Prognostic Indicator For Overall Survival Research Articles

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.

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 < 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.

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.

Long non-coding RNA profile study identifies an immune-related lncRNA prognostic signature for prostate adenocarcinoma

Prostate adenocarcinoma (PRAD) is the highest incidence rate of male urogenital morbidity worldwide. Long non-coding RNAs (lncRNAs), as a significant class of gene expression regulators, play a critical role in immune regulation. The purpose of this study is to explore a new immune related lncRNA signature to exactly predict the prognosis of PRAD patients. In this study, we conducted a genome-wide comparative analysis of lncRNA expression profiles in 532 patients with PRAD from the Cancer Genome Atlas (TCGA) database. The immune-related lncRNAs were identified by Cox regression model, and then a new five immune-related lncRNAs signature (FRMD6-AS2, AC008770.3, AC109460.3, AC011899.2, and AC008063.1) were constructed, which could predict the prognosis of PRAD patients. Univariate and multivariate Cox regression analysis showed that the signature could be an independent prognostic indicator of overall survival (OS). Through further study of different clinic-pathological parameters, we found that PRAD samples can be divided into high-risk groups with shorter OS and low-risk groups with longer OS by the signature. Principal component analysis showed that five immune-related lncRNA signature could distinguish the high-risk group from low-risk group in view of the immune-related lncRNAs. The difference of immune status between the two groups was observed by gene set enrichment analysis and the ESTIMATE algorithm. Except FRMD6-AS2, the expression of the other 4 lncRNAs were remarkably up-regulated in tumor tissues. In conclusion, the identified five immune-related lncRNAs signature had important clinical significance in prognosis prediction, and can be used as potential immunotherapy targets for PRAD patients.

Head and Neck Cancer Patients Under (Chemo-) Radiotherapy Undergoing NUTritional Intervention: Results From the Prospective Randomized HEADNUT-Trial

<h3>Purpose/Objective(s)</h3> Patients with squamous cell carcinoma of the head and neck (HNSCC) under (chemo-)radiotherapy are at high risk of malnutrition. There are no studies investigating the influence of nutritional status on an altered side effect spectrum and only very few studies examining bioelectric impedance analysis (BIA) and its impact as a prognostic indicator in patients with HNSCC undergoing (chemo-)radiotherapy. Our prospective, randomized, and controlled HEADNUT-trial presented here aimed at preventing increasing malnutrition under radiotherapy or concurrent chemoradiotherapy through specialized and individualized nutritional counseling. Additionally, we investigated whether parameters from BIA were suitable indicators for (threatening) malnutrition and inspected their prognostic effect on (clinical) outcome. <h3>Materials/Methods</h3> Between October 2018 and October 2020, 61 patients were randomized into an intervention and control group. Questionnaires (MUST, NRS-2002, and Nutriscore), clinical examinations, laboratory analyses, and BIA were used to assess nutritional status for all patients at the beginning and end of therapy as well as every 2 weeks during therapy. The intervention consisted of an individualized nutritional counseling every 2 weeks during therapy. <h3>Results</h3> Median baseline BMI for all participants was 23.8 (14.5-37.2) kg/m² and dropped to 22.9 (16.8-33) kg/m² after therapy (<i>P</i> < 0.001). In all patients, median baseline fat-free mass index (FFMI) was 18.1 (14-24.7) kg/m² and decreased to 17.8 (13.4-21.6) kg/m² till the end of therapy (<i>P</i> < 0.001). Compliant patients with a BMI < 22 kg/m² presented with less weight loss in the intervention group compared to the control (<i>P</i> = 0.015, CI: 0.33-2.95). At baseline, MUST was the only screening-test which showed both good sensitivity (86%) and specificity (88%) in detecting malnutrition. Median follow-up was 15 (1-26) months. 2-year overall survival rate was 70% in the control and 79% in the intervention group (log-rank <i>P</i> = 0.79). Pretherapeutic phase angle, posttherapeutic FFMI and albumin level were prognostic indicators for overall survival (log-rank <i>P</i> = 0.002, <i>P</i> = 0.008 and <i>P</i> = 0.016). <h3>Conclusion</h3> Malnutrition negatively impacts patients' outcome under (chemo-)radiotherapy. Baseline phase angle, posttherapeutic FFMI and albumin level are proposed as reliable indicators for overall survival.

Predicting the Survival and Immune Landscape of Colorectal Cancer Patients Using an Immune-Related lncRNA Pair Model.

BackgroundAccumulating evidence has demonstrated that immune-related long non-coding ribonucleic acids (irlncRNAs) can be used as prognostic indicators of overall survival (OS) in patients with colorectal cancer (CRC). Our aim in this research, therefore, was to construct a risk model using irlncRNA pairs with no requirement for a specific expression level, in hope of reliably predicting the prognosis and immune landscape of CRC patients.MethodsClinical and transcriptome profiling data of CRC patients downloaded from the Cancer Genome Atlas (TCGA) database were analyzed to identify differentially expressed (DE) irlncRNAs. The irlncRNA pairs significantly correlated with the prognosis of patients were screened out by univariable Cox regression analysis and a prognostic model was constructed by Lasso and multivariate Cox regression analyses. A receiver operating characteristic (ROC) curve was then plotted, with the area under the curve calculated to confirm the reliability of the model. Based on the optimal cutoff value, CRC patients in the high- or low-risk groups were distinguished, laying the ground for evaluating the risk model from the following perspectives: survival, clinicopathological traits, tumor-infiltrating immune cells (TIICs), antitumor drug efficacy, kinase inhibitor efficacy, and molecules related to immune checkpoints.ResultsA prognostic model consisting of 15 irlncRNA pairs was constructed, which was found to have a high correlation with patient prognosis in a cohort from the TCGA (p < 0.001, HR = 1.089, 95% CI [1.067–1.112]). According to both univariate and multivariate Cox analyses, this model could be used as an independent prognostic indicator in the TCGA cohort (p < 0.001). Effective differentiation between high- and low-risk patients was also accomplished, on the basis of aggressive clinicopathological characteristics, sensitivity to antitumor drugs, and kinase inhibitors, the tumor immune infiltration status, and the expression levels of specific molecules related to immune checkpoints.ConclusionThe prognostic model established with irlncRNA pairs is a promising indicator for prognosis prediction in CRC patients.

Prognostic performance of different lymph node classification systems in young gastric cancer.

Accurate staging plays a pivotal role in cancer care. The lymph node (LN) ratio (LNR) and the log odds of positive LNs (LODDS) have been suggested as alternatives to the N staging since the TNM system has the risk of stage migration. The prognostic significance of LNR and LODDS in young patients with gastric cancer (GC) has not been reported. This study aims to investigate the correlations between LNR and LODDS and survival of young patients with GC, and compare the predictive performance of these LN staging methods. GC patients before the age of 40 from 2004 to 2016 in the Surveillance, Epidemiology and End Results database were enrolled. The prognostic evaluation of the N factor, LNR and LODDS was compared using the time-dependent receiver operating characteristic (ROC) analysis, area under the curve (AUC), C-index and Akaike information criterion (AIC). Multivariate survival analysis identified that the LNR and LODDS were significantly independent prognostic indicators for overall survival (OS) in young patients with GC and in the subgroups comprised of patients with ≤15 LNs examined. The time-dependent ROC curves of the LNR and LODDS were continuously superior to that of the N factor in predicting OS during the observation period. And the AUCs revealed that the predictive accuracy of the LNR and LODDS was remarkably superior to the N factor at 1 and 3 years (P<0.05). The model incorporating LNR or LODDS had higher C-index and lower AIC when comparing to the model incorporating the N factor. The LNR and LODDS improve accuracy of survival risk prediction in young patients with GC when comparing to the N factor. These two novel LN classification methods should be considered as alternatives to the N staging for the prognostic prediction of young patients with GC.

Plasma extracellular vesicle microRNA-491-5p as diagnostic and prognostic marker for head and neck squamous cell carcinoma.

Poor survival of patients with locally advanced head and neck squamous cell carcinoma (LA‐HNSCC) is partly due to early diagnosis difficulties and the lack of reliable biomarkers for predicting treatment outcomes. In the discovery cohort, plasma‐derived extracellular vesicles (EVs) from LA‐HNSCC patients (n = 48) and healthy volunteers (n = 12) were used for profiling for microRNA (miRNA) expression by NanoString analysis. Ten EV‐associated miRNAs were differentially expressed between LA‐HNSCC patients and healthy volunteers. Subsequently, the results were validated in the individual discovery and additional cases (HNSCC, n = 73; control, n = 20) by quantitative RT‐PCR. Among 10 EV‐miRNAs, four (miR‐27b‐3p, miR‐491‐5p, miR‐1910‐5p, and miR‐630) were significantly dysregulated in LA‐HNSCC patients (n = 73) compared with healthy volunteers (n = 20). The miRNA prediction models were developed to discriminate HNSCC patients from healthy volunteers. The model using miR‐491‐5p was selected as a diagnostic biomarker for LA‐HNSCC with a sensitivity and specificity of 46.6% and 100%, respectively (P < .001). The dynamic changes of miRNA model score (ΔmiRNAs) were determined using scores pre‐ and postdefinitive treatment to further investigate the prognostic value of miRNA prediction models. The univariate and multivariate analyses indicated that ΔmiR‐491‐5p was the most powerful and independent prognostic indicator for overall survival (hazard ratio [HR] 5.66, 95% confidence interval, 1.77‐18.01; P = .003) and disease‐free survival (HR 2.82, 95% CI, 1.13‐7.05; P = .027) of HNSCC patients. In summary, the miR‐491‐5p prediction model could serve as a blood‐based diagnostic marker for LA‐HNSCC. Moreover, ΔmiR‐491‐5p could be a potential monitoring prognostic marker to reflect the survival of HNSCC patients.

Prognostic value of preoperative circulating tumor cells counts in patients with UICC stage I-IV colorectal cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. There is an urgent need to identify prognostic markers for patients undergoing curative resection of CRC. The detection of circulating tumor cells in peripheral blood is a promising approach to identify high-risk patients with disseminated disease in colorectal cancer. This study aims to evaluate the prognostic relevance of preoperative CTCs using the Cellsearch® system (CS) in patients, who underwent resection with curative intent of different stages (UICC I-IV) of colorectal cancer. Out of 91 Patients who underwent colorectal resection, 68 patients were included in this study. CTC analysis was performed in patients with CRC UICC stages I-IV immediately before surgery. Data were correlated with clinicopathological parameters and patient outcomes. One or more CTCs/7.5 mL were detected in 45.6% (31/68) of patients. CTCs were detected in all stages of the Union of International Cancer Control (UICC), in stage I (1/4, 25%), in stage II (4/12, 33.3%), in stage III (5/19, 26.3%) and in stage IV (21/33, 63.6%). The detection of ≥ 1 CTCs/ 7.5ml correlated to the presence of distant overt metastases (p = 0.014) as well as with shorter progression-free (p = 0.008) and overall survival (p = 0.008). Multivariate analyses showed that the detection of ≥ 1 CTCs/ 7.5ml is an independent prognostic indicator for overall survival (HR, 3.14; 95% CI, 1.18-8.32; p = 0.021). The detection of CTCs is an independent and strong prognostic factor in CRC, which might improve the identification of high-risk patients in future clinical trials.

Prognostic Association between Common Laboratory Tests and Overall Survival in Elderly Men with De Novo Metastatic Castration Sensitive Prostate Cancer: A Population-Based Study in Canada.

Simple SummaryDespite significant advancements in the treatment of metastatic prostate cancer, a validated prognostic tool for patients with de novo metastatic castration-sensitive prostate cancer (mCSPC) is still lacking. Using population-based data from Ontario, Canada, we examined the prognostic association between common laboratory tests and survival for patients with mCSPC. These low-cost commonly available laboratory tests, including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, albumin, hemoglobin, PSA decrease and PSA nadir, were significantly associated with OS. They can provide important prognostic information and should be utilized more frequently among patients with newly diagnosed mCSPC.De novo cases of metastatic prostate cancer (mCSPC) are associated with poorer prognosis. To assist in clinical decision-making, we aimed to determine the prognostic utility of commonly available laboratory-based markers with overall survival (OS). In a retrospective population-based study, a cohort of 3556 men aged ≥66 years diagnosed with de novo mCSPC between 2014 and 2019 was identified in Ontario (Canada) administrative database. OS was assessed by using the Kaplan–Meier method. Multivariate Cox regression analysis was performed to evaluate the association between laboratory markers and OS adjusting for patient and disease characteristics. Laboratory markers that were assessed include neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), albumin, hemoglobin, serum testosterone and PSA kinetics. Among the 3556 older men with de novo mCSPC, their median age was 77 years (IQR: 71–83). The median survival was 18 months (IQR: 10–31). In multivariate analysis, a statistically significant association with OS was observed with all the markers (NLR, PLR, albumin, hemoglobin, PSA decrease, reaching PSA nadir and a 50% PSA decline), except for testosterone levels. Our findings support the use of markers of systemic inflammation (NLR, PLR and albumin), hemoglobin and PSA metrics as prognostic indicators for OS in de novo mCSPC.

P62 Overexpression Promotes Bone Metastasis of Lung Adenocarcinoma out of LC3-Dependent Autophagy.

p62 protein has been implicated in bone metastasis and is a multifunctional adaptor protein usually correlated with autophagy. Herein, we investigated p62 expression and its prognostic significance in bone metastasis of lung adenocarcinoma, and analyzed whether the mechanism involved depends on autophagy. mRNA and protein expression of p62, LC3B and Beclin 1 were detected by reverse transcription-quantitative PCR and western blotting, respectively, in fresh bone metastasis tissues (n=6 cases) and normal cancellous bone tissues (n=3 cases). The association between p62 and LC3B expression and patient prognosis was subsequently analyzed in 62 paraffin-embedded bone metastasis specimens by immunohistochemistry assay. Small interfering RNA (siRNA) was employed to downregulate p62 expression in SPC-A-1 and A549 cells. Cell proliferation and migration ability were tested by CCK8, CCF and Transwell assays respectively. Autophagy was induced by Rapamycin or inhibited by Atg 7 knockout/Chloroquine in A549 cells and p62 and LC3II/I expression were analyzed. After subcutaneous inoculation or intracardial injection of A549 cells into nude mice, the effect of p62 downregulation in vivo was analyzed by histopathological examination. The results showed that p62, LC3B and Beclin 1 mRNA and protein were all overexpressed in bone metastasis tissues (all P<0.01). Patient samples with high p62 expression levels were significantly associated with more bone lesions (>3), shorter overall survival rates and shorter progression free survival rates compared with patients having lower p62 expression (P=0.014, P=0.003, P=0.048, respectively). Cox regression analysis identified p62 expression as an independent prognostic indicator of overall survival of patients with bone metastasis (P=0.007). In vitro p62 downregulation inhibited SPC-A-1 and A549 cells migration but had no effect on cell proliferation. After autophagy induction or inhibition, p62 expression involved in autophagy flux and changed inconsistently according to the switch of LC3I to LC3II in different autophagy conditions. In vivo p62 downregulation had no effect on growth of subcutaneous tumor. Lung or bone metastasis lesion was not found in all mice model. These findings suggested that p62 overexpression promotes tumor cell invasion out of LC3-dependent autophagy, which could be used a potential prognostic biomarker and therapeutic target for bone metastasis of lung adenocarcinoma.

Circulating tumor DNA and circumferential resection margin as key prognostic indicators for survival in rectal cancer.

3579 Background: Recurrence of colorectal cancer has been linked to the presence of epigenetic circulating tumour DNA (ctDNA) in patient plasma after surgery. The prognostic significance of ctDNA prior to treatment remains unknown. This study investigated the correlation between pre-treatment ctDNA and current radiological (MRI) prognostic markers in patients with rectal cancer. Methods: Forty-two patients with rectal cancer were enrolled, with all having staging MRI prior to treatment. Plasma was taken for ctDNA at diagnosis. The presence of either methylated branched-chain amino acid transaminase 1 (BCAT1) or Ikaros family zinc finger (IKZF1) in cell-free DNA from plasma was deemed a positive ctDNA result. Correlation of MRI prognostic indicators and ctDNA results was assessed with chi-square tests. Univariable and multivariable cox regression analyses were performed to determine variables associated with overall survival (OS). Results: Mean age was 64.4 years (SD 12.5) and majority were male (30/42, 71.4%). 11, 13, 9 &amp; 9 patients had stages I, II, III, IV respectively. Patients had a minimum follow-up of 36 months. Thirty-three (78.6%) patients received neoadjuvant chemoradiotherapy. 29 (69.0%) patients underwent surgical resection. 3-year survival rate was 64% in the overall group. 67% (n=28/42) of patients were positive for the methylated ctDNA at diagnosis. 11 out of 12 patients with a positive circumferential resection margin (CRM +) were ctDNA positive (p=0.03). Univariable analysis showed that prognostic indicators for OS were presence of extramural venous invasion (EMVI) (HR 3.0, 95% CI 1.1-8.4), CRM+ (HR 12.2, 95%CI 3.9-37.6), metastatic disease (HR 7.32, 95% CI 2.63-20.37) and ctDNA% methylation (HR 1.1, 95% CI 1.04-1.13) (Table 1). The presence of CRM+ and a positive ctDNA had a HR of 20.5 (95% CI 5.1-82.3). With multivariable analysis, including adjustment for age and EMVI, only CRM+/ctDNA+ variable was an independent predictor for poor survival (HR 20.2, 95% CI 4.5-90.9). Conclusions: In rectal cancer, almost all patients with CRM involvement have ctDNA, and these patients had the worst prognosis. Future studies with longitudinal ctDNA assessment pre and post treatment could potentially inform prognosis and help tailor patients’ treatment.[Table: see text]

The usefulness of 18F-FDG PET/CT in follow-up and recurrence detection for patients with lung carcinoma and its impact on the survival outcome

BackgroundWe assess the usefulness of 18F-FDG PET/CT for detection of recurrent or residual tumor in post treatment patients with NSCLC and comparing the results with CECT, and we evaluate its impact to the clinical assessment and overall survival of lung cancer patients.ResultsA prospective study of 63 patients with potentially resectable NSCLC, were divided into 2 groups according to the initial staging of the disease and the early response to treatment.Group A (n=29) patients were treated by curative treatment, and group B (n=34) patients were treated by palliative treatment.Evaluation of patients was done during the follow-up period clinically every 3 months and by 18F-FDG PET/CT and CECT imaging at 6 months intervals.In group A, 18F-FDG PET/CT correctly diagnosed all recurrent or residual tumors (n=7) whereas CECT diagnosed only 5 with 2 false negative cases.In group B, 18F-FDG PET/CT correctly diagnosed all recurrent or residual tumors (n=23) whereas CECT diagnosed 16 patients with 7 false negative cases.By comparison of 18F-FDG PET/CT and CECT in detection of residual or recurrent lung cancer (n=30), the sensitivity, specificity, PPV, NPV, and accuracy of 18F-FDG PET/CT were 100%, 92%, 92%, 100%, and 96% respectively, while of CECT were 72%, 95%, 94%, 79%, and 84% respectively in correlation with reference standard data. The calculated SUV max ranged from 2.1 to 4.9.There was a significant difference in overall survival between patients in routine scan who had positive 18F FDG PET/CT result (median survival 18 months) and those who had negative result (median survival 45 months) (P<0.0001).Conclusion18 F-FDG PET/CT plays an important role in distinguishing post treatment changes from tumor recurrence in patients with lung cancer. Follow-up or surveillance 18 F-FDG PET/CT is a prognostic indicator for overall survival of patients.

Tertiary lymphoid structures in epithelioid malignant peritoneal mesothelioma are associated with neoadjuvant chemotherapy, but not with prognosis.

Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant peritoneal mesothelioma. The relationship between a strong adaptive immune response and a better prognosis in malignant solid tumors is widely known. Due to the low incidence of epithelioid malignant peritoneal mesothelioma (EMPM), very little is known about their immune micro-environment. We encountered several cases of tertiary lymphoid structures in EMPM in a previous study and aimed to investigate in the same series the prevalence, clinicopathological features, and the prognostic impact associated with tertiary lymphoid structures in EMPM (TLS-EMPM). Cases of EMPM, from 1995 to 2018, were retrieved from 7 French institutions from the RENAPE Network. The predictions in terms of overall survival (OS) and progression-free survival (PFS) of TLS-EMPM were analyzed. We report 52 cases of TLS-EMPM among a series of 138 cases of EMPM. TLS-EMPM was significantly associated with neoadjuvant chemotherapy, and was not a prognostic indicator for OS (p = 0.652) and PFS (p = 0.804) in our series. TLS is a component of the host immune response to EMPM significantly associated with neoadjuvant chemotherapy, but was not a predictor of prognosis for overall and progression-free survivals in this series. These findings provide another possible etiology for tertiary lymphoid structures.

A characterization and prognosis prediction model for primary squamous cell carcinoma of the thyroid.

Primary squamous cell carcinoma of the thyroid (PSCCTh) is a sporadic malignancy arising from the thyroid gland. The factors that affect treatment and survival in patients with PSCCTh remain unclear. Our study aims to characterize PSCCTh and establish a prognosis prediction model for patients with PSCCTh. Clinical data and follow-up information for 277 patients from 1973 to 2016 were collected from the Surveillance, Epidemiology, and End Results Program (SEER) 18-registry database (RRID:SCR_003293). Univariate and multivariate Cox proportional hazards analyses and nomogram modeling of potential prognostic factors were conducted. Among the collected patient cases, 57% were female and 43% were male. The median survival of all cases was 6 months; by gender, median survival was 5 and 8 months in the female and male groups, respectively. Univariate and multivariate Cox proportional hazards analyses revealed that age, extent of disease (EOD), T stage, N stage, and treatment were independent prognostic indicators for overall survival (OS) and disease-specific survival (DSS) in patients with PSCCTh. In addition, it was confirmed that the established nomogram model had good consistency and discrimination for PSCCTh prognosis as measured by the concordance index (C-index), area under the receiver operating characteristic (ROC) curve (AUC), and calibration curves. Our study indicates that age, EOD, T stage, N stage, and treatment may correlate with OS and DSS in patients with PSCCTh. Importantly, our nomogram prediction model, constructed using parameters including age, T stage, N stage, and treatment, may assist physicians in evaluating patients' prognoses and providing precise therapy for PSCCTh.

Inhibition of sphingosine kinase 2 down-regulates ERK/c-Myc pathway and reduces cell proliferation in human epithelial ovarian cancer.

BackgroundEpithelial ovarian cancer (EOC) is the leading cause of death from female cancers. In our previous study, sphingosine kinase 2 (SphK2) inhibitor was shown to display anti-EOC activities. The purpose of this study was to evaluate further the expression characteristics and clinical significance of SphK2 in EOC and to explore the roles and underlying mechanisms of SphK2 in EOC cell survival.MethodsThe expression of SphK2 was examined by immunohistochemistry (IHC) and Western blot, and its clinical implications and prognostic significance were analyzed. We performed a cellular proliferation assay, and a mouse xenograft model was established to confirm the roles of SphK2 in vitro and in vivo. Cell cycle analysis, apoptosis assay, and Western blot were performed to examine cell cycle progression and apoptosis rate. Gene set enrichment analysis (GSEA), and Western blot were used to investigate the downstream signaling pathways related to SphK2 function.ResultsThe expression level of SphK2 was shown to be associated with stage, histological grade, lymph node metastasis, and ascites status. More importantly, a high SphK2 expression level was a prognostic indicator of overall survival (OS) and relapse-free survival (RFS). Moreover, knockdown of SphK2 arrested cell cycle progression and inhibited EOC cell proliferation both in vitro and in vivo. Furthermore, ERK/c-Myc, the key pathway in EOC progression, was important for SphK2-mediated mitogenic action in EOC cells.ConclusionsOur findings provided the first evidence that SphK2 played a crucial role in EOC proliferation by regulating the ERK/c-Myc pathway. This indicated that SphK2 might serve as a prognostic marker and potential therapeutic target in EOC.

Head and neck cancer patients under (chemo-)radiotherapy undergoing nutritional intervention: Results from the prospective randomized HEADNUT-trial

Purpose/objectivePatients with squamous cell carcinoma of the head and neck undergoing (chemo-)radiotherapy are at high risk of malnutrition. Nevertheless, there is still a lack of prospective, randomized trials investigating the influence of nutritional status on therapy-related toxicity and patients’ outcome. Materials and methodsBetween October 2018 and October 2020, 61 patients were randomized into an intervention and control group. Questionnaires (MUST, NRS-2002, and Nutriscore), clinical examinations, laboratory analyses, and bioelectrical impedance analysis (BIA) were used to assess nutritional status for all patients at the beginning and end of therapy as well as every 2 weeks during therapy. The intervention consisted of an individualized nutritional counseling every 2 weeks during therapy. ResultsMedian baseline BMI for all participants was 23.8 (14.5–37.2) kg/m2 and dropped to 22.9 (16.8–33) kg/m2 after therapy (p < 0.001). In all patients, median baseline fat-free mass index (FFMI) was 18.1 (14–24.7) kg/m2 and decreased to 17.8 (13.4–21.6) kg/m2 till the end of therapy (p < 0.001). Compliant patients with a BMI < 22 kg/m2 presented with less weight loss in the intervention group compared to the control (p = 0.015, CI: 0.33–2.95). At baseline, MUST was the only screening-test which showed both good sensitivity (86%) and specificity (88%) in detecting malnutrition. Median follow-up was 15 (1–26) months and is still ongoing. 2-year overall survival rate was 70% in the control and 79% in the intervention group (log-rank p = 0.79). Pretherapeutic phase angle, posttherapeutic FFMI and albumin level were prognostic indicators for overall survival (log-rank p = 0.002, p = 0.008 and p = 0.016). ConclusionsMalnutrition negatively impacts patients’ outcome under (chemo-)radiotherapy. Baseline phase angle, posttherapeutic FFMI and albumin level are proposed as reliable indicators for overall survival.This study was registered within the German Clinical Trials Register (DRKS00016862).

Hepatic stellate cells promote intrahepatic cholangiocarcinoma progression via NR4A2/osteopontin/Wnt signaling axis.

Intrahepatic cholangiocarcinoma (ICC) is a highly fatal malignancy characterized by a vast amount of intra-tumoral fibroblasts. These fibroblasts are potentially implicated in maintaining the high aggressiveness of ICC, whereas its pro-cancer mechanisms remain scarcely reported. Here, by establishing co-culture models of ICC cells and hepatic stellate cells (HSCs), we identified that HSCs triggered the expression of nuclear receptor family 4 subgroup A member 2 (NR4A2), a transcription factor previously reported as a molecular switch between inflammation and cancer, in ICC cells. Functionally, NR4A2 promotes tumor proliferation, metastatic potentiality and represents an independent prognostic indicator for overall survival in ICC patients. Mechanistically, NR4A2 upregulates osteopontin (OPN) expression through transcriptional activation and thereby augments the activity of Wnt/β-catenin signaling. Intriguingly, in the context of co-culture, vascular endothelial growth factor (VEGF), a previously proved NR4A2 stimulus, not only enhances NR4A2 expression, but also can be blunted by the interference of the NR4A2-OPN axis. Altogether, this study suggests the NR4A2/OPN/Wnt signaling axis to be a pivotal executor of HSC-instigated cancer-promoting roles in ICC, and the NR4A2/OPN/VEGF positive feedback loop may help to reinforce the effect.