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Neoadjuvant modified FOLFIRINOX followed by postoperative gemcitabine in borderline resectable pancreatic adenocarcinoma: a Phase 2 study for clinical and biomarker analysis.
Yoo, C, Lee, SS, Song, KB, Jeong, JH, Hyung, J, Park, DH, Song, TJ, Seo, DW, Lee, SK, Kim, MH, et al
British journal of cancer. 2020;(3):362-368
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Abstract
BACKGROUND Patients with borderline resectable pancreatic cancer (BRPC) have poor prognosis with upfront surgery. METHODS This was a single-arm Phase 2 trial for clinical and biomarker analysis. The primary endpoint is 1-year progression-free survival (PFS) rate. Patients received 8 cycles of neoadjuvant modified (m) FOLFIRINOX. Up to 6 cycles of gemcitabine were given for patients who underwent surgery. Plasma immune cell subsets were measured for analysing correlations with overall survival (OS). RESULTS Between May 2016 and March 2018, 44 chemotherapy- and radiotherapy-naïve patients with BRPC were included. With neoadjuvant mFOLFIRINOX, the objective response rate was 34.1%, and curative-intent surgery was done in 27 (61.4%) patients. With a median follow-up duration of 20.6 months (95% confidence interval [CI], 19.7-21.6 months), the median PFS and OS were 12.2 months (95% CI, 8.9-15.5 months) and 24.7 months (95% CI, 12.6-36.9), respectively. The 1-year PFS rate was 52.3% (95% CI, 37.6-67.0%). Higher CD14+ monocyte (quartile 4 vs 1-3) and lower CD69+ γδ T cell (γδ TCR+/CD69+) levels (quartiles 1-3 vs 4) were significantly associated with poor OS (p = 0.045 and p = 0.043, respectively). CONCLUSIONS Neoadjuvant mFOLFIRINOX followed by postoperative gemcitabine were feasible and effective in BRPC patients. Monocyte and γδ T cells may have prognostic implications for patients with pancreatic cancer. ClinicalTrials.gov identifier: NCT02749136.
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Investigation of Potential Genetic Biomarkers and Molecular Mechanism of Ulcerative Colitis Utilizing Bioinformatics Analysis.
Zhang, J, Wang, X, Xu, L, Zhang, Z, Wang, F, Tang, X
BioMed research international. 2020;:4921387
Abstract
OBJECTIVES To reveal the molecular mechanisms of ulcerative colitis (UC) and provide potential biomarkers for UC gene therapy. METHODS We downloaded the GSE87473 microarray dataset from the Gene Expression Omnibus (GEO) and identified the differentially expressed genes (DEGs) between UC samples and normal samples. Then, a module partition analysis was performed based on a weighted gene coexpression network analysis (WGCNA), followed by pathway and functional enrichment analyses. Furthermore, we investigated the hub genes. At last, data validation was performed to ensure the reliability of the hub genes. RESULTS Between the UC group and normal group, 988 DEGs were investigated. The DEGs were clustered into 5 modules using WGCNA. These DEGs were mainly enriched in functions such as the immune response, the inflammatory response, and chemotaxis, and they were mainly enriched in KEGG pathways such as the cytokine-cytokine receptor interaction, chemokine signaling pathway, and complement and coagulation cascades. The hub genes, including dual oxidase maturation factor 2 (DUOXA2), serum amyloid A (SAA) 1 and SAA2, TNFAIP3-interacting protein 3 (TNIP3), C-X-C motif chemokine (CXCL1), solute carrier family 6 member 14 (SLC6A14), and complement decay-accelerating factor (CD antigen CD55), were revealed as potential tissue biomarkers for UC diagnosis or treatment. CONCLUSIONS This study provides supportive evidence that DUOXA2, A-SAA, TNIP3, CXCL1, SLC6A14, and CD55 might be used as potential biomarkers for tissue biopsy of UC, especially SLC6A14 and DUOXA2, which may be new targets for UC gene therapy. Moreover, the DUOX2/DUOXA2 and CXCL1/CXCR2 pathways might play an important role in the progression of UC through the chemokine signaling pathway and inflammatory response.
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Safety, immunogenicity, and clinical efficacy of durvalumab in combination with folate receptor alpha vaccine TPIV200 in patients with advanced ovarian cancer: a phase II trial.
Zamarin, D, Walderich, S, Holland, A, Zhou, Q, Iasonos, AE, Torrisi, JM, Merghoub, T, Chesebrough, LF, Mcdonnell, AS, Gallagher, JM, et al
Journal for immunotherapy of cancer. 2020;(1)
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) to date have demonstrated limited activity in advanced ovarian cancer (OC). Folate receptor alpha (FRα) is overexpressed in the majority of OCs and presents an attractive target for a combination immunotherapy to potentially overcome resistance to ICI in OCs. The current study sought to examine clinical and immunologic responses to TPIV200, a multiepitope FRα vaccine administered with programmed death ligand 1 (PD-L1) inhibitor durvalumab in patients with advanced platinum-resistant OC. METHODS Following Simon two-stage phase II trial design, 27 patients were enrolled. Treatment was administered in 28-day cycles (intradermal TPIV200 and granulocyte-macrophage colony-stimulating factor (GM-CSF) for 6 cycles and intravenous durvalumab for 12 cycles). Primary endpoints included overall response rate and progression-free survival at 24 weeks. Translational parameters focused on tumor microenvironment, PD-L1 and FRα expression, and peripheral vaccine-specific immune responses. RESULTS Treatment was well tolerated, with related grade 3 toxicity rate of 18.5%. Increased T cell responses to the majority of peptides were observed in all patients at 6 weeks (p<0.0001). There was one unconfirmed partial response (3.7%) and nine patients had stable disease (33.3%). Clinical benefit was not associated with baseline FRα or PD-L1 expression. One patient with prolonged clinical benefit demonstrated loss of FRα expression and upregulation of PD-L1 in a progressing lesion. Despite the low overall response rate, the median overall survival was 21 months (13.5-∞), with evidence of benefit from postimmunotherapy regimens. CONCLUSIONS Combination of TPIV200 and durvalumab was safe and elicited robust FRα-specific T cell responses in all patients. Unexpectedly durable survival in this heavily pretreated population highlights the need to investigate the impact of FRα vaccination on the OC biology post-treatment.
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The clinical value and usage of inflammatory and nutritional markers in survival prediction for gastric cancer patients with neoadjuvant chemotherapy and D2 lymphadenectomy.
Li, Z, Li, S, Ying, X, Zhang, L, Shan, F, Jia, Y, Ji, J
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association. 2020;(3):540-549
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Abstract
BACKGROUND The clinical values of inflammatory and nutritional markers remained unclear for gastric cancer with neoadjuvant chemotherapy (NACT). METHODS The inflammatory, nutritional markers and their changes were analyzed for locally advanced gastric cancer with NACT. The predictive value was evaluated by the Cox proportional hazards regressions under three hypothesized scenarios. The nomograms including independent prognostic factors were plotted for survival prediction. RESULTS A total of 225 patients were included in the study. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index, and hemoglobin (Hgb) were significantly reduced, and the body mass index was significantly increased after NACT (all P < 0.05). The pre-NACT NLR [hazard ratio (HR) = 1.176, P = 0.059] showed a trend to correlate with the overall survival (OS) when only pre-NACT markers available; The post-NACT Hgb (HR = 0.982, P = 0.015) was the independent prognostic factor when only post-NACT markers available; The post-NACT Hgb (HR = 0.984, P = 0.025) and the change value of LMR (HR = 1.183, P = 0.036) were the independent prognostic factors when both pre- and post-NACT markers available. The nomogram had a similar Harrell's C-statistic compared to ypTNM stage (0.719 vs. 0.706). CONCLUSION For locally advanced gastric cancer, the NACT could significantly decrease some inflammatory markers. The pre-NACT NLR, the post-NACT Hgb and the change value of LMR had some values in survival prediction combined with age, sex, tumor location and the clinical stages under different clinical scenarios. The elevated initial NLR, the preoperative anemia and the greater change value of LMR implied a poor prognosis.
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Identification of long-term survival-associated gene in breast cancer.
Ning, S, Li, H, Qiao, K, Wang, Q, Shen, M, Kang, Y, Yin, Y, Liu, J, Liu, L, Hou, S, et al
Aging. 2020;(20):20332-20349
Abstract
Breast cancer patients at the same stage may show different clinical prognoses or different therapeutic effects of systemic therapy. Differentially expressed genes of breast cancer were identified from GSE42568. Through survival, receiver operating characteristic (ROC) curve, random forest, GSVA and a Cox regression model analyses, genes were identified that could be associated with survival time in breast cancer. The molecular mechanism was identified by enrichment, GSEA, methylation and SNV analyses. Then, the expression of a key gene was verified by the TCGA dataset and RT-qPCR, Western blot, and immunohistochemistry. We identified 784 genes related to the 5-year overall survival time of breast cancer. Through ROC curve and random forest analysis, 10 prognostic genes were screened. These were integrated into a complex by GSVA, and high expression of the complex significantly promoted the recurrence-free survival of patients. In addition, key genes were related to immune and metabolic-related functions. Importantly, we identified methylation of MEX3A and TBC1D 9 and mutations events. Finally, the expression of UGCG was verified by the TCGA dataset and by experimental methods in our own samples. These results indicate that 10 genes may be potential biomarkers and therapeutic targets for long-term survival in breast cancer, especially UGCG.
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Metabolomic effects of androgen deprivation therapy treatment for prostate cancer.
Chi, JT, Lin, PH, Tolstikov, V, Oyekunle, T, Chen, EY, Bussberg, V, Greenwood, B, Sarangarajan, R, Narain, NR, Kiebish, MA, et al
Cancer medicine. 2020;(11):3691-3702
Abstract
Androgen deprivation therapy (ADT) is the main treatment strategy for men with metastatic prostate cancer (PC). However, ADT is associated with various metabolic disturbances, including impaired glucose tolerance, insulin resistance and weight gain, increasing risk of diabetes and cardiovascular death. Much remains unknown about the metabolic pathways and disturbances altered by ADT and the mechanisms. We assessed the metabolomic effects of ADT in the serum of 20 men receiving ADT. Sera collected before (baseline), 3 and 6 months after initiation of ADT was used for the metabolomics and lipidomics analyses. The ADT-associated metabolic changes were identified by univariable and multivariable statistical analysis, ANOVA, and Pearson correlation. We found multiple key changes. First, ADT treatments reduced the steroid synthesis as reflected by the lower androgen sulfate and other steroid hormones. Greater androgen reduction was correlated with higher serum glucose levels, supporting the diabetogenic role of ADT. Second, ADT consistently decreased the 3-hydroxybutyric acid and ketogenesis. Third, many acyl-carnitines were reduced, indicating the effects on the fatty acid metabolism. Fourth, ADT was associated with a corresponding reduction in 3-formyl indole (a.k.a. indole-3-carboxaldehyde), a microbiota-derived metabolite from the dietary tryptophan. Indole-3-carboxaldehyde is an agonist for the aryl hydrocarbon receptor and regulates the mucosal reactivity and inflammation. Together, these ADT-associated metabolomic analyses identified reduction in steroid synthesis and ketogenesis as prominent features, suggesting therapeutic potential of restricted ketogenic diets, though this requires formal testing. ADT may also impact the microbial production of indoles related to the immune pathways. Future research is needed to determine the functional impact and underlying mechanisms to prevent ADT-linked comorbidities and diabetes risk.
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RNA sequencing reveals PNN and KCNQ1OT1 as predictive biomarkers of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy.
Mini, E, Lapucci, A, Perrone, G, D'Aurizio, R, Napoli, C, Brugia, M, Landini, I, Tassi, R, Picariello, L, Simi, L, et al
International journal of cancer. 2019;(9):2580-2593
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Abstract
Five-year overall survival of stage III colorectal cancer (CRC) patients treated with standard adjuvant chemotherapy (ACHT) is highly variable. Genomic biomarkers and/or transcriptomic profiles identified lack of adequate validation. Aim of our study was to identify and validate molecular biomarkers predictive of ACHT response in stage III CRC patients by a transcriptomic approach. From a series of CRC patients who received ACHT, two stage III extreme cohorts (unfavorable vs. favorable prognosis) were selected. RNA-sequencing was performed from fresh frozen explants. Tumors were characterized for somatic mutations. Validation was performed in stage III CRC patients extracted from two GEO datasets. According to disease-free survival (DFS), 108 differentially expressed genes (104/4 up/downregulated in the unfavorable prognosis group) were identified. Among 104 upregulated genes, 42 belonged to olfactory signaling pathways, 62 were classified as pseudogenes (n = 17), uncharacterized noncoding RNA (n = 10), immune response genes (n = 4), microRNA (n = 1), cancer-related genes (n = 14) and cancer-unrelated genes (n = 16). Three out of four down-regulated genes were cancer-related. Mutational status (i.e., RAS, BRAF, PIK3CA) did not differ among the cohorts. In the validation cohort, multivariate analysis showed high PNN and KCNQ1OT1 expression predictive of shorter DFS in ACHT treated patients (p = 0.018 and p = 0.014, respectively); no difference was observed in untreated patients. This is the first study that identifies by a transcriptomic approach and validates PNN and KCNQ1OT1 as molecular biomarkers predictive of chemotherapy response in stage III CRC patients. After a further validation in an independent cohort, PNN and KCNQ1OT1 evaluation could be proposed to prospectively identify stage III CRC patients benefiting from ACHT.
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The Amount of Bifidobacterium Genus in Colorectal Carcinoma Tissue in Relation to Tumor Characteristics and Clinical Outcome.
Kosumi, K, Hamada, T, Koh, H, Borowsky, J, Bullman, S, Twombly, TS, Nevo, D, Masugi, Y, Liu, L, da Silva, A, et al
The American journal of pathology. 2018;(12):2839-2852
Abstract
Evidence indicates a complex link between microbiota, tumor characteristics, and host immunity in the tumor microenvironment. In experimental studies, bifidobacteria appear to modulate intestinal epithelial cell differentiation. Accumulating evidence suggests that bifidobacteria may enhance the antitumor immunity and efficacy of immunotherapy. We hypothesized that the amount of bifidobacteria in colorectal carcinoma tissue might be associated with tumor differentiation and higher immune response to colorectal cancer. Using a molecular pathologic epidemiology database of 1313 rectal and colon cancers, we measured the amount of Bifidobacterium DNA in carcinoma tissue by a quantitative PCR assay. The multivariable regression model was used to adjust for potential confounders, including microsatellite instability status, CpG island methylator phenotype, long-interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations. Intratumor bifidobacteria were detected in 393 cases (30%). The amount of bifidobacteria was associated with the extent of signet ring cells (P = 0.002). Compared with Bifidobacterium-negative cases, multivariable odd ratios for the extent of signet ring cells were 1.29 (95% CI, 0.74-2.24) for Bifidobacterium-low cases and 1.87 (95% CI, 1.16-3.02) for Bifidobacterium-high cases (Ptrend = 0.01). The association between intratumor bifidobacteria and signet ring cells suggests a possible role of bifidobacteria in determining distinct tumor characteristics or as an indicator of dysfunctional mucosal barrier in colorectal cancer.
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Emerging Role of IL-4-Induced Gene 1 as a Prognostic Biomarker Affecting the Local T-Cell Response in Human Cutaneous Melanoma.
Ramspott, JP, Bekkat, F, Bod, L, Favier, M, Terris, B, Salomon, A, Djerroudi, L, Zaenker, KS, Richard, Y, Molinier-Frenkel, V, et al
The Journal of investigative dermatology. 2018;(12):2625-2634
Abstract
Several studies have emphasized the importance of immune composition of the melanoma microenvironment for clinical outcome. The contribution of IL4I1, a phenylalanine oxidase with immunoregulatory functions, has not been yet explored. Here we studied a primary cutaneous melanoma series from stage I-III patients to investigate the association between in situ IL4I1 expression and clinical parameters or tumor-infiltrating T-cell subsets. IL4I1 was detected in 87% of tumors and was mainly expressed by tumor-associated macrophages and very rare FoxP3+ regulatory T cells. The proportion of IL4I1+ cells was higher in patients with an ulcerated melanoma or with a positive sentinel lymph node and tended to correlate with a rapid relapse and shorter overall survival. This proportion also correlated positively with the presence of regulatory T cells and negatively with the presence of cytotoxic CD8+ T cells. The location of IL4I1+ cells may also be relevant to predict prognosis, because their presence near tumor cells was associated with sentinel lymph node invasion and higher melanoma stage. Collectively, our data show that IL4I1+ cells shape the T-cell compartment and are associated with a higher risk of poor outcome in melanoma, supporting a key role for IL4I1 in immune evasion.