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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: Esophagectomy following neoadjuvant chemoradiotherapy (nCRT) is a curative treatment for locally advanced esophageal cancer. However, pulmonary complications are the most common postoperative issues and can adversely affect survival. While numerous studies have investigated predictors for these complications and survival, morphomic predictors, derived from body composition measurements on computed tomography scans, have been rarely reported. Our study aims to delineate morphomic predictors for post-esophagectomy pulmonary complications and overall survival., Methods: We retrospectively analyzed esophageal cancer patients who received nCRT followed by esophagectomy between 2004 and 2016. Preoperative clinical and morphomic variables were collected to evaluate post-esophagectomy pulmonary complications and overall survival. Multivariable logistic regression and Cox's proportional hazard model were used for analysis., Results: The study involved 221 esophageal cancer patients who received nCRT followed by surgery. Factors such as increased blood loss (P=0.01), more harvested nodes (P<0.001), advanced pT stage (P=0.01), elevated visceral adipose tissue (VAT) density (P=0.04), and reduced skeletal muscle (SM) area (P=0.01) were linked to pulmonary complications. Additionally, being male (P=0.01), increased blood loss (P<0.001), non-R0 resection margin (P=0.001), advanced pStage (P<0.001), advanced pT stage (P=0.02), and decreased SM density (P=0.045) were associated with poorer overall survival., Conclusions: Increased VAT density and decreased SM area were associated with pulmonary complications, while decreased SM density was linked to poorer overall survival. Preoperative analytic morphomics aids in predicting both postoperative pulmonary complications and survival., 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-24-1227/coif). The authors have no conflicts of interest to declare., (Copyright © 2025 AME Publishing Company. All rights reserved.)

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated cancer, and immune checkpoint inhibitors (ICIs) have shown efficacy in its treatment. The combination of chemotherapy and ICIs represents a new trend in the standard care for metastatic NPC. In this study, we aim to clarify the immune cell profile and related prognostic factors in the ICI-based treatment of metastatic NPC. Programmed cell death ligand 1 (PD-L1) expression was measured in 81 metastatic tissue samples that had not received prior ICI treatment. The combined positive score (CPS) was positive in 58.0% of the samples, with a statistically significant correlation to median overall survival (OS) (CPS ≥ 1 vs. CPS < 1: 28 vs. 16 months, P = 0.004). For the combination treatment of metastatic NPC, 62 patients were enrolled in a retrospective analysis, yielding a median OS of 39.3 months. The objective response rate for this combination therapy was 71%, with a complete response rate of 45.2%. With a cutoff value of 4.8 for the pre-treated neutrophil-lymphocyte ratio (NLR) in peripheral blood (PB), the difference in median OS was statistically significant ( P = 0.021). Thirty-seven patients received local treatment following the combination therapy of ICIs and chemotherapy, which provided additional survival benefits. Most hyper-responders exhibited a prolonged low NLR (< 3), a high total lymphocyte count, and an undetectable or stable EBV DNA load in PB during treatment. Peripheral blood mononuclear cells (PBMCs) from most patients receiving the combination treatment were rich in PD-1+CD8+ lymphocytes, which showed high expression of both IFN-γ and Granzyme B, demonstrating the ability to kill the EBV-positive NPC cell line and xenografts in vitro and in vivo. Responders also displayed increased levels of CD4+CD45RA-CCR7-CD28+CD57- cells (effector memory cell subset) in peripheral blood. These results indicate that in the context of combined chemotherapy and ICIs, high PD-L1 expression in pre-treated metastatic tumor tissue, a low NLR before treatment, a decrease in NLR after treatment, and local treatment can provide significant benefits for patients with metastatic NPC., Competing Interests: None., (AJCR Copyright © 2024.)

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.

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.)

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: 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: 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).)

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: 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.

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: 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.

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.

Despite novel therapy regimens and extensive research, chemoresistance remains a challenge in leukemia treatment. Of note, recent studies revealed lysosomes as regulators of cell death and chemotherapy response, suggesting this organelle is a novel target for chemosensitization. Interestingly, drug-resistant VCR-R CEM acute lymphoblastic leukemia (ALL) cells have an increased expression of the lysosomal cation channel Two-Pore-Channel 2 (TPC2) compared to drug-naïve CCRF-CEM ALL cells. Concurrently, knockout (KO) of TPC2 sensitized drug-resistant VCR-R CEM cells to treatment with cytostatics. The chemosensitizing effect could be confirmed in several cell lines as well as in heterogeneous, patient-derived xenograft ALL cells, using the pharmacological TPC2 inhibitors naringenin and tetrandrine. We reveal that a dual mechanism of action mediates chemo sensitization by loss of lysosomal TPC2 function. First, because of increased lysosomal pH, lysosomal drug sequestration is impaired, leading to an increased nuclear accumulation of doxorubicin and hence increased DNA damage. Second, lysosomes of TPC2 KO cells are more prone to lysosomal damage as a result of morphological changes and dysregulation of proteins influencing lysosomal stability. This leads to induction of lysosomal cell death (LCD), evident by increased cathepsin B levels in the cytosol, truncation of pro-apoptotic Bid, as well as the reversibility of cell death by co-treatment with the cathepsin B inhibitor CA-074Me in TPC2 KO cells. In summary, this study establishes TPC2 as a novel, promising, druggable target for combination therapy approaches in ALL to overcome chemoresistance, which could be exploited in the clinic in the future. Additionally, it unravels LCD signaling as an important death-inducing component upon loss of TPC2 function., (© 2022. The Author(s).)

Background: Esophagectomy remains the standard treatment for esophageal cancer or esophagogastric junction cancer. The stomach, or the gastric conduit, is currently the most commonly used substitute for reconstruction instead of the jejunum or the colon. Preservation of the right gastric and the right gastroepiploic vessels is a vital step to maintain an adequate perfusion of the gastric conduit. Compromise of these vessels, especially the right gastroepiploic artery, might result in ischemia or necrosis of the conduit. Replacement of the gastric conduit with jejunal or colonic interposition is reported when a devastating accident occurs; however, the latter procedure requires a more extensive dissection and multiple anastomosis., Case Presentation: A 61-year-old male with a lower third esophageal squamous cell carcinoma (cT3N1 M0) who received neoadjuvant chemoradiation with a partial response. He underwent esophagectomy with a gastric conduit reconstruction. However, the right gastroepiploic artery was accidentally transected during harvesting the gastric conduit, and the complication was identified during the pull-up phase. An end-to-end primary anastomosis was performed by the plastic surgeon under microscopy, and perfusion of the conduit was evaluated by the ICG scope, which revealed adequate vascularization of the whole conduit. We continued the reconstruction with the revascularized gastric conduit according to the perfusion test result. Although the patient developed minor postoperative leakage of the esophagogastrostomy, it was controlled with conservative drainage and antibiotic administration. Computed tomography also demonstrated fully enhanced gastric conduit. The patient resumed oral intake smoothly later without complications and was discharged at postoperative day 43., Conclusion: Although the incidence of vascular compromise during harvesting of the gastric conduit is rare, the risk of conduit ischemia is worrisome whenever it happens. Regarding to our presented case, with the prompt identification of the injury, expertized vascular reconstruction, and a practical intraoperative evaluation of the perfusion, a restored gastric conduit could be applied for reconstruction instead of converting to more complicated procedures., (© 2022. The Author(s).)

Background: The globally dominant treatment with curative intent for locally advanced esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemoradiotherapy (nCRT) with subsequent esophagectomy. This multimodal treatment leads to around 60% overall 5-year survival, yet with impaired post-surgical quality of life. Observational studies indicate that curatively intended chemoradiotherapy, so-called definitive chemoradiotherapy (dCRT) followed by surveillance of the primary tumor site and regional lymph node stations and surgery only when needed to ensure local tumor control, may lead to similar survival as nCRT with surgery, but with considerably less impairment of quality of life. This trial aims to demonstrate that dCRT, with selectively performed salvage esophagectomy only when needed to achieve locoregional tumor control, is non-inferior regarding overall survival, and superior regarding health-related quality of life (HRQOL), compared to nCRT followed by mandatory surgery, in patients with operable, locally advanced ESCC., Methods: This is a pragmatic open-label, randomized controlled phase III, multicenter trial with non-inferiority design with regard to the primary endpoint overall survival and a superiority hypothesis for the experimental intervention dCRT with regard to the main secondary endpoint global HRQOL one year after randomization. The control intervention is nCRT followed by preplanned surgery and the experimental intervention is dCRT followed by surveillance and salvage esophagectomy only when needed to secure local tumor control. A target sample size of 1200 randomized patients is planned in order to reach 462 events (deaths) during follow-up., Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04460352., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nilsson, Olafsdottir, Alexandersson von Döbeln, Villegas, Gagliardi, Hellström, Wang, Johansson, Gebski, Hedberg, Klevebro, Markar, Smyth, Lagergren, Al-Haidari, Rekstad, Aahlin, Wallner, Edholm, Johansson, Szabo, Reynolds, Pramesh, Mummudi, Joshi, Ferri, Wong, O’Callaghan, Lukovic, Chan, Leong, Barbour, Smithers, Li, Kang, Kong, Chao, Crosby, Bruns, van Laarhoven, van Berge Henegouwen, van Hillegersberg, Rosati, Piessen, de Manzoni and Lordick.)

Taiwanese surgeons have pioneered major advances in the field of minimally invasive thoracic surgery. Since the establishment of the Taiwan Association of Thoracic and Cardiovascular Surgery [1986], the landscape of thoracic surgery has rapidly evolved from traditional thoracotomy to multi-port video-assisted thoracoscopic approaches. By early 21st century, further developments have included the single-port and subxiphoid techniques. This paper provides an overview of the Taiwanese thoracic surgery environment and its major accomplishments. With the increasing use of low-dose computed tomography for lung cancer screening, the detection of small pulmonary nodules has been growing steadily. High-end hybrid operating rooms comprising both imaging and surgical equipment are increasingly being applied in Taiwan as platforms for image-guided video-assisted thoracoscopic surgery (iVATS). Recently, we described an iVATS workflow for simultaneous detection and removal of small pulmonary nodules which was entirely performed by thoracic surgeons. With respect to esophageal malignancies, the implementation of robot-assisted esophagectomy has been a significant milestone in Taiwan. This technique allowed conducting an extensive lymph node dissection along the bilateral recurrent laryngeal nerve in a safe and effective manner. With 14 medical schools and 26 medical centers located on the island, Taiwan has been able to maintain a constant doctor-to-population ratio of 1-to-500. By partnering with the National Health Insurance and by taking advantage of state-of-the-art technologies, Taiwanese thoracic surgeons are continuously striving to deliver high-quality and cost-effective surgical care., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-21-1302/coif). The series “Thoracic Surgery Worldwide” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2022 Journal of Thoracic Disease. All rights reserved.)

Esophageal cancer survival has improved as a result of improvements in surgical techniques and preoperative chemoradiation. Excessive alcohol consumption is a shared risk factor for esophageal cancer and chronic alcoholic pancreatitis. Puestow's procedure is a treatment choice for pain relief and pancreatic duct decompression. It is logical to perform Puestow's procedure in patients undergoing esophagectomy with underlying chronic pancreatitis to preserve pancreatic function and restore quality of life in the setting of improved overall survival of patients with esophageal cancer. This report describes a preliminary experience with 2 patients who underwent both procedures during the same operation and achieved acceptable outcomes., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The most beneficial neoadjuvant chemoradiotherapy (nCRT) combination for esophageal squamous cell carcinoma (ESCC) in Asia remains uncertain. Herein, we compared the neoadjuvant carboplatin/paclitaxel (CROSS) regimen versus the cisplatin/5-fluorouracil (PF) regimen in combination with 41.4-50.4 Gy of radiotherapy., Methods: Patients were stratified according to their nCRT regimen: CROSS + 41.4-45.0 Gy (CROSS), PF + 45.0 Gy (PF4500) or PF + 50.4 Gy (PF5040). Propensity score matching by inverse probability of treatment weighting (IPTW) was used to balance the baseline variables., Results: Before IPTW, a total of 334 patients were included. The lowest chemotherapy completion rate was observed in the PF5040 group (76.2% versus 89.4% and 92.0% in the remaining two groups, respectively). Compared with CROSS, both PF groups showed more severe weight loss during nCRT and a higher frequency of post-esophagectomy anastomotic leaks. The use of PF5040 was associated with the highest rate of pathological complete response (45.3%). While CROSS conferred a significant overall survival benefit over PF4500 (hazard ratio [HR] = 1.30, 95% CI = 1.05 to 1.62, p = 0.018), similar survival figures were observed when compared with PF5040 (HR = 1.17, 95% CI = 0.94 to 1.45, p = 0.166)., Conclusions: The CROSS regimen conferred a significant survival benefit over PF4500, although the similar survival figures were similar to those observed with PF5040. Considering the lower incidences of severe weight loss and post-esophagectomy anastomotic leaks, CROSS represents a safe and effective neoadjuvant treatment for Taiwanese patients with ESCC.

Preoperative localization holds promise for overcoming the limitations of video-assisted thoracoscopic surgery (VATS) in the treatment of impalpable lung nodules. The purpose of this study was to assess the safety and efficacy of cone-beam computed tomography (CBCT)-guided localization using near-infrared (NIR) marking. Between 2017 and 2021, patients presenting with a solitary pulmonary nodule (SPN) who had undergone CBCT-guided lesion localization with indocyanine green (ICG) in a hybrid operating room were included. The primary outcomes were the efficacy of localization and the occurrence of complications. The study cohort consisted of 175 patients with the mean age of 58.76 years. The mean size and depth of the 175 SPNs were 8.34 mm and 5.3 mm, respectively. The mean time required for lesion marking was 14.71 min. Upon thoracoscopic inspection, the NIR tattoo was detected in the vast majority of the study participants (98.3%). An utility thoracotomy to allow digital palpation was required in two of the three patients in whom the tattoo was not identifiable. The perioperative survival rate was 100%, and the mean length of hospital stay was 3.09 days. We conclude that needle localization with ICG injection is a safe and feasible technique to localize SPNs prior to resection.

Liver cancers, including hepatocellular carcinoma (HCC), are the second leading cause of cancer death worldwide, and novel therapeutic strategies are still highly needed. Recently, the endolysosomal cation channel TRPML1 (also known as MCOLN1) has gained focus in cancer research because it represents an interesting novel target. We utilized the recently developed isoform-selective TRPML1 activator ML1-SA1 and the CRISPR/Cas9 system to generate tools for overactivation and loss-of-function studies on TRPML1 in HCC. After verification of our tools, we investigated the role of TRPML1 in HCC by studying proliferation, apoptosis and proteomic alterations. Furthermore, we analyzed mitochondrial function in detail by performing confocal and transmission electron microscopy combined with SeahorseTM and Oroboros® functional analysis. We report that TRPML1 overactivation mediated by a novel, isoform-selective small-molecule activator induces apoptosis by impairing mitochondrial function in a Ca2+-dependent manner. Additionally, TRPML1 loss-of-function deregulates mitochondrial renewal, which leads to proliferation impairment. Thus, our study reveals a novel role for TRPML1 as regulator of mitochondrial function and its modulators as promising molecules for novel therapeutic options in HCC therapy., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Background: This study was conducted to identify risk factors for distant interval metastases (IM) in patients with esophageal squamous cell carcinoma (ESCC) who underwent chemoradiotherapy (CRT)., Methods: We retrospectively reviewed the clinical records of 358 patients with ESCC treated with CRT between 2006 and 2017. Distant IM were defined as systemic metastases developing during or shortly after CRT and identified during the restaging work-up period. A risk prediction nomogram for distant IM was developed based on independent pretreatment risk factors identified using multivariable logistic regression analysis., Results: Distant IM occurred in 26 (7.3%) patients and had a significant adverse impact on survival (median survival: 8.7 months). The most common site of distant IM was the lung (n = 9), followed by non-regional lymph nodes (n = 8) and the bone (n = 8). Multivariable logistic regression analysis revealed that high baseline tumor SUVmax values were independently associated with an increased risk of distant IM (odds ratio [OR] = 1.059, p = 0.019), whereas older age was an independent protective factor (OR = 0.946, p = 0.032). A nomogram based on age, tumor SUVmax, tumor length, and the chemotherapy regimen showed a good predictive performance (c-statistic = 0.761), which was internally validated using 200 bias-corrected bootstrap replicates (c-statistic = 0.71)., Conclusion: Distant IM were identified in 7.3% of patients with ESCC undergoing CRT. The nomogram described in our study may prove useful to predict the risk of distant IM in this patient group., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: Thoracoscopic removal of small pulmonary nodules is traditionally accomplished through a two-step approach-with lesion localization in a CT suite as the first step followed by lesion removal in an operating room as the second step. While the advent of hybrid operating rooms (HORs) has fostered our ability to offer a more patient-tailored approach that allows simultaneous localization and removal of small pulmonary nodules within a single-step, randomized controlled trials (RCTs) that compared the two techniques (two- vs. single-step) are still lacking. Methods: This is a RCT conducted in an academic hospital in Taiwan between October 2018 and December 2019. To compare the outcomes of traditional two-step preoperative CT-guided small pulmonary nodule localization followed by lesion removal vs. single-step intraoperative CT-guided lesion localization with simultaneous removal performed by a dedicated team of thoracic surgeons. The analysis was conducted in an intention-to-treat fashion. The primary study endpoint was the time required for lesion localization. Secondary endpoints included radiation doses, other procedural time indices, and complication rates. Results: A total of 24 and 25 patients who received the single- and two-step approach, respectively, were included in the final analysis. The time required for lesion localization was significantly shorter for patients who underwent the single-step procedure (median: 13 min) compared with the two step-procedure (median: 32 min, p < 0.001). Similarly, the radiation dose was significantly lower for the former than the latter (median: 5.64 vs. 10.65 mSv, respectively, p = 0.001). Conclusions: The single-step procedure performed in a hybrid operating room resulted in a simultaneous reduction of both localization procedural time and radiation exposure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fang, Chen, Wen, Wen, Pan, Chiu, Hsieh and Chao.)

Background: Because of its capacity to reduce surgical trauma to the chest wall, thoracoscopic esophagectomy is considered paramount for decreasing the risk of pulmonary complications in the context of minimally invasive esophagectomy. Whether laparoscopy (LS) following thoracoscopic esophagectomy can further improve outcomes compared with open laparotomy (OL) is unknown., Materials and Methods: We retrospectively reviewed the clinical and imaging records of 428 patients who received McKeown esophagectomy with a thoracoscopic approach for cancer. Using propensity score matching based on eight parameters (age, sex, body mass index, Charlson comorbidity index, tumor location, type of preoperative therapy, reconstruction route, and occurrence/severity of postoperative vocal cord palsy), 60 pairs were identified and compared with regard to perioperative complications and overall survival (OS)., Result: Compared with OL, LS resulted in lower blood loss (mean: 171.21 versus 107.58 mL, respectively, p = 0.023) and a reduced incidence of pneumonia (13.3% versus 3.3%, respectively, p = 0.048), albeit at the expense of a longer operating time (mean: 399.37 versus 443.93 min, respectively, p = 0.003). Notably, lymph node yields and OS of patients who were treated with LS were similar to those observed in those who underwent OL., Conclusions: Patients who receive LS after thoracoscopic esophagectomy experience lower blood loss and have a reduced risk of pneumonia than those treated with OL., Competing Interests: Declaration of competing interest All authors have no conflicts of interest or financial ties to disclose., (Copyright © 2021. Published by Elsevier Taiwan LLC.)

Objectives: The use of a hybrid operating room equipped with robotic C-arm cone-beam computed tomography for single-step localization and excision of small pulmonary nodules finds high cost barriers. The new generation of 3D C-arm system not only depicts soft tissues with high contrast but also offers a more affordable and sustainable solution. This approach has been chiefly applied in the field of orthopedic surgery. In this case series, we describe the use of a mobile 3D C-arm system for localizing and removing small pulmonary nodules., Methods: Between July and September 2020, we identified 14 patients who underwent localization and removal of small pulmonary nodules with a 3D C-arm system. We retrospectively reviewed clinical records to document the feasibility and safety of the procedure., Results: The median tumour size was 7.5 mm [interquartile range (IQR): 5 - 9.75 mm], with a median distance from the pleural surface of 4.2 mm (IQR: 0.5 - 6.45 mm). We successfully visualized all of the pulmonary lesions by intraoperative CT imaging. Localization was achieved in 13 patients, who subsequently underwent complete thoracoscopic resection. The median time required to localize lesions was 41.5 min (IQR: 33.75 - 53.25 min), with a median radiation exposure (expressed through the skin absorbed dose) of 143.45 mGy (IQR: 86.1 - 194.6 mGy). Failure to localize occurred in 1 patient because of pneumothorax caused by repeated needle puncture. All patients were successfully discharged and the median length of stay was 2.5 days (IQR: 2 - 3 days)., Conclusions: This case series demonstrates the feasibility of single-step localization and excision of small pulmonary nodules using a mobile 3D C-arm., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) management has evolved over the past two decades, with the development of newer treatment modalities. While various options are available, unmet needs are reflected through the mixed treatment outcome for intermediate-stage HCC. As HCC is radiosensitive, radiation therapies have a significant role in management. Radiation therapies offer local control for unresectable lesions and for patients who are not surgical candidates. Radiotherapy also provides palliation in metastatic disease, and acts as a bridge to resection and transplantation in selected patients. Advancements in radiotherapy modalities offer improved dose planning and targeted delivery, allowing for better tumor response and safer dose escalations while minimizing the risks of radiation-induced liver damage. Radiotherapy modalities are broadly classified into external beam radiation therapy and selective internal radiation therapy. With emerging modalities, radiotherapy plays a complementary role in the multidisciplinary care of HCC patients., Aim: We aim to provide an overview of the role and clinical application of radiation therapies in HCC management., Relevance for Patients: The continuous evolution of radiotherapy techniques allows for improved therapeutic outcomes while mitigating unwanted adverse effects, making it an attractive modality in HCC management. Rigorous clinical studies, quality research and comprehensive datasets will further its application in the present era of evidence-based practice in Medicine., Competing Interests: The authors declare no conflict of interest, (Copyright: © Whioce Publishing Pte. Ltd.)

Background: Although thoracoscopic stapled bullectomy is a standard procedure for primary spontaneous pneumothorax (PSP), the postoperative recurrence rate is high. We investigated whether using a Vicryl (Ethicon, Somerville, NJ) mesh to cover the staple line after bullectomy reduces the postoperative recurrence rate., Methods: Our single-blind, parallel-group, prospective, randomized controlled trial at 2 medical centers in Taiwan studied patients with PSP who were aged 15 to 50 years and required thoracoscopic bullectomy. On the day of operation, patients were randomly assigned (1:1) to receive Vicryl mesh (mesh group) or not (control group) after thoracoscopic bullectomy with linear stapling and mechanical apical pleural abrasion. Randomization was achieved using computer-generated random numbers in sealed envelopes. Our primary end point was the pneumothorax recurrence rate within 1 year after the operation (clinicaltrials.gov number, NCT01848860.) RESULTS: Between June 2013 and March 2016, 102 patients were assigned to the mesh group and 102 to the control group. Within 1 year after operation, recurrent pneumothorax was diagnosed in 3 patients (2.9%) in the mesh group compared with 16 (15.7%) in the control group (P = .005). The short-term postoperative results and hospitalization duration were comparable between the groups., Conclusions: For thoracoscopic bullectomy with linear stapling and mechanical apical pleural abrasion, the use of a Vicryl mesh to cover the staple line is effective for reducing the postoperative recurrence of pneumothorax. Vicryl mesh coverage can be considered an optimal adjunct to the standard surgical procedure for PSP., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Doxorubicin (DOX) is a potent chemotherapeutic agent known to induce cardiotoxicity. Here we applied one-dimensional scanning multiphoton imaging to investigate the derangement of cardiac dynamics induced by DOX on a zebrafish model. DOX changed the cell morphology and significantly prolonged calcium transient and sarcomere contraction, leading to an arrhythmia-like contractile disorder. The restoration phase of calcium transient dominated the overall prolongation, indicating that DOX perturbed primarily the protein functions responsible for recycling cytosolic calcium ions. This novel finding supplements the existing mechanism of DOX cardiotoxicity. We anticipate that this approach should help mechanistic studies of drug-induced cardiotoxicity or heart diseases., Competing Interests: The authors declare no competing financial interests., (© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

The question as to whether an aggressive management of post-operative pleural effusion may improve clinical outcomes after major surgery remains unanswered. The aim of this study was to investigate the effect of ultrasound-guided pleural effusion drainage on oxygenation, respiratory mechanics, and liberation from mechanical ventilation in surgical intensive care unit patients. Oxygenation and respiratory mechanics were measured before and after drainage. Over an 18-month period, a total of 62 patients were analyzed. The mean drainage volume during the first 24 h was 864 ± 493 mL, and there were no procedural complications. Both the mean PaO 2 /FiO 2 ratio and lung compliance improved after drainage. Additionally, 41.9% ( n = 26) of patients were ventilator-free within 72 h after drainage. Multivariable logistic regression analysis revealed that non-cardiovascular or thoracic surgery (odds ratio [OR] = 4.968, p = 0.046), a longer time interval from operation to the onset of pleural effusion (OR = 1.165, p = 0.005), and a higher peak airway pressure (OR = 1.303, p = 0.009) were independent adverse predictors for being free from mechanical ventilation within 72 h after drainage. Specifically, patients with a time from surgery to the onset of pleural effusion ≤6 days-but not those with an interval >6 days-showed a significant post-procedural improvement in terms of PaO 2 /FiO 2 ratio, PaCO 2 , peak airway pressure, and dynamic lung compliance. In summary, ultrasound-guided pleural effusion drainage resulted in significant clinical benefits in mechanically ventilated ICU patients after major surgery-especially in those with early-onset effusion who received thoracic surgery.

The role of two-pore channel 2 (TPC2), one of the few cation channels localized on endolysosomal membranes, in cancer remains poorly understood. Here, we report that TPC2 knockout reduces proliferation of cancer cells in vitro, affects their energy metabolism, and successfully abrogates tumor growth in vivo. Concurrently, we have developed simplified analogs of the alkaloid tetrandrine as potent TPC2 inhibitors by screening a library of synthesized benzyltetrahydroisoquinoline derivatives. Removal of dispensable substructures of the lead molecule tetrandrine increases antiproliferative properties against cancer cells and impairs proangiogenic signaling of endothelial cells to a greater extent than tetrandrine. Simultaneously, toxic effects on non-cancerous cells are reduced, allowing in vivo administration and revealing a TPC2 inhibitor with antitumor efficacy in mice. Hence, our study unveils TPC2 as valid target for cancer therapy and provides easily accessible tetrandrine analogs as a promising option for effective pharmacological interference., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)