MMP2 is a immunotherapy related biomarker and correlated with cancer-associated fibroblasts infiltrate in melanoma.

BACKGROUND: Mounting evidence supports that matrix metalloproteinase (MMPs) are highly associated with tumor progression and that targeting MMPs may overcome the barrier of immune suppression. Among these, whether MMP2 functions as an immunosuppressive role in melanoma, remains unclear. METHODS: The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) databases were used to assess the prognosis of MMP2 in melanoma, after which Tumor immune estimation resource (TIMER) was used to explore the relationship between MMP2 expression and cancer associated fibroblasts (CAFs) infiltration. Finally, we evaluated the efficacy of MMP2 inhibitor on CAFs infiltration and immunotherapy using a mouse melanoma model. RESULTS: In general, the expression of MMP2, MMP13, MMP16, MMP17 and MMP25 were significantly associated with skin cutaneous melanoma (SKCM) patients prognosis, among which MMP2 low expression benefited patients the most. Especially, the overall survival (OS) of BRAF mutation patients with high MMP2 expression was significantly lower than the MMP2 low expression group, but there was no significant difference in BRAF wild-type patients. KEGG and GO enrichment analysis indicated that MMP2 related genes were mostly associated with extracellular structure organization, collagen-containing extracellular matrix and extracellular matrix structural constituent. Furthermore, in almost all cancers, MMP2 expression was positively correlated with CAFs infiltration. MMP2 inhibitor works synergistically with PD-1 antibody and induces tumor regression in a mouse melanoma model, which is dependent on decreased CAFs infiltration. CONCLUSIONS: This suggests that MMP2 plays a vital role in the regulation of CAFs infiltration, potentially participating in immunotherapy response, and thus representing a valuable target of immunotherapy in melanoma.

The predictive value of body mass index on prognosis and adverse events of cancers treated with immunotherapy: a systematic review and meta-analysis.

OBJECTIVE: High body mass index (BMI) greater than 25 kg/m2 has a complex relationship with cancers. The aim of this systematic review and meta-analysis is to explore controversy over whether BMI is correlated with outcomes including survival and immunotherapy-related adverse events (irAEs) in cancer patients treated with immunotherapy. METHODS: We searched PubMed, Embase, Web of Science, and The Cochrane Library for relevant studies published up to June 2020. Title/abstract screening, full-text review, data extraction, and quality assessment were performed independently. Subgroup analysis was based on sex, treatment lines, the status of programmed death-ligand 1 (PD-L1), and tumor types. Sensitivity analysis was performed by synthesizing studies that adjusted for certain covariates or studies with good quality. Statistical heterogeneity was evaluated by the I2 value. Meta-analysis was performed with hazard ratio (HR) / odds ratio (OR) and 95% confidence intervals (CIs) as the effect measures. RESULTS: Twenty studies were included for survival and irAEs analyses. Patients with high BMI who underwent immunotherapy had longer overall survival (OS) (pooled hazard ratio, pHR = 0.71 [95% CI: 0.59-0.85]) and progression-free survival (PFS) (pHR = 0.76 [95% CI: 0.65-0.88]) than those with low BMI; at the same time, high-BMI patients had increased irAEs (OR = 2.54 [95% CI: 1.12-5.79]). CONCLUSION: In general, high BMI was correlated with improved OS and PFS in patients treated with immunotherapy along with a high risk of irAEs. However, discrepant findings from subgroup analyses urgently call for further analysis.

Identification and validation of GIMAP family genes as immune-related prognostic biomarkers in lung adenocarcinoma.

Background: The GIMAP family genes play a key role in immune function. Increasing evidence suggests that GIMAP genes were implicated in the tumorigenesis of lung adenocarcinoma (LUAD). This study aimed to investigate the clinical significance of GIMAP family genes in LUAD. Methods: In this study, we explored the expression, mutation, prognostic value of GIMAP family genes and the correlation with immune microenvironment in LUAD. We further investigated the relationship between GIMAP family genes expression and immunotherapy response in GEO LUAD and melanoma cohorts. Results: Among the GIMAP family genes, the expression levels of GIMAP1, GIMAP2, GIMAP4, GIMAP5, GIMAP6, GIMAP7, and GIMAP8 were significantly lower in LUAD tumor tissues than normal tissues. Most GIMAP genes were closely related to age, tumor grade and T stage, but not significantly related to sex, N stage and M stage. In the overall population, patients with high expression of GIMAP family genes had a significant longer overall survival (OS). GO and KEGG enrichment analysis showed that GIMAP family genes were highly enriched in immune-related biological process. The expression of GIMAP family genes was positively correlated with immune cell infiltration and immune checkpoint molecules. Furthermore, high expression of GIMAP family genes were correlated with therapeutic response to immunotherapy in LUAD and melanoma patients. Conclusion: In this study, we identified that GIMAP family genes were significantly associated with immune cell infiltration and immune checkpoint molecules. They potentially play a critical role in anti-tumor immunity and serve as immunotherapy biomarkers.

Targeting MEK/COX-2 axis improve immunotherapy efficacy in dMMR colorectal cancer with PIK3CA overexpression.

PURPOSE: PIK3CA mutation or overexpression is associated with immunotherapy resistance in multiple cancer types, but is also paradoxically associated with benefit of COX-2 inhibition on patient survival of colorectal cancer (CRC) with mismatch repair deficiency (dMMR). This study examined whether and how PIK3CA status affected COX-2-mediated tumor inflammation and immunotherapy response of dMMR CRC. METHODS: Murine colon cancer cells MC38, CT26, and CT26-Mlh1-KO were used to construct PIK3CA knockdown and overexpression models to mimic dMMR CRC with PIK3CA dysregulation, and xenograft models were used to evaluate how PIK3CA regulate COX-2 expression, CD8+ T cells infiltration, tumor growth, and therapy response to anti-PD-L1 treatment using immunocompetent mice. Western blot was carried out to delineate the signaling pathways in human and mouse cancer cells, and immunohistochemical analysis together with bioinformatics analysis using human patient samples. RESULTS: PIK3CA upregulates COX-2 expression through MEK/ERK signaling pathway independent of AKT signaling to promote tumor inflammation and immunosuppression. PIK3CA knockdown profoundly reduced CT26 tumor growth in a CD8+ T cell-dependent manner, while PIK3CA overexpression significantly inhibited CD8+ T cells infiltration and promoted tumor growth. Furthermore, MEK or COX-2 inhibition augmented the anti-tumor activity of anti-PD-L1 immunotherapy on dMMR CRC mouse models, accompanied with increased CD8+ T cells infiltration and activated tumor microenvironment. CONCLUSION: Our results identified that the PIK3CA hyperactivation in dMMR CRC upregulated COX-2 through MEK signaling, which inhibited CD8+ T cells infiltration and promoted tumor growth, together led to immunotherapy resistance. COX-2 or MEK inhibition may relieve therapy resistance and promote therapy efficacy of anti-PD-1/PD-L1 immunotherapy for treating dMMR CRC with PIK3CA overexpression or activating mutation.

Sleep quality, anxiety and depression in advanced lung cancer: patients and caregivers.

OBJECTIVE: To investigate the clinical implications of sleep quality, anxiety and depression in patients with advanced lung cancer (LC) and their family caregivers (FCs). METHODS: A total of 98 patients with advanced LC and their FCs (n=98) were recruited from the Oncology Department in Nanfang Hospital. The Pittsburgh Sleep Quality Index (PSQI), consisting of seven components that evaluate subjective sleep quality, sleep latency, duration of sleep, sleep efficiency, sleep disturbances, sleep medication usage and daytime dysfunction, was used to assess sleep quality. Using the tool of Zung Self-rating Anxiety Scale (SAS) and Zung Self-rating Depression Scale (SDS), we tested the patients' status of anxiety and depression, respectively. RESULTS: The prevalences of poor sleep quality, anxiety and depression in patients were 56.1%, 48.9% and 56.1%, respectively, while those in FCs were 16.3%, 32.6% and 25.5%, respectively. Patients had higher PSQI, SAS and SDS scores than did FCs (p<0.05). Significant correlations were found between the patients' and FCs' scores of PSQI/SAS/SDS (p<0.05). Multivariate Cox regression analyses indicated that sleep disturbances in patients (HR 0.413, 95% CI 0.21 to 0.80, p=0.01) and the global PSQI score of FCs (HR 0.31, 95% CI 0.14 to 0.71, p=0.00) were independent risk factors for patients' first-line progression-free survival (PFS). Moreover, patients' sleep latency (HR 2.329, 95% CI 1.36 to 3.96, p=0.00) and epidermal growth factor receptor mutations (HR 1.953, 95% CI 1.12 to 3.38, p=0.01) were significant prognostic factors for their overall survival (OS). CONCLUSIONS: We demonstrated that presence of sleep disturbances in patients with advanced LC and the global PSQI Score of their FCs may be risk predictors for patients' poor first-line PFS. Patients' sleep latency was a potential risk factor for their OS.

The prognostic value of adding systemic inflammation response index to Epstein-Barr virus DNA in childhood nasopharyngeal carcinoma: A real-world study.

BACKGROUND: To assess the prognostic value of the systemic inflammation response index (SIRI) combined with plasma load of Epstein-Barr virus (EBV) DNA in children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CALANPC). METHODS: A total of 205 consecutive patients with CALANPC were enrolled. We used recursive partitioning analysis (RPA) to classify patients into various risk groups, with a primary endpoint of overall survival (OS). RESULTS: Elevated SIRI (≥1.53) and EBV DNA (≥4000 copy/ml) were significantly associated with inferior OS in CALANPC. RPA categorized patients into low- and high-risk groups based on prognostic factors. Survival curves showed excellent discrimination in OS (95.3% vs 77.6%; p < 0.001) between the low- and high-risk groups. A significant improvement was confirmed using the prognostic methods for conventional TNM staging systems (p < 0.05). CONCLUSIONS: The combination of SIRI with EBV DNA provided a more detailed understanding of patient risks, and enhanced risk discrimination in CALANPC.

CEP192 is a novel prognostic marker and correlates with the immune microenvironment in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) responds poorly to standard chemotherapy or targeted therapy; hence, exploration for novel therapeutic targets is urgently needed. CEP192 protein is indispensable for centrosome amplification, which has been extensively characterized in both hematological malignancies and solid tumors. Here, we combined bioinformatics and experimental approaches to assess the potential of CEP192 as a prognostic and therapeutic target in HCC. CEP192 expression increased with tumor stage and was associated with poor clinicopathologic features, frequent recurrence, and higher mortality. Upon single-cell RNA sequencing, CEP192 was found to be involved in the proliferation and self-renewal of hepatic progenitor-like cells. This observation was further evidenced using CEP192 silencing, which prevented tumor cell proliferation and self-renewal by arresting cells in the G0/G1 phase of the cell cycle. Notably, CEP192 was highly correlated with multiple tumor-associated cytokine ligand-receptor axes, including IL11-IL11RA, IL6-IL6R, and IL13-IL13RA1, which could promote interactions between hepatic progenitor-like cells, PLVAP+ endothelial cells, tumor-associated macrophages, and CD4+ T cells. Consequently, CEP192 expression was closely associated with an immunosuppressive tumor microenvironment and low immunophenoscores, making it a potential predictor of response to immune checkpoint inhibitors. Taken together, our results unravel a novel onco-immunological role of CEP192 in establishing the immunosuppressive tumor microenvironment and provide a novel biomarker, as well as a potential target for therapeutic intervention of HCC.

Optimal Surgery Type and Adjuvant Therapy for T1N0M0 Lung Large Cell Neuroendocrine Carcinoma.

BACKGROUND: The appropriate treatment strategy for T1N0M0 lung large cell neuroendocrine carcinoma (LCNEC) was not well illustrated. We evaluated the efficacy of different surgery types and adjuvant therapy on patients with T1N0M0 LCNEC. METHODS: Patients diagnosed T1N0M0 LCNEC from 2004 to 2016 were identified in the surveillance, epidemiology, and end results (SEER) database. Clinical characteristics, treatment and survival data were collected. The efficacy of surgery type and adjuvant therapy stratified by tumor size was assessed. Overall survival(OS) was evaluated by the Kaplan-Meier method, and relevant survival variables were identified by the Cox proportional hazard model. RESULTS: From 2004 to 2016, 425 patients were included in this study, 253 (59.5%) patients received lobectomy, and 236 (55.5%) patients had 4 or more lymph nodes removed. Patients received lobectomy had better survival than those received sublobar resection(P=0.000). No matter tumor size less than 2 cm or 2 to 3 cm, lobectomy was significantly prolonged survival. Compared with no lymph nodes removed, lymph nodes dissection was associated with more remarkable OS(P<0.000). 4 or more regional lymph nodes dissection predicted better OS compared with 1 to 3 regional lymph nodes dissection(P=0.014). After surgery, adjuvant chemotherapy did not contribute to extended survival in patients with tumor less than 2 cm(P=0.658), and possibly for tumor 2 to 3 cm(P=0.082). Multivariate analysis showed that age and lobectomy were independent prognostic factors(P=0.000). CONCLUSION: Our results suggest that lobectomy and lymph nodes dissection were associated with significantly better survival. Extensive regional lymph node dissection(4 or more) was more effective in prolonging survival than 1 to 3 lymph nodes dissection. Adjuvant chemotherapy was not associated with extended survival for tumor less than 2 cm, and possibly for tumor 2 to 3 cm.

The effect of adding concurrent chemotherapy to radiotherapy for stage II nasopharyngeal carcinoma with undetectable pretreatment Epstein-Barr virus DNA: Retrospective analysis with a large institutional-based cohort.

Little is known about the value of adding concurrent chemotherapy (CC) to radiotherapy for stage II nasopharyngeal carcinoma (NPC) with undetectable (0 copies/mL) pretreatment Epstein-Barr Virus (EBV) DNA in the intensity-modulated radiotherapy (IMRT) era. To address this question, the present study retrospectively reviewed 514 patients with newly diagnosed stage II NPC and undetectable pretreatment EBV DNA from Sun Yat-sen University Cancer Center between March 2008 and October 2016. Clinical characteristics and survival outcomes between concurrent chemoradiotherapy (CCRT) and IMRT alone groups were compared. Propensity score matching analysis was conducted to control for confounding factors. Although CCRT group had significantly higher proportions of stage N1 disease than IMRT alone group before matching (85% vs. 61%, p < 0.001), no statistically significant differences were noted for OS (97.8% vs. 98.1%, p = 0.700), DFS (93.4% vs. 94.5%, p = 0.846), DMFS (96.0% vs. 96.9%, p = 0.762), and LRFS (97.3% vs. 98.1%, p = 0.701). After 1:1 propensity-score matching, 177 pairs were identified. Patients in each group were found to be well balanced in baseline characteristics and risk factors (all P > 0.05). The five-year OS (96.9% vs. 98.2%, p = 0.302), DFS (92.0% vs. 95.2%, p = 0.777), DMFS (95.2% vs. 97.6%, p = 0.896), and LRFS (97.3% vs. 97.6%, p = 0.328) rates remain comparable for both CCRT and RT alone groups. Additionally, subgroup analysis still failed to observe any significant survival benefit for the addition of CC to IMRT for N1 disease (P>0.05 for all). Our results indicated that IMRT alone appeared to achieve comparable survival to CCRT for stage II NPC with undetectable pretreatment EBV DNA.

Previous Use of Anti-Vascular Endothelial Growth Factor Receptor Agents Decreases Efficacy of Fruquintinib in Metastatic Colorectal Cancer Refractory to Standard Therapies.

PURPOSE: Fruquintinib is an anti-vascular endothelial growth factor receptor (VEGFR) agent. The FRESCO trial demonstrated that patients with metastatic colorectal cancer (mCRC) refractory to standard therapies could benefit from fruquintinib with tolerable adverse events (AEs). However, the efficacy and safety of fruquintinib in clinical practice has scarcely been reported, especially in patients with previous use of anti-VEGFR agents. METHODS: This retrospective study investigated the efficacy and safety of fruquintinib in patients with mCRC between January 2019 and December 2019. Progression-free survival (PFS) and overall survival (OS) were assessed by a Kaplan-Meier analysis and log-rank test. A Cox regression model was performed to identify independent prognostic factors. RESULTS: A total of 46 patients were included. The median PFS and OS were 3.1 months (95% confidence interval [CI], 1.9-4.3 months) and 9.0 months (95% CI, 7.2-10.8 months), respectively. Patients previously treated with anti-VEGFR agents had shorter median PFS compared with those without previous use of anti-VEGFR agents (1.9 vs. 3.7 months, P = 0.006), while the median OS was similar between the two groups (8.5 vs. 9.0 months, P = 0.992). Multivariate analysis revealed that the neutrophil-lymphocyte ratio (NLR) was an independent prognostic factor in PFS (hazard ratio [HR], 2.230; 95% CI, 1.191-4.517, P = 0.014) and OS (HR, 4.221; 95% CI, 1.683-10.586; P = 0.002). The most common non-hematological and hematological AEs were hand-foot syndrome (37.0%) and anemia (39.1%), respectively. CONCLUSION: Fruquintinib was an effective third-line therapy in mCRC with tolerable AEs. Efficacy of fruquintinib was decreased in patients with previous use of anti-VEGFR agents. NLR was an independent prognostic factor in PFS and OS in patients treated with fruquintinib.

Lymphocyte-to-C-reactive protein ratio is a potential new prognostic biomarker for patients with lung cancer.

Aim: To compare and evaluate the prognostic value of various pretreatment combinations of inflammatory factors in patients with lung cancer (LC). Materials & methods: This study enrolled 1005 patients with LC and categorized into a discovery cohort and a validation cohort. Results: A combination of Lymphocyte-to-C-reactive protein levels (LCR) demonstrated the highest correlation with poor first-line progression-free survival (PFS) and overall survival (OS) (p < 0.05), but not disease-free survival (p > 0.05) compared with other parameters in LC patients. Decreased preoperative LCR was an independent prognostic factor for first-line PFS and OS (p < 0.05), but not disease-free survival (p > 0.05) in patients. Conclusion: Pretreatment LCR is a promising biomarker for first-line PFS and OS in patients with LC.

NK homeobox 2.2 functions as tumor suppressor in colorectal cancer due to DNA methylation.

Aim: The role of NK homeobox 2.2 (NKX2.2) in human colorectal cancer (CRC) remains to be unveiled. This study was designed to explore the epigenetic regulation and function of NKX2.2 in human CRC. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to assess the methylation data of NKX2.2 in CRC. Six CRC cell lines (HCT116, SW480, HT29, LOVO, SW1116, SW640) and 20 pairs of primary CRC tumor and normal tissues were utilized to explore the function of NKX2.2 in CRC using Sequenom EpiTYPER®, verified by cloning-based bisulfite sequencing analysis, semi-quantitative reverse transcription PCR, western blot, cell viability assessment, plate clone formation assay , and transwell assays. Results: Bioinformatic analysis showed that NKX2.2 was significantly hypermethylated in primary tumors compared to normal tissues (p < 0.05). Our study also found that NKX2.2 methylation was upregulated (p<0.05) in tumors than normal tissues. In vitro experiments demonstrated that 5-aza-2'-deoxycytidine downregulated the methylation of NKX2.2 and retrieved its expression of mRNA and protein levels (p<0.05). No significant association was found between the NKX2.2 methylation and sex, age, tumor differentiation, TNM stage, CEA, CA199, and fecal occult blood (p>0.05). Kaplan-Meier analysis indicated that NKX2.2 hypermethylation showed a trend but not statistical significance for predicting poor overall survival in CRC patients (p=0.33). NKX2.2 overexpression suppressed cell proliferation, colony formation, and inhibited tumor invasion and migration in CRC cells (both p<0.05). Conclusions: This study indicates that NKX2.2 is a tumor suppressor in CRC due to hypermethylation.

Prognostic Implications of Tripartite Motif Containing 24 Expression Levels in Patients with Solid Tumors: A Systematic Review and Meta-Analysis.

Objective: To systematically investigate the prognostic implications of tripartite motif containing 24 (Trim 24) expression levels in Patients with solid tumors. Materials and Methods: Pubmed, Embase, China National Knowledge Infrastructure, and Wanfang databases were searched through December 2017 to identify studies examining the relationship between Trim 24 expression levels and outcomes in solid tumor patients. The hazard ratios (HRs) with corresponding 95% confidence intervals were used to evaluate the association between Trim 24 and overall survival (OS). Results: Ten studies with 1370 patients were included. The overall pooled prevalence for Trim 24 overexpression was 59.0% (p < 0.01). Moreover, the pooled HR of Trim 24 for OS was 0.43 (p = 0.04) by univariate analysis in 10 articles (1370) and 0.62 (p = 0.08) by multivariate analysis in 5 studies (845). Trim 24 over-expression was associated with tumor invasiveness (odds ratio [OR] = 2.05, p < 0.01) and tumor-node-metastasis stage (OR = 2.42, p = 0.03). Conclusions: This study demonstrated that Trim 24 expression levels may be a useful prognostic biomarker in patients with solid tumors.

Comparisons of metastatic patterns of colorectal cancer among patients by age group: a population-based study.

Population-based evaluations of the incidence of metastatic colorectal cancer at diagnosis among different age groups are lacking. Therefore, we investigated the effects of age at diagnosis on metastatic colorectal cancer and patients' prognoses. The Surveillance, Epidemiology, and End Results database was used to identify patients diagnosed with metastatic colorectal cancer. Multivariate Cox regression analyses were performed to identify factors associated with poor survival. The Kaplan-Meier analysis was used to estimate survival differences between the subgroups. We identified 30,333 adult patients diagnosed with metastatic colorectal cancer between 2010 and 2014. The younger and middle-aged groups had better survival than the older group when brain metastasis was not involved. The liver was the most common site of metastasis followed by the liver and lung combined. Age at diagnosis was an independent factor in patients' survival. Survival differences between two and three-sites of metastases were found in the middle-aged and older groups but not in the younger group. No survival differences between three and four sites of metastases were found in any of the age groups. Therefore, the incidence and prognosis of metastatic sites for metastatic colorectal cancer varied by age group.