Poor Overall Survival Outcomes Research Articles

The prognostic importance of the negative regulators of ferroptosis, GPX4 and HSPB1, in patients with colorectal cancer.

The prognostic value of negative regulators of ferroptosis in patients with colorectal cancer (CRC) has not yet been fully elucidated. The present study performed a systematic in silico identification and selection of candidate negative regulators of ferroptosis using The Cancer Genome Atlas data cohort (n=367), followed by clinical validation through immunohistochemistry of samples from patients with CRC (n=166) and further in vitro evaluation. In silico analysis identified specific light-chain subunit of the cystine/glutamate antiporter, AIFM2, NFE2L2, FTH1, GLS2, glutathione peroxidase 4 (GPX4) and heat shock protein β-1 (HSPB1) genes as possible candidates. Furthermore, patients with high expression of GPX4 or HSPB1 exhibited significantly worse overall survival (OS) compared with those with low expression (P<0.01 for both). Immunohistochemical analysis revealed that both OS and recurrence-free survival (RFS) of patients with CRC and high GPX4 or HSPB1 expression were significantly worse compared with in patients with low expression (P<0.01 for all). Furthermore, multivariate analysis showed that high GPX4 and HSPB1 expression were independent risk factors for poor oncological outcome for OS and RFS (GPX4: RFS, P=0.03; HSPB1: OS, P=0.006 and RFS, P<0.0001). Moreover, the effects of GPX4 and HSPB1 small interfering RNAs on two CRC cell lines (DLD-1 and SW480) indicated that GPX4 and HSPB1 may exhibit important roles in attenuating the cytotoxic effect of 5-fluorouracil-based chemotherapy. In conclusion, the current study confirmed that GPX4 and HSPB1 may serve as substantial prognostic- and recurrence-predictive biomarkers in patients with CRC.

Survival Impacts of Mitochondrial Status in Esophageal Squamous Cell Carcinoma Patients.

Little is known about the survival impacts of mitochondrial status in esophageal squamous cell carcinoma (ESCC) patients who undergo neoadjuvant chemotherapy (NAC) followed by surgery. In total, 260 pre-NAC samples from ESCC patients were analyzed. Mitochondrial status was estimated employing an objective, immunohistochemistry-based system (Mito-score). Mito-scores were dichotomized according to the median value of our cohort. We also evaluated the immune microenvironment (CD4, CD8, Foxp3, HLA class-1, Ki-67 and programmed death ligand-1) on pre-NAC specimens. Multivariate Cox hazards models were applied to determine independent predictors of poor overall survival (OS). Patients with cT3-4 tumors had higher Mito-scores than those with cT1-2 tumors (p=0.06), and good responders to NAC had significantly higher Mito-scores than poor responders to NAC (p=0.04). CD8 cells and Ki-67 expression were significantly higher in Mito-high than Mito-low tumors (p=0.017 and p<0.001, respectively). Patients with low Mito-scores had significantly poorer OS than those with high Mito-scores (3-year OS: 57.6% vs. 68.2%; p=0.03). A survival difference by Mito-score was evident in cStage III-IV patients (3-year OS: low 50.6% vs. high 66.1%; p=0.006). Multivariable analysis revealed that a low Mito-score (hazard ratio 1.59, 95% confidence interval 1.12-2.24; p=0.009) as well as pT3-4 disease (p<0.001) and pN2-3 disease (p<0.001) were independently associated with poor OS outcomes. A low Mito-score before NAC had a significant survival impact in ESCC patients, especially in those with advanced disease. Mitochondrial status might be associated with tumor aggressiveness and responsiveness to NAC, thereby possibly affecting the survival outcomes of ESCC patients.

Genetic alteration analysis of non-pediatric diffuse midline glioma, H3 K27-altered.

Diffuse midline gliomas with H3 K27-alteration (DMGH3) are lethal and inoperable brain tumors. Although DMGH3s mainly occur in pediatric patients, they have also occurred in adult patients. This study aimed to analyze the clinicopathological significance of targetable genetic alterations in non-pediatric DMGH3. Next-generation sequencing (NGS) was conducted on 18 non-pediatric DMGH3 patients to analyze additional genetic alterations. The median age at diagnosis was 35 years, and the mean follow-up duration was 762 days. Fourteen cases involved the thalamus-hypothalamus (77.8%). Histologic high-grade features (WHO histologic grade ≥3) were observed in 11 (61.1%) patients. H3F3A (H3 K27M) alterations were identified in all 18 patients using immunohistochemistry and NGS. TP53 mutations were found in 11 patients (61.1%), FGFR1 or PIK3CA in 3 (16.7%), ATRX in 6 (33.3%), NF1 in 4 (22.2%), and KRAS or ATM in 1 (5.6%). TP53 mutations were significantly correlated with high-grade histological features and worse overall survival (OS) (P < 0.05). Despite non-pediatric DMGH3 cases exhibiting superior OS compared to pediatric DMGH3 cases, TP53 mutations were associated with poorer OS outcomes. Notably, FGFR1 and PIK3CA mutations, which have been identified as potential targetable genes, were detected. In conclusion, non-pediatric DMGH3s showed predominant tumor localization within the thalamus and improved prognosis compared to those in pediatric cases, with TP53 alterations correlating with high-grade histology and shorter survival. Genetic profiling, particularly identifying targetable mutations like FGFR1 and PIK3CA, could inform personalized treatment strategies and improve patient outcomes.

Prognostic value of hemoglobin to red blood cell distribution width ratio in pancreatic ductal adenocarcinoma: a retrospective study

BackgroundPrevious studies have identified the hemoglobin (Hb) to red blood cell distribution width (RDW) ratio (HRR) is associated with the prognosis of a variety of malignant tumors. However, the relationship between HRR and pancreatic ductal adenocarcinoma (PDAC) prognosis remains unexplored. This study aims to ascertain the prognostic significance of HRR in PDAC patients.MethodsIn a retrospective analysis, 128 PDAC patients undergoing initial surgical resection at Ningbo Medical Center Lihuili Hospital between January 2016 and September 2021 were included. Based on receiver operating characteristic curve-derived cut-off values, participants were categorized into low and high HRR groups. The correlation between HRR and patient prognosis was subsequently examined.ResultsSignificant disparities in age, Hb levels, RDW, tumor locality, surgical intervention, and postoperative chemotherapy were observed between the two groups (P < 0.05). Notably, the low HRR cohort exhibited inferior disease-free survival (DFS) and overall survival (OS) rates (P = 0.002 for both). Univariate analysis indicated that male gender, adjacent tissue invasion, TNM stages III/IV, non-O blood types, low HRR, and lack of postoperative chemotherapy were linked to adverse DFS and OS outcomes (P < 0.05). Multivariate analysis further delineated low HRR as an independent predictor of poor DFS and OS outcomes (HR: 1.520, 95% CI: 1.028–2.247, P = 0.036; HR: 1.537, 95% CI: 1.034–2.284, P = 0.034, respectively).ConclusionOur findings suggest that a lower HRR is indicative of poorer DFS and OS in PDAC patients, underscoring its potential utility as a prognostic biomarker for this population.

First-line immunotherapy in patients with mNSCLC with rare molecular alterations.

e20604 Background: Oncogene-addicted non-small cell lung cancer (NSCLC) is an heterogeneous group including different molecular alterations. Most single agent (IO) and combination immunotherapy (CT-IO) trials excluded specific oncogene-addicted NSCLCs such as ALK and EGFR; however, it is likely that other oncogene driven tumours were not tested for but included in these trials and could be actually treated with IO in clinical practice. Methods: Among 428 patients treated with IO or CT-IO as first-line treatment, 30 patients were identified to harbour rare molecular alterations (37% non-smokers, 63% former or current smokers): METex14 skipping mutation (n = 10), MET amplifications (n = 4), BRAF other than V600E mutations (n = 7), HER2 exon 20 insertions (n = 5), RET fusions (n = 2), EGFR exon 20 insertions (n = 2). We analyzed progression-free survival (PFS) and overall survival (OS) in patients harbouring these mutations who underwent first-line IO (if PD-L1≥50%; n = 23) or CT-IO (if PD-L1 &lt; 1-49% n = 2 or &lt; 1% n = 5). Results: In whole population median PFS was 5,1 months (95%CI: 2,39-11,29) and median OS 25,5 months (95%CI: 8,80-60,98); 13 patients experienced progressive disease as best response, the disease control rate (DCR) was 56,7%. Patients treated with IO (n = 22) had a mPFS of 4,7 m (95%CI: 2,13-23,48) and a mOS of 29,8 months (95%CI: 10,08-60,98); those treated with CT-IO (n = 8) had a mPFS of 5,1 m (95%CI: 2,29-6,01) and a mOS of 8,5 m (95%CI: 7,68-12,51). Among the most represented molecular alterations, MET alterations (n = 14, 3 treated with CT-IO and 11 with IO) had a mPFS of 5,1 m (95%CI: 1,67-23,90) and a mOS of 25,5 m (95%CI: 8,80-60,72). In particular METex14 skipping mutations had a mPFS of 5,1 m and a mOS of 25,5 m, while MET amplifications had a mPFS of 2,4 m and mOS of 10,3 m. BRAF nonV600E mutations (n = 7, 2 treated with CT-IO and 5 with IO) had a mPFS 5,3 m and mOS not reached. HER2 exon 20 insertions (n = 5, 2 treated with CT-IO and 3 with IO) had a similar mPFS (6,0 m) but a poorer OS outcome (8,5 m). ( Table 1) Conclusions: Our results show a limited effectiveness of both IO alone and CT-IO as first-line treatment in oncogene addicted mNSCLC, even taking into account survival outcomes of upfront CT compared to targeted agents in pivotal trials. [Table: see text]

Transforming Growth Factor Beta 2 (TGFB2) and Interferon Gamma Receptor 2 (IFNGR2) mRNA Levels in the Brainstem Tumor Microenvironment (TME) Significantly Impact Overall Survival in Pediatric DMG Patients.

This hypothesis-generating study characterized the mRNA expression profiles and prognostic impacts of antigen-presenting cell (APC) markers (CD14, CD163, CD86, and ITGAX/CD11c) in pediatric brainstem diffuse midline glioma (pbDMG) tumors. We also assessed the mRNA levels of two therapeutic targets, transforming growth factor beta 2 (TGFB2) and interferon gamma receptor 2 (IFNGR2), for their biomarker potentials in these highly aggressive pbDMG tumors. The expressions of CD14, CD163, and ITGAX/CD11c mRNAs exhibited significant decreases of 1.64-fold (p = 0.037), 1.75-fold (p = 0.019), and 3.33-fold (p < 0.0001), respectively, in pbDMG tumors relative to those in normal brainstem/pons samples. The pbDMG samples with high levels of TGFB2 in combination with low levels of APC markers, reflecting the cold immune state of pbDMG tumors, exhibited significantly worse overall survival outcomes at low expression levels of CD14, CD163, and CD86. The expression levels of IFNGR2 and TGFB2 (1.51-fold increase (p = 0.002) and 1.58-fold increase (p = 5.5 × 10-4), respectively) were significantly upregulated in pbDMG tumors compared with normal brainstem/pons samples. We performed multivariate Cox proportional hazards modelling that showed TGFB2 was a prognostic indicator (HR for patients in the TGFB2high group of pbDMG patients = 2.88 (1.12-7.39); p = 0.028) for poor overall survival (OS) and was independent of IFNGR2 levels, the age of the patient, and the significant interaction effect observed between IFNGR2 and TGFB2 (p = 0.015). Worse survival outcomes in pbDMG patients when comparing high versus low TGFB2 levels in the context of low IFNGR2 levels suggest that the abrogation of the TGFB2 mRNA expression in the immunologically cold tumor microenvironment can be used to treat pbDMG patients. Furthermore, pbDMG patients with low levels of JAK1 or STAT1 mRNA expression in combination with high levels of TGFB2 also exhibited poor OS outcomes, suggesting that the inclusion of (interferon-gamma) IFN-γ to stimulate and activate JAK1 and STAT1 in anti-tumor APC cells present the brainstem TME can enhance the effect of the TGFB2 blockade.

Comparative efficacy and hematologic safety of different dosages of JAK inhibitors in the treatment of myelofibrosis: a network meta-analysis.

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis associated with substantial morbidity and mortality. The therapeutic landscape for MF has advanced with the development of Janus kinase inhibitors (JAKis) like ruxolitinib (RUX), fedratinib (FED), pacritinib (PAC), and momelotinib (MMB), aiming to alleviate symptoms and enhance patient comfort. A network meta-analysis was conducted to assess the efficacy and safety of eleven JAKi treatment regimens across nine randomized controlled trials (RCTs) with a total of 2340 participants. Outcomes were evaluated in terms of spleen volume reduction (SVR), total symptom score reduction (TSSR), hematological safety profiles, and overall survival (OS). RUX and MMB were superior in achieving SVR and TSSR, with significant dose-response relationships observed. PAC and MMB were associated with a decreased risk of grade 3/4 anemia and thrombocytopenia compared to other JAKis. However, no substantial benefits in OS were observed with newer JAKis compared to RUX. The poorer OS outcomes with certain PAC dosages were likely influenced by baseline patient characteristics, particularly severe cytopenias. The introduction of JAKis significantly changed the treatment of MF. This meta-analysis reaffirms the core role of RUX and positions MMB as a potentially powerful alternative for treating symptoms and reducing spleen size. Meanwhile, MMB and PAC have a positive effect on anemia in MF while FED is more tolerable for patients with thrombocytopenia. However, it should be noted that these results are influenced by baseline patient characteristics, particularly cytopenias, which affects both management and overall survival. Therefore, there is an urgent need for personalized dosing strategies to optimize the balance between efficacy and safety, with careful consideration of patient-specific factors. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023424179.

The coexistence of myosteatosis and the creatinine/cystatin C ratio are determinants of outcomes in cholangiocarcinoma patients undergoing curative surgery.

Myosteatosis is a well-established predictor of poor prognosis in many types of cancer, and a decreased Creatinine/Cystatin C ratio (CCR) is a known indicator of unfavorable outcomes in patients with metabolic disorders and cancer. Despite this knowledge, the significance of concurrent CCR and myosteatosis in predicting the prognosis of patients with cholangiocarcinoma (CCA) who undergo radical surgery remains uncertain. Data from 757 patients with cholangiocarcinoma who underwent the first radical resection in the Affiliated Hospital of Qingdao University from January 2017 to March 2022 were collected. According to the inclusion and exclusion criteria, 149 patients were finally included in the retrospective study cohort. Various clinicopathological, serological, and radiological data were collected at admission. Myosteatosis was evaluated using sliceOmatic software on computed tomography (CT) images. The study used receiver operating characteristic (ROC) curve analysis to determine the critical value of CCR, which predicts overall survival (OS) based on the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were employed to identify the risk factors associated with OS and RFS confidently. The group identified as the myosteatosis cohort consisted of 79 patients with an average age of 64.3 ± 7.8 years. The ROC curve analysis revealed an optimal critical CCR value of 10.834.A low CCR ≤ 10.834 and myosteatosis were found to be associated with poor OS and RFS outcomes (P = 0.022; P = 0.017; P = 0.038; P = 0.030 respectively). Moreover, patients with myosteatosis and a CCR ≤ 10.834 had the worst OS and RFS outcomes (P = 0.035; P = 0.027). After radical excision in CCA patients, the presence of myosteatosis and CCR had a negative correlation with prognosis. A more accurate prediction of OS and RFS was possible by combining CCR and myosteatosis, compared to CCR alone.

Tumor volume features predict survival outcomes for patients diagnosed with diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood central nervous system tumor. Diagnosis and monitoring of tumor response to therapy is based on magnetic resonance imaging (MRI). MRI-based analyses of tumor volume and appearance may aid in the prediction of patient overall survival (OS). Contrast-enhanced T1- and FLAIR/T2-weighted MR images were retrospectively collected from children with classical DIPG diagnosed by imaging (n = 43 patients). MRI features were evaluated at diagnosis (n = 43 patients) and post-radiation (n = 40 patients) to determine OS outcome predictors. Features included 3D tumor volume (Twv), contrast-enhancing tumor core volume (Tc), Tc relative to Twv (TC/Twv), and Twv relative to whole brain volume. Support vector machine (SVM) learning was used to identify feature combinations that predicted OS outcome (defined as OS shorter or longer than 12 months from diagnosis). Features associated with poor OS outcome included the presence of contrast-enhancing tumor at diagnosis, >15% Tc/Twv post-radiation therapy (RT), and >20% ∆Tc/Twv post-RT. Consistently, SVM learning identified Tc/Twv at diagnosis (prediction accuracy of 74%) and ∆Tc/Twv at <2 months post-RT (accuracy = 75%) as primary features of poor survival. This study demonstrates that tumor imaging features at diagnosis and within 4 months of RT can predict differential OS outcomes in DIPG. These findings provide a framework for incorporating tumor volume-based predictive analyses into the clinical setting, with the potential for treatment customization based on tumor risk characteristics and future applications of machine-learning-based analysis.

High pre-chemoradiotherapy pan-immune-inflammation value levels predict worse outcomes in patients with stage IIIB/C non-small-cell lung cancer

Background and objectivesWe explored the prognostic usefulness of the pan-immune-inflammation value (PIV) in patients with stage IIIB/C non-small-cell lung cancer (NSCLC) who underwent concurrent chemoradiotherapy (CCRT).Methods and patientsFor all patients, the PIV was calculated using platelet (P), monocyte (M), neutrophil (N), and lymphocyte (L) measures obtained on the first day of CCRT: PIV = P × M × N ÷ L. Using receiver operating characteristic (ROC) curve analysis, we searched for the existence of an ideal cutoff that may partition patients into two groups with unique progression-free- (PFS) and overall survival (OS) results. The primary endpoint of this retrospective cohort research was to determine whether there were any significant relationships between pretreatment PIV measures and post-CCRT OS outcomes.ResultsThe present research included a total of 807 stage IIIB/C NSCLC patients. According to ROC curve analysis, the ideal PIV cutoff was 516 [area under the curve (AUC): 67.7%; sensitivity: 66.4%; specificity: 66.1%], which divided the whole cohort into two: low PIV (L-PIV: PIV < 516; N = 436) and high PIV (H-PIV: PIV ≥ 516; N = 371). The comparisons between the PIV groups indicated that either the median PFS (9.2 vs. 13.4 months; P < 0.001) or OS (16.7 vs. 32.7 months; P < 0.001) durations in the H-PIV group were substantially inferior to their L-PIV counterpart. Apart from the H-PIV (P < 0.001), the N3 nodal stage (P = 0.006), IIIC disease stage (P < 0.001), and receiving only one cycle of concurrent chemotherapy (P = 0.005) were also determined to be significant predictors of poor PFS (P < 0.05, for each) and OS (P < 0.05, for each) outcomes in univariate analysis. The multivariate analysis findings revealed that all four variables had independent negative impacts on PFS (P < 0.05, for each) and OS (P < 0.05, for each).ConclusionsThe findings of this hypothesis-generating retrospective analysis claimed that the novel PIV was an independent and steadfast predictor of PFS and OS in stage IIIB/C NSCLC patients.

TMIC-85. TGFB2 AND IFNGR2 MRNA EXPRESSION LEVELS IN THE TUMOR MICROENVIRONMENT (TME) PROGNOSITICALLY IMPACT OS IN PEDIATRIC DIPG PATIENTS

Abstract DIPG patients expressed significantly higher levels of TGFB2 and IFNGR2 than control pons samples and the expression profile indicated higher levels of TGFB2 than TGFB1 and TGFB3 in DIPG patients suggesting TGFB2 mRNA level is preferentially increased in DIPG patients. TGFB2 is a prognostic indicator (HR for patients in the TGFB2high group of DIPG patients = 2.88 (1.12-7.39); P = 0.028) for poor overall survival (OS) independent of IFNGR2 levels, the age of the patient, and the significant interaction effect observed between IFNGR2 and TGFB2. Predictive modeling using the Cox regression parameters showed that the context of low expression of IFNGR2, TGFB2low resulted in more favorable OS times compared to TGFB2high whereby the median OS time of 11 months for the TGFB2low group of patients was greater than the upper 95% confidence limit for the TGFB2high group of patients (Median = 7 months; Upper 95% Confidence interval = 10 months). At higher levels of IFNGR2 expression, the TGFB2high group of patients exhibited a median OS time of 15 months that was within the (95% confidence interval for the TGFB2low group of patients (Median = 13 months; 95% CI = 10-17 months). Worse survival outcomes comparing DIPG patients with high versus low TGFB2 levels in the context of low levels of IFNGR2 levels suggest that abrogating the TGFB2 mRNA expression in the immunologically cold tumor microenvironment indicated by low levels of IFNGR2 expression can potentially treat pediatric DIPG patients. Furthermore, DIPG patients with low levels of JAK1 or STAT1 mRNA expression in combination with TGFB2high also exhibited poor OS outcomes suggesting that the inclusion of (Interferon-gamma) IFNγ to stimulate and activate JAK1 and STAT1 in anti-tumor immune cells present the brainstem tumor microenvironment can enhance the effect of TGFB2 blockade.

Cytoplasmic Localization of Thyroid Hormone Receptor (TR) Alpha and Nuclear Expression of Its Isoform TRα2 Determine Survival in Breast Cancer in Opposite Ways.

The aim of this retrospective study was to assess the respective prognostic values of cytoplasmic and nuclear TRα, TRα1, and TRα2 expression in breast cancer (BC) tissue samples and correlate the results with clinico-pathological parameters. In 249 BC patients, the expression patterns of general TRα and the α1 and α2 isoforms were evaluated via immuno-histochemistry. Prognosis-determining aspects were calculated via univariate, as well as multivariate, analysis. Univariate Cox-regression analysis revealed no association between nuclear TRα expression and overall survival (OS) (p = 0.126), whereas cytoplasmic TRα expression was significantly correlated with a poor outcome for both OS (p = 0.034) and ten-year survival (p = 0.009). Strengthening these results, cytoplasmic TRα was found to be an independent marker of OS (p = 0.010) when adjusted to fit clinico-pathological parameters. Analyses of the TRα-subgroups revealed that TRα1 had no prognostic relevance, whereas nuclear TRα2 expression was positively associated with OS (p = 0.014), ten-year survival (p = 0.029), and DFS (p = 0.043). Additionally, nuclear TRα2 expression was found to be an independent positive prognosticator (p = 0.030) when adjusted to fit clinico-pathological parameters. Overall, our results support the hypothesis that subcellular localization of TRα and its isoforms plays an important role in the carcinogenesis and prognosis of breast cancer. Cytoplasmic TRα expression correlates with more aggressive disease progression, whereas nuclear TRα2 expression appears to be a protective factor. These data may help us to prioritize high-risk BC subgroups for possible targeted tumor therapy.

Radiotherapy After Gross Total Resection of Skull Base Chordoma: A Surveillance, Epidemiology, and End Results Database Analysis of Survival Outcomes.

Skull base chordoma is a rare and locally destructive malignancy which presents unique therapeutic challenges. While achieving gross total resection (GTR) confers the greatest survival advantage, the role of adjuvant radiotherapy (RT) for patients who receive GTR remains unclear in the absence of prospective trials. Here, we aim to assess the effect of RT on survival outcomes in skull base chordoma patients who receive GTR by utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Patients with diagnostic, primary site, and resection codes specific for chordoma, skull base, and GTR, respectively, were queried in the SEER database (2000-2018). Kaplan-Meier curves (log-rank test) were constructed and Cox proportional hazards models were used to assess survival outcomes. A total of 115 skull base chordomas undergoing GTR were identified, of which 37 (32%) received no RT and 78 (68%) received RT. Median follow-up was 55.00months (range: 0.00-227.00). Overall survival (OS) of patients with GTR was 85% and 70% at 5 and 10years, respectively. Multivariate Cox proportional hazard analysis among chordoma patients undergoing GTR found age ≥65 (P < 0.01) was associated with poorer OS outcomes. RT appeared to trend toward offering benefit in terms of OS in patients after GTR, however this did not achieve statistical significance in the adjusted model (HR= 0.51, CI= 0.23-1.16, P= 0.09). When comparing, disease-specific survival was also not improved in patients undergoing RT (HR= 0.58, CI= 0.23-1.46, P= 0.25). It remains unclear whether RT after GTR of chordoma improved survival outcomes among SEER database patients.

IDO1/COX2 Expression Is Associated with Poor Prognosis in Colorectal Cancer Liver Oligometastases.

IDO1 and COX2 have emerged as promising immunotherapy targets. It is unclear whether IDO1 and COX2 expression levels in colorectal cancer (CRC) patients with liver oligometastases could be independent predictors of overall survival (OS) and progression-free survival (PFS). The purpose of this study was to investigate the correlation of IDO1 and COX2 expression levels with OS and PFS in CRC patients with liver oligometastases. The expression levels of IDO1 and COX2 were assessed by immunohistochemistry in 107 specimens from patients with liver oligometastases. The correlation between the expression of IDO1 and COX2 and the clinicopathological parameters and OS/PFS in patients was examined. The expression level of IDO1/COX2 was significantly correlated with age and was not associated with gender, BMI, T stage, N stage, primary tumor size, liver metastasis size, CEA, CA19-9, CD3 TILs or CD8 TILs. In univariate analysis, we found that IDO1/COX2 expression, CEA and N stage all yielded significantly poor OS and PFS outcomes. In our multivariate Cox model, IDO1/COX2 coexpression, CEA and N stage were found to be significantly correlated with OS; IDO1/COX2 coexpression and CEA were significantly correlated with PFS. IDO1/COX2 coexpression plays a pivotal role and may act as a potential prognostic biomarker for survival in CRC patients with liver oligometastases.

A Pan-Cancer Analysis Revealing the Dual Roles of Lysine (K)-Specific Demethylase 6B in Tumorigenesis and Immunity.

Introduction: Epigenetic-targeted therapy has been increasingly applied in the treatment of cancers. Lysine (K)-specific demethylase 6B (KDM6B) is an epigenetic enzyme involved in the coordinated control between cellular intrinsic regulators and the tissue microenvironment whereas the pan-cancer analysis of KDM6B remains unavailable. Methods: The dual role of KDM6B in 33 cancers was investigated based on the GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas) databases. TIMER2 and GEPIA2 were applied to investigate the KDM6B levels in different subtypes or stages of tumors. Besides, the Human Protein Atlas database allowed us to conduct a pan-cancer study of the KDM6B protein levels. GEPIA2 and Kaplan–Meier plotter were used for the prognosis analysis in different cancers. Characterization of genetic modifications of the KDM6B gene was analyzed by the cBioPortal. DNA methylation levels of different KDM6B probes in different TCGA tumors were analyzed by MEXPRESS. TIMER2 was applied to determine the association of the KDM6B expression and immune infiltration and DNA methyltransferases. Spearman correlation analysis was used to assess the association of the KDM6B expression with TMB (tumor mutation burden) and MSI (microsatellite instability). The KEGG (Kyoto encyclopedia of genes and genomes) pathway analysis and GO (Gene ontology) enrichment analysis were used to further investigate the potential mechanism of KDM6B in tumor pathophysiology. Results: KDM6B was downregulated in 11 cancer types and upregulated across five types. In KIRC (kidney renal clear cell carcinoma) and OV (ovarian serous cystadenocarcinoma), the KDM6B level was significantly associated with the pathological stage. A high level of KDM6B was related to poor OS (overall survival) outcomes for THCA (thyroid carcinoma), while a low level was correlated with poor OS and DFS (disease-free survival) prognosis of KIRC. The KDM6B expression level was associated with TMB, MSI, and immune cell infiltration, particularly cancer-associated fibroblasts, across various cancer types with different correlations. Furthermore, the enrichment analysis revealed the relationship between H3K4 and H3K27 methylation and KDM6B function. Conclusion: Dysregulation of the DNA methyltransferase activity and methylation levels of H3K4 and H3K27 may involve in the dual role of KDM6B in tumorigenesis and development. Our study offered a relatively comprehensive understanding of KDM6B’s dual role in cancer development and response to immunotherapy.

The preoperative hemoglobin, albumin, lymphocyte, and platelet score is a prognostic factor for non-small cell lung cancer patients undergoing adjuvant chemotherapy: a retrospective study.

BackgroundDeveloping a simple, reliable and low-cost biomarkers is crucial to predict the prognosis of non-small cell lung cancer (NSCLC) patients receiving adjuvant chemotherapy. The score combining hemoglobin and albumin levels and lymphocyte and platelet counts (HALP score) is reportedly related to the prognosis of multiple types of tumors. However, few studies have focused on its prognostic value in patients with NSCLC. Our study aimed to investigate the prognostic role of the HALP score and develop a valuable prognostic model for patients with NSCLC undergoing adjuvant chemotherapy.MethodsA total of 362 individuals with NSCLC undergoing adjuvant chemotherapy between 2013 and 2015 were included. The HALP score was computed according to the following formula: hemoglobin (g/L) × albumin (g/L) × lymphocytes (g/L)/platelets (g/L). Furthermore, demographic characteristic, including age, sex, smoking status, and drinking history, were collected from case report forms at admission. The main outcomes were overall survival (OS) and disease-free survival (DFS), which were assessed using Kaplan-Meier analysis with log-rank test. Furthermore, Cox regression analysis was employed to assess the prognostic role of HALP in NSCLC.ResultsWe found the significant associations of clinicopathological features, including sex, pathological stage, tumor size, and lymph node metastasis (LNMets) in univariate Cox regression analysis. In multivariate analysis, NSCLC patients with a high HALP score were significantly associated with lower OS [hazard ratio (HR): 0.707; 95% confidence interval (CI): 0.503–0.995] and DFS (HR: 0.671; 95% CI: 0.491–0.916). The Kaplan-Meier analysis showed that a low HALP score predicted poorer OS (P=0.02) and DFS (P<0.01) outcomes. Furthermore, we performed stratification analysis by tumor node metastasis (TNM) stage, and the result indicated a low HALP score predicted poor OS (P=0.01) and DFS (P=0.04) outcomes in stage III–IV NSCLC patients.ConclusionsOur study demonstrated that the HALP score might be a suitable prognostic index for NSCLC patients undergoing adjuvant chemotherapy. Combining demographic and clinicopathological features with the HALP score may help clinicians predict survival and treatment outcomes.

Characterizing IMDC prognostic groups in contemporary first-line combination therapies for metastatic renal cell carcinoma (mRCC).

308 Background: The combination of immuno-oncology agents (IO) ipilimumab and nivolumab (IPI-NIVO) and combinations of IO with vascular endothelial growth factor targeted therapies (IOVE) have demonstrated efficacy in clinical trials for the first-line treatment of mRCC. This study seeks to establish real-world clinical benchmarks based on the International mRCC Database Consortium (IMDC) criteria using vascular endothelial growth factor targeted therapy (VEGF-TT) treated patients for context. Methods: The IMDC database (IMDConline.com) was used to identify patients with mRCC who received first-line IPI-NIVO, IOVE (axitinib/pembrolizumab, lenvatinib/pembrolizumab, cabozantinib/nivolumab, or axitinib/avelumab) and VEGF-TT (sunitinib or pazopanib) from 2002-2021. The primary endpoint was overall survival (OS) and was calculated from time of initiation of first-line therapy to death or last follow up. Log-rank tests were conducted to compare favorable, intermediate, and poor risk OS outcomes within treatment groups. Overall response rates (ORR) and complete response (CR) rates were calculated based on physician assessment of best clinical response. Results: In total, 692 patients received IPI-NIVO, 244 received IOVE, and 7152 received VEGF-TT. Baseline characteristics for IPI-NIVO, IOVE, and VEGF-TT, respectively, were as follows: median age (interquartile range) 63 (56-69), 64 (57-70), and 63 (56-70); male 72%, 74%, and 72% (p=0.74); non-clear cell histology 15%, 10%, and 13% (p=0.15); sarcomatoid features 24%, 15%, and 13% (p&lt;0.0001); brain metastasis 8%, 4%, and 8% (p=0.04); liver metastasis 18%, 14%, and 18% (p=0.17); underwent nephrectomy 61%, 79% and 80% (p&lt;0.0001). OS and ORR are reported in the table. P-values (log rank) for OS between risk groups were significant for IPI-NIVO (p&lt;0.0001), IOVE (p=0.0005), and VEGF-TT (p&lt;0.0001). Conclusions: These findings provide real-world survival and response benchmarks for contemporary first-line mRCC treatments and could be helpful for patient counselling. In addition, these findings mirror the efficacy of combination therapies established in clinical trials against VEGF-TT monotherapy. IMDC criteria continue to risk stratify patients in these novel combination therapies.[Table: see text]

A study of the prognostic value of long non-coding RNA CASC15 in human solid tumors utilizing The Cancer Genome Atlas (TCGA) datasets and a meta-analysis.

Several malignant solid tumors have been reported to have an abnormal expression of the long non-coding RNA CASC15 (lncRNA CASC15). However, the clinicopathologic and prognostic importance of CASC15 in solid tumors are unknown. As a result, we examined the interrelationship between CASC15, overall survival length, and clinicopathological attributes of cancers affecting humans by analyzing various studies and The Cancer Genome Atlas (TCGA) data related to CASC15 expression. Web of Science, PubMed, Cochrane Library, Embase, Chinese WanFang, and Chinese CNKI databases were used to conduct a literature search. Hazard ratios (HRs) and Pooled odds ratios (ORs) were calculated taking 95% confidence intervals (CIs). The results of the current meta-analysis were further validated using TCGA datasets. A total of 12 eligible studies enrolling 767 patients were included in this meta-analysis. Findings of the analysis showed that CASC15 expression had a significant relation to the metastasis of lymph node (OR = 3.30, 95%CI = 1.88-5.81, p < 0.001), distant metastasis (OR = 2.64, 95%CI = 1.24-5.63, p = 0.012), and high TNM/clinical stage (OR = 2.67, 95%CI = 1.34-5.32, p = 0.005). Additionally, we found that a poor outcome for overall survival (OS) was predicted by an elevation in CASC15 expression (HR = 2.01, 95%CI = 1.71-2.36, p < 0.001). Further investigation of the TCGA dataset revealed that CASC15 had abnormal expression in many cancers, which at least partially validated the findings of the current meta-analysis. According to the latest meta-analysis and systematic review, high expression levels of CASC15 are associated with poor survival outcomes for solid tumor patients, and the use of CASC15 as a solid tumor prognostic predictor has a solid theoretical foundation.

Prognostic Value of Long Non-coding RNAs in Urological Malignancies: A Systematic Review, and Meta-Analysis

Background: Many studies have explored the potential roles of long non-coding RNAs (lncRNAs) in urological cancer (UC) progression. The clinical outcome and prognosis of UCs remain weak. Therefore, finding clinical prognostic markers is needed to improve therapeutic potential. The aim of this study was to consider the possible association between the lncRNAs expression with the survival time and clinical outcomes in patients with UC. Methods: A literature search was performed in several related databases to find eligible English papers published before 9 February 2021. Hazard ratios (HRs) with 95% CI were calculated to investigate the association between lncRNAs expression and overall survival in patients with UC. Results: A total of 46 studies, including 39 lncRNAs were identified. Results indicated that lncRNAs expression was significantly correlated with poor overall survival (OS) outcome in patients with UCs (HR: 1.923, 95% CI: 1.448-2.554, P&lt;0.001). Also, we divided included studies into up-regulated and down-regulated subgroups according to lncRNAs expression. The results indicated a significant association with poor OS outcomes in both up-regulated (HR=2.546, 95% CI: 1.896-3.41, P&lt;0.001) and down-regulated (HR=0.33, 95% CI: 0.22-0.49, P&lt;0.001). Moreover, expression of lncRNAs was significantly associated with lymph node metastasis (LNM) (OR=0.25, 95% CI: 0.13-0.47, P&lt;0.001) Conclusion: Abnormal expression of various lncRNAs is a potential novel marker for predicting the clinical outcomes of urological tumors.

High-Risk Gene Expression Subtype Provides Molecular Basis for Different Clinical Presentation of Primary and Secondary Plasma Cell Leukemia

Plasma cell leukemia (PCL) is rare but represents an aggressive, advanced form of multiple myeloma where neoplastic plasma cells (PCs) lose dependence on the bone marrow (BM) and circulate in the peripheral blood (PB). PCL is clinically defined by diagnosis of myeloma with ≥20% circulating plasma cells (CPCs), however, several groups have proposed a ≥5% CPC cutoff. PCL is classified as primary (pPCL) if it presents at myeloma diagnosis or secondary (sPCL) if it arises at a later progression event. These presentations of PCL are clinically distinct, with sPCL patients responding poorly to novel therapies and having inferior outcomes compared to pPCL patients. Despite recent advances in myeloma therapy, PCL prognosis remains poor, and the molecular drivers of PCL remain poorly understood.The MMRF CoMMpass study (NCT01454297) is a longitudinal, observational clinical study of 1171 newly-diagnosed myeloma patients. Tumors were characterized using whole genome (WGS), exome (WES), and RNA (RNAseq) sequencing at diagnosis and each progression event. PCs were isolated from BM-derived tumors and when >5% CPCs were detected, PCs were also isolated from the PB, creating a subcohort of patients with sequencing data from both the BM and PB compartments, with some patients assayed longitudinally.The percent CPCs determined using flow cytometry was reported for 982 patients at myeloma diagnosis and 194 patients at progression. Patients with 5-20% CPCs (median = 19 months) at diagnosis had poor overall survival (OS) outcomes compared to those with less than 5% CPCs (median = 95 months, p<0.001). No outcome difference was observed between patients with 5-20% and >20% CPCs (median = 41 months), confirming the findings of previous independent studies. A ≥5% CPC cutoff identified 947 myeloma, 29 pPCL, and 6 sPCL patients in the CoMMpass cohort. Compared to myeloma, pPCL and sPCL patients had poor OS (p<0.001), and after sPCL detection patients had a median OS of only 53 days (range = 0-169 days). For 10 pPCL patients, the percent CPCs was reported at diagnosis and at least one progression event, and patients with persistent CPCs (n = 5, median = 16 months, p<0.01) had poor OS compared to patients with no detectable CPCs at progression (n = 5, median not met, median follow up = 64 months). This underscores the benefit of early eradication of CPCs and repeated CPC measurements in pPCL.The proliferative (PR) gene expression subtype of myeloma has been previously described and defines a high-risk group of patients with diverse genetic backgrounds and inferior outcomes. For PCL patients, we determined the subtype of all BM and PB tumor samples characterized using RNAseq. There was high subtype concordance between paired BM and PB tumor samples (12/13, 92.3%). Overall, 6/23 (26.1%) pPCL patients were in the PR subtype, and PR pPCL patients had poor OS outcomes (median = 10 months, p<0.001) compared to non-PR pPCL patients (median = 55 months). PR emerged as a robust predictor of risk in pPCL, outperforming other molecular and clinical variables including high BM or PB PCs, plasmacytomas, renal failure, high LDH, high B2M, low platelets, t(11;14), del(1p), amp(1q), del(13q), and del(17p), suggesting that RNA subtyping CPCs may represent a non-invasive tool to predict risk in pPCL.At myeloma diagnosis, all sPCL patients with RNAseq data were classified in non-PR subtypes. However, at sPCL, 5/6 (83.3%) patients were in the PR subtype, indicating that sPCL is associated with transition to PR. Two sPCL patients that transitioned to PR acquired biallelic deletion of CDKN2C, and a third acquired biallelic deletion of RB1. Overall, a subset of pPCL (26.1%) but the majority of sPCL (83.3%) patients were in the PR subtype at PCL diagnosis, providing a molecular basis for the different clinical presentations observed between these two groups, including the highly-aggressive nature of sPCL. In summary, this study supports using a lower percent CPC cutoff to clinically define PCL and highlights the importance of repeated CPC measurements in prognosticating pPCL patients. Further, PR RNA subtype emerged as a predictor of risk in pPCL and, given that the majority of sPCL patients were in the PR subtype, provides a molecular basis for the different clinical features observed between pPCL and sPCL patients. DisclosuresMikhael: Amgen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Oncopeptides: Consultancy.