Unfavorable Prognosis In Patients Research Articles

SEPT6_TRIM33 Gene Fusion and Mutated TP53 Pathway Associate With Unfavorable Prognosis in Patients With B-Cell Lymphomas.

BackgroundMounting studies have sought to identify novel mutation biomarkers having diagnostic and prognostic potentials. Nevertheless, the understanding of the mutated pathways related to development and prognosis of B-cell lymphoma is still lacking. We aimed to comprehensively analyze the mutation alterations in genes of canonical signaling pathways and their impacts on the clinic outcomes of patients with B-cell lymphoma.MethodsCirculating cell-free DNA (cfDNA) samples from 79 patients with B-cell lymphomas were used for targeted sequencing with a 560-gene panel for depicting mutation landscapes and identifying gene fusion events. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses of mutated genes were performed. The associations of mutation status of genes and seven canonical oncogenic pathways with progression-free survival (PFS) were assessed using Kaplan-Meier test and multivariate Cox analysis. The variant allele frequencies (VAFs) of genes in TP53 and Hippo pathways in paired baseline and post-treatment samples from 18 B-cell lymphoma patients were compared. Finally, the associations of identified fusion genes, mutated genes, and pathways with treatment response were evaluated based on objective response rates (ORRs) comparisons of groups.ResultsWe identified 666 mutations from 262 genes in baseline cfDNAs from 79 B-cell lymphoma patients, and found some genes were preferentially mutated in our cohort such as GNAQ, GNAS, H3F3A, DNMT3A, HLA-A, and HLA-B. These frequently mutated genes were significantly associated with negative “regulation of gene expression, epigenetic” and virus infections such as cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus 1 infections. We detected five fusion genes in at least two patients with B-cell lymphoma, and among them, TCF7L2_WT1 gene fusion was most frequently detected in 30.4% of patients (24 of 79 cases). SEPT6_TRIM33 gene fusion, mutated TP53 and Hippo pathways were significantly associated with poor PFS, and SEPT6_TRIM33 fusion gene and mutated TP53 pathway were independent prognostic factors for B-cell lymphoma. A decreased VAF of TP53 p.Y88C and LATS2 p.F972L was detected in patients with complete response to treatments. Moreover, a significant difference in ORR was observed in patients with NPM1_NR4A3 and SEPT6_TRIM33 fusions.Conclusions SEPT6_TRIM33 gene fusion and mutated TP53 and Hippo pathways may serve as prognostic makers for B-cell lymphoma patients.

Correlation between promoter methylation of the LDH-C4 gene and DNMT expression in breast cancer and their prognostic significance.

DNA methylation plays an important role in tumorigenesis and development. The potential of aberrant DNA methylation to act as a biomarker for tumor diagnosis and prognostic evaluation is currently being explored. Lactate dehydrogenase C4 (LDH-C4) is a member of the cancer/testis antigen family that is expressed in a broad range of human tumor types, with particularly high expression patterns observed in lung cancer, melanoma and breast cancer. However, whether the methylation of the promoter region of LDH-C4 can be used as a tumor marker and its association with prognosis remain poorly understood. The present study aimed to determine the potential of the methylation status of LDH-C4 and DNA methyltransferase (DNMT) expression to be biological markers for the prognostic evaluation of breast cancer. Methylation-specific PCR was conducted to evaluate alterations in the methylation levels of LDH-C4. Immunohistochemical analysis was performed to assess the expression levels of DNMTs in breast cancer tissues. The association between the methylation status of LDH-C4 or the expression of DNMTs, and clinical pathological parameters was also evaluated. The results of the present study revealed that the demethylation rate of LDH-C4 in breast cancer tissues was significantly increased compared with that of adjacent tissues, and associations were identified between the demethylation of LDH-C4 and the histological grade, estrogen receptor, progesterone receptor and HER-2 status, and lymph node metastasis. The level of LDH-C4 demethylation was negatively correlated with the expression of DNMTs. Demethylation of the LDH-C4 promoter and DNMT expression predicted an unfavorable prognosis of patients with breast cancer. In addition, demethylation of the LDH-C4 promoter, high expression of DNMT3a and DNMT3b, histological grade and lymph node metastasis were all discovered to be independent prognostic factors in patients with breast cancer. In conclusion, results of the present study indicated that the demethylation of LDH-C4 and DNMT expression levels may be closely associated with the occurrence and development of breast cancer, in addition to lymph node metastasis. Thus, both may be used to assist the clinical evaluation of prognosis.

FGFR2 loss sensitizes MYCN-amplified neuroblastoma CHP134 cells to CHK1 inhibitor-induced apoptosis.

Checkpoint kinase 1 (CHK1) plays a key role in genome surveillance and integrity throughout the cell cycle. Selective inhibitors of CHK1 (CHK1i) are undergoing clinical evaluation for various human malignancies, including neuroblastoma. In this study, one CHK1i‐sensitive neuroblastoma cell line, CHP134, was investigated, which characteristically carries MYCN amplification and a chromosome deletion within the 10q region. Among several cancer‐related genes in the chromosome 10q region, mRNA expression of fibroblast growth factor receptor 2 (FGFR2) was altered in CHP134 cells and associated with an unfavorable prognosis of patients with neuroblastoma. Induced expression of FGFR2 in CHP134 cells reactivated downstream MEK/ERK signaling and resulted in cells resistant to CHK1i‐mediated cell growth inhibition. Consistently, the MEK1/2 inhibitor, trametinib, potentiated CHK1 inhibitor–mediated cell death in these cells. These results suggested that FGFR2 loss might be prone to highly effective CHK1i treatment. In conclusion, extreme cellular dependency of ERK activation may imply a possible application for the MEK1/2 inhibitor, either as a single inhibitor or in combination with CHK1i in MYCN‐amplified neuroblastomas.

Prevalence of lesions and risk factors in patients with lower extremities atherosclerosis referred for surgical intervention: gender differences

Background. Atherosclerotic disease of the arteries of the lower extremities or peripheral arterial disease (PAD) affects both men and women. PAD can be combined with the damage of other vascular regions, which is defined as multifocal atherosclerosis (MFA) and suggests the most severe course of the disease and an unfavorable prognosis of patients. The high risk of cardiovascular complications determines the importance of active secondary prevention in patients with PAD and MFA. Data on the frequency of MFA, characteristics of risk factors (RF) and their treatment depending on gender are limited in the literature.Objective. To study the prevalence of atherosclerotic lesions, RF for atherosclerosis and their treatment at out-patient stage in men and women with PAD referred for surgical treatment. Design and methods. According to medical records analyzed the results of a survey of 65 men and 26 women consecutively admitted to the department of cardiosurgery of the Almazov National Medical Research Center from January 2018 to January 2019 for surgical treatment. All patients underwent duplex scanning (DS), X-ray or CT-angiography of the arteries of the lower extremities, 49 patients underwent coronary angiography, and 72 patients underwent DS or CT-angiography of the brachiocephalic arteries (BCA).Results. The average age of men and women did not differ significantly. The most common RF were hypertension and current smoking or the PAD. Smoking was observed less frequently in women. Data on lipid profile were available in 62 patients (68 %), the level of low-density lipoproteins (LDL) was determined in 22 subjects (24 %). The incidence of dyslipidemia and diabetes mellitus did not differ significantly in both groups, however, fasting hyperglycemia was found in 9 women without diabetes mellitus (50 %). The target LDL level was achieved only in 3 men. Two or more RF were detected in 87 % of patients; the groups of men and women did not differ in the number of RF. Signs of involvement of one arterial region were found in 18% of patients, two regions — in 48%, three regions — in 28% without differences in men and women (p > 0,05). In combination with PAD, men were more likely to have coronary artery (CA) disease than women (p < 0,05); the incidence of BCA lesions did not differ significantly (p = 0,02). Women less often, although not significant, received statins (69% versus 84%), beta-blockers (46% versus 66%), antiplatelet agents (77 % versus 84,6%).Conclusions. Both men and women hospitalized for surgical treatment of PAD have multiple RF of comparable frequency, with the exception of smoking. Regardless of gender, the majority of patients show signs of MFA with predominant CA disease in men. The absence of significant differences in the number of RF and the frequency of MFA in men and women may be associated with the presence of comparable severe clinical manifestations of PAD, which determine the indications for revascularization of the lower extremities. The evaluation of patients is inadequate: not all patients have controlled cholesterol and LDL levels, tests are not performed in women with fasting hyperglycemia to exclude diabetes mellitus and prediabetes. There is a clear trend towards less active secondary prevention in women.

The clinical features, prognostic significance, and immune heterogeneity of CD37 in diffuse gliomas

SummaryDiffuse glioma is the most prevalent and malignant brain tumor. The function and significance of CD37 in diffuse gliomas remain largely unknown. Here, we showed CD37 was abnormally expressed in diverse cancers, especially glioma by pan-cancer differential expression analysis. In addition, we found CD37 was upregulated in higher grade and IDH or IDH1-wildtype gliomas, which was further validated by qPCR and IHC. Survival analysis revealed CD37 served as an independent indicator for unfavorable prognosis of patients with diffuse gliomas. Functional enrichment analysis revealed CD37 was associated with immunological processes. Moreover, immune infiltration analyses suggested gliomas with high-expression CD37 had greater infiltration of M2 macrophages and neutrophils, and lower NK cell abundance. CD37 was closely correlated to immune checkpoint molecules, including CD276, CD80, CD86, and PD-L2. Our results indicated CD37 is an independent prognostic factor and plays an immunosuppressive role in diffuse gliomas. Targeting CD37 could be a promising immunotherapeutic strategy for diffuse gliomas.

Long non-coding RNA HLA complex group 18 promotes gastric cancer progression by targeting microRNA-370-3p expression.

Our research was aimed at investigating the biological character of human leukocyte antigen complex group 18 (HCG18) on gastric cancer (GC) progression and its potential mechanisms. The expression characteristics and prognostic values of HCG18 in GC were evaluated through the GEPIA database and Kaplan-Meier plotter database. Quantitative real-time PCR and Western blot were used for quantification of messenger RNA expression, microRNA (miRNA) expression and protein expression. Cell proliferation, migration and invasion were detected by cell counting kit-8 assay, 5'-bromo-2'-deoxyuridine assay and Transwell assay, respectively. Dual-luciferase reporter gene assay and RNA immunoprecipitation assay were used for examination of the interactions among HCG18, miR-370-3p and epidermal growth factor receptor (EGFR) 3'UTR. HCG18 expression was up-regulated in GC tissues, and its high expression was closely associated with increased tumour size, advanced TNM stage, poor differentiation of tumour tissues and unfavourable prognosis of patients with GC. Additionally, HCG18 overexpression promoted the proliferation, migration and invasion of GC cells, and its knockdown suppressed the malignant phenotypes of GC cells. Furthermore, HCG18 served as a miRNA sponge to repress miR-370-3p and indirectly up-regulated EGFR expression in GC cells. HCG18 served as a tumour-promoting factor in GC progression by modulating the miR-370-3p/EGFR axis.

Quantitative Longitudinal Imaging Reveals that Inhibiting Hedgehog Activity Alleviates the Hypoxic Tumor Landscape.

Metastases account for the majority of mortalities related to breast cancer. The onset and sustained presence of hypoxia strongly correlates with increased incidence of metastasis and unfavorable prognosis in patients with breast cancer. The Hedgehog (Hh) signaling pathway is dysregulated in breast cancer, and its abnormal activity enables tumor progression and metastasis. In addition to programming tumor cell behavior, Hh activity enables tumor cells to craft a metastasis-conducive microenvironment. Hypoxia is a prominent feature of growing tumors that impacts multiple signaling circuits that converge upon malignant progression. We investigated the role of Hh activity in crafting a hypoxic environment of breast cancer. We used radioactive tracer [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) to image tumor hypoxia. We show that tumors competent for Hh activity are able to establish a hypoxic milieu; pharmacologic inhibition of Hh signaling in a syngeneic mammary tumor model mitigates tumor hypoxia. Furthermore, in hypoxia, Hh activity is robustly activated in tumor cells and institutes increased HIF signaling in a VHL-dependent manner. The findings establish a novel perspective on Hh activity in crafting a hypoxic tumor landscape and molecularly navigating the tumor cells to adapt to hypoxic conditions. IMPLICATIONS: Importantly, we present a translational strategy of utilizing longitudinal hypoxia imaging to measure the efficacy of vismodegib in a preclinical model of triple-negative breast cancer.

Serum lncRNA-ANRIL and SOX9 expression levels in glioma patients and their relationship with poor prognosis

BackgroundlncRNA-CDKN2B antisense RNA 1 (ANRIL) and SRY-box transcription factor 9 (SOX9) has abnormal expression in many tumors including glioma, but the underlying molecular mechanism is unclear. This study set out to investigate the serum lncRNA-ANRIL and SOX9 levels in glioma patients and their effects on prognosis.MethodsWe enrolled 142 glioma patients admitted to our hospital from May 2014 to May 2016 into the research group (RG) and 120 healthy subjects receiving concurrent physical examinations into the control group (CG). Fasting peripheral blood (4 mL each) was sampled from subjects from the two groups. Using the quantitative real-time polymerase chain reaction (qRT-PCR), lncRNA-ANRIL and SOX9 were measured to explore their values in the early diagnosis of glioma. Patients from RG were followed up for 3 years to analyze the influence of lncRNA-ANRIL and SOX9 on patient prognosis. We purchased glioma cell lines U251 and U87 and grouped them according to the transfection of different plasmids. We conducted CCK8 assay to test cell proliferation, Transwell assay to test cell invasion, the flow cytometry to test cell apoptosis, and Western Blot assay to measure bcl-2 and bax protein levels.ResultsANRIL and SOX9 were evidently higher in RG than in CG (P<0.01). The receiver operating characteristic (ROC) curve revealed that the diagnostic sensitivity of ANRIL combined with SOX9 for glioma was 81.62%, and the specificity was 90.83% (P<0.01). ANRIL and SOX9 were closely related to tumor grade, tumor diameter, distant metastasis, and family history of glioma (P<0.01). In total, 135 patients were successfully followed up (95.07%). Patients with high levels of ANRIL and SOX9 had a markedly poorer prognosis than those with low levels (P<0.05). ANRIL and SOX9 were markedly higher in glioma cell lines (U251 and U87) than in normal brain cells (P<0.01). The proliferation and invasion of U251 cells were notably reduced after the transfection of ANRIL and SOX9 inhibitory sequences (P<0.01), but the apoptosis was notably increased (P<0.01). Bcl-2 expression was markedly increased in lncRNA-ANRIL-inhibitor and SOX9-inhibitor (P<0.01), while bax expression was markedly reduced in lncRNA-ANRIL-inhibitor and SOX9-inhibitor (P<0.01).ConclusionlncRNA-ANRIL and SOX9 levels were higher in glioma patients than in healthy people. High-lncRNA-ANRIL and SOX9 levels were strongly associated with unfavorable prognosis of patients. The testing of biological behaviors revealed that lncRNA-ANRIL and SOX9 worked as tumor-promoting genes in glioma.

Tumor Cell-Derived Exosomal Circ-0072088 Suppresses Migration and Invasion of Hepatic Carcinoma Cells Through Regulating MMP-16.

Background: Tumor-derived exosomes (EXOs), commonly differentially expressed in circular RNAs, have been shown to be crucial determinants of tumor progression and may regulate the development and metastasis of hepatic carcinoma (HCC).Methods: Possibly differentially expressed circRNAs in patients with HCC were screened out from the Gene Expression Omnibus (GEO). EXOs were isolated from the culture medium of HCC cells and plasma of patients with HCC, followed by characterization by transmission electron microscope, NanHCCight, and western blotting. Additionally, RNA immunoprecipitation and luciferase reporter gene assays were carried out to explore the molecular mechanism of hsa_circRNA_103809 (circ-0072088) in HCC cells.Results: The screening results showed that circ-0072088 was highly expressed in patients with HCC, and its increase indicated unfavorable prognosis of patients according to quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Additionally, circ-0072088 was mainly secreted by HCC cells via EXOs in plasma of such patients, and its high level in plasma EXOs was closely associated with tumor node metastasis (TNM) staging and tumor size. Moreover, HCC-secreted EXOs mediated the degradation of miR-375 via circ-0072088 and upregulated MMP-16, thus suppressing the metastasis of HCC.Conclusion: Upregulated in patients with HCC, circ-0072088 may be an index for diagnosis and prognosis of HCC. In addition, HCC-derived EXOs coated with circ-0072088 might be a treatment for HCC, with the ability to inhibit the metastasis of HCC cells.

MM-338: Factors of an Unfavorable Prognosis in Patients with Solitary Plasmacytoma Among Residents of the Gomel Region of Belarus

Introduction Solitary plasmacytoma is a tumor of plasma cells with local proliferation without signs of systemic damage and a high risk of progression to MM. Depending on the presence of a lesion in the bone or soft tissues, there are solitary plasmacytoma of bone and solitary extramedullary plasmacytoma. There are currently few data available on prognostic factors. Methods The study included 24 patients (4 SEP patients, 20 SBP patients) of the Gomel region (Belarus) 2018–2021 with different anatomical localization. The diagnosis was histologically confirmed. The average age was 62 (from 41 to 79 years); female patients prevailed 54.2% (13/11). All patients underwent aspiration biopsy with IFT and FISH, trepanobiopsy with immunohistochemical examination of the BM, and X-ray examination of the skeletal bones. Results were assessed after 3 years of observation. The signs of progression include the appearance of any one of the CRAB-criteria. Results The presence of clonal PCs 5 cm) were detected in 4 patients (all progressed to MM). The progression of the disease to MM was recorded in 7 patients (29.2%). The period to progression was 10 months (media) (3–18). An immunophenotypic study in these patients revealed a significant decrease in the CD95 level (p = 0.001) and in 71.4%, a significant excess of the TNF-a level (p = 0.001) and a significant excess of the B2 microglobulin level (p = 0.001). The 3-year survival rate was 100%. Local relapse developed after 4 courses of PAD in 1 patient who progressed to MM. Conclusion The progression of the disease in patients was associated with the presence of cytogenetic changes in combination with the presence of aberrant or clonal cells in BM 5 cm).

Poster: MM-338: Factors of an Unfavorable Prognosis in Patients with Solitary Plasmacytoma Among Residents of the Gomel Region of Belarus

Poster: MM-338: Factors of an Unfavorable Prognosis in Patients with Solitary Plasmacytoma Among Residents of the Gomel Region of Belarus

An Externally Validated Dynamic Nomogram for Predicting Unfavorable Prognosis in Patients With Aneurysmal Subarachnoid Hemorrhage

Background: Aneurysmal subarachnoid hemorrhage (aSAH) leads to severe disability and functional dependence. However, no reliable method exists to predict the clinical prognosis after aSAH. Thus, this study aimed to develop a web-based dynamic nomogram to precisely evaluate the risk of poor outcomes in patients with aSAH.Methods: Clinical patient data were retrospectively analyzed at two medical centers. One center with 126 patients was used to develop the model. Least absolute shrinkage and selection operator (LASSO) analysis was used to select the optimal variables. Multivariable logistic regression was applied to identify independent prognostic factors and construct a nomogram based on the selected variables. The C-index and Hosmer–Lemeshow p-value and Brier score was used to reflect the discrimination and calibration capacities of the model. Receiver operating characteristic curve and calibration curve (1,000 bootstrap resamples) were generated for internal validation, while another center with 84 patients was used to validate the model externally. Decision curve analysis (DCA) and clinical impact curves (CICs) were used to evaluate the clinical usefulness of the nomogram.Results: Unfavorable prognosis was observed in 46 (37%) patients in the training cohort and 24 (29%) patients in the external validation cohort. The independent prognostic factors of the nomogram, including neutrophil-to-lymphocyte ratio (NLR) (p = 0.005), World Federation of Neurosurgical Societies (WFNS) grade (p = 0.002), and delayed cerebral ischemia (DCI) (p = 0.0003), were identified using LASSO and multivariable logistic regression. A dynamic nomogram (https://hu-ping.shinyapps.io/DynNomapp/) was developed. The nomogram model demonstrated excellent discrimination, with a bias-corrected C-index of 0.85, and calibration capacities (Hosmer–Lemeshow p-value, 0.412; Brier score, 0.12) in the training cohort. Application of the model to the external validation cohort yielded a C-index of 0.84 and a Brier score of 0.13. Both DCA and CIC showed a superior overall net benefit over the entire range of threshold probabilities.Conclusion: This study identified that NLR on admission, WFNS grade, and DCI independently predicted unfavorable prognosis in patients with aSAH. These factors were used to develop a web-based dynamic nomogram application to calculate the precise probability of a poor patient outcome. This tool will benefit personalized treatment and patient management and help neurosurgeons make better clinical decisions.

The prognostic significance of neuroendocrine markers and somatostatin receptor 2 in hepatocellular carcinoma.

Prostatic and colon carcinomas with neuroendocrine differentiation are reported to behave more aggressively than those without such differentiation. In hepatocellular carcinomas (HCCs), however, only a few studies have reported the expression status of neuroendocrine markers and somatostatin receptor 2, the main target of a somatostatin analog. Furthermore, the prognostic significance of the markers in HCCs has not been fully explored. We evaluated the expression of the neuroendocrine makers (chromogranin A, synaptophysin, and CD56) and somatostatin receptor 2 (SSTR2) in 95 HCCs, and investigated the correlation between the expression of these markers and clinicopathological findings. Chromogranin A was immunolocalized in 2 cases, synaptophysin in 15 cases, CD56 in 11 cases, and SSTR2 in 19 cases. Immunoreactivity of synaptophysin and CD56 were the significant unfavorable prognostic factors in terms of 2-year disease-free survival (DFS) and the overall survival (OS) along with a high nuclear mitosis level (>10/10 high-power field), a larger tumor size (>5 cm), the presence of vascular and/or biliary invasion, and high TNM stage (III/IV). Multivariate Cox proportional hazards analysis identified synaptophysin as an independent prognostic factor for 2-year DFS and OS. Synaptophysin expression can be used to predict an unfavorable prognosis in patients with HCC.

OSK-0028 in Patients With Esophageal Cancer Undergoing Esophagectomy: A Double-blind, Randomised Controlled Trial

An excessive postoperative inflammatory response is correlated with the development of pneumonia and an unfavourable prognosis in patients undergoing esophagectomy for esophageal cancer. We assessed the influence of OSK-0028, a synthetic human ghrelin on inflammatory response and energy metabolism, on the postoperative course of patients following radical esophagectomy. Esophageal cancer patients were randomly assigned to low-dose (LD; 0.25 μg/kg/h) or high-dose (HD; 0.5 μg/kg/h) intravenous OSK-0028 or placebo for 7 days after esophagectomy. The primary endpoint was serum interleukin-6 level on postoperative day (POD) 3. A total of 75 patients were enrolled (23 LD, 26 HD, 26 placebo). The median interleukin-6 levels on POD 3 were 40.95, 35.85, and 64.50 pg/ml in the placebo, LD, and HD groups, respectively, with no significant differences (p=0.78). Postoperative complications did not differ between groups. Bodyweight loss was significantly lower in patients receiving OSK-0028 than in those receiving placebo (-0.17% vs. 1.78%, p=0.043). Although OSK-0028 did not attenuate inflammatory response after esophagectomy, it prevented postoperative bodyweight loss.

Abstract 2402: Tid1 deficiency disrupting mitochondria to drive NASH-dependent hepatocellular carcinoma progression

Abstract Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is a significant risk factor to drive hepatocellular carcinoma (HCC). However, a preclinical model of progressive NAFLD/NASH is largely lacking. Here, we report that mice with hepatocyte specific deletion of Tid1, encoding a mitochondrial cochaperone, tended to develop NASH-dependent HCC. Mice with hepatic Tid1 deficiency showed impairing mitochondrial function and causing fatty acid metabolic dysregulation, meanwhile; sequentially developed fatty liver, NASH, and cirrhosis/HCC in a Diethylnitrosamine (DEN) induced oxidative environment. The pathological signatures of human NASH, including cholesterol accumulation and activation of inflammatory and apoptotic signaling pathways, are also present in these mice. Clinically, low Tid1 mRNA expression was associated with unfavorable prognosis in patients with HCC. Empirically, hepatic Tid1 deficiency directly disrupts entire mitochondria that plays a key mechanism involved in the NASH-dependent HCC development. Overall, we established a new mouse model developing NASH-dependent HCC and provided a promising approach for improving the treatment. Citation Format: Ching-Wen Chang, Yu-Syuan Chen, Jeng-Fan Lo, Xin Wei Wang. Tid1 deficiency disrupting mitochondria to drive NASH-dependent hepatocellular carcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2402.

Abstract CT113: Preliminary data on a phase 1b, first-in-human study of the allosteric extracellular FGFR2 inhibitor alofanib in patients with refractory metastatic gastric cancer

Abstract Fibroblast growth factor receptor 2 (FGFR2) is associated with an unfavorable prognosis in patients with gastric cancer. Acquired mutations in FGFR2 develop resistance to multikinase inhibitors. Besides, resistance to monoclonal antibodies depends on the type of FGFR2 isoforms IIIc or IIIb expressed by cancer cells. Alofanib (RPT835) is a small molecule, allosteric inhibitor that binds to the non-active site of FGFR2 extracellular domain. RPT835GC1B (NCT04071184) is an ongoing Phase 1b open-label study evaluating the safety and preliminary efficacy of alofanib in patients with metastatic gastric adenocarcinoma pretreated with ≥ 1 previous lines of therapy. The standard dose-escalation part (design 3+3) aims to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (R2PD) as a primary endpoint. The first part of the study includes a 28-day period when alofanib is administered daily intravenously for 5-days followed by a 2-day interval (rest). There are five dose levels: 50, 100, 165, 250, and 350 mg/m2. Secondary endpoints include pharmacokinetic (PK) parameters, rate of adverse events, progression-free survival (PFS), overall survival (OS), and objective response rate. All patients received alofanib until disease progression or unacceptable toxicity. As of data cutoff on December 30, 2020, 13 patients have been enrolled in the trial. Patients were predominantly male (85%), 54% had 2 and more metastatic sites, including liver metastases (54%), and were heavily pretreated (60% received previous 3-6 lines of therapy). To date, all enrolled patients have been studied for safety and have not experienced any dose-limiting toxicities (DLTs) within the 28-day DLT-assessment window. Grade 3 or higher drug related adverse events have included raised ALT/AST at 50 mg/m2, diarrhea at 165 mg/m2, and hyponatremia at 350 mg/m2. 93% of patients had any grade adverse events. Most common Grade 1-2 adverse events included fatigue, diarrhea, nausea, anemia, thrombocytopenia, increased alkaline phosphatase, and reactions immediately after intravenous injections (facial flushing, dizziness, weakness, sweating, and sinus tachycardia). Grade 1 hyperphosphatemia was founded in 25% of cases. One patient discontinued treatment due to drug related Grade 3 uncontrolled diarrhea. Alofanib has demonstrated evidence of biologic activity in 12 patients in the first 4 dose levels evaluated to date. Disease control rate was 75% (1 durable partial response (13 months) at 50 mg/m2 and 8 stable diseases at 50-250 mg/m2). After a median follow-up of 4.5 months, the median PFS and OS was not reached. In conclusion, dosing up to 350 mg/m2 of alofanib was well tolerated, DLT and MTD were not reached. The early biologic activity of alofanib in the late-line treatment of metastatic gastric cancer is encouraging. In addition to the above, any updated safety, PK, and efficacy data will be presented at the time of the AACR meeting. Citation Format: Ilya Tsimafeyeu, Galina Statsenko, Anastasia Mochalova, Natalia Trenina, Vyacheslav Kurakin, Natalia Besova, Kristina Novoselova, Natalia Abramova, Ekaterina Obarevich, Alina Kashanova, Margarita Suetina, Vladimir Moiseyenko, Mikhail Byakhov, Elena Artamonova, Liubov Vladimirova, Sergei Tjulandin. Preliminary data on a phase 1b, first-in-human study of the allosteric extracellular FGFR2 inhibitor alofanib in patients with refractory metastatic gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT113.

Impact of PD-L Ligands and Indoleamine 2,3-Dioxygenase on Prognosis and Survival of Diffuse Large B-Cell Lymphoma

Background. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin B-cell lymphoma and one of the most chemosensitive malignant diseases. Modern risk-adapted treatment regimens lead to a good control of the disease and high cure rate. However, 30-40% of patients are resistant to standard and salvage chemotherapeutic regimens. New therapeutic methods are needed to improve the outcome. Currently, a lot of studies are aimed to identify the interplay between immune system and tumor for some newly revealed potential biomarkers.Goals. We assessed the impact of PD-L1/2 and IDO expression on clinical outcome in patients with primary DLBCL.Methods: 31 untreated patients were included in the study (median age: 48, range: 23-74 years; males: 9, females: 22). 13 patients were diagnosed with I-II stages and 18 patients with III-IV stages of DLBCL. All patients received R-CHOP/CHOP-like regimens as a 1st-line therapy. PD-L1, PD-L2 and IDO mRNA expression levels were analyzed in fresh pre-treatment lymph node biopsies using qRT-PCR.Results: The overall response rate in the group was 56.4% (22 patients). Five patients had relapses and six patients had refractory disease (follow-up period range: 7-58 months; median duration - 32 months). All patients with refractory disease and three patients with CR/PR had high expression of PD-L ligands. In order to assess the prognostic relevance of PD-L ligands in DLBCL, Kaplan Meier curves were generated. High expression levels of PD-L1 and PD-L2 in tumors were associated with significantly poorer 3-year event free survival (EFS) compared to tumors with low expression (56% vs. 66% and 60% vs .73%, respectively, p<0.05). DLBCL patients with high expression (>0.0006) level of PD-L1 had a significantly higher risk relapse (p=0.03 by Cox' test).ROC analysis revealed that the high expression (>0.6878) of PD-L2 in tumor is an important marker that increases the relapse rate for DLBCL patients (Se=41.6 %; Sp=100 %; AUC=0.71, p=0.007).The mRNA expression of indoleamine 2,3-dioxygenase (IDO) was found in 15 cases (48.4%) and further this group was considered as IDO-positive. The presence of IDO expression was significantly associated with advanced stage of disease (p<0.05), ABC subtype and progression of DLBCL (17.4% vs. 4.3%, p<0.05). Patients with the absence of IDO expression (IDO-negative) tended to have a better response to the 1st line chemotherapy comparing to patients with IDO-positive expression. The overall response rate was achieved in 46.6% (7/15) and 68.7% (11/16) of IDO-positive and IDO-negative cases, respectively (p<0.05).3-year EFS for patients with IDO-positive expression was lower compared to patients with IDO-negative expression (46% vs .70%, p<0.05).Summary: The obtained results suggest the high level of PD-L ligands are associated with unfavorable prognosis for patients with DLBCL. Positive expression of IDO could be considered as an additional unfavorable risk factor for this group of patients. It may represent a promising therapeutic target for DLBCL patients with resistance to chemotherapy. Further studies on a larger group of patients are required in order to evaluate the impact of PD-L ligands and indoleamine 2,3-dioxygenase on prognosis and survival of Diffuse Large B-cell lymphoma. DisclosuresNo relevant conflicts of interest to declare.

SP1 transcriptionally activates NLRP6 inflammasome and induces immune evasion and radioresistance in glioma cells

Glioma accounts for approximately 80% of all malignant brain tumors. This study aimed to investigate the interaction between specificity protein 1 (SP1) and NLR family pyrin domain containing 6 (NLRP6) and their roles in the activity of glioma cells. Differentially expressed genes in glioma were identified using transcriptome analysis tools, and a protein-protein-interaction network was performed based on the DEGs. SP1 and NLRP6 were abundantly expressed in glioma cells and indicated unfavorable prognosis of patients according to the GEO datasets. SP1could bind to the promoter of NLRP6 and induce its transcriptional activity. Downregulation of SP1 reduced proliferation, migration and invasion of glioma U87 cells in vitro as well as tumorigenesis in vivo. The malignancy of cells was restored after NLRP6 upregulation. Downregulation of SP1 in glioma cells also increased proliferation of CD8+ T cells and the immune activity in U87 cells, and it reduced the radioresistance of U87 cells. However, the immune evasion and radioresistance of glioma cells were restored upon NLRP6 upregulation. NLRP6 mediated the innate immune pathway through an ASC/caspase-1/IL-1β axis. To conclude, this study suggested that SP1 interacts with NLRP6 inflammasome to enhance malignant behaviors, immune evasion and radioresistance in glioma cells.

Blocking siglec-10hi tumor-associated macrophages improves anti-tumor immunity and enhances immunotherapy for hepatocellular carcinoma

BackgroundTumor-associated macrophages (TAMs) promote key processes in the modulation of tumor microenvironment (TME). However, the clinical significance of heterogeneous subpopulations of TAMs in hepatocellular carcinoma (HCC) remains unknown.MethodsHCC tissues from Zhongshan Hospital and data from The Cancer Genome Atlas were obtained and analyzed. Immunohistochemistry and flow cytometry were performed to detect the characteristics of sialic acid-binding immunoglobulin-like lectin 10high (Siglec-10hi) TAMs and explore their impact on the TME of HCC. The effect of Siglec-10 blockade was evaluated in vitro based on fresh human tumor tissues.ResultsOur data revealed that Siglec-10 was abundant in a large proportion of HCC specimens and prominently distributed on macrophages. Kaplan–Meier curves and Cox regression analysis showed that intratumoral Siglec-10+ cell enrichment was associated with unfavorable prognosis in patients with HCC. Notably, multiple anti-inflammatory cytokines and inhibitory receptors were enriched in Siglec-10hi TAMs. RNA sequencing data also revealed that numerous M2-like signaling pathways were significantly upregulated in Siglec-10hi TAMs. High infiltration of Siglec-10hi TAMs was associated with impaired CD8+ T cell function in HCC. Of note, blocking Siglec-10 with the competitive binding antibody Siglec-10 Fc led to decreased expression of immunosuppressive molecules and increased the cytotoxic effects of CD8+ T cells against HCC cells. Moreover, blocking Siglec-10 promoted the anti-tumor efficacy of the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab.ConclusionsSiglec-10hi TAMs are associated with immune suppression in the TME, and indicate poor prognosis in patients with HCC. Targeting Siglec-10hi TAMs may serve as a promising immunotherapy approach for HCC.

TGM4: an immunogenic prostate-restricted antigen

BackgroundProstate cancer is the second leading cause of cancer-related death in men in the USA; death occurs when patients progress to metastatic castration-resistant prostate cancer (CRPC). Although immunotherapy with the...