Factor For Poor Overall Survival Research Articles

Abstract 6433: Anti-CD36 monoclonal antibody can sensitize the neoadjuvant chemotherapy response in PDAC by eliminating the senescent tertiary lymphatic structure

Abstract Objective: Pancreatic ductal adenocarcinoma (PDAC) is deadly and aggressive. Neoadjuvant chemotherapy (NAC) may reduce tumor volume and alter the resectability of the tumor. The efficacy of neoadjuvant chemotherapy in patients is still limited. Tertiary lymphoid structures (TLSs) develop in peripheral non-lymphoid tissues and are essential for the immune response and correlate with chemotherapy in various tumor types. However, more research is needed to determine how TLSs affect neoadjuvant chemotherapy in PDAC. We aim to determine how neoadjuvant chemotherapy affects tumor-infiltrating lymphocytes (TLSs) in PDAC patients. We also want to find a biomarker to boost PDAC neoadjuvant chemotherapy response. Methods: We retrospectively collected formalin-fixed paraffin embedded (FFPE) tissues from 115 PDAC patients without preoperative treatment and 72 patients pretreated with neoadjuvant chemotherapy. Multispectral images were processed using AI-powered image analysis software (Tissue Gnostics; Zeiss, Germany). The 10X Genomics platform was used to sequence single cells in tissue samples from five patients who received neoadjuvant chemotherapy (NAC) and five patients who had not received any treatment before analysis (pretreatment naïve, PN). TLS was separated using Laser Microdissection. The mouse model was created by orthotopically injecting tumor cells into the pancreas. Results: Patients who received NAC have a senescent microenvironment. High-throughput single-cell sequencing showed that the senescent gene signature score was enriched in the NAC group, especially in immune cells. The percentage of p16+ CD20+ B cells and P16+ CD3+ T cells in TLSs also increased in the NAC group. Spatial transcriptomics analysis exhibited that CD36 is highly expressed in senescent TLSs, which suggested that CD36 may be a marker for senescent TLSs. Moreover, CD36+ TLSs induced the infiltration of MDSCs and regulatory T cells. CD36+ TLSs were an independent prognostic factor for poor overall survival (OS) (HR=0.67, p=0.002) and progression-free survival (PFS) (HR=0.71, p=0.003). A mice orthotopic xenograft model showed that an anti-CD36 monoclonal antibody eliminated senescent TLSs in pancreatic tissue. MDSCs and Tregs in the surrounding tissue also decreased. Additionally, in vivo KPC mice model showed that the combination of an anti-CD36 and chemotherapy reduced tumor volume and increased survival compared to chemotherapy alone. Conclusion: NAC has the potential to induce the senescence of tumor-associated TLSs, a phenomenon that has been linked to unfavorable prognosis in PDAC. CD36 serves as a viable marker for senescent TLSs that can be targeted. The administration of an anti-CD36 monoclonal antibody can potentially enhance the efficacy of chemotherapy in PDAC by selectively eliminating CD36+ senescent TLSs in mouse models. Citation Format: Jingrui Yan, Tianxing Zhou, Chao Yang, Yongjie Xie, Jun Yu, Jihui Hao. Anti-CD36 monoclonal antibody can sensitize the neoadjuvant chemotherapy response in PDAC by eliminating the senescent tertiary lymphatic structure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6433.

Expression of IZUMO2 in colorectal cancer in association with clinicopathological features

IZUMO2 belongs to the testis-expressed IZUMO family of proteins, which are characterized by an N-terminal IZUMO domain. Based on integrated analysis of expression profiles and matched DNA methylation data from a public database, IZUMO2 represents a prognosis-related methylation-driven gene in colorectal cancer. However, it remains unclear whether IZUMO2 protein expression is suppressed or overexpressed in colorectal cancer cells. In this study, we aimed to elucidate the expression of the IZUMO2 protein in colorectal cancer, with a focus on the clinicopathological features. Sixty-four colorectal cancer tissue specimens were immunohistochemically stained using specific antibodies against IZUMO2. IZUMO2 immunoreactivity was detected at the invasion front in 30 of the 64 colorectal cancer samples. Kaplan–Meier analysis demonstrated that patients with IZUMO2 immunoreactivity had a relatively shorter overall and progression-free survival (log-rank test, P = 0.046 and 0.019, respectively). IZUMO2 immunoreactivity served as an independent factor predictive of poor progression-free survival in colorectal cancer (P = 0.025) as determined via the Cox proportional hazard regression model. Moreover, IZUMO2 immunoreactivity represented an independent factor for poor overall survival (P = 0.035) and progression-free survival (P = 0.013) in patients with colon cancer. The present findings suggest that IZUMO2 is expressed in many colorectal cancers, especially at the cancer invasion front, and may represent an indicator of poor prognosis in colorectal cancer.

Immunotherapy Using Activated Natural Killer Cells Improves Postoperative Neutrophil-to-Lymphocyte Ratio and Long-Term Prognosis of Living Donor Liver Transplant Recipients With Hepatocellular Carcinoma

ObjectivePreoperative neutrophil-to-lymphocyte ratio (NLR) is a well-known prognostic indicator in various malignancies; however, the impact of postoperative NLR on living donor liver transplant (LDLT) recipients is unknown. Immunotherapy with donor liver-derived activated natural killer (NK) cells may improve postoperative NLR by coactivating immune cells or suppressing activated neutrophils. This study aims to clarify the clinical significance of postoperative NLR in recipients after LDLT with HCC and assess whether immunotherapy improves postoperative NLR. MethodsWe conducted a retrospective study of LDLT recipients between 2001 and 2022 to evaluate the clinical significance of postoperative NLR. Furthermore, the correlation between postoperative NLR and the activation marker of infused NK cells was also evaluated. The postoperative NLR was examined 4 weeks after LDLT. ResultsThe postoperative high NLR group (N = 78) had preoperative lower NLR and higher model for end-stage liver disease and a higher rate of postoperative infection within 30 days after LDLT than the postoperative low NLR group (N = 41). Postoperative high NLR (hazard ratio [HR], 2.62; 95% confidence interval [CI], 1.01-6.79; P = .047) and nontreatment of immunotherapy (HR, 3.10; 95% CI, 1.33-7.22; P < .01) were independent risk factors for poor overall survival in multivariate analysis. Furthermore, the activation marker of infused NK cells is inversely correlated with decreased postoperative NLR. ConclusionsThe higher level of postoperative NLR was independently associated with poor prognosis in patients after LDLT with HCC. Immunotherapy using activated NK cells may improve postoperative NLR and long-term prognosis.

SPC25 Functions as a Prognostic-Related Biomarker, and Its High Expression Correlates with Tumor Immune Infiltration and UCEC Progression.

Most tumor tissues expressed spindle pole body component 25 (SPC25), one of the four subunits of the NDC80 complex, at greater levels compared to surrounding normal tissues. According to earlier researches, this subunit strongly encouraged tumor cell proliferation and tumor growth, which resulted in worse prognoses in patients with hepatocellular, breast, lung, and prostate cancer. Precisely because SPC25's role in uterine corpus endometrial carcinoma (UCEC) is understudied, we chose to concentrate on UCEC for gaining a more scientific and thorough understanding of SPC25. Along with examining SPC25's differential expression, prognostic significance, and biological function in UCEC, our research sought to clarify the underlying mechanism by which SPC25 influences the course of UCEC and patient prognosis from the viewpoints of methylation and immune infiltration. We observed differential expression of SPC25 gene in different clinicopathological features of UCEC and identified SPC25 as a hazard factor for poorer overall survival (OS), disease-specific survival (DSS), and progress free interval (PFI) in UCEC, particularly in its multiple clinical subtypes. In addition, we also discovered that SPC25 and its co-expressed genes mostly engaged in biological processes and signal transduction routes linked to cell cycle and cell division in UCEC. After investigating SPC25's methylation status, we discovered that patients with UCEC had elevated SPC25 expression and a poor prognosis due to hypomethylation of CpG sites in the SPC25 gene sequence. Finally, we investigated SPC25's potential role in immunotherapy and discovered that SPC25 might alter the major immune cell infiltration levels in the tumor microenvironment (TME) by regulating the expression of immunoregulatory molecules and chemokines, which would be beneficial for SPC25 to control the progression of UCEC. In conclusion, SPC25 was a useful predictive biomarker as well as a possible therapeutic target for UCEC.

Assessment of Pazopanib-Related Heart Failure in Patients With Advanced Soft Tissue Sarcoma - A Single Institute Analysis.

Heart failure (HF) is one of the potential adverse events of pazopanib treatment for soft tissue sarcoma (STS), but detailed reports of such HF cases are scarce. This study determined the incidence and risk factors of HF following pazopanib treatment for STS at our Institute and the clinical outcomes.Methods and Results:This study retrospectively analyzed the cases of STS patients treated with pazopanib (n=151) between 2012 and 2020. HF occurred in 6 patients (3.9%) at the median onset of 137 (range 14-468) days after the treatment initiation. When their HF was diagnosed, pazopanib was interrupted in all 6 patients. No patients experienced HF-related death, and HF development was not a significant factor for poor overall survival. The cumulative doses of anthracyclines (>225 mg/m2) before pazopanib initiation (83% vs. 37%, P=0.031), pazopanib initiation at age ≥60 years (83% vs. 35%, P=0.026), and the baseline B-type natriuretic peptide (BNP) concentration (≥50 pg/mL) before pazopanib (67% vs. 11%, P=0.002) initiation were predictive factors for post-pazopanib treatment HF. The study findings highlight the effect of past anthracycline exposure and baseline BNP for pazopanib-associated HF. Although the study patients' clinical outcomes were generally favorable, periodic monitoring of cardiac function using ultrasonic echocardiography or serum markers is essential to detect events early and begin therapeutic intervention appropriately under a cardiologist's instructions.

Differential microRNA Expression Analysis in Patients with HPV-Infected Ovarian Neoplasms.

This study aimed to identify microRNAs (miRNAs) whose expression levels are altered by high-risk human papillomavirus (HR-HPV) infection in women with epithelial ovarian neoplasms. MiRNA expression was quantified by real-time polymerase chain reaction, while HR-HPV DNA was quantified using digital-droplet PCR. Analysis of 11 miRNAs demonstrated significantly lower hsa-miR-25-5p expression in HPV-infected compared to uninfected ovarian tissues (p = 0.0405), while differences in miRNA expression in corresponding serum were statistically insignificant. The expression of hsa-miR-218-5p in ovarian tumors was significantly higher in high-grade serous ovarian carcinoma (HGSOC) cases than in other neoplasms (p = 0.0166). In addition, hsa-miR-218-5p was significantly upregulated, whereas hsa-miR-191-5p was significantly downregulated in tissues with stage III/IV FIGO (p = 0.0009 and p = 0.0305, respectively). Using unsupervised clustering, we identified three unique patient groups with significantly varied frequencies of HPV16/18-positive samples and varied miRNA expression profiles. In multivariate analysis, high expression of hsa-miR-16-5p was an independent prognostic factor for poor overall survival (p = 0.0068). This preliminary analysis showed the changes in miRNA expression in ovarian neoplasms during HPV infection and those collected from HGSOCs or patients with advanced disease. This prospective study can provide new insights into the pathogenesis of ovarian neoplasms and host-virus interactions.

A Competing Risk Nomogram for Prediction of Prognosis in Patients With Primary Squamous Cell Thyroid Carcinoma.

Objective: Primary squamous cell thyroid carcinoma (PSCTC) is an extremely rare carcinoma, accounting for less than 1% of all thyroid carcinomas. However, the factors contributing to PSCTC outcomes remain unclear. This study aimed to identify the prognostic factors and develop a prognostic predictive model for patients with PSCTC. Methods: The analysis included patients diagnosed with thyroid carcinoma between 1975 and 2016 from the Surveillance, Epidemiology, and End Results database. Prognostic differences among the 5 pathological types of thyroid carcinomas were analyzed. To determine prognostic factors in PSCTC patients, the Cox regression model and Fine-Gray competing risk model were utilized. Based on the Fine-Gray competing risk model, a nomogram was established for predicting the prognosis of patients with PSCTC. Results: A total of 198,757 thyroid carcinoma patients, including 218 PSCTC patients, were identified. We found that PSCTC and anaplastic thyroid cancer had the worst prognosis among the 5 pathological types of thyroid carcinoma (P < .001). According to univariate and multivariate Cox regression analyses, age (71-95 years) was an independent risk factor for poorer overall survival and disease-specific survival in PSCTC patients. Using Fine-Gray regression analysis, the total number of in situ/malignant tumors for patient (Number 1) (≥2) was identified as an independent protective factor for prognosis of PSCTC. The area under the curve, the concordance index (C-index), calibration curves and decision curve analysis revealed that the nomogram was capable of predicting the prognosis of PSCTC patients accurately. Conclusion: The competing risk nomogram is highly accurate in predicting prognosis for patients with PSCTC, which may help clinicians to optimize individualized treatment decisions.

Clinical Significance of Albumin–Bilirubin Grade in Thoracic Esophageal Squamous Cell Carcinoma

IntroductionThe albumin–bilirubin (ALBI) score evaluates liver dysfunction severity. However, this score had prognostic effects in patients with hepatocellular, pancreatic, and gastric carcinomas. We aimed to assess the predictive value of the ALBI score in patients with esophageal squamous cell carcinoma (ESCC). MethodsData from 154 patients with ESCC who consecutively underwent neoadjuvant chemotherapy (NAC) and subtotal esophagectomy were retrospectively investigated. The ALBI score was calculated as pre-NAC ALBI and categorized into grades 1, 2a, 2b, and 3; low-ALBI group (n = 134) was assigned with ALBI grade 1 and the other grades were assigned to the high-ALBI group (n = 20). ResultsThe pre-NAC ALBI was significantly associated with relapse-free survival (RFS) and overall survival (P = 0.003 and P = 0.014, respectively). Based on multivariate analysis, pre-NAC ALBI, pathological T factor, and N factor were identified as independent prognostic factors for poor RFS. Multivariate and univariate analyses limited to factors were obtained before treatment, indicating high pre-NAC ALBI as an independent prognostic factor of poor overall survival (P = 0.039) and RFS (P = 0.008). With respect to pathological response to NAC, patients in the high pre-NAC ALBI group had a significantly lower response than patients in the low pre-NAC ALBI group (P = 0.010). ConclusionsOur results suggested that the pre-NAC ALBI marker predicts the long-term outcome and pathological response to NAC in patients with ESCC consecutively undergoing NAC and a subtotal esophagectomy.

Usefulness of the preoperative inflammation-based prognostic score and the ratio of visceral fat area to psoas muscle area on predicting survival for surgically resected adenocarcinoma of the esophagogastric junction.

Sarcopenic obesity is associated with gastrointestinal cancer prognosis through systemic inflammation. However, in patients with adenocarcinoma of the esophagogastric junction (AEG), the relationship between the inflammation-based prognostic score (IBPS), muscle loss, visceral fat mass, and prognosis has not been sufficiently evaluated. We investigated the prognostic value of the preoperative IBPS and the visceral fat area ratio to the psoas muscle area (V/P ratio) in patients with AEG undergoing surgery. We retrospectively analyzed 92 patients with AEG who underwent surgery. The prognostic value of the preoperative neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio, systemic inflammation response index, C-reactive protein-to-albumin ratio, prognostic nutritional index, modified Glasgow Prognostic Score, and V/P ratio at the third lumbar vertebra was investigated using univariate and multivariate survival analyses. Multivariate analysis revealed that a high pathological stage (p = 0.0065), high PLR (p = 0.0421), and low V/P ratio (p = 0.0053) were independent prognostic factors for poor overall survival (OS). When restricted to patients with body mass index (BMI) ≥ 25kg/m2, a high V/P ratio was a poor prognostic factor (p = 0.0463) for OS. Conversely, when restricted to patients with BMI < 25kg/m2, a low V/P ratio was a poor prognostic factor (p = 0.0021) for OS. Both PLR and V/P ratios may be useful prognostic biomarkers in surgical cases of AEG. V/P ratio and BMI may provide an accurate understanding of the muscle and fat mass's precise nature and may help predict AEG prognosis.

Clinical Features and Prognosis Analysis of 168 Cases of MYC/BCL2 Double Expression Diffuse Large B Lymphoma

Objective: A retrospective study of the clinical features and prognosis of MYC/BCL2 double-expressor diffuse large B-cell lymphoma (DEL). Methods: A retrospective analysis was conducted on patients diagnosed with MYC/BCL2 double-expressor diffuse large B-cell lymphoma (DEL) for the first time by pathological and fluorescence in situ hybridization (FISH) techniques at Fujian Medical University Affiliated Union Hospital from January 2017 to December 2021. Clinical features, immunohistochemistry, laboratory tests, treatment plans, and follow-up information of all patients were collected. Kaplan-Meier analysis was used for univariate analysis, and Cox proportional hazards model was used for multivariate analysis. Results: Clinical characteristics:Among the 168 patients with diffuse large B-cell lymphoma (DLBCL), 13 cases (7.7%) involved the primary central nervous system. Of the patients, 95 (56.55%) were male and 73 (43.45%) were female, resulting in a male-to-female ratio of 1.3:1. The age of onset was at least 60 years for 93 cases (55.36%), with the youngest being 22 years old and the oldest being 88 years old. The median age was 62 years old. A total of 113 cases (72.90%) were classified as stage III-IV by the Ann Arbor staging system, 40 cases (23.81%) had B symptoms, 82 cases (52.90%) had an International Prognostic Index (IPI) score of 3-4, 84 cases (54.19%) had involvement of two or more extranodal sites, 87 cases (51.79%) had a β2-microglobulin (β2-MG) level of ≥2.53mg/L, 122 cases (72.62%) had a serum albumin (SA) level of &amp;lt;35g/L, and 103 cases (61.31%) had elevated levels of lactate dehydrogenase (LDH).Survival status: Complete follow-up data were available for 162 DEL patients, with a median follow-up time of 20.38 (1-73) months. The median overall survival (OS) was not reached, while the median progression-free survival (PFS) was 37.1 months. Among them, and 58 (34.5%) died. Survival analysis was performed on 168 DEL patients, with 1-year, 3-year, and 5-year OS rates of 82.1%, 61.1%, and 58.9%, respectively. The 1-year, 3-year, and 5-year PFS rates were 69.5%, 51.4%, and 45.6%, respectively. Among the 93 elderly (≥60 years old) DEL patients, the 1-year, 3-year, and 5-year OS rates were 77.2%, 52.7%, and 48.6%, respectively, and the 1-year, 3-year, and 5-year PFS rates were 67.4%, 47.4%, and 43.7%, respectively. The 1-year and 3-year OS rates of the 13 patients with primary central nervous system DLBCL were 25.50%, and the 1-year and 3-year PFS rates were 16.70%.Clinical efficacy analysis: Among 168 patients with DEL, the complete remission (CR) rate was 62.5% (105/168), the partial remission (PR) rate was 3.5% (6/168), the overall effective rate (ORR) was 66.1%, and the relapse/progression rate was 25.6% (43/168). Comparing the efficacy of 88 patients treated with the R-CHOP regimen with 32 patients treated with sildalafil combined with the R-CHOP regimen, the results showed a higher CR rate (81.25% vs. 67.05%) and a lower relapse rate (3.13% vs. 12.5%) in patients treated with sildalafil combined with the R-CHOP regimen.4. Univariate analysis: Age over 60 years ( P=0.031), B symptoms ( P=0.031), advanced Ann Arbor stage (P=0.003), high IPI score ( P&amp;lt;0.001), elevated LDH ( P=0.031), and elevated β2-MG( P&amp;lt;0.001) were significantly correlated with poor prognosis in DEL patients, and were identified as adverse prognostic factors. Non-GCB subtype ( P=0.029), B symptoms ( P&amp;lt;0.001), advanced Ann Arbor stage ( P&amp;lt;0.001), high IPI score ( P&amp;lt;0.001), decreased serum albumin ( P&amp;lt;0.001), elevated LDH (P=0.085), and elevated β2-MG(P&amp;lt;0.001) were significantly associated with poorer progression-free survival (PFS) among DEL patients.5.Multivariate analysis revealed that elevated β2-MG levels and high IPI scores were independent risk factors for poor overall survival (OS) in DEL patients, with HR values of 2.363 and 7.090, respectively. B symptoms, elevated β2-MG levels, and reduced serum albumin (SA) levels were independent risk factors for poor progression-free survival (PFS) in DEL patients, with HR values of 1.819, 2.879, and 1.987, respectively. Conclusion: Elevated β2-microglobulin and high IPI scores in DEL patients are risk factors for OS, while B symptoms, elevated β2-microglobulin, and decreased serum albumin are risk factors for PFS. Keywords: Lymphoma, diffuse large B-cell, clinical features, prognosis, double- expression lymphoma

AHSG, a Gene Promoting Tumour Proliferation, Migration and Invasion, is an Independent Prognostic Factor for Poor Overall Survival in Lung Adenocarcinoma.

Recent studies have shown that the metabolic process-related gene AHSG is involved in multiple pathological processes of tumours. This study will explore the relationship between AHSG and lung adenocarcinoma. Expression analysis, survival analysis and co-expression analysis of AHSG were performed using a public database, and cytological and molecular biology assays were performed to explore the role of AHSG in lung adenocarcinoma. Compared with normal tissues, AHSG expression was significantly higher in cancer tissues in the TCGA-LUAD database, and pan-cancer analysis revealed abnormal AHSG expression in different kinds of tumours. Survival analysis revealed that compared with the low expression group, the patients in the high expression group had a significantly worse overall survival duration in the TCGA-LUAD database, and a subsequent study confirmed that AHSG expression could be an independent prognostic factor of overall survival in lung adenocarcinoma. AHSG-related genes are involved in multiple physiological and pathophysiological pathways. In subsequent cytological and molecular biology experiments, inhibition of AHSG expression suppressed proliferation, migration and invasion in lung adenocarcinoma cell lines, and the EMT process was blocked after knockdown of AHSG. AHSG could be used as a prognostic factor for OS in patients with lung adenocarcinoma. It can promote the biological behaviour of lung adenocarcinoma and may become a potential target for treatment, which is worthy of further study.

FBXO5 acts as a novel prognostic biomarker for patients with cervical cancer.

Background: Cervical cancer (CC) remains one of the most common and deadly malignancies in women worldwide. FBXO5, a protein-coding gene, is highly expressed in a variety of primary tumors and promotes tumor progression, however, its role and prognostic value in CC remain largely unknown. Methods: A key differential gene, FBXO5, was screened according to WGCNA based on immunohistochemical assays of clinical samples, multiple analyses of the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, including survival analysis, tumor mutational burden, GO, KEGG, tumor immune infiltration, and chemotherapeutic drug sensitivity, to explore the expression and prognostic value of FBXO5 in CC. The migration and invasiveness of cervical cancer cells following FBXO5 knockdown and overexpression were examined using wound healing and transwell assays, and the viability of cancer cells was assessed using CCK8 and EdU assays. Results: FBXO5 was discovered to be substantially expressed in CC tissues using data from our CC cohort and the TCGA database, and a survival analysis indicated FBXO5 as a predictive factor for poor overall survival in CC patients. In vitro, CC cells were more inclined to proliferate, migrate, and invade when FBXO5 was upregulated as opposed to when it was knocked down.

LINC01480 as a Prognostic Biomarker Associated With Proliferation, Migration, and Invasion of Clear Cell Renal Cell Carcinoma.

The present study aimed to identify key long noncoding RNAs (lncRNAs) involved in survival and metastasis of clear cell renal cell carcinoma (ccRCC). A systemic screening for genes with differential expression in ccRCC was performed using publicly available databases. Cox regression analysis was used to identify lncRNAs associated with survival. A competing endogenous RNAs (ceRNA) regulation network of metastasis-related lncRNAs was constructed and hub lncRNAs were identified. Functional and pathway enrichment analyses were performed to investigate the role of lncRNA in ccRCC. Cell Counting Kit-8 and Transwell assays were used to determine the levels of cell proliferation, migration, and invasion. A total of 732 lncRNAs were found to be differentially expressed between ccRCC tumors and healthy samples. Among them, 139 lncRNAs were differentially expressed between metastasis and non-metastasis ccRCC samples and 75 lncRNAs were associated with overall survival and curated metastasis-related genes. Notably, LINC01480 was identified as the hub lncRNA involved in regulation of ccRCC metastasis. Clinically, LINC01480 may act as an independent factor for poor overall survival of ccRCC patients (log-rank p<0.05). Reverse transcription-quantitative PCR analysis validated that LINC01480 was significantly up-regulated in ccRCC compared to paired normal samples (n=20). Moreover, LINC01480 silencing inhibited the proliferation, migration, and invasion of ccRCC cells in vitro. Gene set enrichment analysis showed that high LINC01480 expression may promote ccRCC metastasis through enhancing immunodeficiency and amino acid metabolism. LINC01480 may act as a novel biomarker for overall prognosis in ccRCC and exhibit potential as a therapeutic target for the treatment of metastatic ccRCC.

Surgical Treatment Outcomes of Patients with Non-Small Cell Lung Cancer and Lymph Node Metastases

This study aimed to investigate the appropriate subgroups for surgery and adjuvant chemotherapy in patients with non-small-cell lung cancer (NSCLC) and nodal metastases. We retrospectively reviewed 210 patients with NSCLC and nodal metastases who underwent surgery and examined the risk factors for poor overall survival (OS) and recurrence-free probability (RFP) using multivariate Cox proportional hazards analysis. Pathological N1 and N2 were observed in 114 (52.4%) and 96 (47.6%) patients, respectively. A single positive node was identified in 102 patients (48.6%), and multiple nodes were identified in 108 (51.4%). Multivariate analysis revealed that vital capacity &lt; 80% (hazard ratio [HR]: 2.678, 95% confidence interval [CI]: 1.483–4.837), radiological usual interstitial pneumonia pattern (HR: 2.321, 95% CI: 1.506–3.576), tumor size &gt; 4.0 cm (HR: 1.534, 95% CI: 1.035–2.133), and multiple-node metastases (HR: 2.283, 95% CI: 1.517–3.955) were significant independent risk factors for poor OS. Tumor size &gt; 4.0 cm (HR: 1.780, 95% CI: 1.237–2.562), lymphatic permeation (HR: 1.525, 95% CI: 1.053–2.207), and multiple lymph node metastases (HR: 2.858, 95% CI: 1.933–4.226) were significant independent risk factors for recurrence. In patients with squamous cell carcinoma (n = 93), there were no significant differences in OS or RFP between those who received platinum-based adjuvant chemotherapy (n = 25) and those who did not (n = 68), at p = 0.690 and p = 0.292, respectively. Multiple-node metastases were independent predictors of poor OS and recurrence. Patients with NSCLC and single-node metastases should be considered for surgery despite N2 disease. Additional treatment with platinum-based adjuvant chemotherapy may be expected, especially in patients with squamous cell carcinoma.

Lymphocyte-C-reactive protein ratio with calf circumference could better predict survival of patients with non-metastatic cancer

Systemic inflammatory responses caused by tumor cells play an important role in the occurrence and development of tumors. The aim of this study was to identify biomarkers that most accurately predict prognoses in patients with non-metastatic cancer and to evaluate their clinical significance when combined with muscle markers. This study retrospectively evaluated 2,797 cancer patients diagnosed with cancer at TNM stages I, II, and III. Lymphocyte-C-reactive protein ratio (LCR) in conjunction with calf circumference (CC) were used (or chosed) after evaluating the predictive value of 13 inflammatory marker combinations and five anthropometric indicators for patient outcomes using the C-index. The Kaplan–Meier method and Cox’s proportional hazards regression modeling were used to analyze the individual and combined effects of these two potential biomarkers on overall survival. This study enrolled 1,604 men (57.3%) and 1,193 women (42.7%) with a mean age of 58.75 years. Among the 13 inflammatory nutritional indicators, the LCR was the most accurate predictor of prognoses in patients with non-metastatic cancer. After multifactorial adjustment, we found that low LCR had an adverse effect on overall survival (hazard ratio [HR]: 2.50; 95% confidence interval [CI]: 2.17, 2.88; P < 0.001). Low LCR combined with low CC was also shown to be an independent risk factor for poor overall survival (HR: 2.26; 95% CI: 1.80, 2.83; P < 0.001). Compared with LCR or CC alone, the combination of the two had greater prognostic value for patients with non-metastatic cancer. The LCR can be implemented as a useful biomarker to predict prognoses in patients with non-metastatic cancer. CC is the best anthropometric indicator of muscle loss in patients with non-metastatic cancer. The combination of LCR and CC can better predict the prognosis of patients with non-metastatic cancer, and can provide important information for clinicians to formulate diagnosis and treatment plans.

Impact of Geriatric Nutritional Risk Index After Initial Hepatectomy for Hepatocellular Carcinoma: a Retrospective Cohort Study with the Hiroshima Surgical Study Group of Clinical Oncology (HiSCO)

IntroductionThe importance of a nutrition scoring system, including the geriatric nutritional risk index (GNRI), was reported as an objective tool widely used to assess nutritional status in patients with inflammatory disease, chronic heart failure, and chronic liver disease. However, studies on the relationship between GNRI and the prognosis in patients who have undergone initial hepatectomy have been limited. Thus, we conducted a multi-institutional cohort study to clarify the relationship between GNRI and long-term outcomes for hepatocellular carcinoma (HCC) patients after such a procedure. MethodsData from 1,494 patients who underwent initial hepatectomy for HCC between 2009 and 2018 was retrospectively collected from a multi-institutional database. The patients were divided into two groups according to GNRI grade (cutoff: 92), and their clinicopathological characteristics and long-term results were compared. ResultsOf the 1,494 patients, the low-risk group (≥ 92; N = 1,270) was defined as having a normal nutritional status. Meanwhile, low GNRI (< 92; N = 224) were divided into malnutrition as the high-risk group. Multivariate analysis identified seven prognostic factors of poor overall survival (higher tumor markers; α-fetoprotein (AFP) and des-γ-carboxy protein [DCP], higher ICG-R15 levels, larger tumor size, multiple tumors, vascular invasion, and lower GNRI and eight prognostic factors of high recurrence (HCV antibody positive, higher ICG-R15 levels, higher tumor markers such as AFP and DCP, greater bleeding, multiple tumors, vascular invasion, and lower GNRI). ConclusionsIn patients with HCC, preoperative GNRI predicts poorer overall survival and high recurrence.

Abstract P6-10-08: Evaluation of potent novel second-generation MELK-selective inhibitor in aggressive breast cancers

Abstract Background Inflammatory breast cancer (IBC) and triple-negative breast cancer (TNBC) are aggressive breast cancer subtypes with poor clinical outcomes due to the lack of well-validated and actionable targets and the onset of chemo-resistant metastasis. TNBC and IBC account for 15-20% and 2-4% of all breast cancer diagnoses but result in 30% and 8%–10% of breast cancer-related deaths, respectively. MELK (maternal embryonic leucine zipper kinase) is a potential therapeutic target in both TNBC and triple-negative IBC (TN-IBC). We have shown that 1) MELK expression is higher in basal tumors (mostly TNBC) and in IBC than in non-IBC, 2) high MELK expression is an independent prognostic factor for poor overall survival (P=0.0002) and poor distant metastasis-free survival (P=0.008) in breast cancer, and 3) MELK knockout leads to significantly lower metastatic burden and prolonged survival in a xenograft model of TNBC (unpublished data). MELK inhibitor (MELKi) OTS167 is in clinical trials but it lacks specificity and cross-reacts with other essential kinases. It is critical to discover novel, selective inhibitors with good bioavailability that target MELK and minimize adverse effects. We have developed a second-generation small-molecule MELK inhibitor 30e that is a highly potent and slow-binding ATP-competitive inhibitor of MELK. 30e exhibits potent cellular inhibition of MELK (IC50&amp;lt; 10 nM), as assessed using a live cell NanoBRET assay, and is highly selective as assessed by live-cell KiNativ profiling experiments in MDA-MB-231 TNBC cells. Methods We screened a panel of TNBC and IBC cell lines for MELK expression by western blot and qPCR analysis. We assessed the effects of MELK inhibition with the 30e on migration and invasion. The role of MELK in regulating cancer stem cell phenotypes was assessed using the mammosphere assay and flow cytometry (CD44+/CD24-/low surface marker). MELK’s protumorigenic role was determined in vitro using a soft agar assay, and the anti-tumor activity of 30e was assessed in vivo using a TN-IBC orthotopic xenograft mouse model. Results We found that TNBC had high mRNA levels of MELK (62%) compared to non-TNBC cell lines (25%), which correlated with MELK protein levels. 30e inhibited cell viability in TNBC and IBC cells in a dose-dependent manner and with IC50s ranging from 0.45 to 1.76 μM (P≤0.05). However, no significant effect was observed when normal MCF-10A breast cells were treated with 30e (IC50&amp;gt;20 μM). 30e also significantly reduced colony formation ability. Further, we observed that 30e reduced mammosphere formation efficiency and the CD44+/CD24-/low subpopulation in both TNBC and IBC cells in a dose-dependent manner (P≤0.05), suggesting the potential of 30e to inhibit the stem cell population in vitro. The soft agar assay also showed a significant decrease in colony formation in the TNBC and IBC cells after treatment with 30e, an indirect indicator of in vivo tumorigenicity. To assess the efficacy of 30e treatment on tumor growth, we evaluated this inhibitor as a single agent in a SUM-149 (TN-IBC) orthotopic mouse model. The mice were treated with intraperitoneal injections daily with 3 doses (2.5, 5, and 10 mg/kg) of 30e. Our data show that 30e suppressed tumor growth in a dose-dependent manner (P&amp;lt; 0.007). Conclusions and Future Directions Our data demonstrate that a novel, potent and specific MELK inhibitor inhibits tumor growth by suppressing the cancer stem cell phenotype. MELK is a promising target for aggressive cancers such as TNBC and IBC. We are evaluating how MELK inhibition modulates the tumor microenvironment, which is a critical component of breast cancer response to treatment. We performed a cytokine antibody array and are validating the top targets. Further, we will evaluate 30e in combination with standard-of-care treatment for toxicity and inhibition of metastasis. Citation Format: Mohd Mughees, Moises Tacam, Alex Tan, Hector Gonzalez, Emilly S. Villodre, Bisrat Debeb, Debu Tripathy, Geoffrey Bartholomeusz, Juhyeon Lee, Kevin Dalby, Chandra Bartholomeusz. Evaluation of potent novel second-generation MELK-selective inhibitor in aggressive breast cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-08.

Multicentre real-world data of ramucirumab plus docetaxel after combined platinum-based chemotherapy with programmed death-1 blockade in advanced non-small cell lung cancer: NEJ051 (REACTIVE study)

BackgroundRamucirumab plus docetaxel (RD) is a promising treatment for previously treated advanced non-small cell lung cancer (NSCLC). However, its clinical significance after platinum-based chemotherapy plus programmed death-1 (PD-1) blockade remains unclear. Research questionWhat is the clinical significance of RD as a second-line treatment after the failure of chemo-immunotherapy in NSCLC? Study design and methodsIn this multicentre retrospective study, 288 patients with advanced NSCLC who received RDas second-line therapy after platinum-based chemotherapy plus PD-1 blockade, at 62 Japanese institutions from January 2017 to August 2020, were included. Prognostic analyses were performed using the log-rank test. Prognostic factor analyses were performed using a Cox regression analysis. ResultsA total of 288 patients were enrolled: 222 were men (77.1%), 262 were aged <75 years (91.0%), 237 (82.3%) had smoking history and 269 (93.4%) had a performance status (PS) of 0–1. One hundred ninety-nine patients (69.1%) were classified as adenocarcinoma (AC) and 89 (30.9%) as non-AC. The types of PD-1 blockade used in the first-line treatment were anti-PD-1 antibody and anti-programmed death-ligand 1 antibody in 236 (81.9%) and 52 (18.1%) patients, respectively. The objective response rate for RD was 28.8% (95% confidence interval [CI], 23.7–34.4). The disease control rate was 69.8% (95% CI, 64.1–75.0).The median progression free survival and overall survival were 4.1 months (95% CI, 3.5–4.6) and 11.6 months (95% CI, 9.9–13.9), respectively. In a multivariate analysis, non-AC and PS 2–3 were independent prognostic factors for worse progression free survival , while bone metastasis on diagnosis, PS 2–3 and non-AC were identified as independent prognostic factors for poor overall survival. InterpretationRD is a feasible second-line treatment in patients with advanced NSCLC who had received combined chemo-immunotherapy with PD-1 blockade. Clinical trial registration numberUMIN000042333.

Identification of RALA as a Therapeutic Target and Prognostic Predictor of Osteosarcoma.

Osteosarcoma (OS) is the most common primary aggressive sarcoma of bone, with massive aberrant expression of oncogenes related to the development of OS. RALA, a kind of small Ras-like guanosine triphosphatases, has been identified as a potential therapeutic target in several types of tumor, but its role in OS remains largely unknown. Abnormal expression of RALA was proven in the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and RNA-sequence of samples and cell lines. The role of RALA in OS was analyzed in terms of DNA methylation, immune cell infiltration, and patient survival. The cancer-promoting effect of RALA was demonstrated in cell lines and xenograft osteosarcoma models. A prognostic scoring model incorporating RALA as an indicator was established with the clinical samples that we collected. The results showed that RALA was highly expressed in human OS tissues and cell lines. Survival analysis demonstrated that RALA was the sole independent risk factor for poor overall survival and disease-free survival in OS patients and impacted the proportion of infiltrating immune cells and DNA methylation in the OS tumor microenvironment. By gene-gene interaction analysis, we found that the expression of RALA was highly correlated to the expression of ABCE1. Similar to RALA, upregulated ABCE1 is correlated with poor survival outcome of OS patients. In addition, the functional experiment demonstrated that higher expression of RALA promoted the proliferation, migration, and invasion of OS cells. In vivo results were similar with the in vitro results. We examined m6a methylation-related genes and found that m6A methylation is responsible for the abnormal expression of RALA. Finally, the prognostic prediction model of RALA could be used to predict the long-term outcome of OS patients. We identified RALA as an oncogene in OS, and RALA upregulation in a concerted manner with ABCE1 was significantly associated with worse outcomes of OS patients. Targeting RALA may prove to be a novel target for OS immunotherapy in future clinical practice.

Clinical significance of the preoperative prognostic nutritional index on age/comorbidity burdens in patients with resectable non-small cell lung cancer.

Objective nutritional scoring systems using preoperative blood samples have shown the potential to predict the postoperative outcomes of patients with non-small cell lung cancer (NSCLC). However, it remains unclear whether the prognostic impact depends on age and comorbid burdens. We conducted this study to validate the impact of preoperative nutritional status, stratified with age and comorbidity. We reviewed the preoperative prognostic nutritional index (PNI) and postoperative outcomes of 713 consecutive patients with completely resected NSCLC. We identified the optimal cutoff values of the PNI as 46. Significantly higher postoperative complication rates and worse survival rates were observed in the low PNI (≤ 46) group, regardless of age/comorbidity burdens. Multivariate analysis showed that a low PNI (≤ 46) was an independent prognostic factor for poor overall survival (hazard ratio: 2.5). A matched-pair analysis gave consistent results, showing that a low PNI (≤ 46) was an independent prognostic factor for poor overall survival (OS; hazard ratio: 1.8) and recurrence-free survival (RFS; hazard ratio: 1.6). Nutritional status, indexed by the PNI, is a strong prognostic factor for the postoperative outcomes of patients undergoing curative resection for NSCL, regardless of age/comorbidity burdens.