Early and Persistent Dysphagia Relief Predicts Tumor Response in Esophageal Squamous Cell Carcinoma Patients Treated with Immunochemotherapy.

BACKGROUND: In this prospective study, we aimed to investigate the role of patient-reported dysphagia relief in predicting pathological tumor responses to neoadjuvant immunochemotherapy (NAIC) in locally advanced esophageal squamous cell carcinoma (ESCC) patients. METHODS: This study was designed as a multi-center, prospective study including ESCC patients who received NAIC in the discovery and validation cohorts. The patients' responses to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-OES 18 and QLQ-C30 were collected at multiple time points. Subsequent time point-intensive esophageal cancer-specific dysphagia trajectories were depicted using growth mixture modeling (GMM) analysis. Furthermore, univariate and multivariate binary logistic regression was used to assess the independent predictors for pathological tumor responses. RESULTS: A total of 120 patients from the discovery cohort and 42 patients from the validation cohort were included in the analysis. In the discovery cohort, 19 (22.9%) of the 83 patients achieved pCR status. In the independent validation cohort, 24 patients underwent surgery, and 9 (37.5%) patients achieved pCR status. Trajectory analysis showed that, in the pCR group, the beginning of rapid declines in the slope occurred on days 3, 6, and 9. Further multivariate analysis showed that the degree of dysphagia relief (△dysphagia%) was the only significant independent predictor for pCR status (OR = 3.267, 95% CI 1.66-6.428, P < 0.001). The AUC value for △dysphagia% was 0.961 (95% CI: 0.922-0.999, P < 0.001). CONCLUSION: The current study demonstrated that a longitudinal patient-reported outcome (PRO) was an easily obtained, cost-effective, and noninvasive tool for predicting tumor responses to neoadjuvant immunochemotherapy.

Discovery and validation of methylation signatures in circulating cell-free DNA for early detection of esophageal cancer: a case-control study.

BACKGROUND: Plasma cell-free DNA (cfDNA) methylation has shown promising results in the early detection of multiple cancers recently. Here, we conducted a study to investigate the performance of cfDNA methylation in the early detection of esophageal cancer (ESCA). METHODS: Specific methylation markers for ESCA were identified and optimized based on esophageal tumor and paired adjacent tissues (n = 24). Age-matched participants with ESCA (n = 85), benign esophageal diseases (n = 10), and healthy controls (n = 125) were randomized into the training and test sets to develop a classifier to differentiate ESCA from healthy controls and benign esophageal disease. The classifier was further validated in an independent plasma cohort of ESCA patients (n = 83) and healthy controls (n = 98). RESULTS: In total, 921 differentially methylated regions (DMRs) between tumor and adjacent tissues were identified. The early detection classifier based on those DMRs was first developed and tested in plasma samples, discriminating ESCA patients from benign and healthy controls with a sensitivity of 76.2% (60.5-87.9%) and a specificity of 94.1% (85.7-98.4%) in the test set. The performance of the classifier was consistent irrespective of sex, age, and pathological diagnosis (P > 0.05). In the independent plasma validation cohort, similar performance was observed with a sensitivity of 74.7% (64.0-83.6%) and a specificity of 95.9% (89.9-98.9%). Sensitivity for stage 0-II was 58.8% (44.2-72.4%). CONCLUSION: We demonstrated that the cfDNA methylation patterns could distinguish ESCAs from healthy individuals and benign esophageal diseases with promising sensitivity and specificity. Further prospective evaluation of the classifier in the early detection of ESCAs in high-risk individuals is warranted.

TCF19 contributes to cell proliferation of non-small cell lung cancer by inhibiting FOXO1.

Transcription factor 19 (TCF19) harbors a forkhead association (FHA) domain, a proline-rich region, a PHD or RING finger region, suggesting that TCF19 possesses a powerful function. However, its expression and function remains unknown in non-small-cell lung cancer (NSCLC). The function cluster analysis was carried out using Metascape website. 3-(4,5-Dimethyl-2-thiazolyl)2,5-diphenyl-2H-tetrazolium bromide (MTT), colony formation, and anchorage-independent growth ability assay were carried out to detect the effect of TCF19 on cell proliferation. Bromodeoxyuridine (Brdu) labeling and flow cytometry assay were used to evaluate the effect of TCF19 on cell-cycle progression. Quantitative polymerase chain reaction and chromatin immunoprecipitation assay were performed to investigate the mechanism by which TCF19 is involved in cell-cycle transition. By analyzing the publicly available dataset, The Cancer Genome Atlas (TCGA), we found that TCF19 is significantly increased in the lung adenocarcinoma (LAC) and squamous cell carcinoma (SCC), two primary histological subtype of NSCLC. Besides, further function cluster analysis exhibited that TCF19 may mainly participate in cell cycle. MTT, colony formation, and anchorage-independent growth ability assay confirmed that overexpression of TCF19 enhances the proliferation of both LAC and SCC cells. Besides, further experiments revealed that TCF19 contributes to cell cycle G1/S transition. Not only that, upregulation of TCF19 can inhibit the expression of p21, p27, and p57, while promote the expression of cyclin D1 by inhibiting FOXO1. Our research offers important evidence that TCF19 can promote cell-cycle progression of NSCLC cells, and TCF19 may served as novel therapeutic targets.

Early patient-reported outcomes after robotic-assisted versus video-assisted thoracoscopic lobectomy.

BACKGROUND: Robotic-assisted thoracoscopic surgery (RATS) can achieve traditional clinical outcomes comparable to those of video-assisted thoracoscopic surgery (VATS). However, patient-reported outcomes (PROs) during the early period after RATS and VATS remain unclear. This study aimed to utilize longitudinal electronic PRO (ePRO) assessments to evaluate symptom burden and functional status between these approaches from patients' perspective. METHODS: This study comprised patients who underwent lobectomy via RATS or VATS for non-small cell lung cancer. We collected multiple-time-point PROs data from the prospective longitudinal study via an ePRO system. Symptom severity and function status were assessed using the perioperative symptom assessment for patients undergoing lung surgery and were analyzed between groups using linear mixed-effects models. RESULTS: Of the 164 patients, 42 underwent RATS and 122 underwent VATS. After propensity score matching (PSM), 42 RATS and 84 VATS exhibited similar baseline characteristics. During the 7-day postoperative period, participants underwent RATS reported milder pain (p = 0.014), coughing (p < 0.001), drowsiness (p = 0.001), and distress (p = 0.045) compared with those underwent VATS. Moreover, participants in RATS group showed less functional interference with walking (p < 0.001) and general activity (p < 0.001). RATS exhibited a shorter postoperative hospitalization (p = 0.021) but higher hospital cost (p < 0.001). Meanwhile, short-term clinical outcomes of operative time, dissected lymph node stations, chest tube drainage, and postoperative complication rates were comparable. CONCLUSION: PROs are important metrics for assessing patients' recovery after lobectomy. Compared with VATS, RATS may induce less symptom burden and better functional status for patients in the early postoperative period.

Association between co-exposure of polycyclic aromatic hydrocarbons and chronic obstructive pulmonary disease among the US adults: results from the 2013-2016 National Health and Nutrition Examination Survey.

Although existing epidemiological studies have reported the relationship between single polycyclic aromatic hydrocarbon (PAH) exposure and chronic obstructive pulmonary disease (COPD), little is known about the impact of PAH mixture exposure on COPD. Therefore, we aimed to evaluate the associations of single and mixed exposures to PAHs with COPD in US adults using data from NHANES 2013-2016 by fitting three statistical methods, including multiple logistic regression, Bayesian kernel machine regression (BKMR), and quantile-based g-computation (qgcomp) models. This study included 1836 participants aged 40 and older. Multiple logistic regression showed that 2-FLU, 1-PHE, 1-PYR, and 2&3-PHE increased the risk of COPD after adjusting for all covariates. The BKMR model identified positive trends between PAH mixture and the risk of COPD in all adults and males when all PAHs were at or above their 55th percentile compared to all PAHs at their 50th percentile. The qgcomp model suggested that PAH co-exposure increased the risk of COPD (OR:1.44, 95%CI:1.09, 1.90) when each quartile increased in PAH mixture concentration, with 2-FLU having the highest weight. The combined impact also be observed in men. In conclusion, PAHs co-exposure was associated with a higher risk of COPD, especially in males, with the positive impact of 2-FLU being the most important.

Evaluation of combined pathological responses in primary tumor and lymph nodes following neoadjuvant chemoimmunotherapy in non-small cell lung cancer.

BACKGROUND: Inconsistent pathological responses of tumor and lymph nodes (LNs) were frequently observed in non-small cell lung cancer (NSCLC) receiving neoadjuvant chemoimmunotherapy. However, there is a lack of studies to report the prognostic significance and the relevant clinicopathological factors of tumor-nodal inconsistent responses after neoadjuvant immunotherapy or chemoimmunotherapy. Therefore, this study aimed to depict the inconsistent pathological combined tumor-nodal responses in NSCLC patients after neoadjuvant chemoimmunotherapy as well as the underlying clinical significance. METHODS: A total of 81 node-positive NSCLC patients who underwent neoadjuvant chemoimmunotherapy were eligible for inclusion. Demographic, radiologic, and pathological features of patients were recorded. Patients with pathological complete response of both tumor (ypT(pCR)) and LNs (ypN0) were classified into the combined good responder group and the relevant clinicopathological features were evaluated. The event-free survival (EFS) outcome was analyzed using Kaplan-Meier analysis. RESULTS: The ypN0 and ypT(pCR) rates were 74.1 % and 42.0 %, respectively. A significant correlation was observed between ypT(pCR) and ypN0 (P = 0.003), but inconsistent responses remained. The combined responses of the primary tumor and LNs demonstrated a significant association with the prognosis outcome (P = 0.005). Notably,patients who received at least twice of their infusions of immune checkpoint inhibitors after 15:30 had a worse prognosis (P = 0.015). CONCLUSION: A significant but not absolute correlation was observed between good tumor response and good nodal response in NSCLC patients after neoadjuvant chemoimmunotherapy, but inconsistent responses were also found. The combination of tumor and nodal responses is significantly associated with prognosis and combined good responder can be used as a reliable prognosis predictor.

Neoadjuvant nivolumab with or without platinum-doublet chemotherapy based on PD-L1 expression in resectable NSCLC (CTONG1804): a multicenter open-label phase II study.

This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive (N) and nivolumab-chemotherapy (N/C) combinations based on PD-L1 expression. Eligible patients exhibited resectable clinical stage IIA-IIIB (AJCC 8th edition) NSCLC without EGFR/ALK alterations. Patients received either mono-nivolumab (N) or nivolumab + nab-paclitaxel+ carboplatin (N/C) for three cycles based on PD-L1 expression. The primary endpoint was the major pathological response (MPR). Key secondary endpoints included the pathologic complete response (pCR), objective response rate (ORR), and event-free survival (EFS). Baseline PD-L1 expression and perioperative circulating tumor DNA (ctDNA) status were correlated with pCR and EFS. Fifty-two patients were enrolled, with 46 undergoing surgeries. The MPR was 50.0% (26/52), with 25.0% (13/52) achieving pCR, and 16.7% and 66.7% for patients with PD-L1 ≥ 50% in N and N/C groups, respectively. Thirteen (25.0%) patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment. Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR (39.1%) compared with those remained positive (6.7%, odds ratio = 6.14, 95% CI 0.84-Inf, p = 0.077). With a median follow-up of 25.1 months, the 18-month EFS rate was 64.8% (95% CI 51.9-81.0%). For patients with ctDNA- vs. ctDNA + , the 18m-EFS rate was 93.8% vs 47.3% (HR, 0.15; 95% CI 0.04, 0.94; p = 0.005). Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression ≥ 50%. ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits, which requires further confirmation in a prospective clinical trial (NCT04015778).

Long-term follow-up in quality of life before and after endoscopic thoracic sympathicotomy in 367 patients with palmar hyperhidrosis.

BACKGROUND: Palmar hyperhidrosis (PH) hinders daily activities and deteriorates quality of life (QOL). Endoscopic thoracic sympathicotomy (ETS) is safe and efficient as the gold standard treatment for PH. So far, the long-term change of QOL after surgery has not been fully characterized, which is important to evaluate clinical benefits and helped to identify the true beneficiaries. In the current study, we aimed to investigate the long-term outcome of ETS by comparing their preoperative QOL with a follow-up QOL. METHODS: This study enrolled 367 patients with PH who underwent ETS between March 2018 and March 2019. All patients were surveyed by a web-based questionnaire adapted from de Campos Quality-of-life Questionnaire for Evaluation of Hyperhidrosis, and compared to their preoperative results. RESULTS: After a median follow-up of 14 months [interquartile range (IQR), 9-21 months], improvement in QOL was reported in 90.7% of patients. Compared to preoperative QOL [median (Md) =40, IQR, 37-45], postoperative QOL was significantly improved (Md =20, IQR, 13-23; P<0.001). A higher QOL score was noticed in patients with severer PH at diagnosis, whereas no significant difference was observed among postoperative QOL regarding the severity of PH. Subclinical compensatory hyperhidrosis (CH) occurred in 94.6% of post-ETS cases after long-term follow-up. The score of postoperative QOL was significantly positively correlated to the severity of CH (rs=0.14; P=0.009). CONCLUSIONS: Improvement in QOL sustained for a long-term period after receiving ETS for PH. Almost all patients developed subclinical CH on other body sites in the long run, with an impairment in QOL correlating with the severity of CH. Further investigations on the developing patterns of CH and clinical coping strategy are warranted to improve the long-term outcome of ETS.

Predictive value of baseline metabolic tumor volume for non-small-cell lung cancer patients treated with immune checkpoint inhibitors: A meta-analysis.

Background: Immune checkpoint inhibitors (ICIs) have emerged as a promising treatment option for advanced non-small-cell lung cancer (NSCLC) patients, highlighting the need for biomarkers to identify responders and predict the outcome of ICIs. The purpose of this study was to evaluate the predictive value of baseline standardized uptake value (SUV), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) derived from 18F-FDG-PET/CT in advanced NSCLC patients receiving ICIs. Methods: PubMed and Web of Science databases were searched from January 1st, 2011 to July 18th, 2022, utilizing the search terms "non-small-cell lung cancer", "PET/CT", "standardized uptake value", "metabolic tumor volume", " total lesion glycolysis", and "immune checkpoint inhibitors". Studies that analyzed the association between PET/CT parameters and objective response, immune-related adverse events (irAEs) and prognosis of NSCLC patients treated with ICIs were included. We extracted the hazard ratio (HR) with a 95% confidence interval (CI) for progression-free survival (PFS) and overall survival (OS). We performed a meta-analysis of HR using Review Manager v.5.4.1. Results: Sixteen studies were included for review and thirteen for meta-analysis covering 770 patients. As for objective response and irAEs after ICIs, more studies with consistent assessment methods are needed to determine their relationship with MTV. In the meta-analysis, low SUVmax corresponded to poor PFS with a pooled HR of 0.74 (95% CI, 0.57-0.96, P=0.02). And a high level of baseline MTV level was related to shorter PFS (HR=1.45, 95% CI, 1.11-1.89, P<0.01) and OS (HR, 2.72; 95% CI, 1.97-3.73, P<0.01) especially when the cut-off value was set between 50-100 cm3. SUVmean and TLG were not associated with the prognosis of NSCLC patients receiving ICIs. Conclusions: High level of baseline MTV corresponded to shorter PFS and OS, especially when the cut-off value was set between 50-100 cm3. MTV is a potential predictive value for the outcome of ICIs in NSCLC patients.

Exploring the psychological profile: a cross-sectional study of 1,185 patients with pulmonary nodules in an outpatient clinic.

Background: The purpose of this study was to identify the potential risk and protective factors of psychological burden in patients with pulmonary nodules (PNs) and to explore how the psychological status of the patients affects their treatment preferences. Methods: In this questionnaire-based study, 1,185 outpatients were evaluated using the Hospital Anxiety and Depression Scale (HADS), and the correlations between psychological burden and patients' sociodemographic and clinical characteristics were assessed. Results: Prevalence of anxiety and depression was 42.1% and 27.0%, respectively, among patients with PNs. Binary logistic regression analysis revealed that age over 60 years old [odds ratio (OR) =0.57; 95% confidence interval (CI): 0.36-0.89], computed tomography (CT) scan due to physical discomfort (OR =1.58; 95% CI: 1.11-2.24), multiple PNs (OR =1.52; 95% CI: 1.20-1.94), family history of malignancy (OR =1.28; 95% CI: 1.01-1.64), and subjective symptoms (OR =1.70; 95% CI: 1.32-2.19) were independently associated with anxiety, while multiple PNs (OR =1.51; 95% CI: 1.15-1.98), subjective symptoms (OR =1.65; 95% CI: 1.23-2.20), and indeterminate nodules (OR =1.91; 95% CI: 1.08-3.40) were independently associated with depression. There was a tendency for patients with anxiety and depression to choose more aggressive management strategies (P<0.001 and P=0.001, respectively). Univariate analysis showed that symptomatic patients (χ2=9.696; P=0.021) and those with progressive nodules (χ2=18.198, P=0.033) chose more aggressive treatment strategies. Conclusions: Anxiety and depression are common in patients with PNs, which might result in nonnegligible overtreatment. Presence of subjective symptoms can significantly exacerbate psychological burden and influence treatment preference. Taking psychological factors into consideration in the outpatient clinic may facilitate patient-centered communication and promote judicious decision-making.

The staging performance of a modified tumor-node-metastasis staging system incorporated with lymphovascular invasion in patients with esophageal squamous cell carcinoma.

Background: Lymphovascular invasion (LVI) is recognized as an unfavorable prognostic factor for many solid tumors. However, its staging value has not been adequately illustrated in esophageal squamous cell carcinoma (ESCC). Methods: The clinicopathologic relevance and prognostic impact of LVI were retrospectively analyzed in 822 patients with surgically treated ESCC. Univariate and multivariate analyses were used to determine the independent prognostic factors. Subgroup analyses stratified by pathological stages, nodal status and invasive depth were conducted using Kaplan-Meier method and log-rank test. Multiple staging models based on overall survival (OS) were constructed using Cox regression and evaluated by Harrell's concordance index (C-index), integrated discrimination improvement (IDI), and net reclassification index (NRI). Results: LVI was detected in 24.6% of ESCC patients, and its prevalence increased with a higher pathological stage (p < 0.001). In multivariate analysis, LVI was found to be an independent prognostic factor for OS [Hazard ratio (HR) = 1.545, 95% CI, 1.201-1.986), and was associated with unfavorable outcomes in stage I to III ESCC, regardless of nodal status and invasive depth. The staging model that incorporated LVI as an independent factor achieved the greatest improvement in accuracy (ΔC-index: 2.9%), and the greatest added value (IDI 2.8%, p < 0.01; NRI 13.7%, p < 0.05) for prediction of OS in ESCC patients. Conclusions: LVI can facilitate further survival stratification in ESCC patients. The adoption of LVI as an independent staging factor in the current cancer staging system should be considered and further validated.

Salivary microbiota may predict the presence of esophageal squamous cell carcinoma.

The aim is to explore the predictive value of salivary bacteria for the presence of esophageal squamous cell carcinoma (ESCC). Saliva samples were obtained from 178 patients with ESCC and 101 healthy controls, and allocated to screening and verification cohorts, respectively. In the screening phase, after saliva DNA was extracted, 16S rRNA V4 regions of salivary bacteria were amplified by polymerase chain reaction (PCR) with high-throughput sequencing. Highly expressed target bacteria were screened by Operational Taxonomic Units clustering, species annotation and microbial diversity assessment. In the verification phase, the expression levels of target bacteria identified in the screening phase were verified by absolute quantitative PCR (Q-PCR). Receiver operating characteristic (ROC) curves were plotted to investigate the predictive value of target salivary bacteria. LEfSe analysis revealed higher proportions of Fusobacterium, Streptococcus and Porphyromonas, and Q-PCR assay showed significantly higher numbers of Streptococcus salivarius, Fusobacterium nucleatum and Porphyromonas gingivalis in patients with ESCC, when compared with healthy controls (all P < 0.05). The areas under the ROC curves for Streptococcus salivarius, Fusobacterium nucleatum, Porphyromonas gingivalis and the combination of the three bacteria for predicting patients with ESCC were 69%, 56.5%, 61.8% and 76.4%, respectively. The sensitivities corresponding to cutoff value were 69.3%, 22.7%, 35.2% and 86.4%, respectively, and the matched specificity were 78.4%, 96.1%, 90.2% and 58.8%, respectively. These highly expressed Streptococcus salivarius, Fusobacterium nucleatum and Porphyromonas gingivalis in the saliva, alone or in combination, indicate their predictive value for ESCC.

A novel prognostic model: which group of esophageal squamous cell carcinoma patients could benefit from adjuvant chemotherapy.

Background: This study aimed to establish a reliable model for predicting the overall survival (OS) of esophageal squamous cell carcinoma (ESCC) patients and identifying the potential beneficiaries of adjuvant chemotherapy after esophagectomy. Methods: This retrospective study included 819 ESCC patients who underwent esophagectomy as the training cohort. We constructed a prognostic model named GTLN2. Both internal and external validation tests were performed. Potential beneficiaries were defined as ESCC patients who obtained a significantly longer OS after adjuvant chemotherapy. Propensity score matching (PSM) was utilized in the subgroup analysis to screen ESCC beneficiaries of adjuvant chemotherapy. Results: We enrolled a total of 819 cT1b-3 patients in the training cohort. Multiple prognostic factors were associated with adjuvant chemotherapy. Using uni-/multivariate analysis, histological grade (G), tumor invasion depth (T), regional lymph node metastasis (N), and the number of cleared lymph nodes (NCLNs) were identified as independent prognostic factors. Then, we developed the GTLN2 model based on these predictors and validated it using internal calculations [the 1-, 3- and 5-year area under the curves (AUCs) were 0.692, 0.685 and 0.680, respectively; P<0.001] and external cohorts (the 1-, 3-, and 5-year AUCs were 0.651, 0.619 and 0.650, respectively; P<0.001). ESCC patients were categorized into high- and low-risk groups based on their assigned risk scores. After 1:1 patient pairing was performed by PSM in the high-risk group, better OS was noted in patients receiving adjuvant chemotherapy (P=0.024). Conclusions: Differentiating high- and low-risk patient groups via a novel mathematical prediction model allows physicians to identify patients in need of adjuvant chemotherapy accurately.

Should psychological distress be listed as a surgical indication for indeterminate pulmonary nodules: protocol for a prospective cohort study in real-world settings.

Background: Pulmonary nodules (PNs) are documented in up to 30% of computed tomography (CT) reports. PNs of indeterminate nature (IPN) have been reported to be associated with increased psychological distress and deterioration of the quality of life. Despite lack of solid evidence, severe anxiety or depression has been proposed to be one of the surgical indications in expert consensus for IPN management. So far, there is no established criterion to guide the decision-making process, or to ensure evidence-based management. This study aims to evaluate whether psychological distress could be a surgical indication for IPN, and to establish an evidence-based distress threshold for necessary surgical intervention. Methods: This prospective observational study in real-world setting will involve an expected sample size of 1,253 IPN patients from the thoracic clinic of Guangdong Provincial People's Hospital. Web-based questionnaires powered by Wen Juan Xing (WJX) platform will be delivered to the patients for baseline data collection and psychological screening. Based on our pilot study, a total of 376 IPN patients with abnormal or borderline abnormal psychological states, as assessed by the Hospital Anxiety and Depression Scale (HADS), will be followed for 1 year before proceeding to the final analysis. The planned study period is from Jan 1, 2021, to Sept 30, 2022, and will entail two HADS assessments at baseline and follow-up. Sleep quality and indicators of healthcare-seeking behavior, such as the number of unplanned clinic visits or CT scans per year, will be used as anchors of psychological state. Patients who undergo surgical resection against the follow-up plan will be enrolled into a surgical group (expected n=94), while those who adhere to their plan will be automatically classified as a follow-up group after 1-year follow-up (expected n=282). Statistical measures such as independent-samples t-test and receiver operating characteristics (ROC) analysis will be used to assess the difference in psychological changes between the groups, and to generate an optimal threshold alerting surgical need. A Chi-square test or nonparametric test will be used to compare the baseline characteristics. Contributors to psychological burden and their effect sizes will be evaluated using general linear regression. Discussion: To date, data on the psychological benefits of surgical resection of IPN remains scanty. Evidence-based procedure of patient selection using appropriate psychological screening tools is crucial in improving the quality of care and preventing overtreatment. This protocol describes the rationale and methodology to address this unmet clinical need using real-world data, aiming to bridge the gap between clinical guidelines and real-world practice. Trial Registration: ClinicalTrials.gov Identifier: NCT04857333. Registered April 23, 2021.

Accuracy of next-generation sequencing for molecular profiling of small specimen of lung cancer: a prospective pilot study of side-by-side comparison.

BACKGROUND: Successful practice of precision medicine in advanced lung cancers relies on therapeutic regimens tailored to individual molecular characteristics. The aim of this study was to investigate the accuracy of small specimens for molecular profiling using next-generation sequencing (NGS). METHODS: Genetic alternations, tumor mutational burden (TMB), status of microsatellite instability (MSI), and expression of programmed death ligand 1 (PD-L1) were compared side-by-side between the concurrently obtained core needle biopsy (CNB) and resection specimens in 17 patients with resectable non-small cell lung cancers. RESULTS: DNA yield and library complexity were significantly lower in CNB specimens (both p < 0.01), whereas the insert size, sequencing depth, and Q30 ratio were similar between the matched specimens (all p > 0.05). The total numbers of genetic alternations detected in resection and CNB specimens were 186 and 211, respectively, with 156 alternations in common, yielding a specific concordance rate of 83.9%. The prevalence of mutations in 8 major driver genes was 100% identical between surgical and CNB specimens, though the allele frequency was lower in CNB specimens, with a median underestimation of 57%. Results of TMB were similar (p = 0.547) and MSI status was 100% matched in all paired specimens. CONCLUSIONS: Pulmonary CNB specimens were suitable for NGS given the satisfactory accuracy when compared to corresponding surgical specimens. NGS results yielding from CNB specimens should be deemed reliable to provide instructive information for the treatment of advanced lung cancers.

Dynamic alteration in SULmax predicts early pathological tumor response and short-term prognosis in non-small cell lung cancer treated with neoadjuvant immunochemotherapy.

Introduction: Biomarkers predicting tumor response to neoadjuvant immunochemotherapy in non-small cell lung cancer (NSCLC) are still lacking despite great efforts. We aimed to assess the effectiveness of the immune PET Response Criteria in Solid Tumors via SULmax (iPERCIST-max) in predicting tumor response to neoadjuvant immunochemotherapy and short-term survival in locally advanced NSCLC. Methods: In this prospective cohort study, we calculated SULmax, SULpeak, metabolic tumor volume (MTV), total lesion glycolysis (TLG) and their dynamic percentage changes in a training cohort. We then investigated the correlation between alterations in these parameters and pathological tumor responses. Subsequently, iPERCIST-max defined by the proportional changes in the SULmax response (△SULmax%) was constructed and internally validated using a time-dependent receiver operating characteristic (ROC) curve and the area under the curve (AUC) value. A prospective cohort from the Sun Yat-Sen University Cancer Center (SYSUCC) was also included for external validation. The relationship between the iPERCIST-max responsiveness and event-free survival in the training cohort was also investigated. Results: Fifty-five patients with NSCLC were included in this study from May 2019 to December 2021. Significant alterations in post-treatment SULmax (p < 0.001), SULpeak (p < 0.001), SULmean (p < 0.001), MTV (p < 0.001), TLG (p < 0.001), and tumor size (p < 0.001) were observed compared to baseline values. Significant differences in SULpeak, SULmax, and SULmean between major pathological response (mPR) and non-mPR statuses were observed. The optimal cutoff values of the SULmax response rate were -70.0% and -88.0% using the X-tile software. The univariate and multivariate binary logistic regression showed that iPERCIST-max is the only significant key predictor for mPR status [OR = 84.0, 95% confidence interval (CI): 7.84-900.12, p < 0.001]. The AUC value for iPERCIST-max was 0.896 (95% CI: 0.776-1.000, p < 0.001). Further, external validation showed that the AUC value for iPERCIST-max in the SYSUCC cohort was 0.889 (95% CI: 0.698-1.000, p = 0.05). Significantly better event-free survival (EFS) in iPERCIST-max responsive disease (31.5 months, 95% CI 27.9-35.1) than that in iPERCIST-max unresponsive disease (22.2 months, 95% CI: 17.3-27.1 months, p = 0.024) was observed. Conclusion: iPERCIST-max could better predict both early pathological tumor response and short-term prognosis of NSCLC treated with neoadjuvant immunochemotherapy than commonly used criteria. Furthermore, large-scale prospective studies are required to confirm the generalizability of our findings.

IL-1ß-activated mTORC2 promotes accumulation of IFN-γ+ γδ T cells by upregulating CXCR3 to restrict hepatic fibrosis.

Liver fibrosis represents a severe stage of liver damage, with hallmarks of inflammation, hepatic stellate cell activation, and extracellular matrix accumulation. Although previous studies demonstrated γδ T cells are involved in liver fibrosis, the precise role and mechanisms of γδ T cells migrating to fibrotic liver have not been elucidated. Here, we aim to investigate the functional subsets of γδ T cells in hepatic fibrosis and to further explore the underlying causes and drivers of migration. In this study, we observed that γδ T cells accumulate in fibrotic liver. Adoptive transfer of γδ T, especially Vγ4 γδ T subset, can significantly alleviate liver fibrosis. In addition, CCl4 treatment also leads to activation of mTOR signaling in γδ T cells. Genetic deletion of the Rictor gene, but not Raptor, in γδ T cells markedly exacerbated liver fibrosis. Mechanistically, CCl4-induced liver injury causes macrophage accumulation in the liver, and IL-1ß produced by macrophages promotes mTORC2 signaling activation in γδ T cells, which upregulates T-bet expression and eventually promotes CXCR3 transcription to drive γδ T cell migration. Moreover, hepatic γδ T cells ameliorated liver fibrosis by cytotoxicity against activated hepatic stellate cells in FasL-dependent manner, and secrete IFN-γ to inhibit the differentiation of pro-fibrotic Th17 cells. Thus, IL-1ß-activated mTORC2 signaling in γδ T cells upregulates CXCR3 expression, which is critical for IFN-γ+ γδ T cells migration into the liver and amelioration of liver fibrosis. Our findings indicate that targeting the mTORC2 or CXCR3 in γδ T cells could be considered as a promising approach for γδ T cell immunotherapy against liver fibrosis.

Conversion Surgery Following Immunochemotherapy in Initially Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma-A Real-World Multicenter Study (RICE-Retro).

Purpose: The present study sets out to evaluate the feasibility, safety, and effectiveness of conversion surgery following induction immunochemotherapy for patients with initially unresectable locally advanced esophageal squamous cell carcinoma (ESCC) in a real-world scenario. Materials and Methods: In this multi-center, real-world study (NCT04822103), patients who had unresectable ESCC disease were enrolled across eight medical centers in China. All patients received programmed death receptor-1 (PD-1) inhibitor plus chemotherapy every 3 weeks for at least two cycles. Patients with significant relief of cancer-related clinical symptoms and radiological responsive disease were deemed surgical candidates. Feasibility and safety profile of immunochemotherapy plus conversion surgery, radiological and pathological tumor responses, as well as short-term survival outcomes were evaluated. Moreover, data of an independent ESCC cohort receiving induction chemotherapy (iC) were compared. Results: One hundred and fifty-five patients were enrolled in the final analysis. Esophagectomy was offered to 116 patients, yielding a conversion rate of 74.8%. R0 resection rate was 94%. Among the 155 patients, 107 (69.0%) patients experienced at least one treatment-related adverse event (TRAE) and 45 (29.0%) patients reported grade 3 and above TRAEs. Significant differences in responsive disease rate were observed between iC cohort and induction immunochemotherapy (iIC) cohort [objective response rate: iIC: 63.2% vs. iC: 47.7%, p = 0.004; pathological complete response: iIC: 22.4% vs. iC: 6.7%, p = 0.001). Higher anastomosis fistula rate was observed in the iC group (19.2%) compared with the iIC group (4%). Furthermore, Significantly higher event-free survival was observed in those who underwent conversion surgery. Conclusion: Our results supported that conversion surgery following immunochemotherapy is feasible and safe for patients with initially unresectable locally advanced ESCC. Both radiological and pathological response rates were significantly higher in the iIC cohort compared with those in the traditional iC cohort.

Association of acrylamide hemoglobin biomarkers with chronic obstructive pulmonary disease in the general population in the US: NHANES 2013-2016.

Background: Acrylamide is a well-known potential carcinogenic compound formed as an intermediate in the Maillard reaction during heat treatment, mainly from high-temperature frying, and is found in baked goods and coffee, as well as resulting from water treatment, textiles and paper processing. The effects of acrylamide on lung disease in humans remains unclear. We aimed to investigate the association between blood acrylamide and glycidamide and chronic obstructive pulmonary disease (COPD) in the United States of America (U.S.) population using PROC logistic regression models. Results: 2744 participants aged 20 to 80 from the 2013-2016 National Health and Nutrition Examination Survey (NHANES) were enrolled. After adjusting for demographic data, health factors and serum cotinine, the ratio of HbGA to HbAA (HbGA/HbAA) significantly increased the risk of COPD (P for trend = 0.022). The odds ratio (OR) with a 95% confidence interval (95% CI) for HbGA/HbAA in the third tile was 2.45 (1.12-5.31), compared with the lowest tile. The restricted cubic spline (RCS) curve showed a positive linear correlation between the log (HbGA/HbAA) and the risk of COPD (P = 0.030). Conclusion: The ratio of glycidamide and acrylamide (HbGA/HbAA) was associated with COPD. This association was more prominent in males, obese individuals, people with a poverty income ratio (PIR) < 1.85 or people who never exercise. However, null associations were observed between HbAA, HbGA and HbAA + HbGA, and COPD.