.

BACKGROUND: Robotic gastrectomy (RG) using the da Vinci Surgical System for gastric cancer was approved for national medical insurance coverage in Japan in April 2018, and its number has been rapidly increasing since then. AIM: We reviewed and compared current evidence on RG and conventional laparoscopic gastrectomy (LG) to identify the differences in surgical outcomes. METHODS: Three independent reviewers systematically reviewed the data collected from a comprehensive literature search by an independent organization, focusing on the following nine endpoints: mortality, morbidity, operative time, estimated blood loss volume, length of postoperative hospital stay, long-term oncologic outcome, quality of life, learning curve, and cost. RESULTS: Compared to LG, RG has lower intraoperative blood loss volume, shorter length of hospital stay, and shorter learning curve, but both procedures have similar mortality. Contrarily, its disadvantages include longer procedural time and higher costs. Although the morbidity rate and long-term outcomes are almost comparable, RG showed superior potentials. Currently, the outcomes of RG are considered comparable to or better than LG. CONCLUSION: RG might be applicable to all gastric cancer patients who fulfill the indication of LG at institutions that meet specific criteria and are approved to claim the National Health Insurance costs for the use of the surgical robot in Japan.

What can surgeons do to prevent job leave soon after cancer diagnosis? A brief report on colorectal cancer survivors in Japan.

PURPOSE: Colorectal cancer is one of the most diagnosed cancers in Japan and the number of cancer survivors has increased. Work-related issues of cancer survivors have been investigated in relation to occupational health, and sufficient evidence in clinical practice is needed to support this. This study aimed to obtain the relevant information, intending to support the employment of patients with colorectal cancer for clinical settings. METHODS: We conducted a prospective, multicenter cohort study, which included patients who underwent surgery with clinical stage I-III colorectal cancer. An electronic survey was used at the time of hospital admission to collect the patients' occupational information, including job resignation soon after cancer diagnosis. A cross-sectional analysis was performed to evaluate the patients' employment situations. RESULTS: Of 129 eligible patients, 46 (36%) were female. Thirty-nine (30%) were self-employed and 72 (56%) worked at small-sized workplaces, which are not obliged to have occupational physicians. Most patients (89%) expressed their desire to return to work, but eight patients (6%) left their jobs soon after being diagnosed with colorectal cancer before undergoing surgery for several reasons stemming from worries about future treatment and its consequences. Multivariable analyses indicated that nonregular employees and the self-employed might be at a disadvantage in keeping their job at diagnosis. CONCLUSION: Surgeons should address work-related issues for survivorship, which begins at cancer diagnosis and, when available, collaborate with occupational physicians while being mindful that patients working at smaller companies do not have immediate access to occupational physicians.

Three-year outcomes of robotic gastrectomy versus laparoscopic gastrectomy for the treatment of clinical stage I/II gastric cancer: a multi-institutional retrospective comparative study.

BACKGROUND: Oncological benefits of robotic gastrectomy (RG) remain unclear. We aimed to determine and compare the 3-year outcomes of RG and laparoscopic gastrectomy (LG) for the treatment of gastric cancer. METHODS: This was a multi-institutional retrospective study of patients who prospectively underwent RG in a previous study (UMIN000015388) and historical controls who underwent LG. Operable patients with cStage I/II primary gastric cancer were enrolled. The inverse probability of treatment weighting method based on propensity scores was used to balance patient demographic factors and surgeon volume between the RG and LG groups. The primary outcome measure was the 3-year overall survival rate (3yOS). RESULTS: Of the 1,127 patients in the previous study, 326 and 752 patients in the RG and LG groups, respectively, completed the study. The standardized difference of all confounding factors was reduced to 0.09 or less after weighting. In the weighted population, 3yOS was 96.3% and 89.6% in the RG and LG groups, respectively (hazard ratio [HR] 0.34 [0.15, 0.76]; p = 0.009), whereas there was no difference in 3-year recurrence-free survival rate (3yRFS) between the two groups (HR 0.58 [0.32, 1.05]; p = 0.073). Sub-analyses showed that RG improved 3yOS (HR 0.05 [0.01, 0.38]; p = 0.004) and 3yRFS (HR 0.05 [0.01, 0.34]; p = 0.003) in patients with pStage IA disease. Recurrence rates and patterns were similar between the RG and LG groups. RG did not improve the morbidity rate, however, it attenuated some of the adverse events, including anastomotic leakage and intra-abdominal abscess. RG improved estimated blood loss and duration of postoperative hospitalization. CONCLUSION: This study showed surgical and oncological safety of RG for cStage I/II gastric cancer considering the 3-year outcomes, compared with those of LG.

Timing of real-time indocyanine green fluorescence visualization for lymph node dissection during laparoscopic colon cancer surgery.

PURPOSE: Although numerous studies have highlighted the potential value of indocyanine green (ICG) imaging in lymph node dissection of cancer surgery, its efficacy and optimal method remain to be clarified. This study aimed to investigate how lymphatic flow observation via ICG fluorescence could contribute to colon cancer surgery. METHODS: From October 2018 to March 2021, a total of 56 patients with colon cancer who underwent laparoscopic complete mesocolic excision with intraoperative ICG imaging were analyzed. Lymphatic flow was examined at the following time points following ICG injection: within 5 min, 30-60 min, and over 60 min. We also evaluated the distribution of ICG fluorescence per each vascular pedicle. RESULTS: Lymphatic flow was observed within 5 min following ICG injection in 6 cases (10.7%), and at 30-60 min following ICG injection in 43 cases (76.8%). ICG-stained vascular pedicles were variable especially in hepatic flexural, transverse, and splenic flexural colon cancer. Lymph node metastases were observed in 14 cases. Although metastatic lymph nodes were present only in the area along the ICG-stained vascular pedicles in 12 of the 14 cases, two patients exhibited lymph node metastasis in areas along the ICG-unstained vascular pedicles. ICG fluorescence was observed outside the standard range of lymph node dissection in 9 cases (20.9%: 9/43). Although addition of the proposed resection areas was made in 8 of these 9 cases, there was no pathologically positive lymph node. CONCLUSION: Real-time ICG fluorescence imaging of lymph nodes may improve the performance of laparoscopic colon cancer surgery, although its oncological benefit is not yet clear.

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.

Postoperative recurrence in locally advanced rectal cancer: how does neoadjuvant treatment affect recurrence pattern?

BACKGROUND: The treatment strategy for locally advanced rectal cancer (LARC) has recently expanded from total mesorectal excision to additional neoadjuvant chemoradiotherapy (nCRT) and/or systemic chemotherapy (NAC). Data on disease recurrence after each treatment strategy are limited. METHODS: Clinical stage II to III rectal cancer patients who underwent curative surgery between July 2005 and February 2021 were analyzed. The cumulative incidence and site of first recurrence were assessed. The median follow-up duration was 4.6 years. RESULTS: Among the 332 patients, we performed nCRT and NAC in 15.4% (N=51) and 14.8% (N=49), respectively. The overall recurrence rate was 23.5% (N=78). Although several differences in tumor stage or location were observed, there was no significant difference in the rate among the surgery alone (N=54, 23.3%), nCRT (N=11, 21.6%), and NAC (N=13, 26.5%) groups. In this cohort, the local recurrence rate (18.4%) was higher than the rate of distant metastasis in the NAC group (14.3%). All patients with recurrence in the nCRT group had distant metastases (N=11: one patient had distant and local recurrences simultaneously). For pathological stage 0-I, the recurrence rate was higher in the nCRT and NAC groups than in the surgery-alone group (nCRT, 10.0%; NAC, 15.4%; and surgery-alone, 2.0%). Curative-intent resection of distant-only recurrences significantly improved patients' overall survival (hazard ratio [95% confidence interval], 0.34 [0.14-0.84]), which was consistent even when stratified according to neoadjuvant treatment. Regardless of neoadjuvant treatment, >80% of recurrences occurred in the first 2.2 years, and 98.7% within 5 years after surgery. CONCLUSION: Regardless of neoadjuvant treatment, detecting distant metastases with intensive surveillance, particularly in the first 2 years after surgery, is important. Also, even if neoadjuvant treatment can downstage LARC to pathological stage 0-I, careful follow-up is needed.

Prophylactic supraclavicular lymph node dissection for esophageal squamous cell carcinoma: a systematic review and meta-analysis.

The supraclavicular lymph nodes (SCLNs) have been regarded as regional nodes for esophageal squamous cell carcinoma (ESCC) in Japan and eastern Asian countries, whereas their involvement has been regarded as distant metastasis in Western countries. The importance of thorough dissection of the lymphatic chain along the recurrent laryngeal nerve, including the cervical paraesophageal nodes, has become well understood; therefore, the contemporary clinical question is whether prophylactic SCLN dissection (SLND) in addition to cervical paraesophageal node dissection is beneficial for patients with ESCC. We analyzed studies comparing esophagectomy with SLND vs. esophagectomy without SLND, in both of which cervical paraesophageal node dissection had been completed, based on a comprehensive literature search of the PubMed, Scopus, and Cochrane databases. Our meta-analysis focused on two long-term outcomes: 3-year and 5-year overall survival (OS) rates; and three short-term outcomes: pneumonia, recurrent nerve palsy, and anastomotic leakage. Four studies, with a collective total of 1584 patients were included in the review. No significant differences were found between esophagectomy with SLND vs. esophagectomy without SLND in the meta-analysis of both long-term (3-year and 5-year OS; risk ratio 1.09, 95% CI 0.94-1.26, P = 0.28, and risk ratio 1.14, 95% CI 0.96-1.35, P = 0.15, respectively) and short-term outcomes. Based on our analysis, no clear data support prophylactic SLND on the cervical paraesophageal node dissection.

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.

Safe implementation of robotic gastrectomy for gastric cancer under the requirements for universal health insurance coverage: a retrospective cohort study using a nationwide registry database in Japan.

BACKGROUND: Robotic gastrectomy (RG) has increased since being covered by universal health insurance in 2018. However, to ensure patient safety the operating surgeon and facility must meet specific requirements. We aimed to determine whether RG has been safely implemented under the requirements for universal health insurance in Japan. METHODS: Data of consecutive patients with primary gastric cancer who underwent minimally invasive total or distal gastrectomy-performed by a surgeon certified by the Japan Society for Endoscopic Surgery (JSES) endoscopic surgical skill qualification system (ESSQS) between October 2018 and December 2019-were extracted from the gastrointestinal surgery section of the National Clinical Database (NCD). The primary outcome was morbidity over Clavien-Dindo classification grade IIIa. Patient demographics and hospital volume were matched between RG and laparoscopic gastrectomy (LG) using propensity score-matched analysis (PSM), and the short-term outcomes of RG and LG were compared. RESULTS: After PSM, 2671 patients who underwent RG and 2671 who underwent LG were retrieved (from a total of 9881), and the standardized difference of all the confounding factors reduced to 0.07 or less. Morbidity rates did not differ between the RG and LG patients (RG, 4.9% vs. LG, 3.9%; p = 0.084). No difference was observed in 30-day mortality (RG, 0.2% vs. LG, 0.1%; p = 0.754). The reoperation rate was greater following RG (RG, 2.2% vs. LG, 1.2%; p = 0.004); however, the duration of postoperative hospitalization was shorter (RG, 10 [8-13] days vs. LG, 11 [9-14] days; p < 0.001). CONCLUSIONS: Insurance-covered RG has been safely implemented nationwide.

Safety assessment of robotic gastrectomy and analysis of surgical learning process: a multicenter cohort study.

BACKGROUND: The safety of robotic gastrectomy (RG) for gastric cancer in daily clinical settings and the process by which surgeons are introduced and taught RG remain unclear. This study aimed to evaluate the safety of RG in daily clinical practice and assess the learning process in surgeons introduced to RG. METHODS: Patients who underwent RG for gastric cancer at Kyoto University and 12 affiliated hospitals across Japan from January 2017 to October 2019 were included. Any morbidity with a Clavien-Dindo classification grade of II or higher was evaluated. Moreover, the influence of the surgeon's accumulated RG experience on surgical outcomes and surgeon-reported postoperative fatigue were assessed. RESULTS: A total of 336 patients were included in this study. No conversion to open or laparoscopic surgery and no in-hospital mortality were observed. Overall, 50 (14.9%) patients developed morbidity. During the study period, 14 surgeons were introduced to robotic procedures. The initial five cases had surprisingly lower incidence of morbidity compared to the following cases (odds ratio 0.29), although their operative time was longer (+ 74.2 min) and surgeon's fatigue scores were higher (+ 18.4 out of 100 in visual analog scale). CONCLUSIONS: RG was safely performed in actual clinical settings. Although the initial case series had longer operative time and promoted greater levels of surgeon fatigue compared to subsequent cases, our results suggested that RG had been introduced safely.