Poor Progression-free Survival In Patients Research Articles

Visceral obesity and sarcopenia as predictors of efficacy and hematological toxicity in patients with metastatic breast cancer treated with CDK 4/6 inhibitors.

We aimed to investigate whether visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and skeletal muscle area (SMA) index are predictive for efficacy and hematological toxicity in ER+HER2-metastatic breast cancer (BC) patients who received CDK 4/6 inhibitors. This retrospective cohort study analyzed 52 patients who were treated with CDK 4/6 inhibitors between January 2018 and February 2021. The values of VAT, SAT, SMA indices and hematological parameters were noted before the start, at the third and sixth months of this treatment. The skeletal muscle area (SMA) and adipose tissue measurements were calculated at the level of the third lumbar vertebra. A SMA-index value of <40cm2/m2 was accepted as the threshold value for sarcopenia. Patients with sarcopenia had a worse progression-free survival (PFS) compared to patients without sarcopenia (19.6 vs. 9.0months, p=0.005). Patients with a high-VAT-index had a better PFS (20.4 vs. 9.3months, p=0.033). Only the baseline low-SMA- index (HR: 3.89; 95% CI: 1.35-11.25, p=0.012) and baseline low-VAT-index (HR: 2.15; 95% CI: 1.02-4.53, p=0.042) had significantly related to poor PFS in univariate analyses. The low-SMA-index was the only independent factor associated with poor PFS (HR: 3.99; 95% CI: 1.38-11.54, p=0.011). No relationship was observed between body composition parameters and grade 3-4 hematological toxicity. The present study supported the significance of sarcopenia and low visceral adipose tissue as potential early indicators of poor PFS in patients treated with CDK 4/6 inhibitors.

Digital and manual interfollicular Ki-67 are associated with a progression-free survival in patients with low-grade follicular lymphoma.

Novel histopathologic prognostic factors are needed to identify patients with follicular lymphoma (FL) at risk of inferior outcomes. Our primary objective was to evaluate the Ki-67 proliferative index in follicular and interfollicular areas in tissue biopsy specimens from patients with newly diagnosed FL and correlate with clinical outcomes. Our secondary objective was to correlate PD-L1 and LAG-3 with clinical outcomes. Seventy cases of low-grade FL from the University of Minnesota were evaluated with Ki-67 immunohistochemical stain. Ki-67 expression as a continuous variable was interpreted digitally and manually in follicular and interfollicular areas. Progression-free survival (PFS) and overall survival (OS) were analyzed by Cox regression, and hazard ratios (HRs) per 10-point increase in Ki-67 were calculated. Progression-free survival at 4 years was 28% (95% CI, 19%-41%). Interfollicular, but not follicular, Ki-67 was associated with PFS by manual (HR, 1.33; P = .01) and digital (HR, 1.38; P = .02) analysis. Digital and manual Ki-67 were only moderately correlated but demonstrated similar effects on PFS. At 4 years, OS was 90% with no association with follicular or interfollicular Ki-67 proliferation. Higher interfollicular Ki-67 by either digital or manual analysis is associated with a poorer PFS in patients with low-grade FL. These results suggest further validation of this marker is warranted to improve pathologic risk stratification at FL diagnosis. PD-L1 and LAG-3 were not associated with PFS or OS.

Insulin feedback is a targetable resistance mechanism of PI3K inhibition in glioblastoma.

Insulin feedback is a critical mechanism responsible for the poor clinical efficacy of phosphatidylinositol 3-kinase (PI3K) inhibition in cancer, and hyperglycemia is an independent factor associated with poor prognosis in glioblastoma (GBM). We investigated combination anti-hyperglycemic therapy in a mouse model of GBM and evaluated the association of glycemic control in clinical trial data from patients with GBM. The effect of the anti-hyperglycemic regimens, metformin and the ketogenic diet, was evaluated in combination with PI3K inhibition in patient-derived GBM cells and in an orthotopic GBM mouse model. Insulin feedback and the immune microenvironment were retrospectively evaluated in blood and tumor tissue from a Phase 2 clinical trial of buparlisib in patients with recurrent GBM. We found that PI3K inhibition induces hyperglycemia and hyperinsulinemia in mice and that combining metformin with PI3K inhibition improves the treatment efficacy in an orthotopic GBM xenograft model. Through examination of clinical trial data, we found that hyperglycemia was an independent factor associated with poor progression-free survival in patients with GBM. We also found that PI3K inhibition increased insulin receptor activation and T-cell and microglia abundance in tumor tissue from these patients. Reducing insulin feedback improves the efficacy of PI3K inhibition in GBM in mice, and hyperglycemia worsens progression-free survival in patients with GBM treated with PI3K inhibition. These findings indicate that hyperglycemia is a critical resistance mechanism associated with PI3K inhibition in GBM and that anti-hyperglycemic therapy may enhance PI3K inhibitor efficacy in GBM patients.

Prognostic Role of Geriatric Nutritional Risk Index in Patients with Pancreatic Cancer: A Meta-Analysis

Background: The Geriatric Nutritional Risk Index (GNRI) is used to assess the prognosis of patients with pancreatic cancer. Therefore, this meta-analysis was conducted to evaluate the association between the GNRI and prognosis in pancreatic cancer. Methods: We performed a pooled analysis of the hazard ratios (HRs) and 95% confidence intervals (CIs) of the GNRI for survival in pancreatic cancer. Using pooled odds ratios (ORs) and 95% CIs, we investigated the association between the GNRI and clinicopathological characteristics of pancreatic cancer. Results: Six studies were included in this meta-analysis, totaling 1,513 patients. A low GNRI was significantly associated with a poorer overall survival (OS) in the pooled results (HR, 1.95; 95% CI, 1.29–2.94; p = 0.002) in pancreatic cancer. However, GNRI was not significantly associated with progression-free survival (PFS) in pancreatic cancer (HR, 1.57; 95% CI, 0.90–2.73; p = 0.114). The pooled results indicated that a low GNRI was significantly associated with tumor location of pancreas head (OR, 2.18; 95% CI, 1.45–3.29; p < 0.001). Conclusions: This meta-analysis showed that low GNRI was significantly associated with poor OS but not with poor PFS in patients with pancreatic cancer. The GNRI is a novel and effective risk factor and a potential biomarker for the prognosis of pancreatic cancer.

Psychological distress as risk factor for the efficacy of whole-brain radiotherapy in brain metastasis patients.

Aim: To evaluate the relationship between psychological distress and the efficacy of whole-brain radiotherapy (WBRT) in advanced brain metastasis patients. Methods: Brain metastasis patients (40 with psychological distress and 47 without psychological distress) completed distress thermometer tests before WBRT, and progression-free survival (PFS) was acquired during the follow-up period. Results: Psychological distress was a risk factor for poorer PFS in patients treated with WBRT (p<0.01). The PFS of survivors who underwent WBRT was superior for those without psychological distress (hazard ratio: 0.295; 95% CI: 0.173-0.500; p<0.01). Conclusion: The survival of brain metastasis patients receiving WBRT was influenced by psychological distress, which negatively affected the treatment outcome and is likely to be a potential risk indicator in advanced cancer patients receiving WBRT.

SMYD3 promotes aerobic glycolysis in diffuse large B-cell lymphoma via H3K4me3-mediated PKM2 transcription

Genetic abnormalities in histone methyltransferases (HMTs) frequently occur in diffuse large B-cell lymphoma (DLBCL) and are related to its progression. SET and MYND domain containing 3 (SMYD3) is an HMT that is upregulated in various tumors and promotes their malignancy. However, to the best of our knowledge, the function of SMYD3 in DLBCL has not been investigated thus far. In the present study, 22 HMT genes related to cancer development were first selected according to current literature, and it was found that high SMYD3 expression was significantly associated with poor progression-free survival in patients with DLBCL. SMYD3 protein levels were upregulated and positively associated with poor prognosis and poor responsiveness to chemotherapy in patients with DLBCL. Functional examinations demonstrated that SMYD3 increased cell proliferation and the flux of aerobic glycolysis in DLBCL cells in vitro and in vivo and decreased cell sensitivity to doxorubicin in vitro. Moreover, SMYD3 could directly bind to specific sequences of Pyruvate Kinase M2 (PKM2) and promote DLBCL cell proliferation and aerobic glycolysis via H3K4me3-mediated PKM2 transcription. Clinically, SMYD3 expression positively correlated with that of PKM2, and high SMYD3 was significantly associated with high maximum standardized uptake value (SUVmax) detected by [(18)F]-fluorodeoxyglucose ((18)F-FDG) PET/computed tomography (PET/CT) in DLBCL samples. Concomitant expression of SMYD3 and PKM2 positively correlated with poor progression-free and overall survival in patients with DLBCL and may serve as novel biomarkers in DLBCL.

Clinical Usefulness of Monitoring Muscle Volume during Atezolizumab Plus Bevacizumab Therapy in Patients with Unresectable Hepatocellular Carcinoma.

Simple SummaryDecrease of skeletal muscle mass index during atezolizumab plus bevacizumab therapy was significantly associated with poor progression-free survival in patients with unresectable hepatocellular carcinoma, while pretreatment sarcopenia was not a significant factor. These findings suggest that monitoring skeletal muscle volume during immunotherapy may be useful for predicting clinical outcomes.Background: Sarcopenia is associated with overall survival in patients with hepatocellular carcinoma (HCC). However, it is not known whether muscle volume is associated with clinical outcomes during combination therapy with immune checkpoint inhibitors. We investigated the relationship between changes in muscle volume and treatment outcomes in patients treated with atezolizumab plus bevacizumab. Methods: Thirty-two patients with HCC who received atezolizumab plus bevacizumab as the first-line treatment between October 2020 and February 2022 were included. Skeletal muscle mass index (SMI) was calculated from the skeletal muscle area at the L3 level of the lumbar vertebrae. We compared pretreatment SMI and SMI at 6–14 weeks after administration. Results: Of the 32 patients, 18 had a decreased SMI, while 14 did not. Progression-free survival (PFS) was significantly longer in patients without SMI decrease than in patients with SMI decrease (8.5 vs. 5.8 months, p = 0.011). There were no significant differences in treatment-related adverse events between the patients with and without SMI. Presarcopenia at baseline was not significantly associated with PFS. Conclusions: Decreased SMI was significantly associated with PFS. Monitoring muscle volume during atezolizumab plus bevacizumab therapy is useful in clinical practice.

A comprehensive analysis of Glasgow Prognostic Score (GPS)/the modified Glasgow Prognostic Score (mGPS) on immune checkpoint inhibitor efficacy among patients with advanced cancer.

The association between Glasgow Prognostic Score (GPS) and the modified Glasgow Prognostic Score (mGPS) and clinical outcomes in patients receiving immune checkpoint inhibitors (ICIs) remains controversial. Thus, this meta-analysis aimed to examine the prognostic performance of GPS and mGPS in patients treated with ICIs. Eligible studies were retrieved from searches of EMBASE, PubMed, Web of Science, and Cochrane Library until July 2021. The hazard ratio (HR) and 95% confidence intervals (CIs) were pooled by using fixed-effect or random-effects model to evaluate the influence of GPS/mGPS on overall survival (OS) and progression-free survival (PFS). A total of 1164 patients were included. Overall, mGPS score of 2 and 1 were related to inferior OS (p < 0.001) and PFS (p < 0.001). Subgroup analyses showed no significant association between mGPS score of 1 and OS in patients with non-small cell lung cancer (NSCLC), while this score was significantly associated with poor PFS in patients with NSCLC and head and neck squamous cell carcinoma. Higher GPS (score of 1 or 2) were associated with poor clinical outcomes (OS: p < 0.001; PFS: p=0.036). Subgroup analysis showed high GPS levels were linked to worse OS in patients with NSCLC and gastric cancer, but not for PFS in these patients. Regarding test time point, GPS was related to worse OS and PFS in pre-treatment GPS group, but not in post-treatment GPS group. GPS and mGPS showed great potential to predict survival in patients treated with ICIs. Large and perspective trial are warranted to further validate these findings.

Extravesicular TIMP-1 is a non-invasive independent prognostic marker and potential therapeutic target in colorectal liver metastases

Molecular reprogramming of stromal microarchitecture by tumour-derived extracellular vesicles (EVs) is proposed to favour pre-metastatic niche formation. We elucidated the role of extravesicular tissue inhibitor of matrix metalloproteinase-1 (TIMP1EV) in pro-invasive extracellular matrix (ECM) remodelling of the liver microenvironment to aid tumour progression in colorectal cancer (CRC). Immunohistochemistry analysis revealed a high expression of stromal TIMP1 in the invasion front that was associated with poor progression-free survival in patients with colorectal liver metastases. Molecular analysis identified TIMP1EV enrichment in CRC-EVs as a major factor in the induction of TIMP1 upregulation in recipient fibroblasts. Mechanistically, we proved that EV-mediated TIMP1 upregulation in recipient fibroblasts induced ECM remodelling. This effect was recapitulated by human serum-derived EVs providing strong evidence that CRC release active EVs into the blood circulation of patients for the horizontal transfer of malignant traits to recipient cells. Moreover, EV-associated TIMP1 binds to HSP90AA, a heat-shock protein, and the inhibition of HSP90AA on human-derived serum EVs attenuates TIMP1EV-mediated ECM remodelling, rendering EV-associated TIMP1 a potential therapeutic target. Eventually, in accordance with REMARK guidelines, we demonstrated in three independent cohorts that EV-bound TIMP1 is a robust circulating biomarker for a non-invasive, preoperative risk stratification in patients with colorectal liver metastases.

Simultaneous in situ detection of protein expression of multiple tumor markers of circulating tumor cells and heteroploid of chromosome 8 in primary lung cancer

BackgroundPreviously published studies have shown that circulating tumor cells (CTC) play an important role in clinical staging, efficacy monitoring and prognostic evaluation of lung cancer. The aim of the present study was to investigate the significance of simultaneous in situ detection of multiple tumor marker protein expression and chromosome 8 aneuploid of CTC in the diagnosis and treatment of primary lung cancer.MethodsWe investigated the expression of cytokeratin 18 (CK18) and Vimentin on the surface of CTC and the aneuploidy of chromosome 8 in the peripheral blood of 24 patients with metastatic primary lung cancer, which were detected by subtraction enrichment (SE) and immunofluorescence in situ hybridization (iFISH). Their correlation with clinicopathological features, curative effect, and prognosis was analyzed.ResultsThe positive rate of CTC was 95.83% (23/24). There was a certain correlation between the positive rate of CTC and smoking, and a correlation between the number of CTC and histopathological type. The number of monoploid, diploid, triploid, and polyploid CTC had no statistical correlation with progression-free survival (PFS) or overall survival (OS). However, a tetraploid CTC count of ≥2 was an unfavorable predictor of response; a tetraploid CTC count ≥1 was an unfavorable prognostic predictor of poor OS. The rate of CK18+ CTC in all 24 patients was 4.35% (1/23). Seven out of these 24 patients were also tested for Vimentin, and the rate of Vimentin+ CTC was 85.71% (6/7). Small-cell (≤5 µm) CTC was found in 6 of these 7 patients and accounted for 11.83% (11/93) of the total CTC. The tumor marker phenotype of small-cell CTC was CK18– and Vimentin+. In addition, circulating tumor microthrombi (CTM) were found in 2 of these 7 patients (28.57%).ConclusionsSE-iFISH has a high detection rate of CTC in the peripheral blood of patients with metastatic primary lung cancer, and it can identify small cell CTC. Tetraploid CTC count ≥2 can predict poor PFS in patients with advanced lung cancer. Tetraploid CTC count ≥1 could predict poor OS in patients with advanced lung cancer. CTM can predict poor prognosis in patients with lung cancer.

SLCO4A1 is a Prognosis-Associated Biomarker Involved in Neutrophil-Mediated Immunity in Thyroid Cancer.

ObjectiveThe study aimed to investigate the value of solute carrier organic anion transporter family member 4A1 (SLCO4A1) in thyroid cancer mainly from three aspects: expression, prognosis, and biological function analyses.MethodsBased on various bioinformatic approaches, genes co-expressed with vascular endothelial growth factor C (VEGFC) in thyroid cancer were used for further survival and expression analyses to identify the target gene. After evaluation of the SLCO4A1 expression levels in thyroid cancer, Cox regression analysis was utilized to predict the risk factors for survival of thyroid cancer patients. And receiving operating characteristic curve analysis was performed to validate the prognostic value of SLCO4A1. Additionally, WebGestalt was employed for enrichment analysis of SLCO4A1 and its co-expressed genes. Further, the relation between SLCO4A1 and neutrophil was analyzed, followed by exploring the association of SLCO4A1 with immunomodulators.ResultsA total of 38 consistent VEGFC co-expressed genes were generated, and SLCO4A1 was selected as the target gene due to its oncogenic characteristics. SLCO4A1 was highly expressed in thyroid cancer at both gene and protein levels, and SLCO4A1 mRNA expression was significantly associated with the cancer stage (all P <0.05). Besides, high SLCO4A1 expression led to unfavorable progression-free survival (PFS) of thyroid cancer patients (P =0.0066). Further, Cox regression analysis indicated that high SLCO4A1 expression was an independent predictor of poor PFS in patients with papillary thyroid cancer, particularly in patients at stage 1 and female patients (all P <0.001). The enrichment analysis results showed that SLCO41A was involved in the neutrophil-mediated immunity pathway. Moreover, SLCO4A1 had a positive relation with neutrophils (all P <0.05). Finally, a significant correlation between SLCO4A1 and immunomodulators was observed (all P <0.001).ConclusionSLCO4A1 was a potential prognostic biomarker for papillary thyroid cancer patients. And SLCO4A1 might affect PFS in thyroid cancer patients by positive regulation of neutrophil-mediated immunity pathway.

Pregnancy Does not Affect the Prognoses of Differentiated Thyroid Cancer Patients With Lung Metastases.

Pregnancy-related hormones may stimulate thyroid cancer growth, but whether pregnancy affects the prognoses of patients with lung metastases from differentiated thyroid cancer (DTC-LM) after surgery and radioiodine therapy is unclear. To assess the impact of pregnancy on DTC-LM through the comparison of prognoses between female patients with DTC-LM who did and did not become pregnant after surgery and radioiodine therapy. We retrospectively analyzed the records of 124 female patients aged 16 to 35 years who underwent surgery and radioiodine therapy for DTC-LM. These patients were divided into pregnancy group (n = 37) and nonpregnancy group (n = 87) according to whether they became pregnant after surgery and radioiodine therapy, regardless of whether they had a pregnant history before treatment. The 5- and 10-year progression-free survival rates were 94.52% and 63.22% in pregnancy group versus 89.82% and 58.13% in nonpregnancy group. The 5- and 10-year cumulative overall survival rates of pregnancy group were 97.30% and 85.77% versus 93.50% and 81.95% in nonpregnancy group (all P > 0.05). The median time of follow-up in the pregnancy and nonpregnancy groups was 82 months (25-136 months) and 68 months (13-133 months), respectively. Non-radioiodine-avid LM and primary tumors needing repeated resection were independent predictors of poor progression-free survival for patients in pregnancy group. Pregnancy does not affect the prognoses of patients with DTC-LM after surgery and radioiodine therapy. Non-radioiodine-avid LM and repeated primary tumor surgeries are independent risk factors for poor prognoses of pregnant patients.

Leptin-elicited PBX3 confers letrozole resistance in breast cancer.

Aberrant leptin signaling and overexpression of fibroblast growth factor receptor 1 (FGFR1) are both implicated in the pathogenesis of letrozole resistance in breast cancer (BCa), but it remains unknown whether these two pathways are involved in letrozole resistance in a coordinated manner. Here, we demonstrate that expression levels of the pre-B-cell leukemia homeobox transcription factor 3 (PBX3), a pioneer factor that governs divergent biological processes, were significantly upregulated in letrozole-resistant BCa cells and tissues, and this upregulation correlated to a poorer progression-free survival in patients. By leveraging a patient-derived xenograft model with pharmacological approaches, we demonstrated that leptin activated PBX3 expression in a STAT3 (signal transducer and activator of transcription 3)-dependent manner. Our loss- and gain-of-function study further showed that PBX3 attenuated response to letrozole by potentiating BCa cell survival and anchorage-independent growth in BCa cells. By profiling BCa cells with ectopic PBX3 expression, we revealed that PBX3 conferred letrozole resistance via transactivation of the FGFR1 signaling, and this molecular event must coordinate a synergistic transcription activation programs through interacting with MTA1-HDAC2 (metastasis associated 1-histone deacetylase 2) complex. Overall, the available data reveal a novel role of leptin/PBX3 cascade linking energy homeostasis (i.e. hyperleptinemia) and endocrine therapy failure (i.e. letrozole resistance) in BCa.

Microphthalmia-Associated Transcription Factor-Dependent Melanoma Cell Adhesion Molecule Activation Promotes Peritoneal Metastasis of Ovarian Cancer.

Ovarian cancer (OvCa) is one of the leading causes of death due to its high metastasis rate to the peritoneum. Recurrent peritoneal tumors also develop despite the use of conventional platinum-based chemotherapies. Therefore, it is still important to explore the factors associated with peritoneal metastasis, as these predict the prognosis of patients with OvCa. In this study, we investigated the function of microphthalmia-associated transcription factor (MITF), which contributes to the development of melanoma, in epithelial ovarian cancer (OvCa). High MITF expression was significantly associated with a poor prognosis in OvCa. Notably, MITF contributed to the motility and invasion of OvCa cells, and specifically with their peri-mesothelial migration. In addition, MITF-positive cells expressed the melanoma cell adhesion molecule (MCAM/CD146), which was initially identified as a marker of melanoma progression and metastasis, and MCAM expression was regulated by MITF. MCAM was also identified as a significant prognostic factor for poor progression-free survival in patients with OvCa. Collectively, our results suggest that MITF is a novel therapeutic target that potentially promotes peritoneal metastasis of OvCa.

Abstract 6491: Prognostic potential of carcinoembryonic antigen expression patterns in lung adenocarcinoma

Abstract Carcinoembryonic antigen (CEA) is one of the most commonly used tumor markers. Although the suitability of CEA as an effective marker for lung cancer remains debatable, characteristics such as noninvasiveness and lack of other reliable markers make CEA an attractive option in lung cancer. Divergent CEA expression patterns before and after EGFR-tyrosine kinase inhibitor (TKI) treatment have been reported. However, whether these patterns are associated with tumor progression remain elusive. We hypothesized that divergent patterns of serum carcinoembryonic antigen at initial diagnosis (CEAIn) and disease progression (CEAPd) may reflect the diversity of lung cancer cells selected by TKI, conferring distinct progression profiles in patients. Our objective was to verify the prognostic potential of divergent CEA patterns before and after TKI treatment in lung cancer patients with wild-type or mutant EGFR. Of the 1736 lung cancer patients identified from the cancer registry group between 2011 to 2016, we selected 517 patients with advanced stage adenocarcinoma, data on EGFR mutation status and CEAIn, among whom were 288 patients with data on CEAPd, eligible for inclusion in the correlation analysis of clinical characteristics and survival. EGFR wild-type lung adenocarcinoma patients displayed lower CEAIn level than those with EGFR mutations. Multivariable analysis revealed that CEAIn expression was associated with poor progression-free survival in patients harboring mutant EGFR but not in those with wild-type EGFR. Moreover, CEAIn and CEAPd were associated with the good and poor post-progression survival, respectively, only in the EGFR-mutant and not in the wild-type group. In vitro cell line experiments revealed that CEA expression, cancer dissemination, and chemoresistant properties can be affected by EGFR-TKI selection. EGFR-mutant patients, exhibiting high CEAIn (≥ 5 ng/mL) and low CEAPd (&amp;lt; 5 ng/mL), showed a potential toward displaying new metastasis. Our findings support the notion that EGFR mutation status is a critical factor in determining prognostic potential of CEAIn and CEAPd in patients under EGFR-TKI treatment, and divergent CEAIn and CEAPd patterns are associated with distinct cancer progression profiles. Citation Format: Ming-Yi Zheng, Yen-Shou Kuo, Yu-Ting Chou. Prognostic potential of carcinoembryonic antigen expression patterns in lung adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6491.

Association of Divergent Carcinoembryonic Antigen Patterns and Lung Cancer Progression

Changes in expression patterns of serum carcinoembryonic antigen at initial diagnosis (CEAIn) and disease progression (CEAPd) in lung cancer patients under EGFR-tyrosine kinase inhibitors (TKI) treatment may reflect different tumor progression profiles. Of the 1736 lung cancer patients identified from the cancer registry group between 2011 to 2016, we selected 517 patients with advanced stage adenocarcinoma, data on EGFR mutation status and CEAIn, among whom were 288 patients with data on CEAPd, eligible for inclusion in the correlation analysis of clinical characteristics and survival. Multivariable analysis revealed that CEAIn expression was associated with poor progression-free survival in patients harboring mutant EGFR. Moreover, CEAIn and CEAPd were associated with the good and poor post-progression survival, respectively, in the EGFR-mutant group. Cell line experiments revealed that CEA expression and cancer dissemination can be affected by EGFR-TKI selection. EGFR-mutant patients, exhibiting high CEAIn (≥5 ng/mL) and low CEAPd (<5 ng/mL), showed a potential toward displaying new metastasis. Taken together, these findings support the conclusion that EGFR mutation status is a critical factor in determining prognostic potential of CEAIn and CEAPd in patients under EGFR-TKI treatment, and CEAIn and CEAPd are associated with distinct cancer progression profiles.

Vimentin expression in circulating tumor cells (CTCs) associated with liver metastases predicts poor progression-free survival in patients with advanced lung cancer

ObjectiveTo investigate the presence of vimentin expression in CTCs and its clinical relevance in patients with advanced lung cancer.MethodsPeripheral blood was obtained from 61 treatment-naive patients with advanced lung cancer. Subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) platform was applied to identify, enumerate and characterize CTCs based on cell size, aneuploidy of chromosome 8 (Chr8) and vimentin expression. Quantification and analysis of CTCs were performed on patients before chemotherapy administration and after two cycles of therapy.ResultsBefore treatment, CTCs were detected in 60 (98.4%) patients, small cell CTCs (≤ 5 µm of WBCs) accounted for 52.8% of the absolute CTCs number, while 12 (19.7%) of the included patients had detectable vimentin-positive CTCs (vim+ CTCs). Liver metastases were reported in 7 (11.5%) patients and were significantly correlated to the presence of Vim+ CTCs (p = 0.002), with a high positivity rate of 71.4% (5/7). Vim+ CTCs were mostly in small cell size and Chr8 aneuploidy (77.0% and 82.05%, respectively). Baseline small cell CTCs ≥ 2/6 ml, triploid CTCs ≥ 2/6 ml, Vim+ CTCs ≥ 1/6 ml were found to significantly correlate with poor progression-free survival (PFS) (p = 0.017, p = 0.009 and p = 0.001, respectively). After adjusting for clinically significant factors, baseline Vim+ CTCs ≥ 1/6 ml was the only independent predictor of poor PFS [hazard ratio (HR):2.756, 95% confidence interval (CI): 1.239–6.131; p = 0.013].ConclusionsThis study demonstrates an important morphologic, karyotypic and phenotypic CTCs heterogeneity in advanced lung cancer patients. The majority of Vim+ CTCs are in small size and Chr8 aneuploidy. Baseline presence of Vim+ CTCs is correlated with liver metastases and may help predict poor PFS.

Annexin A8 can serve as potential prognostic biomarker and therapeutic target for ovarian cancer: based on the comprehensive analysis of Annexins

BackgroundAnnexins are involved in vesicle trafficking, cell proliferation and apoptosis, but their functional mechanisms in ovarian cancer remain unclear. In this study, we analyzed Annexins in ovarian cancer using different databases and selected Annexin A8 (ANXA8), which showed the greatest prognostic value, for subsequent validation in immunohistochemical (IHC) assays.MethodsThe mRNA expression levels, genetic variations, prognostic values and gene–gene interaction network of Annexins in ovarian cancer were analyzed using the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), cBioPortal, Kaplan–Meier plotter and GeneMANIA database. ANXA8 was selected for analyzing the biological functions and pathways of its co-expressed genes, and its correlation with immune system responses via the Database for Annotation, Visualization, and Integrated Discovery (DAVID) and the TISIDB database, respectively. We validated the expression of ANXA8 in ovarian cancer via IHC assays and analyzed its correlation with clinicopathological parameters and prognosis.ResultsANXA2/3/8/11 mRNA expression levels were significantly upregulated in ovarian cancer, and ANXA5/6/7 mRNA expression levels were significantly downregulated. Prognostic analysis suggested that significant correlations occurred between ANXA2/4/8/9 mRNA upregulation and poor overall survival, and between ANXA8/9/11 mRNA upregulation and poor progression-free survival in patients with ovarian serous tumors. Taken together, results suggested that ANXA8 was most closely associated with ovarian cancer tumorigenesis and progression. Further analyses indicated that ANXA8 may be involved in cell migration, cell adhesion, and vasculature development, as well as in the regulation of PI3K-Akt, focal adhesion, and proteoglycans. Additionally, ANXA8 expression was significantly correlated with lymphocytes and immunomodulators. The IHC results showed that ANXA8 expression was higher in the malignant tumor group than in the borderline and benign tumor groups and normal ovary group, and high ANXA8 expression was an independent risk factor for survival and prognosis of ovarian cancer patients (P = 0.013).ConclusionsMembers of the Annexin family display varying degrees of abnormal expressions in ovarian cancer. ANXA8 was significantly highly expressed in ovarian cancer, and high ANXA8 expression was significantly correlated with poor prognosis. Therefore, ANXA8 is a high candidate as a novel biomarker and therapeutic target for ovarian cancer.

CHTOP in Chemoresistant Epithelial Ovarian Cancer: A Novel and Potential Therapeutic Target.

Objective: Chemoresistance is a major challenge in epithelial ovarian cancer (EOC) treatment. Chromatin target of protein arginine methyltransferase (CHTOP) was identified as a potential biomarker in chemoresistant EOC cell lines using label-free LC-MS/MS quantitative proteomics. Thus, the aim of this study is to investigate the role of CHTOP in chemoresistant EOC and the underlying mechanism.Methods: The expression of CHTOP in human ovarian cancer cells and tissues was detected using immunofluorescence (IF), western blot (WB), and immunohistochemistry (IHC), respectively. Flow cytometry and TUNEL assay were employed to detect the effect of CHTOP knockdown (KD) in chemoresistant EOC cell apoptosis, while colony and sphere formation assays were used to evaluate its effect on cell stemness. The association of CHTOP with cell metastasis was determined using Matrigel invasion and wound-healing assays.Results: The higher level expression of CHTOP protein was found in chemoresistant EOC cells as compared to their sensitive parental cells or normal epithelial ovarian cells. Results from IHC and bioinformatic analysis showed CHTOP was highly expressed in human ovarian cancer tissues and associated with a poor progression-free survival in patients. In addition, CHTOP KD significantly enhanced cisplatin-induced apoptosis, reduced the stemness of chemoresistant EOC cells, and decreased their metastatic potential.Conclusion: Our findings suggest that CHTOP is associated with apoptosis, stemness, and metastasis in chemoresistant EOC cells and might be a promising target to overcome chemoresistance in EOC treatment.

The Prognostic Value and Regulatory Mechanisms of microRNA-145 in Various Tumors: A Systematic Review and Meta-analysis of 50 Studies.

Acting as an important tumor-related miRNA, the clinical significance and underlying mechanisms of miR-145 in various malignant tumors have been investigated by numerous studies. This study aimed to comprehensively estimate the prognostic value and systematically illustrate the regulatory mechanisms of miR-145 based on all eligible literature.Relevant studies were acquired from multiple online databases. Overall survival (OS) and progression-free survival (PFS) were used as primary endpoints. Detailed subgroup analyses were performed to decrease the heterogeneity among studies and recognize the prognostic value of miR-145. All statistical analyses were performed with RevMan software version 5.3 and STATA software version 14.1. A total of 48 articles containing 50 studies were included in the meta-analysis. For OS, the pooled results showed that low miR-145 expression in tumor tissues was significantly associated with worse OS in patients with various tumors [HR = 1.70; 95% confidence interval (CI), 1.46-1.99; P < 0.001). Subgroup analysis based on tumor type showed that the downregulation of miR-145 was associated with unfavorable OS in colorectal cancer (HR = 2.17; 95% CI, 1.52-3.08; P < 0.001), ovarian cancer (HR = 2.15; 95% CI, 1.29-3.59; P = 0.003), gastric cancer (HR = 1.78; 95% CI, 1.35-2.36; P < 0.001), glioma (HR = 1.65; 95% CI, 1.30-2.10; P < 0.001), and osteosarcoma (HR = 2.28; 95% CI, 1.50-3.47; P < 0.001). For PFS, the pooled results also showed that the downregulation of miR-145 was significantly associated with poor PFS in patients with multiple tumors (HR = 1.39; 95% CI, 1.16-1.67; P < 0.001), and the subgroup analyses further identified that the low miR-145 expression was associated with worse PFS in patients with lung cancer (HR = 1.97; 95% CI, 1.25-3.09; P = 0.003) and those of Asian descent (HR = 1.50; 95% CI, 1.23-1.82; P < 0.001). For the regulatory mechanisms, we observed that numerous tumor-related transcripts could be targeted by miR-145-5p or miR-145-3p, as well as the expression and function of miR-145-5p could be regulated by multiple molecules.This meta-analysis indicated that downregulated miR-145 in tumor tissues or peripheral blood predicted unfavorable prognostic outcomes for patients suffering from various malignant tumors. In addition, miR-145 was involved in multiple tumor-related pathways and the functioning of significant biological effects. miR-145 is a well-demonstrated tumor suppressor, and its expression level is significantly correlated with the prognosis of patients with multiple malignant tumors.