The Novel Tumor Microenvironment-Related Prognostic Gene AIF1 May Influence Immune Infiltrates and is Correlated with TIGIT in Esophageal Cancer.

BACKGROUND: Esophageal carcinoma (EC) is the sixth most common cause of cancer-related mortality worldwide. Studying the associations of the tumor microenvironment (TME) with pathology and prognosis would illustrate the underlying mechanism of prognostic prediction and provide novel targets for immunotherapy in the treatment of EC. METHODS: Transcriptomic profiles of 159 EC patients were obtained from The Cancer Genome Atlas (TCGA) database. Stromal and immune scores were calculated using the ESTIMATE algorithm. Differentially expressed genes (DEGs) were identified by the optimal score cutoff. Functional enrichments were analyzed by DAVID, while prognostic genes were explored using the Kaplan-Meier method. Validation analysis was performed using immunohistochemistry in tissue microarrays containing samples from 145 EC patients. Multiplex immunofluorescence staining was performed to detect a panel of 6 immune markers, including T-cell immunoreceptor with Ig and ITIM domains (TIGIT), in 90 EC patients. RESULTS: Immune scores significantly increased with increasing age, while stromal scores were dramatically elevated with increasing tumor stage. Fifteen TME-related DEGs including allograft inflammatory factor 1 (AIF1) were identified as prognostic factors of EC. Furthermore, the validation cohort indicated that AIF1 was negatively associated with the prognosis of esophageal squamous cell carcinoma patients. Subsequent analyses suggested that AIF1 may affect immune infiltrates, including T cells and natural-killer cells. Moreover, a correlation between AIF1 and TIGIT was identified. CONCLUSIONS: These results indicate that the TME-related gene AIF1 is a promising predictor of prognosis and is related to immune infiltrates and TIGIT expression in EC. However, further mechanistic studies are needed.

Real-world utilization of EGFR TKIs and prognostic factors for survival in EGFR-mutated non-small cell lung cancer patients with brain metastases.

Brain metastases (BMs) cause morbidity and mortality in patients with non-small cell lung cancer (NSCLC). The optimal management of epidermal growth factor receptor (EGFR)-mutated NSCLC with BM is debatable. We aimed to investigate the impact of different treatments among patients with EGFR-mutated NSCLC. A cohort of 2058 lung cancer patients with BM between 2013 and 2018 was retrospectively studied. A total of 571 patients with EGFR-mutated NSCLC and BM were enrolled. All patients had received EGFR tyrosine kinase inhibitors (TKIs). Overall survival (OS) was measured from the diagnosis of BM to death or last follow-up. With a median follow-up of 35.2 months (95% confidence interval [CI], 31.8-38.6), the median survival after BM was 21.3 months (95% CI, 19.0-23.6). Osimertinib resulted in significantly superior survival after resistance to front-line TKIs (P < 0.0035); the median OS reached 28.0 months (95% CI, 23.0-32.9), and the T790M status showed no difference in clinical effectiveness (P = 0.386). The combination of TKIs and chemotherapy/vascular endothelial growth factor (VEGF) inhibitors (anti-VEGF) tended to have longer OS (P = 0.271). Intracranial local radiotherapy significantly improved survival (P = 0.0008). In multivariable analysis, we noted that age, Karnofsky performance score, EGFR mutation type, number of BMs and the presence of extracranial metastasis were independent pretreatment prognostic factors. In conclusion, EGFR TKIs have a significant effect on patients with EGFR-mutant BM, and the application of osimertinib further improves survival outcomes regardless of T790M status. Patients who undergo intracranial local therapy can achieve a survival benefit.

Real-world treatment and prognostic factors for survival in ALK+ non-small cell lung cancer (NSCLC) patients with brain metastases in China.

BACKGROUND: To explore the efficacy and prognostic factors of different treatment modalities on anaplastic lymphoma kinase (ALK)+ non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). METHODS: A total of 86 patients were enrolled into the study. They were divided into two cohorts based on their history of treatment with ALK tyrosine kinase inhibitors (ALK-TKIs) prior to the incidence of BMs. ALK-TKI-naïve patients with BMs were included in cohort 1 (n = 59); patients who developed BMs after ALK-TKIs treatment were enrolled in cohort 2 (n = 27). Prognostic factors related with overall survival (OS) when treated with ALK-TKIs were assessed in multivariable analysis. RESULTS: With a median follow-up of 41.8 months, the median OS was 34.8 months. In cohort 1, the OS, intracranial progression-free survival (iPFS), and progression-free survival (PFS) were 38.7 months (95% CI: 23.3 to 54.1), 18.5 months (95% CI: 9.6 to 27.4), and 19.1 months (95% CI: 13.7 to 24.5), respectively. Significantly improved OS and iPFS were noted in those patients in which second-generation ALK-TKIs versus crizotinib were initiated (OS: not reached vs. 29.0 months, p = 0.040; iPFS: 22.8 vs. 11.9 months, p = 0.035). In cohort 2, patients who experienced BMs as a result of the treatment failure of ALK-TKIs had a median OS of 27.1 months. Considerable duration of stable disease in patients with measurable BMs was observed (iPFS: 11.5 months, 95% CI: 4.4 to 18.6; PFS: 12.2 months, 95% CI: 3.2 to 21.1). CONCLUSION: Second-generation ALK-TKIs further improved the duration of intracranial response and survival in ALK+ NSCLC patients with BMs in a real-world setting. The potent intracranial efficacy of second-generation ALK-TKIs might generate the lowered urgency of local treatment.

Abduction causes increased strain gradient compared to forward flexion: Evidence from a cadaver model of simultaneous strain study of the rotator cuff tendons.

BACKGROUND: Various strain studies of the supraspinatus have been done in isolation. Given that rotator cuff muscles function as a group, it may be physiologically representative to measure strain behaviour with the glenohumeral joint intact. Here, we explored a novel method in measuring simultaneous strain behaviour of the rotator cuff tendons and investigated the effect of full-thickness anterior tear of the supraspinatus on the infraspinatus and subscapularis tendons. METHODS: Nine cadaveric shoulders were evaluated on a customized rig. Using linear differential variable transducers to measure strain, each shoulder was subjected to up to 60° of elevation in the coronal, scapular, and sagittal planes. We also assessed 30° of external rotation and up to 60° of internal rotation of the humerus. Full-thickness anterior tear of the supraspinatus was then made before re-assessing strain patterns in the scapular plane. FINDINGS: Strain measurements of the intact tendons revealed a significant strain gradient between the articular and bursal sides of the supraspinatus during increasing degrees of elevation in the coronal and scapular planes. Full thickness anterior tear of the supraspinatus is localised to the tendon and does not affect the surrounding cuff musculature, with a potential shielding effect of the infraspinatus during early glenohumeral abduction. INTERPRETATION: Significant strain gradient exists between the articular and bursal sides of the supraspinatus during abduction but not during forward flexion in an intact glenohumeral joint. Rehabilitation exercises for anterior supraspinatus tears can be appropriately targeted on the remaining intact rotator cuff musculature.

The Efficacy of PD-1/PD-L1 Inhibitors in Patients with Liver Metastasis of Non-Small Cell Lung Cancer: A Real-World Study.

BACKGROUND: A controversy exists regarding the efficacy of programmed death-1 (PD-1)/ programmed death ligand-1 (PD-L1) inhibitors for patients with non-small cell lung cancer (NSCLC) and liver metastases. Our study retrospectively evaluated the efficacy of PD-1/PD-L1 inhibitors in NSCLC patients with liver metastases. METHODS: This retrospective study included 1627 lung cancer patients who received immunotherapy. Among 648 patients who had advanced NSCLC and received PD-1/PD-L1 inhibitors, 61 had liver metastases and 587 did not have. We analyzed patient characteristics, progression-free survival (PFS) and overall survival (OS). An exploratory analysis of biomarkers including CD4, CD8 and CD68 for efficacy in patients with liver metastases was also performed. RESULTS: In liver metastasis patients receiving PD-1/PD-L1 inhibitors, the objective response rate (ORR) was 29.5%, the disease control rate (DCR) was 72.1%, PFS was 6.4 months and OS was 15.2 months, which were all worse than those of patients without liver metastases (ORR: 35.8%; DCR: 81.8%; PFS: 7.9 months, p = 0.001; OS: 20.6 months, p = 0.008). When compared to non-liver lesions, the ORR (26.2 vs. 39.3%) and DCR (75.4 vs. 88.5%) of liver lesions were lower. During the analysis of PD-L1 expression, 27 PD-L1-positive patients had a longer PFS than 21 patients in the negative group (p = 0.012). Being PD-L1 positive was the independent prognostic indicators for PFS (p = 0.006). Additionally, the PD-L1 and CD8 dual-positive group responded favorably to PD-1/PD-L1 inhibitors. CONCLUSIONS: PD-1/PD-L1 inhibitors are effective in liver metastasis-NSCLC patients. However, the efficacy is inferior when compared to those of patients without liver metastases. In NSCLC patients with liver metastases, PD-L1 expression and CD8+ T cell infiltration can predict the response of PD-1/PD-L1-directed immunotherapy.

Real-world utilization of PD-1/PD-L1 inhibitors with palliative radiotherapy in patients with metastatic non-small cell lung cancer.

BACKGROUND: Programmed cell death protein 1 (PD-1) blockade plus radiotherapy may be a promising strategy to improve the prognosis of patients with metastatic non-small cell lung cancer (NSCLC). However, the optimum combined scheme, treatment time of radiotherapy, and irradiated lesion have not been fully determined. METHODS: A total of 321 metastatic NSCLC patients treated with immunotherapy were identified. Among them, 107 patients received PD-1/PD-ligand 1 (PD-L1) inhibitors with radiotherapy, while the remaining cases did not receive radiotherapy. Data on overall survival (OS), progression-free survival (PFS), treatment response and adverse events were collected. Comparisons based on type of radiation, timing of radiotherapy and number of irradiated lesions were performed. RESULTS: The median OS in PD-1/PD-L1 inhibitors plus radiotherapy was longer than in nonradiotherapy (22.8 vs. 16.6 months, p = 0.022). The median PFS showed a similar trend in this study (9.4 vs. 6.2 months, p = 0.042). Moreover, the combined strategy demonstrated a superior disease control rate and abscopal control rate versus without radiotherapy (both p ≤ 0.001). Further multivariate analysis in the immunotherapy and radiotherapy groups revealed that age below 65 (p = 0.004), Eastern Cooperative Oncology Group performance scores of 0-1 (p = 0.001), oligometastasis (p = 0.006), concurrent combination (p = 0.002), and treated with SRT (p = 0.013) were associated with longer OS. There was a similar incidence of adverse events between the two groups (both p ≥ 0.05). CONCLUSIONS: The combination of PD-1/PD-L1 inhibitors plus palliative radiotherapy demonstrated favorable survival and good tolerability in metastatic NSCLC patients.

Clinical features and prognosis of resectable pulmonary primary invasive mucinous adenocarcinoma.

Background: According to the latest the World Health Organization (WHO) classification in 2015, invasive mucinous adenocarcinoma (IMA) is defined as a new pathological subtype of lung adenocarcinoma (LUAD). However, whether this rare subtype of lung pathology has any difference in prognosis than conventional LUAD is debatable. Our study attempted to compare clinical characteristics and prognosis of IMA vs. noninvasive mucinous adenocarcinomas (NMA). Methods: A total of 1,857 patients with LUAD who underwent radical resection were screened from 2010 to 2015 at Zhejiang Cancer Hospital. Patients with pulmonary IMA were matched 1:1 by using propensity scores with LUAD adjusted for clinicopathological characteristics. After follow-up, overall survival (OS) and disease-free survival (DFS) were explored by Kaplan-Meier and Cox regression analyses. Forest plots were used for subgroup analyses. Results: Following screening, 499 patients with LUAD were enrolled, with 97 IMA and 402 NMA. Compared to NMA of the lung, IMA was proportionately lower in women (50.5% vs. 63.4%; P=0.026) and nonsmokers (P<0.001). IMA was also associated with earlier tumor stage I (68.0% vs. 55.5%; P=0.033) and lower frequency of upper lobe tumors compared to NMA (P=0.007). Following propensity score matching, 97 pairs were selected, among which we found that patients with pulmonary IMA had a longer OS than those with NMA (P=0.014). According to the subgroup analysis, improved OS in the IMA cohort versus the NMA cohort was observed across various factors, including the absence of lymphovascular invasion or perineural invasion. Conclusions: In this study, we found that resectable IMA patients had a better OS than NMA patients. This study contributes to the understanding of IMA in depth, but it needs to be validated through additional multicenter studies.

The correlation between the abundance of EGFR T790M mutation and osimertinib response in advanced non-small cell lung cancer.

BACKGROUND: Osimertinib has been adopted as the standard therapy for T790M-mediated acquired resistance to first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC). The detection of EGFR T790M can be evaluated using different methods. The association between baseline T790M abundance and osimertinib efficacy has not been fully determined. METHODS: A total of 144 advanced NSCLC patients positive for T790M, at the time of progression, were retrospectively enrolled in this study. The effect of abundance of T790M mutation on the efficacy of osimertinib was explored. RESULTS: Among the 144 patients receiving T790M testing, 20 (13.9%) had adopted amplification refractory mutation system (ARMS), 63 (43.8%) adopted droplet digital PCR (ddPCR), and 61 (42.4%) used next-generation sequencing (NGS). The objective response rate was 54.2%, the median progression-free survival was 12.0 months, and the overall survival was 23.0 months for the NSCLC patients treated with osimertinib. Three different technologies to assess T790M mutation (including ARMS, ddPCR, and NGS) could accurately predict the efficacy of osimertinib. There was no significant relationship between the abundance of T790M mutation and the efficacy of osimertinib. CONCLUSIONS: ARMS, ddPCR, and NGS are reliable methods to evaluate EGFR T790M mutation. Osimertinib was equally effective for NSCLC patients with various abundance of T790M mutation.

Efficacy of PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer and brain metastases: A real-world retrospective study in China.

BACKGROUND: There is only limited knowledge of the treatment responses and clinical outcomes of immune checkpoint inhibitors (ICIs) in driver gene-negative non-small cell lung cancer (NSCLC) patients with brain metastases (BM). This study aims to assess the efficacy of immunotherapy in these patients in a real world setting. METHODS: NSCLC-BM patients without driver gene mutations who received ICIs were retrospectively identified between July 2017 and December 2019. The primary observation endpoint was intracranial objective response rate (iORR), and secondary objectives were objective response rate (ORR), intracranial and systemic progression-free survival (iPFS, PFS), and overall survival (OS). RESULTS: We reviewed 1578 patients with lung cancer and BM. According to the exclusion criteria, 41 patients were finally enrolled. Among these 41 patients, iORR was 36.6% (95% confidence interval [CI] = 21.2%-52.0%), whereas iPFS was 6.8 (95% CI = 3.32-10.35) months. Additionally, ORR, PFS, and OS were 24.4% (95% CI = 10.7%-38.1%), 6.2 (95% CI = 4.57-7.83) months and 13.7 (95% CI = 11.20-16.26) months, respectively. ICIs combined with concurrent radiotherapy group exhibited preferred iORR (p = 0.030) compared with no radiotherapy group, and ICIs plus chemotherapy showed improved OS (p = 0.024) compared to ICI monotherapy. Moreover, the lines of ICI treatment ≥2 (p = 0.005) and derived neutrophil-to-lymphocyte ratio (dNLR) ≥3 (p = 0.010) were independently negative factors for OS. CONCLUSION: In NSCLC-BMs patients lacking driver genes, ICIs exhibited an effective drug regime. A combination of ICIs with concurrent radiotherapy showed a better intracranial response, whereas ICIs plus chemotherapy were associated with superior OS.

Association Between the Prognostic Nutritional Index and Cognitive Function Among Older Adults in the United States: A Population-Based Study.

BACKGROUND: Nutritional status has been recognized as an important factor influencing cognitive function-related diseases, but few comprehensive nutrition indicators are available to assess the risk of cognitive decline. OBJECTIVE: This study aimed to investigate the relationship between the prognostic nutritional index (PNI) and cognitive function in an elderly population, and the differences in nutrient intake between different levels of nutritional risk. METHODS: Based on cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014, we included 2,564 older participants. The lower quartile of each of the four cognitive tests was considered to have cognitive function impairment (CFI). Binary and multivariate logistic regression models were used to estimate the relationship between the PNI and the odds ratio of CFI. RESULTS: After adjustment for confounding variables, we found that the odds of CFI were significantly lower for participants with normal PNI levels than for those with low PNI levels. In a comparison of global cognitive impairment scores, participants with a normal PNI had lower ratios of poor cognitive performance than those with a low PNI. By comparing the nutrient intake at different PNI levels, we found a reduction in the intake of protein, dietary fiber, total saturated fatty acids, and multiple micronutrients in the low PNI group. CONCLUSION: Our study shows that the PNI can be a good predictor of the odds of CFI in the elderly population and that it is a convenient indicator of reduced intake of nutrients which may be important to brain health.

[Progress of Immunotherapy Mechanisms and Current Evidence of PD-1/PD-L1 
Checkpoint Inhibitors for Non-small Cell Lung Cancer with Brain Metastasis].

Brain metastasis (BM) is a common complication in non-small cell lung cancer (NSCLC), which associates with poor prognosis. Recently, immune checkpoint inhibitors (ICIs) has revolutionized the treatment of tumors. Programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors could produce antitumor effect by activating the autoimmune system. The immunotherapy has already show to have a promising outcome for NSCLC patients with BM, while its specific curative effect and the most ideal mode of the treatment remain to be explored. Here we reviewed the tumor microenvironment (TME) in BM lesions and summarized the role of PD-1/PD-L1 inhibitors in cerebral and its current status in clinical studies.
.

Predictive values of genomic variation, tumor mutational burden, and PD-L1 expression in advanced lung squamous cell carcinoma treated with immunotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) prolong overall survival (OS) in patients with advanced lung squamous cell carcinoma (LUSC). However, predictive and prognostic factors related to ICIs in LUSC remain elusive. This study aimed to identify predictors that are related to better clinical benefit and outcomes in LUSC patients treated with immunotherapy. METHODS: Capture-based targeted sequencing was performed in 64 patients with advanced LUSC who underwent immunotherapy. Tumor mutational burden (TMB) was defined as the sum of nonsynonymous single nucleotide and indel variants. Programmed cell death ligand-1 (PD-L1) expression was evaluated by immunohistochemical analysis. Clinicopathological characteristics including age, sex, performance status, smoking history, body mass index (BMI), blood fat, brain metastases, liver metastases, previous thoracic radiotherapy, and treatment lines were analyzed. RESULTS: The most commonly mutated genes included TP53, CDKN2A, KEAP1, CREBBP, KRAS, BIM, AMER1, and APC. Copy number variations most frequently occurred in AR, SOX2, PIK3CA, EGFR, RICTOR, FGFR1, and ZNF703. The median and mean TMB was 9.35 and 10.62 mutations per megabase, respectively. Positive PD-L1 expression was detected in 29.7% patients. Patients with a history of heavy smoking (≥ 40 pack-years) were more likely to have positive PD-L1 expression (35% vs. 16.7%, P=0.04) and higher TMB (11.1 vs. 9.8 mut/Mb, P=0.04). Gene alterations had no impact on PD-L1 expression or TMB level. The median progression-free survival (PFS) was 6.7 months and median OS was 13.7 months. Higher TMB was independently associated with longer PFS (P=0.01) and OS (P=0.02), and this correlation was more pronounced in patients treated with ICIs as a single agent (P=0.0001). Higher TMB was also associated with better disease control rate (DCR) (P=0.02). Compared with wild-type, patients with KRAS mutation and EGFR amplification had higher objective response rates (ORR, P=0.01). CONCLUSIONS: The predictive value of TMB is more significant in LUSC patients receiving ICI as a single agent than as a combination therapy. The combination of Eastern Cooperative Oncology Group performance status (ECOG-PS), smoking status, TMB, PD-L1, and genomic variation might be helpful for personalized immunotherapy decisions in clinical practice for advanced LUSC.

Carbonic Anhydrase 12 Protects Endplate Cartilage From Degeneration Regulated by IGF-1/PI3K/CREB Signaling Pathway.

Lumbar intervertebral disc degeneration (IVDD) is the most common cause of low back pain (LBP). Among all the factors leading to IVDD, lumbar cartilage endplate (LCE) degeneration is considered a key factor. In the present study, we investigate the effect and regulation of carbonic anhydrase 12 (CA12) in LCE, which catalyzes hydration of CO2 and participates in a variety of biological processes, including acid-base balance and calcification. Our results show that CA12, downregulated in degenerated LCE, could maintain anabolism and prevent calcification in the endplate. Furthermore, CA12 is regulated by the IGF-1/IGF-1R/PI3K/CREB signaling pathway. When we overexpressed CA12 in LCE, the decreased anabolism induced by inflammatory cytokine could be rescued. In contrast, reducing CA12 expression, either with siRNA, PI3Kinhibitor, or CREB inhibitor, could downregulate anabolism and cause apoptosis and then calcification in LCE. The protective effects of IGF-1 are even diminished with low-expressed CA12. Similar results are also obtained in an ex vivo model. Consequently, our results reveal a novel pathway, IGF-1/IGF-1R/PI3K/CREB/CA12, that takes a protective role in LCE degeneration by maintaining anabolism and preventing calcification and apoptosis. This study proposes a novel molecular target, CA12, to delay LCE degeneration.