Indicator Of Overall Survival Research Articles

Very high PD-L1 expression as a prognostic indicator of overall survival among patients with advanced non-small cell lung cancer receiving anti-PD-(L)1 monotherapies in routine practice.

Programmed death or ligand-1 (PD-(L)1) pathway inhibitors confer improved survival as the first-line treatment for advanced non-small cell lung cancer (aNSCLC) in patients with PD-L1 expression (PD-L1 + e ≥ 50%) compared to platinum-doublet chemotherapy and have become a standard therapy. Some recent evidence suggests that among aNSCLC patients with PD-L1 + e of ≥50% receiving pembrolizumab monotherapy, very high levels of PD-L1 + e (≥90%) may be associated with better outcomes. We sought to assess whether very high PD-L1 + e (≥90%) compared to high PD-L1 + e (50%-89%) is associated with an overall survival benefit in aNSCLC patients receiving anti-PD-(L)1 monotherapies. We conducted a single-site retrospective cohort study of aNSCLC patients who initiated PD-(L)1 inhibitor monotherapy as the first-line treatment from October 24, 2016, to August 25, 2021, and had a PD-L1 + e ≥ 50%. The primary outcome was overall survival, measured from the start of the first-line PD-(L)1 inhibitor monotherapy (index date) to date of death or last confirmed activity prior to the cohort exit date. Propensity score-based inverse probability weighting (IPW) was used to control for confounding in Kaplan-Meier curves and Cox proportional hazard regression analysis. One hundred sixty-six patients with aNSCLC receiving PD-(L)1 inhibitor monotherapy met inclusion criteria. 54% were female, 90% received pembrolizumab, median age was 68 years, 70% had non-squamous cell carcinoma, 94% had a history of smoking, 29% had a KRAS mutation, and 37% had very high PD-L1 + e. Unweighted covariates at cohort entry were similar between groups (absolute standardized mean differences [SMDs] <0.1) except for race (SMD=0.2); age at therapy initiation (SMD=0.13); smoking status (SMD=0.13), and BRAF mutation status (SMD=0.11). After weighting, baseline covariates were well balanced (all absolute SMDs <0.1). In the weighted analysis, having a very high PD-L1 + e was associated with lower mortality (weighted hazard ratio 0.57, 95% CI 0.36-0.90) and longer median survival: 3.85 versus 1.49 years. Very high PD-L1 + e (≥90%) was associated with an overall survival benefit over high PD-L1 + e (50%-89%) in patients receiving the first-line PD-(L)1 inhibitor monotherapy in a model controlling for potential confounders. These findings should be confirmed in a larger real-world data set.

Abstract 6350: Very high PD-L1 expression as a prognostic indicator of overall survival amongst advanced non-small cell lung cancer patients receiving anti PD-(L)1 monotherapies in the first line setting: An IPW weighted health system analysis

Abstract Background Programmed death or ligand-1 (PD-(L)1) pathway inhibitors, a type of immunotherapy (IO), have become a standard anti-tumor strategy for advanced non-small cell lung cancer (aNSCLC) resulting in improved survival compared to platinum-doublet chemotherapy in PD-L1 expression (PD-L1+e ≥50%) in the 1L treatment setting. Limited evidence to suggest that amongst aNSCLC patients with PD-L1+e of 50%-100%, very high levels of PD-L1e (≥90%) would have any additional prognostic value leading to improved outcomes. Identifying additional PDL1+e cutoffs in aNSCLC with PDL1+e of 50%-100% would help treatment selection in routine practice as well as future IO clinical trials design ensuring trial groups are evenly balanced based on PD-L1+e levels. Objective To assess very high PD-L1+e (≥90%) as a prognostic indicator of overall survival in aNSCLC patients with PDL1+e ≥50% receiving anti PD-(L)1 monotherapies, using a single university EMR based health database. Methods Cohort study of aNSCLC patients, who initiated IO monotherapy in the 1L treatment setting from October 2016, to August 2021, and had a PDL1+e ≥ 50%. This study was conducted in the University of Pennsylvania Health System. Patients with incomplete treatment data or those harboring sensitizing alterations in EGFR, ALK, or ROS1 genes were excluded. The primary outcome was overall survival, measured from the start of 1L IO monotherapy (index date) to date of death or last confirmed activity. Propensity score-based inverse probability weighting (IPW) was used to address confounding in KM curves and Cox hazard regression. Baseline characteristics included age at therapy initiation, race, gender, smoking status, tumor histology, presence of KRAS or BRAF mutation, and ECOG PS. Results 196 aNSCLC receiving IO monotherapy met the inclusion criteria; n=30 had missing ECOG PS. 53% of the cohort were female, the median age at therapy initiation was 68 years, 72% had non-squamous cell carcinoma with 92% having a history of smoking, 28% had a KRAS mutation, and 37% had very high PDL1+e. Covariates were well balanced between groups after IPW weighting (all │standardized differences│&amp;lt;0.1). 92% received Pembrolizumab IO monotherapy. Median overall survival was 3.85 years (v high -PDL1+e) vs 1.52 years (high -PDL1+e), respectively. In the complete case analysis (n=166), having a very high PDL1+e (HR 0.57, 95% CI 0.36-0.90) was associated with lower mortality. Study limitations include the potential for unmeasured confounding and potentially limited generalizability. Conclusion Patients with aNSCLC having very high PDL1+e (≥90%) receiving IO monotherapy appear to have improved survival in the 1L setting. These findings should be confirmed in a larger real-world data set. Citation Format: Mohsin Shah, Rebecca A. Hubbard, Ronac Mamtani, Sean Hennessy. Very high PD-L1 expression as a prognostic indicator of overall survival amongst advanced non-small cell lung cancer patients receiving anti PD-(L)1 monotherapies in the first line setting: An IPW weighted health system analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6350.

Transmembrane Protein 170B is a Prognostic Biomarker and Associated With Immune Infiltrates in Pancreatic Adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) is among the most common types of cancer with a poor prognosis. Transmembrane protein 170B (TMEM170B) has been reported to suppress breast cancer proliferation, metastasis, and tumorigenesis and is related to prognosis. However, its role in PAAD and the underlying molecular mechanisms are yet to be investigated. Patients and methods: We performed a comprehensive analysis of RNA sequencing data obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases to determine TMEM170B expression. Immunostaining and real-time polymerase chain reaction (RT-PCR) were done to determine TMEM170B expression in human pancreatic cancer cell lines and tissue specimens. Furthermore, the correlation of TMEM170B with clinicopathological features and PAAD prognosis was investigated, and the mechanisms were explored through enrichment analysis and immune cell infiltration analysis. Results: TCGA and GEO dataset analysis revealed that TMEM170B expression in PAAD tissue samples was significantly lower than that in non-tumorous tissues, which was further confirmed by immunohistochemistry and RT-PCR. Low TMEM170B expression was associated with poor differentiation (p = 0.014). Multivariate analysis identified that TMEM170B is an independent indicator for overall survival [hazard ratio (HR) = 0.116, 95% confidence interval (CI) = 0.014–0.995; p = 0.049] and disease-free survival (HR = 0.19, 95% CI = 0.04–0.910; p = 0.038) in patients with PAAD. Additionally, TMEM170B was involved in immune-related gene sets, including those related to chemokine signaling pathways and innate and adaptive immunity. High TMEM170B expression was linked to antitumor immune microenvironment with a high infiltration of B cells, T cells, dendritic cells, monocytes, M1 macrophages, neutrophil, and natural killer cells and a low infiltration of Tregs and myeloid-derived suppressor cells (all p < 0.05). Plain Language Summary: There is an urgent need to identify clinical prognostic biomarkers and targeted drugs for pancreatic cancer treatment. In this study, the expression status and prognostic value of transmembrane protein 170B (TMEM170B) in pancreatic adenocarcinoma were elucidated. Furthermore, TMEM170B, as a tumor suppressor gene, induced antitumor immune effects, including increased tumor infiltration of immune effector cells and reduced levels of inhibitory immune molecules and regulatory cells. Therefore, TMEM170B could be regarded as a novel target in preventing the progression of pancreatic cancer. Conclusion: The findings suggest that low TMEM170B expression is remarkably correlated with poor PAAD prognosis, which might provide a therapeutic target for PAAD.

LINC00668 is Highly Expressed in Lung Squamous Cell Carcinoma and Promotes Tumor Cell Migration and Invasion

背景与目的由于缺乏有效的治疗措施，肺鳞癌(lung squamous cell carcinoma, LUSC)仍是制约非小细胞肺癌(non-small cell lung cancer, NSCLC)5年生存率的重要影响因素。长链非编码RNA 00668(LINC00668)参与调控多种肿瘤的发生发展，但其在LUSC中的研究尚不完善。本研究旨在探讨LINC00668在NSCLC特别是LUSC中的预后价值及生物学功能。方法本研究利用癌症基因组图谱(The Cancer Genome Altas, TCGA)数据库分析了LINC00668在NSCLC特别是LUSC中的表达模式及其与患者临床特征和预后的关系; 并通过体外实验探索了其在LUSC细胞中的功能。结果LINC00668在LUSC组织中高表达，并与患者的肿瘤原发灶-淋巴结-转移(tumor-node-metastasis, TNM)分期显著相关。同时，LINC00668在吸烟患者中的表达量明显升高，并与吸烟LUSC患者的总生存期(overall survival, OS)显著相关。体外实验显示，相较于正常支气管上皮细胞和癌旁组织，LINC00668在LUSC细胞系和组织样本中表达量显著升高; 同时，在LUSC细胞系中敲低LINC00668可有效抑制细胞的侵袭转移能力。结论LINC00668可能与肺鳞癌发生发展密切相关，抑制LINC00668可在一定程度上减少LUSC的转移。

Grading of endocervical adenocarcinoma: a novel prognostic system based on tumor budding and cell cluster size

A novel 3-tiered grading system based on tumor budding activity and cell nest size has been validated to be highly prognostic in organ-wide squamous cell carcinomas. In this study, we applied a similar grading system with slight modification to assess the prognostic value in an institutional cohort of well annotated endocervical adenocarcinomas (EAC) consisting of 398 consecutive cases with surgical resection, no neoadjuvant chemotherapy, and higher than stage pT1a. Each case was reviewed by the International Endocervical Adenocarcinoma Criteria and Classification (IECC) and Silva pattern classification, and scored on tumor budding activity and cell cluster size to form the basis of a novel grading system. High budding activity, small tumor cell cluster size, and novel grade 3 were more frequently associated with a decreased overall survival time and tumor recurrence time (p < 0.001), and several other clinicopathologic factors including HPV-independent adenocarcinoma, lymphovascular invasion, lymph node metastasis, advanced FIGO stage, and Silva pattern C (p < 0.05). Moreover, the novel grading system was helpful in stratifying overall survival in HPV-associated adenocarcinoma (p = 0.036) and gastric-type adenocarcinoma (p = 0.033). On multivariate analysis, novel grade 3 was an adverse indicator for overall survival and tumor recurrence independently of age and FIGO stage (p < 0.05). By comparison, Silva pattern C was only associated with tumor relapse (p = 0.020) in HPV-associated adenocarcinomas whereas the conventional FIGO system was not associated with overall survival and tumor recurrence in EAC (p > 0.05). In conclusion, our study demonstrates that the grading system based on tumor budding activity and cell cluster size is robust in prognostic assessment that outperforms the conventional FIGO grading and Silva pattern classification in EAC. The novel grading system, if further validated, could be applicable in routine pathologic descriptions of EAC by providing useful information in clinical decision-making.

Total Number of Lymph Nodes in Neck Dissection and its Relation to Cancer-Positive Lymph Nodes as a Prognostic Indicator in Aerodigestive Tract Cancers

<h3>Purpose/Objective(s)</h3> Few studies have been conducted on the total number of lymph nodes (LNs) in neck dissection and the lymph node ratio (LNR; number of positive LNs divided by number of excised LNs), or their potential use as a prognostic indicator for cancers of the upper aerodigestive tract (UADT) and its treatment. We aimed to measure the number of LNs dissected and the LNR to assess their prognostic value for cancers of the UADT, as well as their effect on overall survival and disease-free survival. <h3>Materials/Methods</h3> We performed a retrospective study of patients diagnosed with cancer of the UADT who underwent neck dissection as the primary or secondary modality of their treatment plan at King Abdulaziz University Hospital and the National Guard Hospital, Jeddah, Saudi Arabia. Data were collected through medical records and analyzed to assess prognosis and calculate survival rates in relation to the number of LNs and LNR. <h3>Results</h3> A total of 121 patients were included:14 women (11.57%) and 107 men (88.43%). The median age was 60 years and the mean follow-up period 2.7 years. Of the malignancies, 44.63%were of the oral tongue and 35.54% were laryngeal. A median of 38 LNs were dissected during neck dissections. The distribution of the individual LNRs was characterized by mean values. A mean LNR of 0.04 was considered the cutoff value, an LNR of >0.04 a high LNR, and an LNR of <0.04 a low LNR. Kaplan-Meier survival estimates for the cohort showeda3-year overall survival rate of 88% (95%confidence interval [CI]: 77% to 94%) for patients with a low LNR, but 71% (95% CI: 47% to 85%) for patients with a high LNR, which was statistically significant. A similar significant decreasing trend persisted at the 4-yearfollow-up, where the disease-free survival rate was 73% (95% CI: 61% to 82%) for patients with a low LNR compared with 56% (95% CI: 35% to 72%) for patients with a high LNR. <h3>Conclusion</h3> The number of excised LNs in neck dissections and the LNR might be a good prognostic indicator for overall survival and disease-free survival in patients with cancers of the UADT and may serve as a valuable tool in deciding on different treatment plans.

Exploration of Potential Roles of m5C-Related Regulators in Colon Adenocarcinoma Prognosis.

Objectives: The purpose of this study was to investigate the role of 13 m5C-related regulators in colon adenocarcinoma (COAD) and determine their prognostic value. Methods: Gene expression and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) datasets. The expression of m5C-related regulators was analyzed with clinicopathological characteristics and alterations within m5C-related regulators. Subsequently, different subtypes of patients with COAD were identified. Then, the prognostic value of m5C-related regulators in COAD was confirmed via univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. The prognostic value of risk scores was evaluated using the Kaplan-Meier method, receiver operating characteristic (ROC) curve. The correlation between the two m5C-related regulators, risk score, and clinicopathological characteristics were explored. Additionally, Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and Gene Ontology (GO) analysis were performed for biological functional analysis. Finally, the expression level of two m5C-related regulators in clinical samples and cell lines was detected by quantitative reverse transcription-polymerase chain reaction and through the Human Protein Atlas database. Results: m5C-related regulators were found to be differentially expressed in COAD with different clinicopathological features. We observed a high alteration frequency in these genes, which were significantly correlated with their mRNA expression levels. Two clusters with different prognostic features were identified. Based on two independent prognostic m5C-related regulators (NSUN6 and ALYREF), a risk signature with good predictive significance was constructed. Univariate and multivariate Cox regression analyses suggested that the risk score was an independent prognostic factor. Furthermore, this risk signature could serve as a prognostic indicator for overall survival in subgroups of patients with different clinical characteristics. Biological processes and pathways associated with cancer, immune response, and RNA processing were identified. Conclusion: We revealed the genetic signatures and prognostic values of m5C-related regulators in COAD. Together, this has improved our understanding of m5C RNA modification and provided novel insights to identify predictive biomarkers and develop molecular targeted therapy for COAD.

IL4Rα and IL13Rα1 Are Involved in the Development of Human Gallbladder Cancer.

Background: Gallbladder cancer is commonly associated with inflammation, which indicates that inflammation-related cytokines and cytokine receptors are related to the progression of gallbladder cancers. Interleukin 4 (IL4) is a well-known cytokine that promotes the differentiation of naive helper T cells (Th0) to T helper type 2 cells (Th2). IL13 is a cytokine that is secreted by Th2 cells. IL4 and IL13 are closely related in immune responses. However, the role of IL4Rα and IL13Rα1 signaling pathway has not been fully understood in the development of gallbladder cancer. Methods: In human gallbladder carcinomas, the expression of IL4Rα and IL13Rα1 were evaluated with immunohistochemical staining in tissue microarray tissue sections. After knockdown of IL4Rα or IL13Rα1, cell assays to measure the proliferation and apoptosis and Western blotting analysis were conducted in SNU308 human gallbladder cancer cells. Since Janus kinases2 (JAK2) was considered as one of the down-stream kinases under IL4Rα and IL13Rα1 complex, the same kinds of experiments were performed in SNU308 cells treated with AZD1480, Janus-associated kinases2 (JAK2) inhibitor, to demonstrate the cytotoxic effect of AZD1480 in SNU308 cells. Results: Immunohistochemical expression of IL4Rα was significantly associated with the expression of IL13Rα1 in human carcinoma tissue. In univariate analysis, nuclear expression of IL4Rα, cytoplasmic expression of IL4Rα, nuclear expression of IL13Rα1, and cytoplasmic expression of IL13Rα1 were significantly associated with shorter overall survival and shorter relapse-free survival. Multivariate analysis revealed nuclear expression of IL4Rα as an independent poor prognostic indicator of overall survival and relapse-free survival. Then, we found that knockdown of IL4Rα or IL13Rα1 decreased viability and induced apoptosis in SNU308 cells via activation of FOXO3 and similarly, AZD1480 decreased viability and induced apoptosis in SNU308 cells with dose dependent manner. Conclusions: Taken together, our results suggest that IL4Rα and IL13Rα1 might be involved in the development of human gallbladder cancer cells and IL4Rα and IL13Rα1 complex/JAK2 signaling pathway could be efficient therapeutic targets for gallbladder cancer treatment.

Prognostic significance of Naples prognostic score in non-small-cell lung cancer patients with brain metastases.

Aims: The authors aimed to evaluate the prognostic value of Naples prognostic score (NPS) in advanced non-small-cell lung cancer patients with brain metastases. Materials & methods: A total of 186 consecutive advanced non-small-cell lung cancer patients were retrospectively analyzed. Kaplan-Meier survival analysis and Cox proportional regression models were used to assess the significance of NPS in overall survival and disease-free survival. Results: Multivariate Cox proportional regression analysis revealed that NPS was a significant independent predictive indicator for overall survival (hazard ratio: 1.897; 95% CI: 1.184-3.041; p=0.008) and disease-free survival (hazard ratio: 2.169; 95% CI: 1.367-3.44; p=0.001). Conclusion: NPS was a powerful prognostic indicator for outcome in advanced non-small-cell lung cancer patients with brain metastases.

Perirenal Fat as a New Independent Prognostic Factor in Patients With Surgically Treated Clear Cell Renal Cell Carcinoma.

Recently increasing evidence has suggested that obesity is associated with the development and prognosis of renal cell carcinoma. The aim of the study was to investigate the association between different obesity measurements and overall survival in patients with surgically treated clear cell renal cell carcinoma. The data of 342 consecutive patients who underwent radical or partial nephrectomy at Peking University People's Hospital from January 2009 to November 2014 were retrospectively reviewed. Median follow-up was 82 months. The association between different obesity measurements and overall survival was evaluated using the Kaplan-Meier method and Cox regression models. In univariate Cox regression analyses, perirenal fat accumulation was significantly associated with overall survival (HR: 2.271; 95% CI: 1.311-3.935; P = .003), as well as age, sex, clinical manifestation, surgical option, tumor size, and grade. The other obesity measurements, including body mass index, waist circumference, total adipose tissue, visceral adipose tissue, and percentage of visceral adipose tissue, were not assessed as prognostic indicators of overall survival in this study (P > .05). After adjusting for age, sex, clinical manifestation, surgical option, tumor size, T stage, and tumor grade, perirenal fat accumulation was still identified as an independent predictor of overall survival (HR: 2.264; 95% CI: 1.305-3.926; P==.004). The results of Kaplan-Meier model also revealing that patients with higher percentage of perirenal fat showed poorer overall survival (P==.003). Higher percentage of perirenal adipose tissue is independently associated with increased mortality risk in surgically treated clear cell renal cell carcinoma.

ARID1A Is a Prognostic Biomarker and Associated with Immune Infiltrates in Hepatocellular Carcinoma.

Objective ARID1A has been discovered as a potential cancer biomarker. But its role in hepatocellular carcinoma (HCC) is subject to considerable dispute. Methods The relationship between ARID1A and clinical factors was investigated. Clinicopathological variables related to overall survival in HCC subjects were identified using Cox and Kaplan–Meier studies. The connection between immune infiltrating cells and ARID1A expression was investigated using the tumor Genome Atlas (TCGA) dataset for gene set enrichment analysis (GSEA). Finally, a cell experiment was used to confirm it. Results The gender and cancer topography (T) categorization of HCC were linked to increased ARID1A expression. Participants with advanced levels of ARID1A expression had a worse prognosis than someone with lower levels. ARID1A was shown to be a risk indicator of overall survival on its own. ARID1A expression is inversely proportional to immune cell infiltration. In vitro, decreasing ARID1A expression substantially slowed the cell cycle and decreased HCC cell proliferation, migration, and invasion. Conclusion The expression of ARID1A could be used to predict the outcome of HCC. It is closely related to tumor immune cell infiltration.

Modified microvessel density based on perfusion distance: a preferable NSCLC prognostic factor.

BackgroundDespite the vital role of blood perfusion in tumor progression, the prognostic value of typical blood perfusion markers, such as microvessel density (MVD) or microvessel area (MVA), in patients with non-small cell lung cancer (NSCLC) is still unclear. This study established a modified MVD (mMVD) measurement based on perfusion distance and determined its prognostic value in patients with NSCLC.MethodsA total of 100 patients with NSCLC were enrolled in this retrospective study. The intratumor microvessels of NSCLC patients were visualized using immunohistochemical staining for CD31. The blood perfusion distance was evaluated as the distance from each vessel to its nearest cancer cell (Dmvcc), and the cutoff value for prognosis was determined. Apart from the total MVD (tMVD), microvessels near cancer cells within the cutoff-Dmvcc were counted as mMVD. Predictive values for mortality and recurrence were evaluated and compared.ResultsThe Dmvcc ranged from 1.6 to 269.8 µm (median, 13.1 µm). The mMVD (range: 2–70; median 23) was counted from tMVD according to the cutoff-Dmvcc (~20 µm). Compared with tMVD, a larger fraction of mMVD (80% vs. 2.9%) played a significant role in overall survival, with an improved area under the receiver operating characteristic (ROC) curve (AUC) (0.74 vs. 0.56). A high mMVD was an independent positive indicator of overall survival (OS) and progression-free survival (PFS). In contrast, tMVD was only related to PFS at the optimal cutoff.ConclusionsPerfusion-distance-based mMVD is a promising prognostic factor for NSCLC patients with superior sensitivity, specificity, and clinical applicability compared to tMVD. This study provides novel insights into the prognostic role of tumor vessel perfusion in patients with NSCLC.

Prognosis and Biological Function of miR-3195 in Non-Small Cell Lung Cancer.

PurposeLung cancer has the highest mortality and morbidity rates worldwide. Among the subtypes of lung cancer, non-small cell lung cancer (NSCLC) accounts for approximately 85% of cases. The present study evaluated the potential prognostic value and biological function of miR-3195 in NSCLC.Patients and MethodsIn total, 129 patients with NSCLC were enrolled in this study. The expression of miR-3195 expression in NSCLC tissues and cell lines was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan–Meier survival curve analysis and multivariate Cox regression analysis were used to elucidate the prognostic value of miR-3195. The Cell Counting Kit-8 (CCK-8) assay and Transwell cell migration experiments were carried out to explore the effective effect of miR-3195 on the biological behavior of NSCLC cells.ResultsThe expression of miR-3195 was downregulated in NSCLC tissues and cell lines. Moreover, the decreased expression of miR-3195 was correlated with positive lymph node metastasis and high TNM stage. The overall survival of patients with low expression of miR-3195 was worse than those with high expression of miR-3195. Furthermore, miR-3195 was an independent prognostic indicator for overall survival in patients with NSCLC. Enhanced expression of miR-3195 restrained cell growth, migration, and invasion of NSCLC tumor cells, while attenuation of miR-3195 expression augmented cell proliferation activities, migration, and invasion potential.ConclusionOur findings suggest that miR-3195 may be used as a prognostic biomarker for NSCLC and is likely to act as a tumor suppressor for NSCLC.

Surrogate Indicators of Overall Survival in Advanced Hepatocellular Carcinoma

To the Editor, For more than a decade, the targeted drug sorafenib[1, 2] has been the dominant first-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, due to the low overall response rate and high drug resistance rate, many new targeted drugs have been developed, including sunitinib, brivanib, linifanib, nintedanib, dovitinib, sorafenib plus erlotinib, lenvatinib, and donafenib. On the other hand, with the increasing use of immune checkpoint inhibitors in solid tumors, several trials investigated the efficacy and safety of immune checkpoint inhibitors in advanced HCC. Among these trials, only lenvatinib and donafenib as monotherapy were non-inferior to sorafenib in overall survival in untreated advanced HCC. Most of other trials did not meet their primary end point of overall survival. However, the efficacy of the combination therapy with PD-1 or PD-L1 inhibitor plus bevacizumab (VEGF inhibitor) is amazing.[3, 4] An expert panel convened by the American Association for the Study of Liver Diseases recommended time to progression as the primary endpoint in randomized phase 2 trials and overall survival as the main endpoint to measure effectiveness in phase 3 trials.[5, 6] In real world clinical practice, subsequent antitumor therapies after tumor progression and/or therapies for concurrent liver disease can confound the assessment of clinical benefit. In the recent issue of Journal of Hepatology, on behalf of EASL, Bruix and coworkers updated the recommendations of systemic treatment of HCC.7 This review proposed that “overall survival is the sole robust endpoint to assess the benefit from any intervention in advanced HCC” and “all proposed surrogates lack adequate validation”. Here, we tried to reveal the relationship among objective response rate (ORR), median overall survival (OS) time and median progression-free survival (PFS) time by presenting them in a same curve graph. The potential relationship between PFS and OS is revealed by representing the hazard ratio (with 95% confidence interval) of PFS and OS with a forest plot. We systematically searched PubMed and EMBASE databases and analyzed phase 3 clinical trials with large sample size. A total of 11 trials about first-line systemic therapies for advanced HCC published from 2008 to 2021 were included into analysis. All these 11 trials included a group of patients treated with sorafenib. In addition, 7 trials about second-line systemic therapies published from 2015 to 2021 were also included into analysis. The control group received placebo treatment in all these 7 trials. All these 18 trials reported ORR, median PFS and OS time. The ORR according to RECIST 1.1 in the sorafenib group ranged from 0.7% to 11.9% (median 6.1%). Among patients with sorafenib therapy, the median PFS and OS time was 3.75 (range 2.8 to 5.5) and 10.4 (range 6.5 to 14.7) months, re-spectively. The mean ORR of sorafenib was also calculated. The denominator equals the sum of the sample sizes for each sorafenib group. Percentage was obtained by the sum number of cases with complete or partial response in each trial divided by the denominator. The mean ORR of sorafenib was 6.0%. Actually, atezolizumab plus bevacizumab was associated with the highest ORR (27.3%) while donafenib with the lowest (4.6%). In addition, the median OS time of each trial tended to increase gradually with the increase of ORR and median PFS time (Fig. 1a). However, this trend was not significant in second-line treatment (Fig. 1b). And then, we describe the association between PFS and OS with forest plot (Fig. 1c). We found (1) PD-1 (sintilimab) or PD-L1 (atezolizumab) inhibitor plus bevacizumab was associated with the best survival benefit for patients with advanced HCC;[3, 4] (2) the significant benefit of PFS may not translate into significant benefit of OS (linifanib, lenvatinib, ramucirumab in REACH trial, S-1); (3) similar PFS generally does not translate into OS benefits (sunitinib, brivanib, sorafenib plus erlotinib), except in the ZGDH3 trial (donafenib); (4) a benefit in PFS could predict a benefit in OS when the hazard ratio for PFS is lower than 0.6 in most trials, except ZGDH3[8] (hazard ratio 0.91) and KEYNOTE 240 trial (hazard ratio 0.72).[9] Tumor progression is the leading cause of death in patients with HCC. Increased ORR and PFS may increase OS in firstline setting, but not in second-line therapy. In addition, the optimum cut-off value of hazard ratio for PFS in predicting benefit in OS is still pending.

A NOD-Like Receptor Signaling-Based Gene Signature Identified as a Novel Prognostic Biomarker for Predicting Overall Survival of Colorectal Cancer Patients

Background: Colorectal Cancer (CRC) is the most frequently diagnosed gastrointestinal tract malignant tumor worldwide, which is closely associated with distant metastasis and poor prognosis. Due to high degree of heterogeneity, reliable prognostic biomarkers are urgently needed to guide the therapeutic intervention of CRC patients. Objective: The present study aimed to develop a NOD-Like Receptors (NLRs) signaling-based gene signature that can successfully predict the overall survival of CRC patients. Methods: Firstly, differentially expressed NLR signaling-related genes were identified between primary and metastatic human CRC samples. Genes with prognostic value were then screened through univariate Cox regression analysis. Next, the NLR signaling-based prognostic signature was constructed by LASSO-penalized Cox regression analysis, and its predictive ability was further confirmed in an independent cohort. Furthermore, functional studies including GO, GSEA, ssGSEA and chemotherapeutic response analyses were performed to explore the role of the NLR signaling-based signature in CRC pathogenesis and therapy. Results: The established prognostic signature that consisted of 7 NLR signaling-related genes can effectively stratify the high-risk and low-risk CRC patients in both training and validation cohorts. Moreover, the signature proved to be an independent indicator of overall survival in CRC patients. Functional annotation and chemotherapeutic response analyses showed that the signature was closely associated with immune status and chemotherapeutic sensitivity of CRC patients. Conclusion: The novel NLR signaling-based gene signature could serve as a potential tool for survival prediction and therapeutic evaluation, thereby contributing to the personalized prognostic management of CRC patients.

Study of IL4Rα and IL13Rα1 Expression in Gallbladder Cancer

Recently, IL4Rα, IL13Rα1, and constituents of type II IL4 receptors are involved in the progression of human cancers through activation of the JAK2 pathway. However, studies on IL4Rα and IL13Rα1 in gallbladder (GB) cancers have been limited. To investigate the expression of IL4Rα and IL13Rα1 in 122 GB carcinomas and the effect of inhibition of JAK2 in SNU308 GB cancer cells. In human GB carcinomas, the expression of IL4Rα and IL13Rα1 were evaluated with immunohistochemical staining in tissue microarray sections. Immunohistochemical expression of IL4Rα was significantly associated with the expression of IL13Rα1 in human carcinoma tissue. In univariate analysis, nuclear expression of IL4Rα, cytoplasmic expression of IL4Rα, nuclear expression of IL13Rα1, and cytoplasmic expression of IL13Rα1 were significantly associated with overall shorter survival and shorter relapse-free survival. Multivariate analysis revealed nuclear expression of IL4Rα as an independent poor prognostic indicator of overall survival and relapse-free survival. In SNU308 gallbladder cancer cells, knock-down of IL4Rα or IL13Rα1 decreased expression of phosphorylated JAK2. The treatment of AZD1480, a JAK2 inhibitor, inhibited proliferation and increased apoptosis of SNU308 cells. In the western blot, treatment of AZD1480 increased expression of cleaved PARP1, cleaved caspase-3, Bax, Bim, p21, p27, and FOXO3, but decreased expression of Bcl2 and pJAK2 in SNU308 cells. This study showed that the expression of IL4Rα and IL13Rα1, especially nuclear expression of IL4Rα, was a potential prognostic indicator of GB carcinomas. Furthermore, suppression of the IL4R pathway with the treatment of JAK2 inhibitor might be an effective therapeutic approach to GB carcinomas.

P-P13 Long-term outcome after portal vein resection during pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: a propensity score matched analysis

Abstract Background Portal vein resection (PVR) with pancreaticoduodenectomy (PD) is often performed to achieve clear margins for patients with vascular involvement in pancreatic ductal adenocarcinoma (PDAC). However, there is evidence to suggest that patients undergoing PVR often have more advanced cancers, therefore the impact of PVR on survival and recurrence remains unclear. The aim of this study is to assess overall (OS) and recurrence free (RFS) survival in patients who underwent PVR during PD, with particular attention to margin positivity. Methods A retrospective analysis was performed on 638 patients who underwent PD during a 12-year period. Exclusion criteria included PD for non-PDAC tumours, neoadjuvant chemotherapy or intra-operative radiotherapy. 374 patients were included in the study (90 PVR and 284 non-PVR). Patient characteristics and histopathological factors associated with OS and RFS were then evaluated using univariate and multivariate Cox regression analyses. 270 patients (90 PVR and 180 non-PVR), were matched by propensity score based on perineural invasion, pT and pN staging. The Kaplan-Meier method was used to calculate survival and log-rank tests. Results Resection margin positivity was associated with shorter OS and RFS (p &amp;lt; 0.0001), and the superior mesenteric vein (SMV) margin was the most significant risk factor for survival on competing risks analysis. Absent adjuvant chemotherapy, nodal metastasis and margin positivity were independent risk factors for OS and RFS on multivariate analysis. PVR was associated with higher intra-operative blood loss (p = 0.009), but was not associated with increased length of stay, complications or readmissions. PVR patients had increased pT staging, nodal metastasis and perineural invasion, however, there was no difference in OS (p = 0.551) or RFS (p = 0.256) between PVR and non-PVR after propensity matching. Conclusions Positive resection margins are associated with shorter survival times, and the SMV margin is the most significant prognostic indicator for overall survival and recurrence compared to other margins. PVR is a relatively safe procedure, however, it does not achieve the intended survival benefits of complete margin clearance. The impact on survival for margin positivity, particularly the SMV margin, and nodal metastasis should be considered when making decisions with regards to vein resection and adjuvant treatments.

Analysis of relapse-free and overall survival in oncoplastic and organ-preserving surgeries in patients with breast cancer

Purpose of the study. To study the results of relapse-free and overall survival during organ- preserving and oncoplastic surgeries in patients with breast cancer.Materials and methods. A prospective clinical study of 84 patients was carried out in the mammology department on the basis of GBUZ NSO "GKB № 1". The first group of patients (40 patients) underwent OPR with ALAE - oncoplastic resection of the mammary gland with axillary lymphadenectomy. The second group (44 patients) WSR with ALAE - wide sector resection of the mammary gland with axillary lymphadenectomy.During the study, the patients were comparable in age, stage (TNM), histological type, and morphogenetic data. The survival rate was studied by the number of local relapses and distant metastases, using laboratory and instrumental studies. The quality of life was assessed on the basis of anamnestic data (Karnofsky index, ECOG scale).Results. In the first group of patients, disease-free and overall survival rate was 97.5 %. At the same time, a local recurrence was found in a patient with a triple negative tumor type, distant metastases to the lungs in a patient with a HER2/neu-positive type. In the second group, relapse-free survival was 95.4 %, overall - 97.7 %. Relapses in two patients with HER2/neu-positive type, metastases to the lungs in a patient with triple negative type.Conclusion. Relapse-free survival rates are 2.1 % higher in group I patients who underwent oncoplastic resection with axillary lymphadenectomy. And the indicators of overall survival in patients of both groups do not differ relatively.

The Systematic Landscape of Nectin Family and Nectin-Like Molecules: Functions and Prognostic Value in Low Grade Glioma.

Objective: Nectin and nectin-like molecules (Necls) are molecules that are involved in cell–cell adhesion and other vital cellular processes. This study aimed to determine the expression and prognostic value of nectin and Necls in low grade glioma (LGG). Materials and Methods: Differentially expressed nectin and Necls in LGG samples and the relationship of nectin family and Necls expression with prognosis, clinicopathological parameters, and survival were explored using The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and Repository of Molecular Brain Neoplasia Data (REMBRANDT) databases. Univariate and multivariate Cox analysis models were performed to construct the prognosis-related gene signature. Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curves and multivariate Cox regression analysis, were utilized to evaluate the prognostic capacity of the four-gene signature. Gene ontology (GO)enrichment analysis and Gene Set Enrichment Analyses (GSEA) were performed to further understand the underlying molecular mechanisms. The Tumor Immune Estimation Resource (TIMER) was used to explore the relationship between the four-gene signature and tumor immune infiltration. Results: Several nectin and Necls were differentially expressed in LGG. Kaplan–Meier survival analyses and Univariate Cox regression showed patients with high expression of NECTIN2 and PVR and low expression of CADM2 and NECTIN1 had worse prognosis among TCGA, CGGA, and REMBRANDT database. Then, a novel four-gene signature was built for LGG prognosis prediction. ROC curves, KM survival analyses, and multivariate COX regression indicated the new signature was an independent prognostic indicator for overall survival. Finally, GSEA and GO enrichment analyses revealed that immune-related pathways participate in the molecular mechanisms. The risk score had a strong negative correlation with tumor purity and data of TIMER showed different immune cell proportions (macrophage and myeloid dendritic cell) between high- and low-risk groups. Additionally, signature scores were positively related to multiple immune-related biomarkers (IL 2, IL8 and IFNγ). Conclusion: Our results offer an extensive analysis of nectin and Necls levels and a four-gene model for prognostic prediction in LGG, providing insights for further investigation of CADM2, NECTIN1/2, and PVR as potential clinical and immune targets in LGG.

CircCHST15 is a novel prognostic biomarker that promotes clear cell renal cell carcinoma cell proliferation and metastasis through the miR-125a-5p/EIF4EBP1 axis

BackgroundCircular RNAs (circRNAs) have been indicated as potentially critical mediators in various types of tumor progression, generally acting as microRNA (miRNA) sponges to regulate downstream gene expression. However, the aberrant expression profile and dysfunction of circRNAs in human clear cell renal cell carcinoma (ccRCC) need to be further investigated. This study mined key prognostic circRNAs and elucidates the potential role and molecular mechanism of circRNAs in regulating the proliferation and metastasis of ccRCC.MethodscircCHST15 (hsa_circ_0020303) was identified by mining two circRNA microarrays from the Gene Expression Omnibus database and comparing matched tumor versus adjacent normal epithelial tissue pairs or matched primary versus metastatic tumor tissue pairs. These results were validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. We demonstrated the biological effect of circCHST15 in ccRCC both in vitro and in vivo. To test the interaction between circCHST15 and miRNAs, we conducted a number of experiments, including RNA pull down assay, dual-luciferase reporter assay and fluorescence in situ hybridization.ResultsThe expression of circCHST15 was higher in ccRCC tissues compared to healthy adjacent kidney tissue and higher in RCC cell lines compared to normal kidney cell lines. The level of circCHST15 was positively correlated with aggressive clinicopathological characteristics, and circCHST15 served as an independent prognostic indicator for overall survival and progression-free survival in patients with ccRCC after surgical resection. Our in vivo and in vitro data indicate that circCHST15 promotes the proliferation, migration, and invasion of ccRCC cells. Mechanistically, we found that circCHST15 directly interacts with miR-125a-5p and acts as a microRNA sponge to regulate EIF4EBP1 expression.ConclusionsWe found that sponging of miR-125a-5p to promote EIF4EBP1 expression is the underlying mechanism of hsa_circ_0020303-induced ccRCC progression. This prompts further investigation of circCHST15 as a potential prognostic biomarker and therapeutic target for ccRCC.