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.

Development and validation of a preoperative CT-based radiomic nomogram to predict pathology invasiveness in patients with a solitary pulmonary nodule: a machine learning approach, multicenter, diagnostic study.

OBJECTIVES: To develop and validate a preoperative CT-based nomogram combined with radiomic and clinical-radiological signatures to distinguish preinvasive lesions from pulmonary invasive lesions. METHODS: This was a retrospective, diagnostic study conducted from August 1, 2018, to May 1, 2020, at three centers. Patients with a solitary pulmonary nodule were enrolled in the GDPH center and were divided into two groups (7:3) randomly: development (n = 149) and internal validation (n = 54). The SYSMH center and the ZSLC Center formed an external validation cohort of 170 patients. The least absolute shrinkage and selection operator (LASSO) algorithm and logistic regression analysis were used to feature signatures and transform them into models. RESULTS: The study comprised 373 individuals from three independent centers (female: 225/373, 60.3%; median [IQR] age, 57.0 [48.0-65.0] years). The AUCs for the combined radiomic signature selected from the nodular area and the perinodular area were 0.93, 0.91, and 0.90 in the three cohorts. The nomogram combining the clinical and combined radiomic signatures could accurately predict interstitial invasion in patients with a solitary pulmonary nodule (AUC, 0.94, 0.90, 0.92) in the three cohorts, respectively. The radiomic nomogram outperformed any clinical or radiomic signature in terms of clinical predictive abilities, according to a decision curve analysis and the Akaike information criteria. CONCLUSIONS: This study demonstrated that a nomogram constructed by identified clinical-radiological signatures and combined radiomic signatures has the potential to precisely predict pathology invasiveness. KEY POINTS: • The radiomic signature from the perinodular area has the potential to predict pathology invasiveness of the solitary pulmonary nodule. • The new radiomic nomogram was useful in clinical decision-making associated with personalized surgical intervention and therapeutic regimen selection in patients with early-stage non-small-cell lung cancer.

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.

An atomistic fingerprint algorithm for learning ab initio molecular force fields.

Molecular fingerprints, i.e., feature vectors describing atomistic neighborhood configurations, is an important abstraction and a key ingredient for data-driven modeling of potential energy surface and interatomic force. In this paper, we present the density-encoded canonically aligned fingerprint algorithm, which is robust and efficient, for fitting per-atom scalar and vector quantities. The fingerprint is essentially a continuous density field formed through the superimposition of smoothing kernels centered on the atoms. Rotational invariance of the fingerprint is achieved by aligning, for each fingerprint instance, the neighboring atoms onto a local canonical coordinate frame computed from a kernel minisum optimization procedure. We show that this approach is superior over principal components analysis-based methods especially when the atomistic neighborhood is sparse and/or contains symmetry. We propose that the "distance" between the density fields be measured using a volume integral of their pointwise difference. This can be efficiently computed using optimal quadrature rules, which only require discrete sampling at a small number of grid points. We also experiment on the choice of weight functions for constructing the density fields and characterize their performance for fitting interatomic potentials. The applicability of the fingerprint is demonstrated through a set of benchmark problems.

Pan-cancer analysis for the prognostic and immunological role of CD47: interact with TNFRSF9 inducing CD8 + T cell exhaustion.

PURPOSE: The research endeavors to explore the implications of CD47 in cancer immunotherapy effectiveness. Specifically, there is a gap in comprehending the influence of CD47 on the tumor immune microenvironment, particularly in relation to CD8 + T cells. Our study aims to elucidate the prognostic and immunological relevance of CD47 to enhance insights into its prospective utilities in immunotherapeutic interventions. METHODS: Differential gene expression analysis, prognosis assessment, immunological infiltration evaluation, pathway enrichment analysis, and correlation investigation were performed utilizing a combination of R packages, computational algorithms, diverse datasets, and patient cohorts. Validation of the concept was achieved through the utilization of single-cell sequencing technology. RESULTS: CD47 demonstrated ubiquitous expression across various cancer types and was notably associated with unfavorable prognostic outcomes in pan-cancer assessments. Immunological investigations unveiled a robust correlation between CD47 expression and T-cell infiltration rather than T-cell exclusion across multiple cancer types. Specifically, the CD47-high group exhibited a poorer prognosis for the cytotoxic CD8 + T cell Top group compared to the CD47-low group, suggesting a potential impairment of CD8 + T cell functionality by CD47. The exploration of mechanism identified enrichment of CD47-associated differentially expressed genes in the CD8 + T cell exhausted pathway in multiple cancer contexts. Further analyses focusing on the CD8 TCR Downstream Pathway and gene correlation patterns underscored the significant involvement of TNFRSF9 in mediating these effects. CONCLUSION: A robust association exists between CD47 and the exhaustion of CD8 + T cells, potentially enabling immune evasion by cancer cells and thereby contributing to adverse prognostic outcomes. Consequently, genes such as CD47 and those linked to T-cell exhaustion, notably TNFRSF9, present as promising dual antigenic targets, providing critical insights into the field of immunotherapy.

Plasma EBV quantification is associated with the efficacy of immune checkpoint blockade and disease monitoring in patients with primary pulmonary lymphoepithelioma-like carcinoma.

Objectives: Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein-Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation. Methods: We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB-treated PLELC. Viral EBNA-1 and BamHI-W DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction. Results: Progression-free survival (PFS) was significantly longer in EBNA-1 high or BamHI-W high groups. A longer PFS was also observed in patients with both high plasma EBNA-1 or BamHI-W and PD-L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with EBNA-1 and BamHI-W. Plasma EBV load was negatively associated with intratumoral CD8+ immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months. Conclusions: Plasma EBV DNA could be a useful and easy-to-use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging.

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.

Pretreatment radiomic biomarker for immunotherapy responder prediction in stage IB-IV NSCLC (LCDigital-IO Study): a multicenter retrospective study.

BACKGROUND: The predictive efficacy of current biomarker of immune checkpoint inhibitors (ICIs) is not sufficient. This study investigated the causality between radiomic biomarkers and immunotherapy response status in patients with stage IB-IV non-small cell lung cancer (NSCLC), including its biological context for ICIs treatment response prediction. METHODS: CT images from 319 patients with pretreatment NSCLC receiving immunotherapy between January 2015 and November 2021 were retrospectively collected and composed a discovery (n=214), independent validation (n=54), and external test cohort (n=51). A set of 851 features was extracted from tumorous and peritumoral volumes of interest (VOIs). The reference standard is the durable clinical benefit (DCB, sustained disease control for more than 6 months assessed via radiological evaluation). The predictive value of combined radiomic signature (CRS) for pathological response was subsequently assessed in another cohort of 98 patients with resectable NSCLC receiving ICIs preoperatively. The association between radiomic features and tumor immune landscape on the online data set (n=60) was also examined. A model combining clinical predictor and radiomic signatures was constructed to improve performance further. RESULTS: CRS discriminated DCB and non-DCB patients well in the training and validation cohorts with an area under the curve (AUC) of 0.82, 95% CI: 0.75 to 0.88, and 0.75, 95% CI: 0.64 to 0.87, respectively. In this study, the predictive value of CRS was better than programmed cell death ligand-1 (PD-L1) expression (AUC of PD-L1 subset: 0.59, 95% CI: 0.50 to 0.69) or clinical model (AUC: 0.66, 95% CI: 0.51 to 0.81). After combining the clinical signature with CRS, the predictive performance improved further with an AUC of 0.837, 0.790 and 0.781 in training, validation and D2 cohorts, respectively. When predicting pathological response, CRS divided patients into a major pathological response (MPR) and non-MPR group (AUC: 0.76, 95% CI: 0.67 to 0.81). Moreover, CRS showed a promising stratification ability on overall survival (HR: 0.49, 95% CI: 0.27 to 0.89; p=0.020) and progression-free survival (HR: 0.43, 95% CI: 0.26 to 0.74; p=0.002). CONCLUSION: By analyzing both tumorous and peritumoral regions of CT images in a radiomic strategy, we developed a non-invasive biomarker for distinguishing responders of ICIs therapy and stratifying their survival outcome efficiently, which may support the clinical decisions on the use of ICIs in advanced as well as patients with resectable NSCLC.

ECM-Mimicking Hydrogels Loaded with Bone Mesenchymal Stem Cell-Derived Exosomes for the Treatment of Cartilage Defects.

It is well-established that treating articular cartilage injuries is clinically challenging since they lack blood arteries, nerves, and lymphoid tissue. Recent studies have revealed that bone marrow stem cell-derived exosomes (BMSCs-Exos) exert significant chondroprotective effects through paracrine secretions, and hydrogel-based materials can synergize the exosomes through sustained release. Therefore, this research aims to synthesize an ECM (extracellular matrix)-mimicking gelatin methacryloyl (GelMA) hydrogel modified by gelatin combined with BMSCs-derived exosomes to repair cartilage damage. We first isolated and characterized exosomes from BMSCs supernatant and then loaded the exosomes into GelMA hydrogel to investigate cartilage repair effects in in vitro and in vivo experiments. The outcomes showed that the GelMA hydrogel has good biocompatibility with a 3D (three-dimensional) porous structure, exhibiting good carrier characteristics for exosomes. Furthermore, BMSCs-Exos had a significant effect on promoting chondrocyte ECM production and chondrocyte proliferation, and the GelMA hydrogel could enhance this effect through a sustained-release effect. Similarly, in vivo experiments showed that GelMA-Exos promoted cartilage regeneration in rat joint defects and the synthesis of related cartilage matrix proteins.

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.

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.

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.

PD-1/PD-L1 combined with LAG3 is associated with clinical activity of immune checkpoint inhibitors in metastatic primary pulmonary lymphoepithelioma-like carcinoma.

Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is an Epstein-Barr virus (EBV)-related, rare subtype of non-small-cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) show durable responses in advanced NSCLC. However, their effects and predictive biomarkers in PLELC remain poorly understood. We retrospectively analyzed the data of 48 metastatic PLELC patients treated with ICI. Pretreated paraffin-embedded specimens (n = 19) were stained for PD-1, PD-L1, LAG3, TIM3, CD3, CD4, CD8, CD68, FOXP3, and cytokeratin (CK) by multiple immunohistochemistry (mIHC). Next-generation sequencing was performed for 33 PLELC samples. Among patients treated with ICI monotherapy (n = 30), the objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and overall survival (mOS) were 13.3%, 80.0%, 7.7 months, and 24.9 months, respectively. Patients with PD-L1 ≥1% showed a longer PFS (8.4 vs. 2.1 months, p = 0.015) relative to those with PD-L1 <1%. Among patients treated with ICI combination therapy (n = 18), ORR, DCR, mPFS, and mOS were 27.8%, 100.0%, 10.1 months, and 19.7 months, respectively. Patients with PD-L1 ≥1% showed a significantly superior OS than those with PD-L1 <1% (NA versus 11.7 months, p = 0.001). Among the 19 mIHC patients, those with high PD-1/PD-L1 and LAG3 expression showed a longer PFS (19.0 vs. 3.9 months, p = 0.003). ICI also showed promising efficacy for treating metastatic PLELC. PD-L1 may be both predictive of ICI treatment efficacy and prognostic for survival in PLELC. PD-1/PD-L1 combined with LAG3 may serve as a predictor of ICI treatment effectiveness in PLELC. Larger and prospective trials are warranted to validate both ICI activity and predictive biomarkers in PLELC. This study was partly presented as a poster at the IASLC 20th World Conference on Lung Cancer 2019, 7-10 September 2019, Barcelona, Spain.

Prognostic impact of lymph node metastasis along the left gastric artery in esophageal squamous cell carcinoma.

BACKGROUND: Although the incidence of lymph node (LN) metastasis (LNM) along the left gastric artery is high, its relationship with the prognosis in postoperative patients with esophageal squamous cell carcinoma (ESCC) is rarely reported. This study clarified the prognostic impact of LNM along the left gastric artery in postoperative patients with ESCC. METHODS: This study assessed data of 1521 patients with ESCC who underwent esophagectomy at the Sun Yat-sen University Cancer Center between March 1992 and March 2012. A chi-squared test and Mann-Whitney U test were used to explore the preliminary correlation between clinical factors and LNM along the left gastric artery. Univariate and multivariate Cox regression analyses were used to assess whether LNM along the left gastric artery was an independent predictor of overall survival. Kaplan-Meier analysis and the log-rank test were used to present a classifying effect based on LN status. RESULTS: LNM was observed in 598 patients (39.3%) and was found along the branches of the left gastric artery in 256 patients (16.8%). The patients were classified into two groups based on the presence of LNM along the left gastric artery. Patients without LNM along the left gastric artery had better cancer-specific survival than those with positive LNs (P <  0.001). CONCLUSIONS: This study indicated that LNM along the left gastric artery was an important independent prognostic factor for long-term survival among ESCC patients (P = 0.011).

Exploring the Role and Mechanism of pAMPKα-Mediated Dysregulation of Brf1 and RNA Pol III Genes.

TF IIB-related factor 1 (Brf1) is a key transcription factor of RNA polymerase III (Pol III) genes. Our early studies have demonstrated that Brf1 and Pol III genes are epigenetically modulated by histone H3 phosphorylation. Here, we have further investigated the relationship of the abnormal expression of Brf1 with a high level of phosphorylated AMPKα (pAMPKα) and explored the role and molecular mechanism of pAMPKα-mediated dysregulation of Brf1 and Pol III genes in lung cancer. Brf1 is significantly overexpressed in lung cancer cases. The cases with high Brf1 expression display short overall survival times. Elevation of Brf1 expression is accompanied by a high level of pAMPKα. Brf1 and pAMPKα colocalize in nuclei. Further analysis indicates that the carcinogen MNNG induces pAMPKα to upregulate Brf1 expression, resulting in the enhancement of Pol III transcription. In contrast, inhibiting pAMPKα decreases cellular levels of Brf1, resulting in the reduction of Pol III gene transcription to attenuate the rates of cell proliferation and colony formation of lung cancer cells. These outcomes demonstrate that high Brf1 expression reveals a worse prognosis in lung cancer patients. pAMPKα-mediated dysregulation of Brf1 and Pol III genes plays important roles in cell proliferation, colony formation, and tumor development of lung cancer. Brf1 may be a biomarker for establishing the prognosis of lung cancer. It is a new mechanism that pAMPKα mediates dysregulation of Brf1 and Pol III genes to promote lung cancer development.