Validity of Using Pathological Response as a Surrogate for Overall Survival in Neoadjuvant Studies for Esophageal Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Pathological response is a critical factor in predicting long-term survival of patients with esophageal cancer after preoperative therapy. However, the validity of using pathological response as a surrogate for overall survival (OS) for esophageal cancer has not yet been established. In this study, a literature-based meta-analysis was conducted to evaluate pathological response as a proxy endpoint for survival in esophageal cancer. METHODS: Three databases were systematically searched to identify relevant studies investigating neoadjuvant treatment for esophageal cancer. The correlation between pathological complete response (pCR) and OS were assessed using a weighted multiple regression analysis at the trial level, and the coefficient of determination (R2) was calculated. The research design and histological subtypes were considered in the performance of subgroup analysis. RESULTS: In this meta-analysis, a total of 40 trials, comprising 43 comparisons and 55,344 patients were qualified. The surrogacy between pCR and OS was moderate (R2 = 0.238 in direct comparison, R2 = 0.500 for pCR reciprocals, R2 = 0.541 in log settings). pCR could not serve as an ideal surrogate endpoint in randomized controlled trials (RCTs) (R2 = 0.511 in direct comparison, R2 = 0.460 for pCR reciprocals, R2 = 0.523 in log settings). A strong correlation was observed in studies comparing neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy (R2 = 0.595 in direct comparison, R2 = 0.840 for pCR reciprocals, R2 = 0.800 in log settings). CONCLUSIONS: A lack of surrogacy of pathological response for long-term survival at trial level is established in this study. Hence, caution should be exercised when using pCR as the primary endpoint in neoadjuvant studies for esophageal cancer.

Development and Validation of PET/CT-Based Nomogram for Preoperative Prediction of Lymph Node Status in Esophageal Squamous Cell Carcinoma.

PURPOSE: This study was conducted to predict the lymph node status and survival of esophageal squamous cell carcinoma before treatment by PET-CT-related parameters. METHODS: From January 2013 to July 2018, patients with pathologically diagnosed ESCC at our hospital were retrospectively enrolled. Completed esophagectomy and two- or three-field lymph node dissections were conducted. Those with neoadjuvant therapy were excluded. The first 65% of patients in each year were regarded as the training set and the last 35% as the test set. Nomogram was constructed by the "rms" package. Five-year, overall survival was analyzed based on the best cutoff value of risk score determined by the "survivalROC" package. RESULTS: Ultimately, 311 patients were included with 209 in the training set and 102 in the test set. The positive rate of the lymph node in the training set was 36.8% and that in the test set was 32.4%. The C-index of the training set was 0.763 and the test set was 0.766. The decision curve analysis showed that it was superior to the previous methods based on lymph node uptake or long/short axis diameter or axial ratio. Risk score > 0.20 was significantly associated with 5-year, overall survival (p = 0.0015) in all patients. CONCLUSIONS: The nomogram constructed from PET-CT parameters including primary tumor metabolic length and thickness can accurately predict the risk of lymph node metastasis in ESCC. The risk score calculated by our model accurately predicts the patient's 5-year overall survival.

Crowd-sourced and expert video assessment in minimally invasive esophagectomy.

BACKGROUND: Video-based assessment by experts may structurally measure surgical performance using procedure-specific competency assessment tools (CATs). A CAT for minimally invasive esophagectomy (MIE-CAT) was developed and validated previously. However, surgeon's time is scarce and video assessment is time-consuming and labor intensive. This study investigated non-procedure-specific assessment of MIE video clips by MIE experts and crowdsourcing, collective surgical performance evaluation by anonymous and untrained laypeople, to assist procedure-specific expert review. METHODS: Two surgical performance scoring frameworks were used to assess eight MIE videos. First, global performance was assessed with the non-procedure-specific Global Operative Assessment of Laparoscopic Skills (GOALS) of 64 procedural phase-based video clips < 10 min. Each clip was assessed by two MIE experts and > 30 crowd workers. Second, the same experts assessed procedure-specific performance with the MIE-CAT of the corresponding full-length video. Reliability and convergent validity of GOALS for MIE were investigated using hypothesis testing with correlations (experience, blood loss, operative time, and MIE-CAT). RESULTS: Less than 75% of hypothesized correlations between GOALS scores and experience of the surgical team (r < 0.3), blood loss (r = - 0.82 to 0.02), operative time (r = - 0.42 to 0.07), and the MIE-CAT scores (r = - 0.04 to 0.76) were met for both crowd workers and experts. Interestingly, experts' GOALS and MIE-CAT scores correlated strongly (r = 0.40 to 0.79), while crowd workers' GOALS and experts' MIE-CAT scores correlations were weak (r = - 0.04 to 0.49). Expert and crowd worker GOALS scores correlated poorly (ICC ≤ 0.42). CONCLUSION: GOALS assessments by crowd workers lacked convergent validity and showed poor reliability. It is likely that MIE is technically too difficult to assess for laypeople. Convergent validity of GOALS assessments by experts could also not be established. GOALS might not be comprehensive enough to assess detailed MIE performance. However, expert's GOALS and MIE-CAT scores strongly correlated indicating video clip (instead of full-length video) assessments could be useful to shorten assessment time.

CircBCAR3 accelerates esophageal cancer tumorigenesis and metastasis via sponging miR-27a-3p.

RATIONALE: Circular RNAs (circRNAs) have been demonstrated to contribute to esophageal cancer progression. CircBCAR3 (hsa_circ_0007624) is predicted to be differentially expressed in esophageal cancer by bioinformatics analysis. We investigated the oncogenic roles and biogenesis of circBCAR3 in esophageal carcinogenesis. METHODS: Functions of circBCAR3 on cancer cell proliferation, migration, invasion, and ferroptosis were explored using the loss-of-function assays. A xenograft mouse model was used to reveal effects of circBCAR3 on xenograft growth and lung metastasis. The upstream and downstream mechanisms of circBCAR3 were investigated by bioinformatics analysis and confirmed by RNA immunoprecipitation and luciferase reporter assays. The dysregulated genes in hypoxia-induced esophageal cancer cells were identified using RNA-seq. RESULTS: CircBCAR3 was highly expressed in esophageal cancer tissues and cells and its expression was increased by hypoxia in vitro. Silencing of circBCAR3 repressed the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells in vitro, as well as inhibited the growth and metastasis of esophageal xenograft in mice in vivo. The hypoxia-induced promotive effects on esophageal cancer cell migration and ferroptosis were rescued by circBCAR3 knockdown. Mechanistically, circBCAR3 can interact with miR-27a-3p by the competitive endogenous RNA mechanism to upregulate transportin-1 (TNPO1). Furthermore, our investigation indicated that splicing factor quaking (QKI) is a positive regulator of circBCAR3 via targeting the introns flanking the hsa_circ_0007624-formed exons in BCAR3 pre-mRNA. Hypoxia upregulates E2F7 to transcriptionally activate QKI. CONCLUSION: Our research demonstrated that splicing factor QKI promotes circBCAR3 biogenesis, which accelerates esophageal cancer tumorigenesis via binding with miR-27a-3p to upregulate TNPO1. These data suggested circBCAR3 as a potential target in the treatment of esophageal cancer. Hypoxia induces the upregulation of E2F7, which transcriptionally activates QKI in esophageal cancer cells. QKI increases the formation of circBCAR3 by juxtaposing the circularized exons. CircBCAR3 binds with miR-27a-3p to promote TNPO1 expression. CircBCAR3 promoted the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells by miR-27a-3p.

Advancing Gastroscope From Intraluminal to Extraluminal Dissection: Primary Experience of Laparo-gastroscopic Esophagectomy.

Transhiatal esophagectomy facilitates esophageal resection without the need for thoracotomy. However, this procedure carries the risks of blind and blunt dissection within the mediastinum. More recently, video-assisted or mediastinoscopic transhiatal esophagectomy was introduced to mobilize the esophagus under direct visualization. Even though, the procedure is technically demanding and animal studies have shown that the CO2 pneumomediastinum may be associated with hemodynamic instability. By further developing already established techniques, we pioneered the transhiatal esophageal mobilization by using hybrid gastroscope (Fig. 1). Laparo-gastroscopic esophagectomy, which integrates gastroscope and laparoscope for esophageal mobilization, was successfully implemented on an esophageal cancer patient with a history of lung cancer surgery. The operative duration was 240 minutes with an estimated blood loss of 110 mL. The patient experienced an uneventful recovery and was discharged on postoperative day 9. Further studies will be required to confirm the surgical and oncological efficacy of this innovation.

The effect of enhanced recovery after minimally invasive esophagectomy: a randomized controlled trial.

BACKGROUND: The purpose of this randomized controlled trial was to determine if enhanced recovery after surgery (ERAS) would improve outcomes for three-stage minimally invasive esophagectomy (MIE). METHODS: Patients with esophageal cancer undergoing MIE between March 2016 and August 2018 were consecutively enrolled, and were randomly divided into 2 groups: ERAS+group that received a guideline-based ERAS protocol, and ERAS- group that received standard care. The primary endpoint was morbidity after MIE. The secondary endpoints were the length of stay (LOS) and time to ambulation after the surgery. The perioperative results including the Surgical Apgar Score (SAS) and Visualized Analgesia Score (VAS) were also collected and compared. RESULTS: A total of 60 patients in the ERAS+ group and 58 patients in the ERAS- group were included. Postoperatively, lower morbidity and pulmonary complication rate were recorded in the ERAS+ group (33.3% vs. 51.7%; p = 0.04, 16.7% vs. 32.8%; p = 0.04), while the incidence of anastomotic leakage remained comparable (11.7% vs. 15.5%; p = 0.54). There was an earlier ambulation (3 [2-3] days vs. 3 [3-4] days, p = 0.001), but comparable LOS (10 [9-11.25] days vs. 10 [9-13] days; p = 0.165) recorded in ERAS+ group. The ERAS protocol led to close scores in both SAS (7.80 ± 1.03 vs. 8.07 ± 0.89, p = 0.21) and VAS (1.74 ± 0.85 vs. 1.78 ± 1.06, p = 0.84). CONCLUSIONS: Implementation of an ERAS protocol for patients undergoing MIE resulted in earlier ambulation and lower pulmonary complications, without a change in anastomotic leakage or length of hospital stay. Further studies on minimizing leakage should be addressed in ERAS for MIE.

Comparison of pulmonary function changes between patients receiving neoadjuvant chemotherapy and chemoradiotherapy prior to minimally invasive esophagectomy: a randomized and controlled trial.

PURPOSE: Adequate pulmonary function is important for patients undergoing surgical resection of esophageal cancer, especially those that received neoadjuvant therapy. However, it is unknown if pre-operative radiation affects pulmonary function differently compared to chemotherapy. The purpose of this study was to compare changes in pulmonary function between patients undergoing minimally invasive esophagectomy (MIE) who received neoadjuvant chemotherapy or chemoradiotherapy. METHODS: Between March 2017 and March 2018, esophageal cancer patients requiring neoadjuvant therapy were prospectively enrolled and randomly assigned to receive chemotherapy (CT) or chemoradiotherapy (CRT) before MIE. All patients received pulmonary function testing before and after the neoadjuvant therapy. Changes in pulmonary function, operative data, and pulmonary complications were compared between the 2 groups. RESULTS: A total of 71 patients were randomized and underwent MIE after receiving CT (n = 34) or CRT (n = 37). Baseline clinical characteristics were comparable between the 2 groups. The CRT group experienced a greater decrease of forced expiratory volume at 1 s (FEV1) (2.66 to 2.18 L, p = 0.023) and diffusion capacity of the lung for carbon monoxide divided by the mean alveolar volume (DLCO/Va) (17.3%, p < 0.001) than the CT group (FEV1 2.53 to 2.41 L; DLCO/Va 4.8%). The incidence of pulmonary complications was higher in the CRT group (13.51 vs. 8.82%), but the difference was not significant (p = 0.532). CONCLUSIONS: Preoperative CRT affects pulmonary function more than CT alone, but does not increase the risk of pulmonary complications in patients undergoing MIE.

Treatment of anastomotic leak after esophagectomy: insights of an international case vignette survey and expert discussions.

Anastomotic leak (AL) is a severe complication after esophagectomy. Clinical presentation of AL is diverse and there is large practice variation regarding treatment of AL. This study aimed to explore different AL treatment strategies and their underlying rationale. This mixed-methods study consisted of an international survey among upper gastro-intestinal (GI) surgeons and focus groups with expert upper GI surgeons. The survey included 10 case vignettes and data sources were integrated after separate analysis. The survey was completed by 188 respondents (completion rate 69%) and 6 focus groups were conducted with 20 international experts. Prevention of mortality was the most important goal of primary treatment. Goals of secondary treatment were to promote tissue healing, return to oral feeding and safe hospital discharge. There was substantial variation in the preferred treatment principles (e.g. drainage or defect closure) and modalities (e.g. stent or endoVAC) within different presentations of AL. Patients with local symptoms were treated by supportive means only or by non-surgical drainage and/or defect closure. Drainage was routinely performed in patients with intrathoracic collections and often combined with defect closure. Patients with conduit necrosis were predominantly treated by resection and reconstruction of the anastomosis or by esophageal diversion. This mixed-methods study shows that overall treatment strategies for AL are determined by vitality of the conduit and presence of intrathoracic collections. There is large variation in preferred treatment principles and modalities. Future research may investigate optimal treatment for specific AL presentations and aim to develop consensus-based treatment guidelines for AL after esophagectomy.

The temporal distribution of platinum group elements (PGEs) in PM2.5.

In this paper, Changji, Xinjiang, northwest China, was selected as the study area, and platinum group elements (PGEs) in PM2.5 were quantified by ICP-MS using microwave digestion. The results indicated that the average concentrations (and range) of Rh, Pd, and Pt in PM2.5 were 0.21 (n.d. -1.41) ng/m3, 8.09 (n.d. -59.50) ng/m3, and 0.12 (n.d. -0.83) ng/m3, respectively. The concentration of Pd was significantly higher than Rh and Pt. Moreover, the seasonal variations of Rh and Pd were the same: highest in summer and lower in other seasons. However, the seasonal variation of Pt was opposite to that of Rh and Pd: highest in winter and lower in other seasons. Seasonal differences in emission sources of PGEs and the climatic characteristics of arid regions played important roles in the seasonal changes of PGEs. Rh and Pd had a common source and similar diurnal variation. The major influencing factors were traffic volume and meteorological conditions. The diurnal variation regularity of Pt was different from Rh and Pd. The superimposed effect of vehicle exhaust emissions and coal-fired emissions was the main reason why the diurnal variation of Pt was more complicated than those of Rh and Pd. The diurnal concentration of Pt varied with the seasons. It is caused by seasonal coal combustion and meteorological conditions.

Relative metabolic tumor burden is associated with residual lymph node status after neoadjuvant chemoradiotherapy in locally advanced esophageal cancer.

BACKGROUND: Extended lymph node involvement could indicate limited survival benefit from neoadjuvant chemoradiotherapy with surgery in resectable locally advanced esophageal cancer. However, the threshold of node involvement is unclear. METHODS: We retrospectively measured and calculated metabolic parameters derived from 18F-FDG PET/CT of the patients with nCRT and surgery. The parameters included metabolic tumor volume of the whole body (MTVwb), of the primary tumor (MTVp), of the lymph nodes (MTVn), and relative metabolic tumor burden (R-MTB, defined as the ratio of MTVwb and MTVp). RESULTS: A total of 67 patients were enrolled in the study. The MTVp with thresholds as 3.0, 3.5, 4.0, 4.5 and 5.0 were significantly correlated with clinical T categories (Spearman's rank correlation coefficient, all P < 0.0001) and clinical tumor length categories (Spearman's rank correlation coefficient, all P ≤ 0.005). However, the MTVn were marginally correlated with clinical lymph node categories (P = 0.023). Among the 31 (31/67, 46.3%) patients with MTVn as 0 (R-MTB as 100.00%), 5 (5/5, 100.0%) were initially restaged as cLym- (MTVn as 0, R-MTB as 100.00%), while 26 (26/62, 41.9%) were initially restaged as cLym + (MTVn > 0, R-MTB > 100.00%). After nCRT, 43 (64.2%) patients achieved ypN0. The univariate and multivariate regression revealed that R-MTB (≤ 106.00% vs. > 106.00%) was an independent factor associated with ypN + status (OR 0.093, 95%CI 0.023-0.378, P = 0.001). CONCLUSION: The preliminary study revealed a great heterogeneity in clinical lymph node categories in esophageal cancer. It suggested that R-MTB was significantly associated with ypN status after neoadjuvant chemoradiotherapy in locally advanced esophageal cancer. The findings with the indications needed to be further studied in a prospective study with a large patient cohort.

Video-assisted thoracoscopic total thymectomy: two-lung ventilation with artificial pneumothorax.

Objectives: Double-lumen endotracheal tube (DLET) and one-lung ventilation (OLV) have been generally accepted as the classic anesthetic method in video-assisted thoracoscopic total thymectomy (VATT). However, there are still some disadvantages of DLET. Two-lung ventilation (TLV) with single-lumen endotracheal tube (SLET) is considered to be an alternative in VATT to avoid these disadvantages. This study evaluated the safety and feasibility of TLV in VATT by comparing it with OLV cases.Material and methods: We retrospectively screened 198 patients who received TLV unilateral thoracic incision VATT and 117 patients who received OLV unilateral thoracic incision VATT. Perioperative data were analyzed, including surgical variables, intraoperative hemodynamic parameters, and postoperative complications and hospital stay.Results: No significant differences with regard to operative time (p = .146), postoperative hospital stay (p = .553), complications (p = .254), hemodynamic parameters and pulse oxygen saturation (SpO2) were found between TLV group and OLV group. However, end-tidal CO2 (EtCO2) was higher in TLV group at 15 min (39.95 ± 5.03 vs 38.70 ± 4.57, p = .021) and 30 min (41.91 ± 5.50 vs 38.91 ± 4.51, p < .001) after initiation of the operation.Conclusions: It is safe and feasible to adopt TLV using SLET with CO2 insufflation artificial pneumothorax in unilateral thoracic incision VATT.

CMISG1701: a multicenter prospective randomized phase III clinical trial comparing neoadjuvant chemoradiotherapy to neoadjuvant chemotherapy followed by minimally invasive esophagectomy in patients with locally advanced resectable esophageal squamous cell carcinoma (cT3-4aN0-1M0) (NCT03001596).

BACKGROUND: Neoadjuvant chemoradiation is not recommended as an approach for treatment of esophageal squamous cell carcinoma due to its significant postoperative mortality. However, it is assumed the combination of neoadjuvant chemoradiation with minimally invasive esophagectomy (MIE) may reduce postoperative mortality, which can revive preoperative chemoradiation. No randomized controlled studies comparing neoadjuvant chemoradiation plus MIE with neoadjuvant chemotherapy plus MIE have been performed so far. The present trial is initiated to obtain valid information whether neoadjuvant chemoradiation plus MIE yields better survival without worse postoperative morbidity and mortality in the treatment of locally advanced resectable esophageal squamous cell carcinoma(cT3-4aN0-1M0). METHODS/DESIGN: CMISG1701 is a multicenter, prospective, randomized, phase III clinical trial, investigating the safety and efficacy of neoadjuvant chemoradiation plus MIE compared with neoadjuvant chemotherapy plus MIE. Patients with locally advanced resectable esophageal squamous cell carcinoma (cT3-4aN0-1M0) are eligible for the study. A total of 264 patients are randomly assigned to neoadjuvant chemoradiation (arm A) or neoadjuvant chemotherapy (arm B) with a 1:1 allocation ratio. The primary outcome is overall survival assessed with a minimum follow-up of 36 months. Secondary outcomes are progression-free survival, recurrence-free survival, postoperative pathologic stage, treatment-related complications, postoperative mortality as well as quality of life. DISCUSSION: The objective of this trial is to identify the superior protocol with regard to patient survival, treatment morbidity/mortality and quality of life between neoadjuvant chemoradiation plus MIE and neoadjuvant chemotherapy plus MIE. TRIAL REGISTRATION: NCT03001596 (December 17, 2016).

Is minimally invasive esophagectomy beneficial to elderly patients with esophageal cancer?

BACKGROUND: Open esophagectomy (OE) in elderly patients with esophageal cancer is hazardous due to high surgical mortality and limited survival. The aim of this study was to explore whether minimally invasive esophagectomy (MIE) has perioperative or long-term benefits in elderly patients with esophageal cancer compared with OE. METHODS: Between February 2005 and June 2013, 407 patients older than 70 years underwent esophagectomy for esophageal cancer, including 89 who received MIE and 318 who received OE. A retrospective pair-matched study was performed to compare 116 patients (58 pairs) who underwent either OE or MIE. Patients were matched by age, sex, comorbidity, tumor location, histology, TNM stage, and operative approach. Perioperative and long-term outcomes were compared between the two groups. RESULTS: The overall incidence of postoperative complications was significantly lower in the MIE group than in the OE group (37.9 vs. 60.3 %, P = 0.016), especially incidence of pulmonary complications (20.7 vs. 39.7 %, P = 0.026). The mean length of hospital stay was also significantly shorter (10 days [range 7-70] vs. 12 days [range 8-106], P = 0.032). The perioperative mortality rate trended lower in the MIE group but was not significantly different (3.4 vs. 8.6 %, P = 0.435). Kaplan-Meier analysis showed that the median disease-specific survival time in the MIE group was significantly longer than in the OE group (>27 months [range 1-82] vs. 24 months [range 1-99], P = 0.003). No difference was found in overall survival (39 ± 8.9 vs. 22 ± 3.4 months, P = 0.070). CONCLUSION: In surgical management of elderly patients with esophageal cancer, MIE is associated with lower rates of morbidity and pulmonary complications as well as longer disease-specific survival time. Whether it provides benefit to patients' long-term survival requires further research.

A Video-Based Procedure-Specific Competency Assessment Tool for Minimally Invasive Esophagectomy.

Importance: Minimally invasive esophagectomy (MIE) is a complex procedure with substantial learning curves. In other complex minimally invasive procedures, suboptimal surgical performance has convincingly been associated with less favorable patient outcomes as assessed by peer review of the surgical procedure. Objective: To develop and validate a procedure-specific competency assessment tool (CAT) for MIE. Design, Setting, and Participants: In this international quality improvement study, a procedure-specific MIE-CAT was developed and validated. The MIE-CAT contains 8 procedural phases, and 4 quality components per phase are scored with a Likert scale ranging from 1 to 4. For evaluation of the MIE-CAT, intraoperative MIE videos performed by a single surgical team in the Esophageal Center East Netherlands were peer reviewed by 18 independent international MIE experts (with more than 120 MIEs performed). Each video was assessed by 2 or 3 blinded experts to evaluate feasibility, content validity, reliability, and construct validity. MIE-CAT version 2 was composed with refined content aimed at improving interrater reliability. A total of 32 full-length MIE videos from patients who underwent MIE between 2011 and 2020 were analyzed. Data were analyzed from January 2021 to January 2023. Exposure: Performance assessment of transthoracic MIE with an intrathoracic anastomosis. Main Outcomes and Measures: Feasibility, content validity, interrater and intrarater reliability, and construct validity, including correlations with both experience of the surgical team and clinical parameters, of the developed MIE-CAT. Results: Experts found the MIE-CAT easy to understand and easy to use to grade surgical performance. The MIE-CAT demonstrated good intrarater reliability (range of intraclass correlation coefficients [ICCs], 0.807 [95% CI, 0.656 to 0.892] for quality component score to 0.898 [95% CI, 0.846 to 0.932] for phase score). Interrater reliability was moderate (range of ICCs, 0.536 [95% CI, -0.220 to 0.994] for total MIE-CAT score to 0.705 [95% CI, 0.473 to 0.846] for quality component score), and most discrepancies originated in the lymphadenectomy phases. Hypothesis testing for construct validity showed more than 75% of hypotheses correct: MIE-CAT performance scores correlated with experience of the surgical team (r = 0.288 to 0.622), blood loss (r = -0.034 to -0.545), operative time (r = -0.309 to -0.611), intraoperative complications (r = -0.052 to -0.319), and severe postoperative complications (r = -0.207 to -0.395). MIE-CAT version 2 increased usability. Interrater reliability improved but remained moderate (range of ICCs, 0.666 to 0.743), and most discrepancies between raters remained in the lymphadenectomy phases. Conclusions and Relevance: The MIE-CAT was developed and its feasibility, content validity, reliability, and construct validity were demonstrated. By providing insight into surgical performance of MIE, the MIE-CAT might be used for clinical, training, and research purposes.

Video-assisted radiofrequency ablation for pleural disseminated non-small cell lung cancer.

BACKGROUND: Clinically, some patients would have false-negative results in the diagnosis of non-small cell lung cancer (NSCLC) with pleural dissemination, losing their chances of prolonged survival from surgery. Hence, this study aimed to clarify the benefit of radiofrequency ablation (RFA) for NSCLC with malignant pleural dissemination that is detected during thoracoscopic lobectomy. METHODS: From July 2006, we started the application of RFA in combination with talc pleurodesis (R-TP) for pleural disseminated NSCLCs diagnosed by thoracoscopy. Patients who underwent TP alone (from December 30, 2005 to June 30, 2006) were retrospectively evaluated in compared with R-TP (from July 1, 2006 to June 30, 2008). Clinical features were collected and compared to identify the difference in clinical outcomes between R-TP and TP alone. After discharge (three months after surgery), tumor response to treatment was assessed, and follow-up results were recorded to determine the perioperative and mid-time survival difference between the two groups. RESULTS: In our study, the two groups were comparable in age, sex, performance status (PS) score, tumor location, and histological diagnosis. The incidence rate of intraoperative pleural dissemination was 5.98%, as diagnosed by video-assisted thoracoscopy. All the surgeries were completed without conversion to open thoracotomy. Except for the longer operation duration in the R-TP group (p < 0.001), there was no significant difference between the two groups in terms of surgical features. Postoperatively, no mortality occurred in either group during hospital stay; however, two patients from the R-TP group developed complications (9.52%). The complete and partial remission rates in the R-TP group were 80% and 10%, respectively, and the stabilization rate was 10%. After the three-year follow-up, the overall survival (OS) rates of the R-TP and TP groups were 14.29% and 0%, respectively. The median survival and median tumor progression-free survival (PFS) periods were longer in the R-TP group than in the TP group (OS: 19 months versus 12.5 months, p = 0.045; PFS: 9.5 months versus 5.5 months, p = 0.028). CONCLUSIONS: The introduction of RFA to TP offered survival benefits to pleural disseminated NSCLC patients, making it a potential alternative palliative treatment for local tumor. However, multicenter randomized controlled trials are required to confirm these findings.

Exosome-mediated metabolic reprogramming: Implications in esophageal carcinoma progression and tumor microenvironment remodeling.

Esophageal carcinoma is among the most fatal malignancies with increasing incidence globally. Tumor onset and progression can be driven by metabolic reprogramming, especially during esophageal carcinoma development. Exosomes, a subset of extracellular vesicles, display an average size of ∼100 nanometers, containing multifarious components (nucleic acids, proteins, lipids, etc.). An increasing number of studies have shown that exosomes are capable of transferring molecules with biological functions into recipient cells, which play crucial roles in esophageal carcinoma progression and tumor microenvironment that is a highly heterogeneous ecosystem through rewriting the metabolic processes in tumor cells and environmental stromal cells. The review introduces the reprogramming of glucose, lipid, amino acid, mitochondrial metabolism in esophageal carcinoma, and summarize current pharmaceutical agents targeting such aberrant metabolism rewiring. We also comprehensively overview the biogenesis and release of exosomes, and recent advances of exosomal cargoes and functions in esophageal carcinoma and their promising clinical application. Moreover, we discuss how exosomes trigger tumor growth, metastasis, drug resistance, and immunosuppression as well as tumor microenvironment remodeling through focusing on their capacity to transfer materials between cells or between cells and tissues and modulate metabolic reprogramming, thus providing a theoretical reference for the design potential pharmaceutical agents targeting these mechanisms. Altogether, our review attempts to fully understand the significance of exosome-based metabolic rewriting in esophageal carcinoma progression and remodeling of the tumor microenvironment, bringing novel insights into the prevention and treatment of esophageal carcinoma in the future.

Machine learning developed a programmed cell death signature for predicting prognosis and immunotherapy benefits in lung adenocarcinoma.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths worldwide with poor prognosis. Programmed cell death (PCD) plays a crucial function in tumor progression and immunotherapy response in lung adenocarcinoma (LUAD). METHODS: Integrative machine learning procedure including 10 methods was performed to develop a prognostic cell death signature (CDS) using TCGA, GSE30129, GSE31210, GSE37745, GSE42127, GSE50081, GSE68467, GSE68571, and GSE72094 dataset. The correlation between CDS and tumor immune microenvironment was evaluated using various methods and single cell analysis. qRT-PCR and CCK-8 assay were conducted to explore the biological functions of hub gene. RESULTS: The prognostic CDS developed by Lasso + survivalSVM method was regarded as the optimal prognostic model. The CDS had a stable and powerful performance in predicting the clinical outcome of LUAD and served as an independent risk factor in TCGA and 8 GEO datasets. The C-index of CDS was higher than that of clinical stage and many developed signatures for LUAD. LUAD patients with low CDS score had a higher PD1&CTLA4 immunophenoscore, higher TMB score, lower TIDE score and lower tumor escape score, indicating a better immunotherapy benefit. Single cell analysis revealed a strong and frequent communication between epithelial cells and cancer-related fibroblasts by specific ligand-receptor pairs, including COL1A2-SDC4 and COL1A2-SDC1. Vitro experiment showed that SLC7A5 was upregulated in LUAD and knockdown of SLC7A5 obviously suppressed tumor cell proliferation. CONCLUSION: Our study developed a novel CDS for LUAD. The CDS served as an indicator for predicting the prognosis and immunotherapy benefits of LAUD patients.

The development and validation of pathological sections based U-Net deep learning segmentation model for the detection of esophageal mucosa and squamous cell neoplasm.

Background: Deep learning methods have demonstrated great potential for processing high-resolution images. The U-Net model, in particular, has shown proficiency in the segmentation of biomedical images. However, limited research has examined the application of deep learning to esophageal squamous cell carcinoma (ESCC) segmentation. Therefore, this study aimed to develop deep learning segmentation systems specifically for ESCC. Methods: A Visual Geometry Group (VGG)-based U-Net neural network architecture was utilized to develop the segmentation models. A pathological image cohort of surgical specimens was used for model training and internal validation, with two additional endoscopic biopsy section cohort for external validation. Model efficacy was evaluated across several metrics including Intersection over Union (IOU), accuracy, positive predict value (PPV), true positive rate (TPR), specificity, dice similarity coefficient (DSC), area under the receiver operating characteristic curve (AUC), and F1-Score. Results: Surgical samples from ten patients were analyzed retrospectively, with each biopsy section cohort encompassing five patients. Transfer learning models based on U-Net weights yielded optimal results. For mucosa segmentation, the in internal validation achieved 93.81% IOU, with other parameters exceeding 96% (96.96% accuracy, 96.45% PPV, 96.65% TPR, 98.41% specificity, 96.81% DSC, 96.11% AUC, and 96.55% F1-Score). The tumor segmentation model attained an IOU of 91.95%, along with other parameters surpassing 95% (95.90% accuracy, 95.62% PPV, 95.71% TPR, 97.88% specificity, 95.81% DSC, 94.92% AUC, and 95.67% F1-Score). In the external validation for tumor segmentation model, IOU was 59.86% for validation database 1 (72.74% for accuracy, 76.03% for PPV, 77.17% for TPR, 83.80% for specificity, 74.89% for DSC, 71.83% for AUC, and 76.60% for F1-Score), and 50.88% for validation cohort 2 (68.03% for accuracy, 59.02% for PPV, 66.87% for TPR, 78.48% for specificity, 67.44% for DSC, 64.68% for AUC, and 62.70% for F1-Score). Conclusions: The models exhibited satisfactory results, paving the way for their potential deployment on standard computers and integration with other artificial intelligence models in clinical practice in the future. However, limited to the size of study, the generalizability of models is impaired in the external validation, larger pathological section cohort would be needed in future development to ensure robustness and generalization.

Mechanisms and characteristics of subcapsular sinus macrophages in tumor immunity: a narrative review.

Background and Objective: Lymph nodes constitute an integral component of the secondary lymphoid organs, housing a diverse population of macrophages. Macrophages exhibit heterogeneity in terms of localization, phenotype and ontogeny. Recent evidence has established that subcapsular sinus macrophages (SCSMs) are the initial cells exposed to antigens from afferent lymph vessels, playing a crucial role in the host immune response against invading pathogens and tumor cells. In order to summarize the role and mechanisms of SCSM in tumor immunity, this study systematically reviews research on SCSMs in tumor immunity. Methods: A systematic search was conducted in PubMed and Web of Science to identify articles investigating clinical significance and mechanisms of SCSMs. Study eligibility was independently evaluated by two authors based on the assessment of titles, abstracts and full-texts. Key Content and Findings: The narrative review included a total of 17 studies. Previous research consistently showed that a high level of SCSM in patients with various carcinomas is associated with a favorable long-term prognosis. SCSM acts as the front-line defender in antitumor activity, engaging in intricate communication with other immune cells. Moreover, SCSM could directly and indirectly modulate tumor immunity, and the integrity of SCSM layer is interrupted in disease status. Several studies explored the feasibility of targeting SCSM to activate immunity against tumors. However, the direct molecular interactions and alternation in signal pathway in the tumor immunity of SCSM are less well established in previous researches. Conclusions: This narrative review underscores the critical role of SCSM in tumor immunity. Future studies should focus on the deeper mechanism underlying SCSMs and explore their clinical applications.