A combined pre- and intra-operative nomogram in evaluation of degrees of liver cirrhosis predicts post-hepatectomy liver failure: a multicenter prospective study.

Background: Adequate evaluation of degrees of liver cirrhosis is essential in surgical treatment of hepatocellular carcinoma (HCC) patients. The impact of the degrees of cirrhosis on prediction of post-hepatectomy liver failure (PHLF) remains poorly defined. This study aimed to construct and validate a combined pre- and intra-operative nomogram based on the degrees of cirrhosis in predicting PHLF in HCC patients using prospective multi-center's data. Methods: Consecutive HCC patients who underwent hepatectomy between May 18, 2019 and Dec 19, 2020 were enrolled at five tertiary hospitals. Preoperative cirrhotic severity scoring (CSS) and intra-operative direct liver stiffness measurement (DSM) were performed to correlate with the Laennec histopathological grading system. The performances of the pre-operative nomogram and combined pre- and intra-operative nomogram in predicting PHLF were compared with conventional predictive models of PHLF. Results: For 327 patients in this study, histopathological studies showed the rates of HCC patients with no, mild, moderate, and severe cirrhosis were 41.9%, 29.1%, 22.9%, and 6.1%, respectively. Either CSS or DSM was closely correlated with histopathological stages of cirrhosis. Thirty-three (10.1%) patients developed PHLF. The 30- and 90-day mortality rates were 0.9%. Multivariate regression analysis showed four pre-operative variables [HBV-DNA level, ICG-R15, prothrombin time (PT), and CSS], and one intra-operative variable (DSM) to be independent risk factors of PHLF. The pre-operative nomogram was constructed based on these four pre-operative variables together with total bilirubin. The combined pre- and intra-operative nomogram was constructed by adding the intra-operative DSM. The pre-operative nomogram was better than the conventional models in predicting PHLF. The prediction was further improved with the combined pre- and intra-operative nomogram. Conclusions: The combined pre- and intra-operative nomogram further improved prediction of PHLF when compared with the pre-operative nomogram. Trial Registration: Clinicaltrials.gov Identifier: NCT04076631.

Subchronic Toxicity Evaluation of Idesia polycarpa Fruit Oil by 90-Day Oral Exposure in Wistar Rats.

Idesia polycarpa, belonging to the Flacourtiaceae family, is a tall deciduous tree, widely distributed in some Asian countries. It is famous for its high yield of fruit known as oil grape, which is rich of linoleic acid and linolenic acid, and so on. To provide evidences for its safe use as food, subchronic toxicity of I. polycarpa fruit oil and no observed adverse effect level were performed in male and female specific pathogen-free Wistar rats. Based on the Organization for Economic Co-operation and Development guidelines, the oil was orally administered to rats by gavage at 0, 1.0, 2.0, and 4.0mL/kg.bw/day for 90 days, followed by a 28-day recovery period. The results showed that no sign of oil-related toxicity, clinically or histologically, was observed in both male and female rats. Although there was a slight increase or decrease in some indicators such as hematology, serum chemistry, and so on, those changes were all within the normal ranges, and as presented in the 90-day study, the oil exhibited no toxic effect compared to the control rats. I. polycarpa might be a potential excellent and healthy vegetable oil resource.

Olive oil intake and cardiovascular disease, cancer, and all-cause mortality: a systematic review and dose-response meta-analysis of prospective cohort studies.

Background: Currently, the reported links between olive oil intake and cardiovascular disease (CVD), cancer morbidity and mortality, and all-cause mortality are inconsistent. The aim of this meta-analysis is to study the reported correlations of olive oil intake with CVD, coronary heart disease (CHD), stroke and cancer incidence and mortality, and all-cause mortality. Methods: PubMed, Embase, and Web of Science were searched until March 7, 2024. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were estimated by the random-effects model. Nonlinear dose-response relationships were modeled with restricted cubic splines. This study has been registered at PROSPERO (CRD42023419001). Results: Overall, 30 articles covering 2 710 351 participants were identified. Higher olive oil intake was linked with a reduced risk of CVD incidence (RR: 0.85; 95% CI: 0.77, 0.93), CHD incidence (RR: 0.85; 95% CI: 0.72, 0.99), CVD mortality (RR: 0.77; 95% CI: 0.67, 0.88), and all-cause mortality (RR: 0.85; 95% CI: 0.81, 0.89). For a 10 g d-1 increment of olive oil intake, the risk of CVD incidence, stroke incidence, CVD mortality, and all-cause mortality decreased by 7%, 5%, 8%, and 8%, respectively. No association was found between olive oil intake and cancer incidence and mortality. Nonlinear relationships between olive oil intake and CVD and all-cause mortality were observed, with a reduced risk from intakes ranging from 0 to 18 g d-1 and 0 to 22 g d-1, respectively. Conclusion: Our study found that high olive oil intake was related to a lower risk of CVD and CHD incidence and CVD mortality and all-cause mortality.

SLAM medical imaging enabled by pre-chirp and gain jointly managed Yb-fiber laser.

We demonstrate a pre-chirp and gain jointly managed Yb-fiber laser that drives simultaneous label-free autofluorescence-multiharmonic (SLAM) medical imaging. We show that a gain managed Yb-fiber amplifier produces high-quality compressed pulses when the seeding pulses exhibit proper negative pre-chirp. The resulting laser source can generate 43-MHz, 34-fs pulses centered at 1110 nm with more than 90-nJ energy. We apply this ultrafast source to SLAM imaging of cellular and extracellular components in various human tissues of intestinal adenocarcinoma, lung adenocarcinoma, and liver.

Association of methylation risk score with incident type 2 diabetes mellitus: A nested case-control study.

AIMS: To investigate the association of methylation risk score (MRS) and its interactions with environmental factors with type 2 diabetes mellitus (T2DM) risk. METHODS: We conducted a nested case-control study with 241 onset cases and 241 matched controls. Conditional logistic regression models were employed to identify risk CpG sites. Simple and weighted MRSs were constructed based on the methylation levels of ATP-binding cassette G1 gene, fat mass and obesity associated gene, potassium voltage-gated channel member 1 gene, and thioredoxin-interacting protein gene previously associated with T2DM to estimate the association of MRS with T2DM risk. Stratified analyses were used to investigate interactions between MRS and environmental factors. RESULTS: A total of 10 CpG loci were identified from the aforementioned genes to calculate MRS. After controlling for potential confounding factors, taking tertile 1 as reference, the odds ratios (ORs) and 95% confidence intervals (CIs) for T2DM of tertile 3 was 2.39 (1.36-4.20) for simple MRS and 2.59 (1.45-4.63) for weighted MRS. With per SD score increment in MRS, the OR (95% CI) was 1.66 (1.29-2.14) and 1.60 (1.24-2.08) for simple and weighted MRSs, respectively. J-curved associations were observed between both simple and weighted MRSs and T2DM risks. Additionally, multiplication interactions for smoking and hypertension with simple MRS on the risk of T2DM were found, similarly for smoking and obesity with weighted MRS on the risk of T2DM (all Pinteraction < .05). CONCLUSION: Elevated simple and weighted MRSs were associated with increased risk of T2DM. Environmental risk factors may influence the association between MRS and T2DM.

Focalizing regions of biomarker relevance facilitates biomarker prediction on histopathological images.

Image-based AI has thrived as a potentially revolutionary tool for predicting molecular biomarker statuses, which aids in categorizing patients for appropriate medical treatments. However, many methods using hematoxylin and eosin-stained (H&E) whole-slide images (WSIs) have been found to be inefficient because of the presence of numerous uninformative or irrelevant image patches. In this study, we introduced the region of biomarker relevance (ROB) concept to identify the morphological areas most closely associated with biomarkers for accurate status prediction. We actualized this concept within a framework called saliency ROB search (SRS) to enable efficient and effective predictions. By evaluating various lung adenocarcinoma (LUAD) biomarkers, we showcased the superior performance of SRS compared to current state-of-the-art AI approaches. These findings suggest that AI tools, built on the ROB concept, can achieve enhanced molecular biomarker prediction accuracy from pathological images.

Artifact Detection and Restoration in Histology Images With Stain-Style and Structural Preservation.

The artifacts in histology images may encumber the accurate interpretation of medical information and cause misdiagnosis. Accordingly, prepending manual quality control of artifacts considerably decreases the degree of automation. To close this gap, we propose a methodical pre-processing framework to detect and restore artifacts, which minimizes their impact on downstream AI diagnostic tasks. First, the artifact recognition network AR-Classifier first differentiates common artifacts from normal tissues, e.g., tissue folds, marking dye, tattoo pigment, spot, and out-of-focus, and also catalogs artifact patches by their restorability. Then, the succeeding artifact restoration network AR-CycleGAN performs de-artifact processing where stain styles and tissue structures can be maximally retained. We construct a benchmark for performance evaluation, curated from both clinically collected WSIs and public datasets of colorectal and breast cancer. The functional structures are compared with state-of-the-art methods, and also comprehensively evaluated by multiple metrics across multiple tasks, including artifact classification, artifact restoration, downstream diagnostic tasks of tumor classification and nuclei segmentation. The proposed system allows full automation of deep learning based histology image analysis without human intervention. Moreover, the structure-independent characteristic enables its processing with various artifact subtypes. The source code and data in this research are available at https://github.com/yunboer/AR-classifier-and-AR-CycleGAN.

Lower intensity of physical activity strengthens the effect of dietary inflammatory index on the risk of all-cause and cause-specific mortality.

To examine the independent and joint associations of dietary inflammation index (DII) and physical activity (PA) with mortality risk. We analyzed data for 20,165 study participants aged ≥ 18 from The Rural Chinese Cohort Study. The Cox proportional hazard model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) of mortality associated with DII and PA. The dose-response association between DII and mortality risk was intuitively generated by the restricted cubic splines model. During the mean 5.03-year follow-up, a total of 1110 cases of all-cause mortality were identified. Compared with people in quartile 1 of DII, positive associations were found in quartile 4 for all-cause (HR 1.27; 95%CI 1.06-1.52), CVD (HR 1.45; 95%CI 1.09-1.91), and other mortality (HR 1.52; 95%CI 1.10-2.09), while a linear association was demonstrated. Compared with people of quartile 1 of DII and high intensity of PA, those with quartile 4 of DII and low intensity of PA had higher risk of all-cause (HR 1.96; 95%CI 1.50-2.56), CVD (HR 2.68; 95%CI 1.71-4.19), and other mortality (HR 1.83; 95%CI 1.19-2.83). A pro-inflammatory diet was significantly associated with increased risk of mortality and lower PA may strengthen the effect.

Role of modified nasopharyngeal oxygen therapy in apnoeic oxygenation under general anaesthesia: a single-centre, randomized controlled clinical study.

Apnoeic oxygenation is not only important for patients who cannot be intubated/ventilated, but also can be routinely employed when planning to secure the airway.We aimed to compare safe apnoea times between patients receiving modified nasopharyngeal oxygen therapy and those receiving high-flow nasal oxygen therapy (HFNO) following the induction of general anaesthesia.This was a single-centre, randomized controlled clinical study. Eighty-four female patients undergoing elective laparoscopic gynaecological surgery under general anaesthesia were randomly assigned to the high-flow nasal oxygen therapy group (Group HFNO) or the modified nasopharyngeal oxygen therapy group (Group Naso). A Kaplan-Meier survival curve was used to describe the apnoeic oxygenation time.The safe apnoea time of the patients in the Group Naso was higher than that of the patients in the Group HFNO (20 (19.3 to 20.0) vs. 16.5 (12.9 to 20) minutes, P < 0.05). The incidence of SpO2 < 95% in the Group Naso was lower than that in the Group HFNO; hazard ratio 0.3 (95% confidence interval 0.2 to 0.6, P < 0.0001). Modified nasopharyngeal oxygen therapy which uses far less oxygen than HFNO is a convenient and effective method of apnoeic oxygenation in normal female patients.Trial registration: https://www.chictr.org.cn , ChiCTR2000039433; date of registration: 28/10/2020.

Virtual liver needle biopsy from reconstructed three-dimensional histopathological images: Quantification of sampling error.

INTRODUCTION: Prevalently considered as the "gold-standard" for diagnosis of hepatic fibrosis and cirrhosis, the clinical liver needle biopsy is known to be subject to inadequate sampling and a high mis-sampling rate. However, quantifying such sampling bias has been difficult as generating a large number of needle biopsies from the same living patient is practically infeasible. We construct a three-dimension (3D) virtual liver tissue volume by spatially registered high resolution Whole Slide Images (WSIs) of serial liver tissue sections with a novel dynamic registration method. We further develop a Virtual Needle Biopsy Sampling (VNBS) method that mimics the needle biopsy sampling process. We apply the VNBS method to the reconstructed digital liver volume at different tissue locations and angles. Additionally, we quantify Collagen Proportionate Area (CPA) in all resulting virtual needle biopsies in 2D and 3D. RESULTS: The staging score of the center 2D longitudinal image plane from each 3D biopsy is used as the biopsy staging score, and the highest staging score of all sampled needle biopsies is the diagnostic staging score. The Mean Absolute Difference (MAD) in reference to the Scheuer and Ishak diagnostic staging scores are 0.22 and 1.00, respectively. The absolute Scheuer staging score difference in 22.22% of sampled biopsies is 1. By the Ishak staging method, 55.56% and 22.22% of sampled biopsies present score difference 1 and 2, respectively. There are 4 (Scheuer) and 6 (Ishak) out of 18 3D virtual needle biopsies with intra-needle variations. Additionally, we find a positive correlation between CPA and fibrosis stages by Scheuer but not Ishak method. Overall, CPA measures suffer large intra- and inter- needle variations. CONCLUSIONS: The developed virtual liver needle biopsy sampling pipeline provides a computational avenue for investigating needle biopsy sampling bias with 3D virtual tissue volumes. This method can be applied to other tissue-based disease diagnoses where the needle biopsy sampling bias substantially affects the diagnostic results.

Associations of IFT20 and GM130 protein expressions with clinicopathological features and survival of patients with lung adenocarcinoma.

BACKGROUND: Lung cancer is the leading cause of malignancy-related mortality and lung adenocarcinoma accounts for about 40% of lung malignancies. The aim of this study was to investigate the associations of intraflagellar transport protein 20 (IFT20) and Golgi matrix protein 130 (GM130) expression with clinicopathological features and survival in patients with lung adenocarcinoma. METHODS: The expressions of IFT20 and GM130 protein in cancerous and matched adjacent lung tissues of 235 patients with lung adenocarcinoma were assessed by tissue microarray and immunohistochemistry, which were indicated by the mean optical density (IOD/area), the rate of positive staining cells and staining intensity score. The correlation between IFT20 and GM130 protein was assessed by Spearman's rank correlation. Associations of IFT20 and GM130 protein expression with clinicopathological features of patients were analyzed by multivariate logistic regression models. The survival analysis of patients was performed by Cox proportional hazard regression models. RESULTS: With adjustment for multiple potential confounders, each one-point increase in IFT20 protein staining intensity score was significantly associated with 32% and 29% reduced risk for TNM stage in II ~ IV and lymphatic metastasis of patients, respectively (P < 0.05). And each one-point increase in GM130 protein staining intensity score was associated with a significant reduction in the risk of poor differentiation and tumors size > 7 cm by 29% and 38% for lung adenocarcinoma patients, respectively (P < 0.05). In stratified Cox model analysis, enhanced IFT20 staining intensity score was significantly decreased the risk of death by 16% for patients without distant metastasis. And elevated the IOD/area of GM130 expression significantly decreased the death risk of lung adenocarcinoma patients with tumor size > 7 cm or distant metastasis by 54% and 65%, respectively (P < 0.05). CONCLUSION: IFT20 and GM130 protein expressions were negatively associated with tumor differentiated types, size, TNM stage and lymphatic metastasis of lung adenocarcinoma. Both IFT20 and GM130 proteins have some protective effects on the survival of lung adenocarcinoma patients with specific clinicopathological features.

Dose-Response Association of Dietary Inflammatory Potential with All-Cause and Cause-Specific Mortality.

Although the association of dietary inflammatory potential, evaluated by the dietary inflammatory index (DII), with all-cause and cause-specific mortality has been reported, evidence remains equivocal, with no relevant dose-response meta-analysis having been conducted. To examine the dose-response association of dietary inflammatory potential with risk of all-cause, cancer, and cardiovascular disease (CVD) mortality, PubMed, Embase, and Web of Science were systematically searched up to August 9, 2021. Cohort studies were included if DII was reported as ≥3 levels or per incremental increase, and if the associations of DII with all-cause, cancer, and CVD mortality were assessed. Generalized least squares regression was used to estimate study-specific dose-response associations, and the random effect model was used to pool the RRs and 95% CIs of all-cause, cancer, and CVD mortality per 1-unit increase in DII. Restricted cubic splines were used to intuitively display the dose-response association between dietary inflammatory potential and mortality. Of the 1415 studies retrieved, 15 articles (17 cohort studies involving 397,641 participants) were included in this meta-analysis. With per 1-unit increase in DII, the risks were significantly increased for all-cause mortality (RR: 1.04; 95% CI: 1.03, 1.05, I2 = 51.8%; P-heterogeneity = 0.009), cancer mortality (RR: 1.02; 95% CI: 1.00, 1.04, I2 = 58.6%; P-heterogeneity = 0.013), and CVD mortality (RR: 1.04; 95% CI: 1.02, 1.06, I2 = 85.7%; P-heterogeneity <0.001), respectively. Restricted cubic splines showed significant positive linear associations between DII and the above 3 outcomes. Our study indicated that proinflammatory diets can increase the risk of all-cause, cancer, and CVD mortality in a linear manner.

Differential early diagnosis of benign versus malignant lung cancer using systematic pathway flux analysis of peripheral blood leukocytes.

Early diagnosis of lung cancer is critically important to reduce disease severity and improve overall survival. Newer, minimally invasive biopsy procedures often fail to provide adequate specimens for accurate tumor subtyping or staging which is necessary to inform appropriate use of molecular targeted therapies and immune checkpoint inhibitors. Thus newer approaches to diagnosis and staging in early lung cancer are needed. This exploratory pilot study obtained peripheral blood samples from 139 individuals with clinically evident pulmonary nodules (benign and malignant), as well as ten healthy persons. They were divided into three cohorts: original cohort (n = 99), control cohort (n = 10), and validation cohort (n = 40). Average RNAseq sequencing of leukocytes in these samples were conducted. Subsequently, data was integrated into artificial intelligence (AI)-based computational approach with system-wide gene expression technology to develop a rapid, effective, non-invasive immune index for early diagnosis of lung cancer. An immune-related index system, IM-Index, was defined and validated for the diagnostic application. IM-Index was applied to assess the malignancies of pulmonary nodules of 109 participants (original + control cohorts) with high accuracy (AUC: 0.822 [95% CI: 0.75-0.91, p < 0.001]), and to differentiate between phases of cancer immunoediting concept (odds ratio: 1.17 [95% CI: 1.1-1.25, p < 0.001]). The predictive ability of IM-Index was validated in a validation cohort with a AUC: 0.883 (95% CI: 0.73-1.00, p < 0.001). The difference between molecular mechanisms of adenocarcinoma and squamous carcinoma histology was also determined via the IM-Index (OR: 1.2 [95% CI 1.14-1.35, p = 0.019]). In addition, a structural metabolic behavior pattern and signaling property in host immunity were found (bonferroni correction, p = 1.32e - 16). Taken together our findings indicate that this AI-based approach may be used for "Super Early" cancer diagnosis and amend the current immunotherpay for lung cancer.

KIF18B as a regulator in tumor microenvironment accelerates tumor progression and triggers poor outcome in hepatocellular carcinoma.

BACKGROUND: The tumor microenvironment plays an important role in the progression and recurrence of tumors and immunotherapy outcomes. The use of immune checkpoint blockers to improve the overall survival rate of patients with advanced hepatocellular carcinoma has yielded inconsistent outcomes. We examined the tumor microenvironment-related genes for their clinical significance and biological functions in hepatocellular carcinoma. METHODS: Bioinformatic analysis was performed to screen the differentially expressed genes and to identify the core gene of the tumor microenvironment in hepatocellular carcinoma. The expression of KIF18B in hepatocellular carcinoma cell lines and tumor samples was determined using western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry. The malignancy-promoting ability of KIF18B was evaluated using Cell Counting Kit-8, colony formation, cell proliferation, migration and invasion, and xenograft tumor assays. RESULTS: KIF18B was identified as one of the core genes in the hepatocellular carcinoma microenvironment and was significantly associated with infiltrating immune cell subtypes and tumor cell stemness. Upregulation of KIF18B was associated with poor clinicopathological characteristics and poor patient outcomes; its downregulation inhibited the proliferation ability of hepatocellular carcinoma cells, which was consistent with the findings of in vivo experiments. Knockdown of KIF18B inhibited epithelial-mesenchymal transition which reduced the migration and invasion abilities of tumor cells. A pulmonary metastasis model confirmed that the downregulation of KIF18B inhibited hepatocellular carcinoma cell metastasis in vivo. CONCLUSION: KIF18B could be a useful marker for determining the treatment outcomes of immune checkpoint blockers in the context of hepatocellular carcinoma.

The Expression of Three Negative Co-Stimulatory B7 Family Molecules in Small Cell Lung Cancer and Their Effect on Prognosis.

BACKGROUND: In recent years, immune checkpoint inhibitors have shown significant effects in a variety of solid tumors. However, due to the low incidence of small cell lung cancer (SCLC) and its unclear mechanism, immune checkpoints in SCLC have not been fully studied. METHODS: We evaluated the expression of PD-L1, B7-H3, and B7-H4 in 115 SCLC tissue specimens using immunohistochemistry. The clinical data of patients with SCLC were retrospectively reviewed to investigate three negative co-stimulatory B7 family molecules' ability to affect the prognosis of SCLC. RESULTS: Among the SCLC patients with complete follow-up data (n = 107), sixty-nine (64.49%) expressed moderate to high B7-H3 levels, which correlated positively with tumor sizes (P < 0.001). Eighty (74.77%) patients expressed moderate to high B7-H4 levels, which correlated positively with metastases (P = 0.049). The positive expression of B7-H3 and B7-H4 correlated significantly with shortened overall survival (OS) (B7-H3, P = 0.006; B7-H4, P = 0.019). PD-L1 was positively expressed only in 13.08% of cancer tissues, and there was no significant correlation with prognosis. The Cox proportional hazards regression showed that B7-H3 was an independent prognostic indicator of OS (P = 0.028; HR = 2.125 [95% CI = 0.985-4.462]). CONCLUSIONS: Our results suggest that B7-H3 has a negative predictive effect on SCLC. This outcome provides a theoretical basis for the subsequent research on immune checkpoint inhibitors targeting B7-H3.

Interaction of Analgesic Effects of Dezocine and Sufentanil for Relief of Postoperative Pain: A Pilot Study.

PURPOSE: The combination of dezocine and sufentanil is often used for postoperative analgesia in China and other areas, but the interaction of both two drugs is still unclear. The purpose of this study was to evaluate the interaction of the analgesic effects of dezocine and sufentanil in the patients after gynecological laparoscopic surgery. PATIENTS AND METHODS: We conducted a prospective, randomized, double-blinded clinical trial. A total of 150 patients were divided into 5 groups (30 in each group) in the post-anesthesia care unit, namely, dezocine group (Group D), sufentanil group (Group S) and dezocine mixed sufentanil groups (Group DS1-3). In group D and S, the initial dose of dezocine or sufentanil was 5mg and 5µg intravenously, respectively. In Group DS1, the initial dose was dezocine 5mg × 3/4 and sufentanil 5µg × 1/4. In Group DS2, the initial dose was dezocine 5mg × 1/2 and sufentanil 5µg × 1/2. In Group DS3, the initial dose was dezocine 5mg × 1/4 and sufentanil 5µg × 3/4. RESULTS: The median effective dose (ED50) of dezocine and sufentanil alone was 3.92 (95% confidence interval (CI) 3.01~4.64) mg and 3.71 (95% CI 2.78~4.39) µg, respectively. The isobolographic analysis showed that the combination of dezocine and sufentanil at 1:3, 1:1 or 3:1 appeared in the additive line. CONCLUSION: In conclusion, when simultaneously administered intravenously, combined dezocine and sufentanil produce an additive effect for relieving the acute nociception after gynecological laparoscopic surgery.

CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer.

BACKGROUND: The cyclin-dependent kinase 7 (CDK7) subunit of TFIIH regulates RNA polymerase-II-based transcription and promotes tumor progression. However, the mechanisms involved in CDK7-mediated immune evasion are unclear in non-small cell lung cancer (NSCLC). METHODS: RNA silencing and pharmacologic inhibitors were used to evaluate the functions of CDK7/p38α/MYC/PD-L1 axis in cancer cell proliferation and antiPD-1 therapy resistance. Flow cytometry was performed to detect the status of the immune microenvironment after CDK7 inhibition and antiPD-1 therapy in vivo. CD8 depletion antibodies were used to assess the role of CD8+ T cells in combined CDK7 and PD-1 blockade. The associations among CDK7, p38α, MYC, PD-L1, infiltrating T cells, and survival outcomes were validated in two tissue microarrays and public transcriptomic data of NSCLC. RESULTS: High CDK7 mRNA and protein levels were identified to be associated with poor prognosis in NSCLC. CDK7 silencing and CDK7 inhibitor THZ1 elicited apoptosis and suppressed tumor growth. Moreover, CDK7 ablation specifically suppressed p38α/MYC-associated genes, and THZ1 inhibited MYC transcriptional activity through downregulating p38α. CDK7 inhibition sensitized NSCLC to p38α inhibitor. Further, THZ1 suppressed PD-L1 expression by inhibiting MYC activity. THZ1 boosted antitumor immunity by recruiting infiltrating CD8+ T cells and synergized with antiPD-1 therapy. The CDK7/MYC/PD-L1 signature and infiltrating T cell status collectively stratified NSCLC patients into different risk groups. CONCLUSION: These data suggest that the combined CDK7 inhibitor THZ1 and antiPD-1 therapy can be an effective treatment in NSCLC.

Validation and proposed modification of the 8th edition American Joint Committee on Cancer staging system for patients with esophageal neuroendocrine neoplasms: Evaluation of a revised lymph node classification.

There is currently no universally accepted staging system for esophageal neuroendocrine neoplasms (ENENs). In the present study, patients with ENENs, identified from the Surveillance, Epidemiology, and End Results registry (SEER) (n=191 patients) and the multicentric series (n=51 patients), were stratified to assess the validity of the 8th American Joint Committee on Cancer (AJCC) staging systems, particularly for esophageal squamous cell carcinoma and esophageal adenocarcinoma. The Kaplan-Meier method was used to assess disease-specific survival (DSS), according to the Tumor-Node-Metastasis (TNM) status, and the Cox model was applied to evaluate differences in prognosis after adjustment for potential confounders. For the 8th AJCC staging classifications, only the pathological stage groups (pTNM) conferred increased hazard ratios from stage I to stage IV, with overlaps between adjacent stages. According to the current findings, the regional lymph nodes involvement status other than the current N classification was a significant predictor of DSS. Consequently, a revised N(Nr) classification was proposed and therefore a new TNrM staging system was adopted, for which progressively poorer DSS associated with increasing stage was observed. Moreover, the concordance index with the modified staging system was slightly higher in patients with ENENs from the SEER registry compared with that of the 8th pTNM system. In conclusion, lymph node status, rather than the number of positive lymph nodes, was a marker of poorer DSS and the modified staging system provided an easier and more accurate staging tool. The present results indicate that revisions to the current staging classifications may be improve the assessment of patient prognosis.

Development and Validation of a Prognostic Nomogram to Guide Decision-Making for High-Grade Digestive Neuroendocrine Neoplasms.

BACKGROUND: The objective of this study was to develop and validate a nomogram to predict 1-year overall survival (OS) and 2-year OS in patients with high-grade digestive neuroendocrine neoplasms (NENs) as well as to guide selection of subgroups that could benefit from systemic chemotherapy. SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective analysis of 223 patients with NENs of the gut and hepato-biliary-pancreatic system from four centers included in the development cohort. The nomogram was externally validated in a cohort of 90 patients from another one. RESULTS: The final model included lactate dehydrogenase, performance status, stage, Ki67, and site of primary tumor, all of which had a significant effect on OS. The uncorrected C-index was 0.761 for OS, and the bias-corrected C-index was 0.744. Predictions correlated well with observed 1-year and 2-year outcomes (judged by eye). The area under the time-dependent receiver operating characteristic curve at 12 months and 24 months was 0.876 and 0.838, respectively. The nomogram performed well in terms of both discrimination and calibration when applied to the validation cohort, and OS was significantly different between the two groups classified by nomogram score (log-rank p < .001). CONCLUSION: The validated nomogram provided useful prediction of OS, which can be offered for clinicians to improve their abilities to assess patient prognosis, to create clinical risk groups for informing treatment or for patient stratification by disease severity in clinical trials. IMPLICATIONS FOR PRACTICE: The high-grade neuroendocrine neoplasms of the digestive system are rare malignancies with great heterogeneity. An overall survival nomogram was developed and externally validated in this study. Two subgroups were classified by the nomogram score, and platinum-based chemotherapy may not bring clinical benefit for the low-risk patients.