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Yin-Kai Chao,1 Cheng-Hung Lee,2 Kuo-Sheng Liu,1 Yi-Chuan Wang,3 Chih-Wei Wang,4 Shih-Jung Liu3 1Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital-Linkou, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 2Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Mechanical Engineering, Chang Gung University, Taoyuan, Taiwan; 4Department of Pathology, Chang Gung Memorial Hospital-Linkou, College of Medicine, Chang Gung University, Taoyuan, Taiwan Background: Inadequate intrapleural drug concentrations caused by poor penetration of systemic antibiotics into the pleural cavity is a major cause of treatment failure in empyema. Herein, we describe a novel antibiotic-eluting pigtail catheter coated with electrospun nanofibers used for the sustained release of bactericidal concentrations of penicillin in the pleural space.Methods: Electrospun nanofibers prepared using polylactide-polyglycolide copolymer and penicillin G sodium dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol were used to coat the surface of an Fr6 pigtail catheter. The in vitro patterns of drug release were tested by placing the catheter in phosphate-buffered saline. In vivo studies were performed using rabbits treated with penicillin either intrapleurally (Group 1, 20 mg delivered through the catheter) or systemically (Group 2, intramuscular injection, 10 mg/kg). Penicillin concentrations in the serum and pleural fluid were then measured and compared.Results: In vitro studies revealed a burst release of penicillin (10% of the total dose) occurring in the first 24 hours, followed by a sustained release in the subsequent 30 days. Intrapleural drug levels were significantly higher in Group 1 than in Group 2 (P

Background: Robot-assisted minimally invasive esophagectomy (RAMIE) is increasingly adopted in centers worldwide, with ongoing refinements to enhance results. This study aims to assess the current state of RAMIE worldwide and to identify potential areas for improvement., Methods: This descriptive study analyzed prospective data from esophageal cancer patients who underwent transthoracic RAMIE in Upper GI International Robotic Association (UGIRA) centers. Main endpoints included textbook outcome rate, surgical techniques, and perioperative outcomes. Analyses were performed separately for intrathoracic (Ivor-Lewis) and cervical anastomosis (McKeown), divided into three time cohorts (2016-2018, 2019-2020, 2021-2023). A sensitivity analysis was conducted with cases after the learning curve (> 70 cases)., Results: Across 28 UGIRA centers, 2012 Ivor-Lewis and 1180 McKeown procedures were performed. Over the time cohorts, textbook outcome rates were 39%, 48%, and 49% for Ivor-Lewis, and 49%, 63%, and 61% for McKeown procedures, respectively. Fully robotic procedures accounted for 66%, 51%, and 60% of Ivor-Lewis procedures, and 53%, 81%, and 66% of McKeown procedures. Lymph node yield showed 27, 30, and 30 nodes in Ivor-Lewis procedures, and 26, 26, and 34 nodes in McKeown procedures. Furthermore, high mediastinal lymphadenectomy was performed in 65%, 43%, and 37%, and 70%, 48%, and 64% of Ivor-Lewis and McKeown procedures, respectively. Anastomotic leakage rates were 22%, 22%, and 16% in Ivor-Lewis cases, and 14%, 12%, and 11% in McKeown cases. Hospital stay was 13, 14, and 13 days for Ivor-Lewis procedures, and 12, 9, and 11 days for McKeown procedures. In Ivor-Lewis and McKeown, respectively, the sensitivity analysis revealed textbook outcome rates of 43%, 54%, and 51%, and 47%, 64%, and 64%; anastomotic leakage rates of 28%, 18%, and 15%, and 13%, 11%, and 10%; and hospital stay of 11, 12, and 12 days, and 10, 9, and 9 days., Conclusions: This study demonstrates favorable outcomes over time in achieving textbook outcome after RAMIE. Areas for improvement include a reduction of anastomotic leakage and shortening of hospital stay., (© 2024. The Author(s).)

Intraoperative fluorescence imaging using indocyanine green (ICG) is an innovative and safe tool in minimally invasive thoracic surgery. It provides real-time imaging capabilities that can enhance surgical precision. We describe several clinical uses of ICG including intersegmental plane identification, thoracic duct injury localisation, anomalous systemic artery identification in pulmonary sequestration, phrenic nerve identification, and sentinel lymph node mapping. Successful visualisation of ICG was achieved to identify intra-thoracic anatomical structures and boundaries, allowing for safe and precise dissection., Competing Interests: Conflicts of Interest C.C. proctors for Device Technologies., (Copyright © 2024 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate the impact of chemoradiotherapy on the physical fitness of patients with oesophageal cancer, and the clinical factors influencing it., Method: A total of 67 participants successfully completed the study, with 18 of them engaging in supervised, in-hospital aerobic training at moderate intensity for a minimum of 20 sessions. Cardiopulmonary exercise testing, hand grip strength, body composition assessed via bioelectrical impedance analysis, patient-generated subjective global assessment, albumin, and the Functional Oral Intake Scale (FOIS) were evaluated before chemoradiotherapy and 6-8 weeks after its completion., Result: Among the participants, cardiopulmonary fitness, hand grip strength, and phase angle of BC-BIA declined during chemoradiotherapy. Before and after chemoradiotherapy, V̇O2peak was 19.6 ± 4.4 and 17.4 ± 3.9 mL/min/kg respectively. The improvement in FOIS during chemoradiotherapy showed a positive correlation with changes in aerobic capacity. Additionally, exercise training was associated with attenuating the decline in aerobic capacity., Conclusion: Physical fitness deteriorated in patients with oesophageal cancer following chemoradiotherapy. Improvement in dysphagia helps maintain aerobic capacity. Additionally, exercise training has the potential to mitigate the decline. This discovery can serve as a reference for enhancing holistic care for patients with oesophageal cancer.

Deciphering the context-specific relationship between sequence and function is a major challenge in genomics. Existing tools for inducing locus-specific hypermutation and evolution in the native genome context are limited. Here we present a programmable platform for long-range, locus-specific hypermutation called helicase-assisted continuous editing (HACE). HACE leverages CRISPR-Cas9 to target a processive helicase-deaminase fusion that incurs mutations across large (>1000-base pair) genomic intervals. We applied HACE to identify mutations in mitogen-activated protein kinase kinase 1 (MEK1) that confer kinase inhibitor resistance, to dissect the impact of individual variants in splicing factor 3B subunit 1 (SF3B1)-dependent missplicing, and to evaluate noncoding variants in a stimulation-dependent immune enhancer of CD69. HACE provides a powerful tool for investigating coding and noncoding variants, uncovering combinatorial sequence-to-function relationships, and evolving new biological functions.

Background: The prognosis for patients with esophageal cancer who received neoadjuvant chemoradiotherapy (nCRT) followed by surgery has shown improvement in recent years. We sought to identify the critical factors contributing to enhanced survival outcomes., Patients and Methods: We retrospectively examined 427 patients with esophageal cancer treated with nCRT and esophagectomy across two periods: P1 (from 1 January 2004 to 31 December 2011) and P2 (from 1 January 2012 to 31 December 2017). The introduction of the CROSS regimen and total meso-esophagectomy in P2 prompted an evaluation of their effects on perioperative outcomes and overall survival (OS)., Results: During P2, the occurrence of recurrent laryngeal nerve palsy increased significantly from 3.9 to 16.8% (p < 0.001), while pneumonia and in-hospital mortality rates remained unchanged. The median OS improved from 19.2 to 29.2 months (p < 0.001) between P1 and P2. Multivariable analysis identified higher nodal yields and the achievement of major response as favorable prognostic factors. Conversely, an involved circumferential resection margin (CRM), an advanced ypN stage, and pneumonia were independently associated with poor outcomes. Patients treated during P2 had a lower prevalence of involved CRM (10% vs. 25.1%, p < 0.001), a higher rate of major response (52.7% vs. 34.8%, p < 0.01), and a greater nodal yield (27.8 vs. 10.9, p < 0.001)., Conclusions: The clinical outcomes following nCRT and surgery have improved significantly over time. This progress can be attributed to multiple factors, with the primary drivers being the refinement of nCRT protocols and the application of radical surgery., (© 2024. Society of Surgical Oncology.)

Background: In patients with locally advanced esophageal cancer who had undergone chemoradiotherapy (CRT), the limitations of radiological evaluation may necessitate surgical exploration to ascertain disease resectability. Upon intraoperative confirmation of T4b disease (sT4b), the optimal management strategy remains unclear. While some surgeons may opt against resection, others advocate for palliative esophagectomy (PE). Regrettably, the current literature does not provide a consensus on the most effective approach for managing these intricate cases., Methods: The study cohort consisted of 68 patients with esophageal squamous cell carcinoma (ESCC) who presented with sT4b disease following CRT. The perioperative outcomes and overall survival (OS) were compared between patients who underwent PE (n = 56) and those who received an open-close (OC) procedure (n = 12)., Results: Patients who underwent an OC procedure experienced a shorter hospital stay (16.5 vs. 28.8 days; p = 0.052) and showed a non-significant reduction in the rate of major complications (33.9% vs. 25%; p = 0.549) and in-hospital mortality (0% vs. 5.4%; p = 0.412) than those who received PE; however, PE was associated with a superior 2-year OS rate than OC (9.6% vs. 0%; p = 0.009). In multivariable analysis, a pretreatment clinical stage of II/III (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.31-0.87; p = 0.013) and PE with retrosternal reconstruction (HR 0.38, 95% CI 0.15-0.49; p = 0.010) were independently associated with a more favorable OS., Conclusion: PE with retrosternal reconstruction may be a feasible approach for patients with ESCC exhibiting sT4b disease after CRT., (© 2024. Society of Surgical Oncology.)

Background: Robot-assisted minimally invasive oesophagectomy and conventional minimally invasive oesophagectomy are superior to open techniques. However, few studies have directly compared the outcomes of the two minimally invasive approaches., Methods: A retrospective study of patients from six medical centres with oesophageal squamous cell carcinoma who underwent minimally invasive oesophagectomy between 2015 and 2022. Perioperative outcomes were compared after applying inverse probability of treatment weighting., Results: The study included 577 patients (robot-assisted minimally invasive oesophagectomy: 206; conventional minimally invasive oesophagectomy: 371). After applying inverse probability of treatment weighting, robot-assisted minimally invasive oesophagectomy was found to yield a higher number of mediastinal nodes compared with conventional minimally invasive oesophagectomy (14.86 versus 12.66, P = 0.017). Robot-assisted minimally invasive oesophagectomy was notably effective in retrieving upper mediastinal left recurrent laryngeal nerve nodes, averaging 1.97 nodes versus 1.14 nodes harvested by conventional minimally invasive oesophagectomy (P < 0.001). This was coupled by a significant decrease in nerve palsy rates (13.9% versus 22.8%, P = 0.020). A significantly larger percentage of patients in the robot-assisted minimally invasive oesophagectomy group had an uncomplicated postoperative course (51.8% versus 34%, P < 0.001). Robot-assisted minimally invasive oesophagectomy also led to a reduction in pneumonia rates (8.6% versus 15.2%, P = 0.041) and was linked to a shorter length of stay (length of stay; 16.64 versus 21.14 days, P = 0.007). The advantage of robot-assisted minimally invasive oesophagectomy in reducing the length of stay was especially pronounced in patients with a high Charlson co-morbidity index (≥2, mean difference 8.46 days; P = 0.0069) and those who underwent neoadjuvant therapy (mean difference 5.63 days; P < 0.001)., Conclusion: In oesophageal squamous cell carcinoma, the use of robot-assisted minimally invasive oesophagectomy led to fewer cases of pneumonia and faster recovery compared with conventional minimally invasive oesophagectomy. Additionally, robot-assisted minimally invasive oesophagectomy significantly improved the feasibility and safety of performing lymph node dissection along the recurrent laryngeal nerve., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Background: Surgery for oesophageal squamous cell carcinoma involves dissecting lymph nodes along the recurrent laryngeal nerve. This is technically challenging and injury to the recurrent laryngeal nerve may lead to vocal cord palsy, which increases the risk of pulmonary complications. The aim of this study was to compare the efficacy and safety of robot-assisted oesophagectomy (RAO) versus video-assisted thoracoscopic oesophagectomy (VAO) for dissection of lymph nodes along the left RLN., Methods: Patients with oesophageal squamous cell carcinoma who were scheduled for minimally invasive McKeown oesophagectomy were allocated randomly to RAO or VAO, stratified by centre. The primary endpoint was the success rate of left recurrent laryngeal nerve lymph node dissection. Success was defined as the removal of at least one lymph node without causing nerve damage lasting longer than 6 months. Secondary endpoints were perioperative and oncological outcomes., Results: From June 2018 to March 2022, 212 patients from 3 centres in Asia were randomized, and 203 were included in the analysis (RAO group 103; VAO group 100). Successful left recurrent laryngeal nerve lymph node dissection was achieved in 88.3% of the RAO group and 69% of the VAO group (P < 0.001). The rate of removal of at least one lymph node according to pathology was 94.2% for the RAO and 86% for the VAO group (P = 0.051). At 1 week after surgery, the RAO group had a lower incidence of left recurrent laryngeal nerve palsy than the VAO group (20.4 versus 34%; P = 0.029); permanent recurrent laryngeal nerve palsy rates at 6 months were 5.8 and 20% respectively (P = 0.003). More mediastinal lymph nodes were dissected in the RAO group (median 16 (i.q.r. 12-22) versus 14 (10-20); P = 0.035). Postoperative complication rates were comparable between the two groups and there were no in-hospital deaths., Conclusion: In patients with oesophageal squamous cell carcinoma, RAO leads to more successful left recurrent laryngeal nerve lymph node dissection than VAO, including a lower rate of short- and long-term recurrent laryngeal nerve injury. Registration number: NCT03713749 (http://www.clinicaltrials.gov)., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Technique: The surgical management for high-output postoperative chylothorax typically necessitates ligation of the thoracic duct (TD) above the leak site and/or sealing the leak with a clip. However, pinpointing these structures during subsequent surgeries can be challenging due to their variable course and the presence of traumatized tissues surrounding the leak area. In response to this, we have developed a novel, fluorescence-guided technique that significantly enhances intraoperative identification of the leak point and the TD. This method was applied in the case of a 52-year-old man suffering from refractory chylothorax following a previous lung cancer surgery. This study documents the surgical procedure and includes a video vignette for a comprehensive understanding., Results: A bilateral inguinal lymph node injection of saline (10 mL), guided by ultrasound and containing 2.5 mg/mL indocyanine green (ICG), was administered 20 min prior to surgery. During thoracoscopic exploration, the leak point was precisely pinpointed in the right paratracheal area by transitioning from bright light to fluorescent mode. The TD was clearly identified, and upon ligation, there was no further leakage of fluorescent lymph, indicating a successful closure of the lymphatic structure. The surgery proceeded uneventfully, and the patient was able to resume oral intake on the third postoperative day. There was no evidence of recurring symptoms, leading to his discharge., Conclusion: The intralymphatic injection of ICG offers a rapid visualization of the TD's anatomy and can effectively pinpoint the leak point, even amidst traumatized tissues. Moreover, it provides prompt feedback on the efficacy of ligation., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2024 Asian Surgical Association and Taiwan Society of Coloproctology. Published by Elsevier B.V. All rights reserved.)

Objective: Locally advanced oesophageal squamous cell carcinoma can be treated with neoadjuvant chemoradiotherapy or chemotherapy followed by oesophagectomy. Discrepancies in pathological response rates have been reported between studies from Eastern versus Western countries. The aim of this study was to compare the pathological response to neoadjuvant chemoradiotherapy in Eastern versus Western countries., Methods: Databases were searched until November 2022 for studies reporting pCR rates after neoadjuvant chemoradiotherapy for oesophageal squamous cell carcinoma. Multi-level meta-analyses were performed to pool pCR rates separately for cohorts from studies performed in centres in the Sinosphere (East) or in Europe and the Anglosphere (West)., Results: For neoadjuvant chemoradiotherapy, 51 Eastern cohorts (5636 patients) and 20 Western cohorts (3039 patients) were included. Studies from Eastern countries included more men, younger patients, more proximal tumours, and more cT4 and cN+ disease. Patients in the West were more often treated with high-dose radiotherapy, whereas patients in the East were more often treated with a platinum + fluoropyrimidine regimen. The pooled pCR rate after neoadjuvant chemoradiotherapy was 31.7% (95% c.i. 29.5% to 34.1%) in Eastern cohorts versus 40.4% (95% c.i. 35.0% to 45.9%) in Western cohorts (fixed-effect P = 0.003). For cohorts with similar cTNM stages, pooled pCR rates for the East and the West were 32.5% and 41.9% respectively (fixed-effect P = 0.003)., Conclusion: The pathological response to neoadjuvant chemoradiotherapy is less favourable in patients treated in Eastern countries compared with Western countries. Despite efforts to investigate accounting factors, the discrepancy in pCR rate cannot be entirely explained by differences in patient, tumour, or treatment characteristics., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: In recent years, there has been an increasing focus on minimally invasive mediastinal surgery using a trans-subxiphoid single-port thoracoscopic approach. Despite its potential advantages, the widespread adoption of this method has been hindered by the intricate surgical maneuvers required within the confined retrosternal space. Robotic surgery offers the potential to overcome the limitations inherent in the thoracoscopic technique., Methods: This was a clinical trial (NCT05455840) to evaluate the feasibility and safety of utilizing the da Vinci ® SP system (Intuitive Surgical, Sunnyvale, CA, USA) for trans-subxiphoid single-port surgery in patients with anterior mediastinal disease. The primary endpoints encompassed conversion rates and the secondary endpoints included the occurrence of perioperative complications., Results: Between August 2022 and April 2023, a total of 15 patients (7 men and 8 women; median age = 56 years, interquartile range [IQR]: 49 to 65 years) underwent trans-subxiphoid robotic surgery using da Vinci SP platform for maximal thymectomy ( n = 2) or removal of anterior mediastinal masses ( n = 13). All surgical procedures were carried out with success, with no need for conversion to open surgery or the creation of additional ports. The median docking time was 2 min (IQR: 1 to 4 min), while the console time had a median of 152 min (IQR: 95 to 191 min). There were no postoperative complications and patients experienced a median postoperative hospital stay of 2 days with no unplanned 30-day readmission., Conclusions: This study shows that trans-subxiphoid single-port robotic surgery employing the da Vinci SP system in patients with anterior mediastinal disease is clinically viable with acceptable safety and short-term outcomes., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Yin-Kai Chao has received honoraria for speaking and/or education from Intuitive Surgical Sarl, Taiwan Branch. Yu Ya Huang is an employee of Intuitive Surgical Sarl, Taiwan Branch with ownership of Intuitive Surgical stock. The other authors do not report any potential conflicts of interest.

Objective: Robot-assisted thoracoscopic surgery typically necessitates the use of multiple ports. The new single-port robotic system (da Vinci SP system) platform is designed to perform uniportal surgery. The purpose of this clinical trial is to evaluate the feasibility, efficacy, and safety of the da Vinci SP system when used for anatomical lung resection., Methods: Patients diagnosed with clinical stage I lung cancer requiring anatomical lung resections were considered eligible for this trial. The primary outcome measure was the rate of conversion, whereas the secondary objective focused on assessing the incidence of perioperative complications., Results: The study included 35 patients with a median age of 63 years (range, 48-74 years). Of these, 30 underwent lobectomy and 5 received segmentectomy. All surgeries were successfully performed using a subcostal approach, except for 1 patient, who required a thoracotomy conversion due to bleeding (conversion rate: 2.9%). The median docking time was 2 minutes (range, 1-8 minutes). For the 34 patients who completed uniportal surgery, the median total operating time was 194 minutes (range, 63-405 minutes), whereas the console time was 153 minutes (range, 93-267 minutes). The median number of harvested nodes was 13 (range, 5-37), while the median number of nodal stations was 6 (rang, 4-8). There were no in-hospital fatalities, and the median postoperative stay was 3 days (range, 2-12 days)., Conclusions: This study demonstrates the feasibility and safety of using the da Vinci SP system for anatomical lung resection through a subcostal approach., Clinicaltrialsgov Identifier: NCT05535712., Competing Interests: Y.K.C. has received honoraria for speaking engagements and single-port surgical training from Intuitive Surgical Sarl, Taiwan Branch. C.-F.W. has received single-port surgical training from Intuitive Surgical Sarl, Taiwan Branch. Y.Y.H. is an employee of Intuitive Surgical Sarl, Taiwan Branch, and holds ownership of Intuitive Surgical stocks. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2024 The Author(s).)

Purpose: The textbook outcome (TBO), a multidimensional indicator that reflects an optimal perioperative course, has emerged as a significant prognostic variable in surgical oncology. Our study aimed to assess the occurrence and determinants of TBO following minimally invasive esophagectomy (MIE) for cancer., Methods: A total of 945 patients who had undergone MIE at two high-volume centers between 2008 and 2022 were analyzed. Multivariable logistic regression analysis was applied to identify the independent predictors of TBO. The potential selection bias associated with choosing between different MIE techniques-namely, robotic esophagectomy (RE) and video-assisted thoracoscopic esophagectomy (VATE)-was addressed by applying inverse probability of treatment weighting (IPTW)., Results: TBO was realized in 46.6% of cases ( n = 440), correlating with markedly better overall and disease-free survival. Multivariable analysis showed that treatment with RE (odds ratio (OR) = 1.527; 95% confidence interval (CI) = 1.149-2.028) was associated with a higher likelihood of achieving TBO, whereas a Charlson Comorbidity Index (CCI) of 2 or higher showed an opposite association (CCI2: OR = 0.687, 95% CI = 0.483-0.977; CCI ≥ 3: OR = 0.604, 95% CI = 0.399-0.915). The advantage of RE in attaining a higher rate of TBO, compared to VATE, remained statistically significant after applying IPTW, with rates of 53.3% for RE and 42.2% for VATE. Notably, RE contributed to a greater probability of thorough lymph node dissection, resection with negative margins, and the avoidance of major complications., Conclusion: TBO was realized in 46.6% of the patients who underwent MIE for cancer. Patients with a lower CCI and those who received RE were more likely to achieve TBO.

Background: Recurrent laryngeal nerve (RLN) palsy is a serious complication of esophagectomy that affects the patient's phonation and the ability to prevent life-threatening aspiration events. The aim of this single-center, retrospective study was to investigate the clinical course of left RLN palsy and to identify the main prognostic factors for recovery., Methods: The study cohort consisted of 85 patients who had developed left RLN palsy after minimally invasive McKeown esophagectomy. Vocal cord function was assessed in all participants through laryngoscopic examinations, both in the immediate postoperative period and during follow-up. Permanent palsy was defined as no evidence of recovery after 6 months. Univariate and multivariable logistic regression analyses were applied to evaluate the associations between different variables and the outcome of palsy., Results: Twenty-two (25.8%) patients successfully recovered from left RLN palsy. On multivariable logistic regression analysis, active smoking (odds ratio [OR] 0.335, p = 0.038) and the use of thoracoscopic surgery (vs. robotic surgery; OR 0.264, p = 0.028) were identified as independent unfavorable predictors for recovery from palsy. The estimated rates of recovery derived from a logistic regression model for patients harboring two, one, or no risk factors were 13.16%, 31.15-34.75%, and 61.39%, respectively., Conclusion: Only one-quarter of patients who had developed left RLN palsy after minimally invasive McKeown esophagectomy were able to fully recover. Smoking habits and the surgical approach were identified as key determinants of recovery. Patients harboring adverse prognostic factors are potential candidates for early intervention strategies., (© 2023. Society of Surgical Oncology.)

G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC , c-KIT , and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene-arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets.

Anterior mediastinal procedures are increasingly being performed using robot-assisted thoracic surgery (RATS) or video-assisted thoracoscopic surgery (VATS). While both approaches have shown superior outcomes compared to open surgery, their comparative benefits are not as distinct. The aim of this retrospective study was to bridge this knowledge gap using a multicenter dataset. Patients who underwent elective minimally invasive surgery for anterior mediastinal disease between 2015 and 2022 were deemed eligible. The study participants were grouped based on whether a robot was used or not, and perioperative outcomes were compared. To mitigate selection bias, inverse probability of treatment weighting (ITPW) was applied using the propensity score. The final analysis included 312 patients (RATS = 120; VATS = 192). Following the application of IPTW, RATS was found to be associated with a longer operating time (215.3 versus 139.31 min, P < 0.001), fewer days with a chest tube (1.96 versus 2.61 days, P = 0.047), and a shorter hospital stay (3.03 versus 3.91 days, P = 0.041) compared to VATS. Subgroup analyses indicated that the benefit of RATS in reducing the length of hospital stay was particularly pronounced in patients with tumors larger than 6 cm (mean difference [MD] =  - 2.28 days, P = 0.033), those diagnosed with myasthenia gravis (MD =  - 3.84 days, P = 0.002), and those who underwent a trans-subxiphoid surgical approach (MD =  - 0.81 days, P = 0.04). Both VATS and RATS are safe and effective approaches for treating anterior mediastinal disease. However, RATS holds distinct advantages over VATS including shorter hospital stays and reduced chest tube drainage periods., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Background: Nasopharyngeal carcinoma (NPC) is associated with Epstein-Barr virus (EBV) infection. To test preclinical NPC drugs, we established two patient-derived xenograft (PDX) mouse models, EBV-positive PDX-B13 and EBV-negative PDX-Li41, for drug screening., Methods: Based on next generation sequencing (NGS) studies, PDX-B13 had CCND1 copy number (CN) gain but CDKN2A CN loss, whereas PDX-Li41 had CDKN2A and RB1 CN loss, TSC1 (negative regulator of mTOR) frameshift deletion mutation, and increased activation of mTOR, a serine/threonine kinase that governs metabolism, autophagy, and apoptosis. Increased mTOR was also associated with poor NPC prognosis., Results: Everolimus, an mTOR inhibitor, suppressed tumor growth in the two PDX NPC models and had an additive antitumor effect with palbociclib, a CDK4/6 inhibitor. PDX tumors treated with various drugs or untreated were subjected to RNA sequencing, transcriptome profile analysis, and selective Western blotting to understand the interactions between these drugs and gene expression profiles. Palbociclib also suppressed EB viral nuclear antigen (EBNA1) expression in PDX-B13. Everolimus together with autophagy inhibitor, hydroxychloroquine, had additive anti-tumor effect on PDX-B13 tumor. Immunohistochemistry revealed that high mTOR levels were correlated with poor overall survival in patients with metastatic NPC (N = 90)., Conclusions: High mTOR levels are a poor prognostic factor in NPC, and cell cycle, mTOR and autophagy pathways may serve as therapeutic targets in NPC. In addition, PDX models can be used for efficiently testing potential NPC drugs., Competing Interests: Declaration of Competing Interest The authors have declared that no competing interest exists., (Copyright © 2023. Published by Elsevier Inc.)

The gut microbiome and its metabolites are increasingly implicated in several cardiovascular diseases, but their role in human myocardial infarction (MI) injury responses have yet to be established. To address this, we examined stool samples from 77 ST-elevation MI (STEMI) patients using 16 S V3-V4 next-generation sequencing, metagenomics and machine learning. Our analysis identified an enriched population of butyrate-producing bacteria. These findings were then validated using a controlled ischemia/reperfusion model using eight nonhuman primates. To elucidate mechanisms, we inoculated gnotobiotic mice with these bacteria and found that they can produce beta-hydroxybutyrate, supporting cardiac function post-MI. This was further confirmed using HMGCS2-deficient mice which lack endogenous ketogenesis and have poor outcomes after MI. Inoculation increased plasma ketone levels and provided significant improvements in cardiac function post-MI. Together, this demonstrates a previously unknown role of gut butyrate-producers in the post-MI response., (© 2023. The Author(s).)

Background: To investigate the value of [18F]FDG-PET/MRI in predicting treatment response and survival in patients with primary M0 esophageal squamous cell carcinoma., Methods: Patients with esophageal squamous cell carcinoma received [18F]FDG-PET/MRI at baseline and during neoadjuvant or definitive chemoradiotherapy. The treatment response was classified according to the Response Evaluation Criteria for Solid Tumors 1.1. We used Kaplan-Meier and Cox regression analyses to assess the association between PET/MRI parameters and overall survival (OS) or progression-free survival (PFS)., Results: We included 40 M0 patients in the final analysis. The volume transfer constant (K trans ) from baseline PET/MRI (area under the curve (AUC) = 0.688, P = 0.034) and total lesion glycolysis (TLG) from baseline PET/MRI (AUC = 0.723, P = 0.006) or interim PET/MRI (AUC = 0.853, P < 0.001) showed acceptable AUC for predicting treatment response. The TLG from interim PET/MRI (interim TLG, P < 0.001) and extracellular volume fraction (Ve) on interim PET/MRI (interim Ve, P = 0.001) were identified as independent prognostic factors for OS. Baseline Ve (P = 0.044) and interim TLG (P = 0.004) were significant predictors of PFS. The c-indices of the prognostic models combining interim TLG with Ve for predicting OS, and baseline Ve and interim TLG for predicting PFS were 0.784 and 0.699, respectively. These values were significantly higher than the corresponding c-indices of the TNM staging system (P = 0.002 and P = 0.047, respectively)., Conclusions: Combining the baseline and interim [18F]FDG-PET/MRI qualitative imaging parameters aids in predicting the prognosis of patients with M0 esophageal squamous cell carcinoma., Trial Registration: The study was registered at Clinicaltrials.gov (identifier: NCT05855291 and NCT05855278)., (© 2023. The Author(s).)

High-quality evidence indicated that both neoadjuvant carboplatin/paclitaxel (CROSS) and cisplatin/5-fluorouracil (PF) regimens in combination with radiotherapy improve survival outcomes compared to surgery alone in patients with esophageal cancer. It is not yet known whether they may differ in terms of treatment burden and healthcare costs. A total of 232 Taiwanese patients with esophageal squamous cell carcinoma who had undergone neoadjuvant chemoradiotherapy (nCRT) with either the CROSS (n = 153) or the PF (n = 79) regimens were included. Hospital encounters and adverse events were assessed for determining treatment burden. Cost-effectiveness analysis was undertaken using the total costs incurred over 3 years in relation to overall survival (OS) and progression-free survival (PFS). Compared with PF, the CROSS regimen was associated with a lower treatment burden: shorter inpatient days on average (4.65 ± 10.05 vs. 15.14 ± 17.63 days; P < 0.001) and fewer admission requirements (70% of the patients were never admitted vs. 20% in the PF group; P < 0.001). Patients in the CROSS group experienced significantly less nausea, vomiting, and diarrhea. While the benefits observed in the CROSS group were associated with additional nCRT-related expenditures (1388 United States dollars [USD] of added cost per patient), this regimen remained cost-effective. At a willingness-to-pay threshold of 50,000 USD per life-year, the probability of the CROSS regimen to be more cost-effective than PF was 94.1% for PFS but decreased to 68.9% for OS. The use of the CROSS regimen for nCRT in patients with ESCC was associated with a lower treatment burden and was more cost-effective than PF., (© The Author(s) 2023. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This retrospective study examined outcomes in esophageal squamous cell carcinoma (ESCC) patients who did not undergo surgical resection after neoadjuvant chemoradiotherapy (nCRT)., Methods: Patients receiving nCRT between 2012 and 2020 were divided into two groups: group 1 (scheduled surgery) and group 2 (no surgery). Group 2 was further categorized into subgroups based on reasons for not proceeding to surgery: group 2a (disease progression), group 2b (poor general conditions), and group 2c (patient refusal). Overall survival (OS) was the primary outcome., Results: Group 1 comprised 145 patients, while subgroups 2a, 2b, and 2c comprised 24, 16, and 31 patients, respectively. The 3-year OS rate was significantly lower in group 2 compared with group 1 (34% versus 56%, p < 0.001). A subgroup analysis showed varying 3-year OS rates: 13% for group 2a, 25% for group 2b, and 58% for group 2c ( p < 0.001). Propensity score matching for group 2c and group 1 revealed no significant difference in 3-year OS rates ( p = 0.91)., Conclusion: One-third of ESCC patients receiving nCRT did not undergo surgical resection. Overall survival in this group was generally poorer, except for those who refused surgery (group 2c).

Background: Few studies have compared robotic-arm-assisted unisurgeon uniportal surgeries with conventional human-assisted uniportal video-assisted thoracoscopic surgeries (VATSs) in terms of surgical efficacy and patient safety. In the present study, we compared the aforementioned surgeries., Methods: We explored two robotic endoscope holders-a passive robotic platform (ENDOFIX exo , EA group) and a pedal-controlled active robotic platform (MTG-100, MA group)-for unisurgeon uniportal surgeries and compared the surgical outcomes with those of human-assisted uniportal surgeries (HA group) in 228 patients with a lung lesion (size, <5 cm). The primary parameters for this comparison were surgical efficacy, patient safety, and short-term patient outcomes., Results: No significant differences were observed among the EA, MA, and HA groups. The success rate of robotic-arm-assisted unisurgeon uniportal wedge resection was 100%, regardless of the group. No major differences were noted in preparation time between the EA and MA groups. Segmentectomy was more favorable in the EA group than in the MA group. The rates of surgical conversion were 5% and 60% in the EA and MA groups, respectively. The EA and MA groups did not differ considerably from the HA group in terms of postoperative complications., Conclusions: Unisurgeon uniportal wedge resection may be effectively performed using a robotic endoscope holder, without the need for any human assistants with an expert hand. However, the rate of surgical conversion increases with the complexity of uniportal anatomic resections. The passive platform appears to be more suitable for unisurgeon uniportal surgery than the active pedal-controlled platform given the equipment in contemporary operating rooms., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-19/coif). The authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Objectives: The aim of this study was to examine the impact of surgical learning curve on short-term clinical outcomes of patients after bilateral lung transplantation (LTx) performed by a surgical multidisciplinary team (MDT)., Methods: Forty-two patients underwent double LTx from December 2016 to October 2021. All procedures were performed by a surgical MDT in a newly established LTx program. The time required for bronchial, left atrial cuff and pulmonary artery anastomoses was the main end point to assess surgical proficiency. The associations between the surgeon's experience and procedural duration were examined by linear regression analysis. We employed the simple moving average technique to generate learning curves and evaluated short-term outcomes before and after achieving surgical proficiency., Results: Both total operating time and total anastomosis time were inversely associated with the surgeon's experience. On analysing the learning curve for bronchial, left atrial cuff and pulmonary artery anastomoses using moving averages, the inflection points occurred at 20, 15 and 10 cases, respectively. To assess the learning curve effect, the study cohort was divided into early (cases 1-20) and late (cases 21-42) groups. Short-term outcomes-including intensive care unit stay, in-hospital stay and severe complications-were significantly more favourable in the late group. Furthermore, there was a notable tendency for patients in the late group to experience a decreased duration of mechanical ventilation along with reduced instances of grade 3 primary graft dysfunction., Conclusions: A surgical MDT can perform double LTx safely after 20 procedures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Endoscopic thoracic sympathectomy may be complicated by the onset of disabling compensatory sweating (CS). The objective of this case series is to report the 2-year outcomes after robotic sympathetic trunk reconstruction (STR) for the reversal of CS in patients who had undergone endoscopic thoracic sympathectomy., Methods: We prospectively followed-up a total of 23 patients who had undergone robotic STR because of intolerable CS between October 2017 and January 2021. A visual analog scale ranging from 0 to 10 (with 10 indicating the highest degree) was used to assess the severity of CS at different anatomical locations, thermoregulatory alterations, and gustatory hyperhidrosis. Measurements were performed before STR and at 6-month and 2-year follow-up., Results: The mean age of the study participants was 43.3 ± 7.8 years, and 20 (87%) were men. The reversal procedure was performed after a mean of 19.6 ± 7.8 years from endoscopic thoracic sympathectomy. In all patients, nerve defects were successfully bridged using sural nerves (mean length, 9.7 cm on the right and 9.8 cm on the left). No cases of Horner syndrome were noted. At 6 postoperative months, the severity of CS decreased significantly at all body surface areas. The observed improvements were effectively maintained at 24 post-STR months. There was no evidence of either recurrent hyperhidrosis at the primary site or transition of CS to other anatomical locations. Similar improvements were evident for thermoregulatory alterations and gustatory hyperhidrosis., Conclusions: Robotic STR is safe and effective in reversing intolerable CS after endoscopic thoracic sympathectomy., (© 2023 The Author(s).)

Background: Currently, little is known regarding the optimal technique for the abdominal phase of RAMIE. The aim of this study was to investigate the outcome of robot-assisted minimally invasive esophagectomy (RAMIE) in both the abdominal and thoracic phase (full RAMIE) compared to laparoscopy during the abdominal phase (hybrid laparoscopic RAMIE)., Methods: This retrospective propensity-score matched analysis of the International Upper Gastrointestinal International Robotic Association (UGIRA) database included 807 RAMIE procedures with intrathoracic anastomosis between 2017 and 2021 from 23 centers., Results: After propensity-score matching, 296 hybrid laparoscopic RAMIE patients were compared to 296 full RAMIE patients. Both groups were equal regarding intraoperative blood loss (median 200 ml versus 197 ml, p = 0.6967), operational time (mean 430.3 min versus 417.7 min, p = 0.1032), conversion rate during abdominal phase (2.4% versus 1.7%, p = 0.560), radical resection (R0) rate (95.6% versus 96.3%, p = 0.8526) and total lymph node yield (mean 30.4 versus 29.5, p = 0.3834). The hybrid laparoscopic RAMIE group showed higher rates of anastomotic leakage (28.0% versus 16.6%, p = 0.001) and Clavien Dindo grade 3a or higher (45.3% versus 26.0%, p < 0.001). The length of stay on intensive care unit (median 3 days versus 2 days, p = 0.0005) and in-hospital (median 15 days versus 12 days, p < 0.0001) were longer for the hybrid laparoscopic RAMIE group., Conclusions: Hybrid laparoscopic RAMIE and full RAMIE were oncologically equivalent with a potential decrease of postoperative complications and shorter (intensive care) stay after full RAMIE., (© 2023. The Author(s).)

Background: We examined the impact of the weekend effect on the survival outcomes of patients undergoing elective esophagectomy for cancer., Methods: This was a retrospective analysis of a nationwide, health administrative dataset that included all patients (n = 3235) who had undergone elective esophagectomy for cancer in Taiwanese hospitals between 2008 and 2015. Patients were categorized according to the day of surgery (weekday group: surgical procedures starting Monday through Friday, n = 3148; weekend group: surgical procedures starting on Saturday or Sunday, n = 87). Inverse probability of treatment weighting (IPTW) using the propensity score was used to account for selection bias due to baseline differences., Results: After IPTW, patients undergoing esophagectomy on weekends had a higher 90-days mortality rate compared with those undergoing surgery on a weekday (10.5% vs. 5.5%, respectively, P < 0.001). After controlling for potential confounders, weekend surgery was identified as an independent adverse predictor of 2-years, overall survival [hazard ratio (HR) = 1.38, P < 0.001]. Importantly, inferior weekend outcomes were especially evident in certain subgroups, including patients aged > 60 years (HR = 1.61, P < 0.001), as well as those with a high burden of comorbidities (HR = 1.32, P < 0.001), advanced tumor stage (HR = 1.50, P < 0.001), histological diagnosis of squamous cell carcinoma (HR = 1.20, P < 0.001), and treated with minimally invasive esophagectomy (HR = 1.26, P < 0.001)., Conclusions: Elective esophagectomy for cancer during weekends has an adverse impact on short- and long-term survival., (© 2023. Society of Surgical Oncology.)

Background: Fluorescence imaging using indocyanine green in thoracic and esophageal surgery is gaining popularity because of the potential to facilitate surgical planning, to stage disease, and to reduce postoperative complications. To optimize use of fluorescence imaging in thoracic and esophageal surgery, an expert panel sought to establish a set of recommendations at a consensus meeting., Methods: The panel included 12 experts in thoracic and upper gastrointestinal surgery from Asia-Pacific countries. Before meeting, 7 focus areas were defined: intersegmental plane identification for sublobar resections; pulmonary nodule localization; lung tumor detection; bullous lesion detection; lymphatic mapping of lung tumors; evaluation of gastric conduit perfusion; and lymphatic mapping in esophageal surgical procedures. A literature search of the PubMed database was conducted using keywords indocyanine green, fluorescence, thoracic, surgery, and esophagectomy. At the meeting, panelists addressed each focus area by discussing the most relevant evidence and their clinical experiences. Consensus statements were derived from the proceedings, followed by further discussions, revisions, finalization, and unanimous agreement. Each statement was assigned a level of evidence and a grade of recommendation., Results: A total of 9 consensus recommendations were established. Identification of the intersegmental plane for sublobar resections, localization of pulmonary nodules, lymphatic mapping in lung tumors, and assessment of gastric conduit perfusion were applications of fluorescence imaging that have the most robust current evidence., Conclusions: Based on best available evidence and expert opinions, these consensus recommendations may facilitate thoracic and esophageal surgery using fluorescence imaging., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Spontaneous esophageal perforation is a challenging surgical emergency with significant morbidity and mortality, and timely primary repair carries good outcomes. However, direct repair for a delayed spontaneous esophageal perforation is not always feasible and is associated with high mortality. Esophageal stenting can provide therapeutic benefits in the management of esophageal perforations. In this study, we review our experience with placing esophageal stents in combination with minimally-invasive surgical drainage to treat delayed spontaneous esophageal perforations., Methods: We retrospectively analyzed patients with delayed spontaneous esophageal perforations between September 2018 and March 2021. All patients were treated using a hybrid approach, including esophageal stenting across the gastroesophageal junction (GEJ) to reduce continued contamination, gastric decompression with extraluminal sutures to prevent stent migration, early enteral nutrition, and aggressive minimally-invasive thoracoscopic debridement and drainage of infected material., Results: There were 5 patients with delayed spontaneous esophageal perforation treated with this hybrid approach. The mean duration between symptoms and diagnosis was 5 days, and the interval between symptoms and esophageal stent insertion was 7 days. The median time to oral nutrition and to esophageal stent removal was 43 and 66 days. There was no stent migration or hospital mortality. Three patients (60%) had postoperative complications. All patients were successfully resumed on oral nutrition with esophageal preservation., Conclusions: A hybrid approach combining endoscopic esophageal stent placement with extraluminal sutures to prevent stent migration, thoracoscopic decortication with chest tube drainage, gastric decompression, and jejunostomy tube placement for early nutrition was feasible and effective in the treatment of delayed spontaneous esophageal perforations. This technique offers a less invasive treatment approach for a challenging clinical problem which has traditionally carried a high rate of morbidity and mortality., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1316/coif). The authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Despite the recent introduction of technologically advanced single-port (SP) robotic systems, their use in the field of thoracic surgery has been rarely explored. Here, we report our preclinical experience concerning SP robotic thoracic surgery using the da Vinci ® SP system. The da Vinci ® SP system was used to perform subcostal anatomical lung resection and subxiphoid thymectomy in three cadavers. The operative settings that best met the surgeon's requirements for each resection were also determined. Four subcostal anatomical lung resections and two subxiphoid thymectomies were completed. While both procedures did not require additional incisions, the use of an observation port in the intercostal spaces was strongly recommended to safely create subcostal access. Dissection of hilar structures and mediastinal lymph nodes was feasible. However, due to the current unavailability of a robotic stapler, a handheld stapling instrument was required to perform a transection of vital structures. When the stapling process proved to be difficult, the table surgeon temporarily removed a robotic arm to acquire the necessary space to complete the procedure. Our data represent a promising preclinical step in understanding the feasibility of using the da Vinci ® SP system to perform an SP subcostal anatomical lung resection and a subxiphoid thymectomy.

Combination chemo-photothermal therapy with nanomaterials can reduce the dose of chemotherapeutic drugs required for effective cancer treatment by minimizing toxic side effects while improving survival times. Toward this end, we prepare hyaluronic acid (HA)-modified poly(lactic-co-glycolic acid) (PLGA) magnetic nanoparticles (MNP) for the CD44 receptor-mediated and magnetic field-guided dual-targeted delivery of cisplatin (CDDP). By co-encapsulating the CDDP and oleic acid-coated iron oxide MNP (IOMNP) in PLGA, the PMNPc was first prepared in a single emulsification/solvent evaporation step and successively surface modified with chitosan and HA to prepare the HA/PMNPc. Spherical HA/PMNPc nanoparticles of ~300 nm diameter can be prepared with 18 and 10% ( w / w ) loading content of CDDP and IOMNP and a pH-sensitive drug release to facilitate the endosomal release of the CDDP after intracellular uptake. This leads to the higher cytotoxicity of the HA/PMNPc toward the U87 glioblastoma cells than free CDDP with reduced IC50, a higher cell apoptosis rate, and the enhanced expression of cell apoptosis marker proteins. Furthermore, the nanoparticles show the hyperthermia effect toward U87 after short-term near-infrared (NIR) light exposure, which can further elevate the cell apoptosis/necrosis rate and upregulate the HSP70 protein expression due to the photothermal effects. The combined cancer therapeutic efficacy was studied in vivo using subcutaneously implanted U87 cells in nude mice. By using dual-targeted chemo-photothermal combination cancer therapy, the intravenously injected HA/PMNPc under magnetic field guidance and followed by NIR laser irradiation was demonstrated to be the most effective treatment modality by inhibiting the tumor growth and prolonging the survival time of the tumor-bearing nude mice.

Among the infectious diseases caused by pathogenic microorganisms such as bacteria, viruses, parasites, or fungi, the most prevalent ones today are malaria, tuberculosis, influenza, HIV/AIDS, Ebola, dengue fever, and methicillin-resistant Staphylococcus aureus (MRSA) infection, and most recently Covid-19 (SARS-CoV2). Others with a rather devastating history and high fatality rates such as plague, cholera, or typhus seem less threatening today but have not been eradicated, and with a declining efficacy of current antibiotics they ought to be watched carefully. Another emerging issue in this context is health-care associated infection. About 100,000 hospitalized patients in the USA ( www.cdc.gov ) and 33,000 in Europe ( https://www.ecdc.europa.eu ) die each year as a direct consequence of an infection caused by bacteria resistant to antibiotics. Among viral infections, influenza is responsible for about 3-5 million cases of severe illness, and about 250,000 to 500,000 deaths annually ( www.who.int ). About 37 million people are currently living with HIV infection and about one million die from it each year. Coronaviruses such as MERS-CoV, SARS-CoV, but in particular the recent outbreak of Covid-19 (caused by SARS-CoV2) have resulted in large numbers of infections worldwide with an estimated several hundred thousand deaths (anticipated fatality rate: <5%). With a comparatively low mortality rate dengue virus causes between 50 and 100 million infections every year, leading to 50,000 deaths. In contrast, Ebola virus is the causative agent for one of the deadliest viral diseases. The Ebola outbreak in West Africa in 2014 is considered the largest outbreak in history with more than 11,000 deaths. Many of the deadliest pathogens such as Ebola virus, influenza virus, mycobacterium tuberculosis, dengue virus, and cholera exploit the endo-lysosomal trafficking system of host cells for penetration into the cytosol and replication. Defects in endo-lysosomal maturation, trafficking, fusion, or pH homeostasis can efficiently reduce the cytotoxicity caused by these pathogens. Most of these functions critically depend on endo-lysosomal membrane proteins such as transporters and ion channels. In particular, cation channels such as the mucolipins (TRPMLs) or the two-pore channels (TPCs) are involved in all of these aspects of endo-lysosomal integrity. In this review we will discuss the correlations between pathogen toxicity and endo-lysosomal cation channel function, and their potential as drug targets for infectious disease therapy., (© 2020. Springer Nature Switzerland AG.)

Since excessive alcohol consumption is a shared risk factor for esophageal cancer and liver fibrosis, it is possible that patients with esophageal cancer may develop unknown liver fibrosis or cirrhosis. We applied preoperative transient elastography (TE) to patients without recorded cirrhosis undergoing esophagectomy to clarify the validity in predicting postesophagectomy hepatic failure. The cohort consisted of 107 patients who received TE before esophagectomy between June 2018 and December 2021. Patients were categorized into two groups based on the fibrosis score yielded by preoperative TE (mild group: 0~2, n = 92; severe group: 3~4, n = 15). There was no significant difference in demographic data nor surgical variables between the two groups. None of the cohort encountered hepatic failure, yet the severe fibrosis group had a significantly higher rate of pleural effusion (40.0% versus 15.2%, p = 0.03). The areas under the curve (AUCs) of TE in predicting postoperative complications and 180-day mortality were 0.60 (95% CI: 0.46-0.74) and 0.67 (95% CI: 0.51-0.83), respectively. In conclusion, stratification of patients with esophageal cancer who had liver fibrosis by preoperative TE demonstrates significant validity in predicting postoperative pleural effusions. Recruitment of noncirrhotic patients with higher TE scores is warranted to examine its power in other parameters.

Background: Patients with different ethnic and genetic backgrounds may respond differently to anticancer therapies. This study aimed to assess whether patients with oesophageal squamous cell carcinoma (OSCC) treated with neoadjuvant chemoradiotherapy (nCRT) in East Asia had an inferior pathological response compared with patients treated in Northwest Europe., Methods: Patients with OSCC who underwent nCRT according to the CROSS regimen (carboplatin and paclitaxel with concurrent 41.4 Gy radiotherapy) followed by oesophagectomy between June 2012 and April 2020 were identified from East Asian and Dutch databases. The primary outcome was pCR, defined as ypT0 N0. Groups were compared using propensity score matching, adjusting for sex, Charlson Co-morbidity Index score, tumour location, cT and cN categories, interval between nCRT and surgery, and number of resected lymph nodes., Results: Of 725 patients identified, 133 remained in each group after matching. A pCR was achieved in 37 patients (27.8 per cent) in the Asian database and 58 (43.6 per cent) in the Dutch database (P = 0.010). The rate of ypT1-4 was higher in Asian than Dutch data (66.2 and 49.6 per cent; P = 0.004). The ypN1-3 rate was 44.4 per cent in the Asian and 33.1 per cent in the Dutch data set. Clear margins were achieved in 92.5 per cent of Asian and 95.5 per cent of Dutch patients., Conclusion: Regional differences in responses to CROSS nCRT for oesophageal cancer were apparent, the origin of which will need evaluation., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: The prognosis of patients with resected esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy is particularly poor in those who were staged as ypT3/T4 and/or ypN+. This study investigated whether adjuvant chemoradiotherapy was associated with improved clinical outcomes in these patients., Methods: we identified patients with esophageal squamous cell carcinoma who were staged as ypT3/T4 and/or ypN+ after being treated with neoadjuvant chemoradiotherapy followed by esophagectomy between the years 2013 and 2019. Patients were divided into two groups based on whether they received adjuvant chemoradiotherapy. The Kaplan-Meier method and Cox regression modeling were performed for survival analyses and multivariable analysis, respectively., Results: 76 eligible patients were included in the analyses. The median follow-up for the study cohort was 43.4 months. On Kaplan-Meier analyses of the overall population, adjuvant chemoradiotherapy was associated with significantly improved median overall survival (31.7 months vs. 16.3 months, p = 0.036). On Kaplan-Meier analyses of the 35 matched pairs generated by propensity score matching, adjuvant chemoradiotherapy was associated with significantly longer median overall survival (31.7 months vs. 14.3 months; p = 0.004) and median recurrence-free survival (18.9 months vs. 11.7 months; p = 0.020). In multivariable analysis, adjuvant chemoradiotherapy was independently associated with a 60% reduction in mortality ( p = 0.003) and a 48% reduction in risk of recurrence ( p = 0.035) after adjusting for putative confounders. In addition, microscopic positive resection margin and Mandard tumor regression grade 3-4 were independently associated with increased mortality and risk of recurrence. While a greater number of lymph nodes dissected was independently associated with significantly improved overall survival, the number of positive lymph nodes was independently associated with significantly worse overall survival and a trend ( p = 0.058) towards worse recurrence-free survival., Conclusions: This study demonstrated that adjuvant CRT was independently associated with a significantly improved survival and lower risk of recurrence than observation in esophageal squamous cell carcinoma patients staged as ypT3 and/or ypN+ after receiving neoadjuvant chemoradiotherapy and radical surgery. The results of this study have implications for the design of future clinical trials and may improve treatment outcomes of patients in this setting who cannot afford or are without access to adjuvant nivolumab.

Objective: This study aims at constructing a staging system incorporating tumor regression grade and ypN-category (TRG-N) in patients with neoadjuvant therapy before esophagectomy. It is hypothesized that this would prognosticate better than the current American Joint Committee on Cancer (AJCC) postneoadjuvant therapy (ypTNM) stage groups., Background: Conventional pathological T-category is defined by the depth of invasion, and may lose prognostic relevance after neoadjuvant therapy. TRG defines treatment response by the degree of tumor regression, and when combined with ypN-category may be more prognostic than AJCC postneoadjuvant therapy (ypTNM) stage groups., Methods: A training cohort of 210 patients with esophageal squamous cell carcinoma and who had had neoadjuvant therapy before esophagectomy were studied. A validation cohort comprised 107 patients from another hospital. Resected esophagi were assessed by ypT-category and TRG, the latter assigned according to the Becker 4-tier system. These categories were grouped with ypN-category into a TRG-N system. Patients' survival was compared between the current AJCC postneoadjuvant therapy (ypTNM) stage groups and this TRG-N system., Results: In the training cohort, 5-year survival rates according to ypTNM stage I, II, IIIA, IIIB, and IVA were 53%, 39.4%, 47%, 18.3%, and 0%, respectively. For TRG-N stages I, II, III, and IV, the respective figures were 59.6%, 43.5%, 23.8%, and 15.6%. TRG-N stage showed better fit in survival than ypTNM stage groups, indicated by lower Akaike Information Criteria (AIC) and Bayesian Information Criterion values. Similar results were found in the validation cohort. Multivariate analysis showed that TRG-N stage ( P =0.02), age ( P =0.006), and sex ( P =0.005) were independent prognostic factors., Conclusion: TRG-N stage shows better prognostication than the AJCC postneoadjuvant therapy (ypTNM) stage groups., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This international multicenter study by the Upper GI International Robotic Association aimed to gain insight in current techniques and outcomes of RAMIE worldwide., Background: Current evidence for RAMIE originates from single-center studies, which may not be generalizable to the international multicenter experience., Methods: Twenty centers from Europe, Asia, North-America, and South-America participated from 2016 to 2019. Main endpoints included the surgical techniques, clinical outcomes, and early oncological results of ramie., Results: A total of 856 patients undergoing transthoracic RAMIE were included. Robotic surgery was applied for both the thoracic and abdominal phase (45%), only the thoracic phase (49%), or only the abdominal phase (6%). In most cases, the mediastinal lymphadenectomy included the low paraesophageal nodes (n=815, 95%), subcarinal nodes (n = 774, 90%), and paratracheal nodes (n = 537, 63%). When paratracheal lymphadenectomy was performed during an Ivor Lewis or a McKeown RAMIE procedure, recurrent laryngeal nerve injury occurred in 3% and 11% of patients, respectively. Circular stapled (52%), hand-sewn (30%), and linear stapled (18%) anastomotic techniques were used. In Ivor Lewis RAMIE, robot-assisted hand-sewing showed the highest anastomotic leakage rate (33%), while lower rates were observed with circular stapling (17%) and linear stapling (15%). In McKeown RAMIE, a hand-sewn anastomotic technique showed the highest leakage rate (27%), followed by linear stapling (18%) and circular stapling (6%)., Conclusion: This study is the first to provide an overview of the current techniques and outcomes of transthoracic RAMIE worldwide. Although these results indicate high quality of the procedure, the optimal approach should be further defined., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The gut microbiota plays a vital role in maintaining tissue homeostasis and regulating disease pathophysiology; however, the underlying mechanisms remain to be elucidated. We previously showed that mice depleted of gut microbiota with antibiotics (ABX mice) were more prone to cardiac rupture after infarction, suggesting that the gut microbiota impacts cardiac structural remodeling following injury. Here, we aimed to determine whether the gut microbiota is required for adaptive cardiac remodeling in response to pressure overload stress. Methods: Transverse aortic constriction (TAC) surgery was performed and cardiac function was evaluated by echocardiography and catheterization, followed by mechanical tests and extracellular matrix (ECM) studies. Germ-free mice with cecal microbiota transplantation were used for validation. 16S ribosomal DNA sequencing and PICRUSt2 analysis were applied to predict the key metabolic pathways. ABX mice were supplemented with the derived metabolic products and their efficacy was tested. To elucidate the underlying mechanism, we isolated mouse primary cardiac fibroblasts and treated them with the metabolites. Lastly, G-coupled protein receptor 41 (GPR41) and GPR43 double knockdown cardiac fibroblasts were generated and the anti-fibrogenic effect of metabolites was determined. Results: Cardiac hypertrophy and dysfunction were more severe in ABX-TAC mice compared to the controls. Moreover, TAC-induced fibrosis was more profound in ABX hearts, which was accompanied by disrupted ECM structure making the heart tissues mechanically weaker and more brittle. Reconstruction of healthy gut microbiota in germ-free mice successfully restored cardiac function and prevented excessive fibrosis and ECM disarray under stress. Furthermore, functional prediction identified acetate and propionate as critical mediators in the gut microbiota-modulated cardiac mechanics. Supplementation of acetate and propionate improved heart function, attenuated fibrosis, and reversed ECM disarray after TAC. In addition, treating primary cardiac fibroblasts with acetate and propionate attenuated cell contraction, inhibited myofibroblast formation, and reduced collagen formation after TGF-β1 stimulus. Finally, knocking down GPR41 and GPR43 receptors in cardiac fibroblasts blunted the inhibitory effects of acetate and propionate. Conclusions: The gut microbiota is a potential therapeutic target for cardiac ECM remodeling and heart structural integrity. By establishing a healthy gut microbiome or replenishing the derived metabolites, we could improve cardiac health under dysbiosis after pressure-overload stress., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

We hypothesized that the host microbiome may influence foreign body responses following biomaterial implantation. To test this, we implanted a variety of clinically relevant biomaterials into germ-free or antibiotic-treated mice. Surprisingly, these mice displayed less fibrous tissue deposition, reduced host cell recruitment to the implant site, and differential expression of angiogenic and inflammatory markers. These observations were reversed upon fecal microbiome reconstitution, confirming a causal role of the host microbiome. In a clinically relevant disease model, microbiome-depleted mice cleared hyaluronic acid and bone marrow mononuclear cells from ischemic hind limb tissues more slowly, resulting in an improved therapeutic response. Findings were confirmed in pigs which showed reduced fibrotic responses to a variety of implanted materials. Lastly, we profiled changes in the host microbiome following material implantation, implicating several key bacteria phyla., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: A "surgery as needed" approach may be offered to patients with esophageal cancer (EC) who achieve major histopathological response (MaHR) after neoadjuvant chemoradiotherapy (nCRT). However, the utility of clinical response assessment (CRE) for predicting histopathological response to nCRT remains limited. Circulating tumor cells (CTCs) hold promise as biomarkers of response to nCRT., Methods: We analyzed the clinical utility of post-nCRT CTCs, alone or in combination with CRE, in the prediction of MaHR. We defined MaHR as either the lack or a limited presence (≤10%) of vital residual tumor cells in the resected esophageal specimen in the absence of nodal involvement., Results: Of the 48 study patients, 27 (56%) achieved MaHR. Patients with MaHR had a significantly lower CTCs count compared with those without (3.61 ± 4.53 versus 6.83 ± 5.22 per mL of blood, respectively; P = 0.027). Using a cutoff for positivity of 5 CTCs per mL of blood, the combination of CTCs and CRE allowed achieving a negative predictive value for MaHR of 93% (95% confidence interval [CI] = 70-99%) along with a false negative rate of 5% (95% CI = 1-33%)., Conclusion: CTCs count assessed in combination with CRE can potentially help identify patients with EC who achieved MaHR after nCRT.

Purpose: Left upper mediastinal lymph node dissection (UMLND)-a technically demanding step of McKeown esophagectomy-is frequently complicated by recurrent laryngeal nerve (RLN) palsy. Under the hypothesis that robotic esophagectomy (RE) could increase the safety and feasibility of UMLND, we retrospectively investigated the degree to which a pre-existing experience in video-assisted thoracoscopic esophagectomy (VATE) may affect the learning curves of this critical part of RE., Methods: Surgeon A had previously performed > 150 VATE procedures before transitioning to RE. While surgeon B had previously assisted to 50 RE, his pre-existing VATE experience consisted of less than five procedures. A total of 103 and 76 McKeown RE procedures were performed by surgeons A and B, respectively. The learning curve of left UMLND for each surgeon was examined using the cumulative sum method., Results: The inflection point of RLN palsy for surgeon A occurred at patient 31. While the nerve palsy rate decreased from 32.3 to 4.2% (p < 0.001), the number of nodes harvested during left UMLND did not appreciably change. Surgeon B showed a bimodal learning curve for RLN palsy with primary and secondary inflection points at patients 15 and 49, respectively. The RLN palsy rate initially decreased from 66.7% (patients 1-15) to 14.7% (patients 16-49), followed by an additional decline to 3.7% (patients 50-76). However, the number of nodes harvested during left UMLND showed a downtrend which was paralleled by decreasing rates of RLN palsy. These results indicate that surgeon B has not yet reached an ideal balance between an extensive UMLND and nerve protection., Conclusion: The pre-existing VATE experience seems to affect the learning curves of left UMLND during RE., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)