Hemangioblastoma Instead of Renal Cell Carcinoma Plays a Major Role in the Unfavorable Overall Survival of Von Hippel-Lindau Disease Patients.
Zhou B1,2,3,4, Wang J4,5, Liu S1,2,3, Peng X1,2,3,6, Hong B1,2,3, Zhou J1,2,3, Ma K1,2,3, Zhang J1,2,3, Cai L1,2,3, Gong K1,2,3.
Author information
1
Department of Urology, Peking University First Hospital, Beijing, China.
2
Institute of Urology, Peking University, Beijing, China.
3
National Urological Cancer Center, Beijing, China.
4
Department of Urology, Beijing Hospital, Beijing, China.
5
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
6
Department of Urology, The Second Affiliated Hospital of NanChang University, Jiangxi, China.
Abstract
Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome characterized by poor survival. The effect of the involvement of each organ on survival remains unclear. Our study aimed to study the effect of the involvement of each organ on survival in VHL disease patients. We retrospectively analyzed 336 patients from 125 families. The onset age was compared between different groups using Mann-Whitney U test and Kruskal-Wallis test. Univariate and multivariate time-dependent Cox regression analyses were conducted to evaluate how survival was influenced by the involvement of each organ. The median survival time for VHL disease patients was 66 years. The onset age was earlier in the central nervous system (CNS) group than in the abdominal group. The involvement of central nervous system hemangioblastoma (CHB) and retinal hemangioblastoma (RA) were independent risk factors for overall survival. The involvement of renal cell carcinoma (RCC) was not a significant risk factor for overall survival. Only RA was a risk factor for CHB-specific survival. This study analyzed the relationship between organ involvement and survival of VHL patients. This may help guide future genetic counseling and clinical decision-making.

Copyright © 2019 Zhou, Wang, Liu, Peng, Hong, Zhou, Ma, Zhang, Cai and Gong.

KEYWORDS:
genetic cancer syndrome; prognosis; risk factor; survival; von Hippel-Lindau disease

PMID: 31649892 PMCID: PMC6794496 DOI: 10.3389/fonc.2019.01037
Similar articles
Select item 31649891
2.
Front Oncol. 2019 Oct 10;9:1036. doi: 10.3389/fonc.2019.01036. eCollection 2019.
Hypoxia Can Induce Migration of Glioblastoma Cells Through a Methylation-Dependent Control of ODZ1 Gene Expression.
Velásquez C1,2, Mansouri S2, Gutiérrez O3, Mamatjan Y2, Mollinedo P3, Karimi S2, Singh O2, Terán N4, Martino J1, Zadeh G2,5, Fernández-Luna JL3.
Author information
1
Department of Neurological Surgery and Spine Unit, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
2
MacFeeters-Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, Toronto, ON, Canada.
3
Genetics Unit, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
4
Department of Pathology, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
5
Division of Neurosurgery, Toronto Western Hospital/University Health Network, University of Toronto, Toronto, ON, Canada.
Abstract
The transmembrane protein ODZ1 has been associated with the invasive capacity of glioblastoma (GBM) cells through upregulation of RhoA/ROCK signaling, but the mechanisms triggering the ODZ1 pathway remain elusive. In addition, it is widely accepted that hypoxia is one of the main biological hallmarks of the GBM microenvironment and it is associated with treatment resistance and poor prognosis. Here we show that hypoxic tumor regions express higher levels of ODZ1 and that hypoxia induces ODZ1 expression in GBM cells by regulating the methylation status of the ODZ1 promoter. Hypoxia-induced upregulation of ODZ1 correlates with higher migration capacity of GBM cells that is drastically reduced by knocking down ODZ1. In vitro methylation of the promoter decreases its transactivation activity and we found a functionally active CpG site at the 3'end of the promoter. This site is hypermethylated in somatic neural cells and mainly hypomethylated in GBM cells. Mutagenesis of this CpG site reduces the promoter activity in response to hypoxia. Overall, we identify hypoxia as the first extracellular activator of ODZ1 expression and describe that hypoxia controls the levels of this migration-inducer, at least in part, by regulating the methylation status of the ODZ1 gene promoter.

Copyright © 2019 Velásquez, Mansouri, Gutiérrez, Mamatjan, Mollinedo, Karimi, Singh, Terán, Martino, Zadeh and Fernández-Luna.

KEYWORDS:
ODZ1; glioblastoma; hypoxia; methylation; migration; teneurin

PMID: 31649891 PMCID: PMC6795711 DOI: 10.3389/fonc.2019.01036
Similar articles
Select item 31649890
3.
Front Oncol. 2019 Oct 9;9:1035. doi: 10.3389/fonc.2019.01035. eCollection 2019.
SEMA3C Promotes Cervical Cancer Growth and Is Associated With Poor Prognosis.
Liu R1,2,3, Shuai Y2,3,4, Luo J2,3,4, Zhang Z2,3,4.
Author information
1
Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
2
Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
3
Tianjin's Clinical Research Center for Cancer, Tianjin, China.
4
Department of Maxillofacial and Otorhinolaryngology Oncology and Department of Head and Neck Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
Abstract
Introduction: Aberrant activation of Semaphorin3C(SEMA3C) is widespread in human cancers. We aimed to analyze SEMA3C expression in cervical cancer and investigate the role of SEMA3C in cervical cancer and its underlying mechanism, which is important for exploring new therapeutic targets and prognostic factors. Materials and Methods: The expression of SEMA3C was examined in paraffin-embedded cervical cancer specimens. In vivo and in vitro assays were performed to validate the effect of SEMA3C on cervical cancer cell proliferation and p-ERK pathway activation. Gene Set Enrichment Analysis (GSEA) was performed using The Cancer Genome Atlas (TCGA) data set. Results: SEMA3C expression was associated with poor survival in both the TCGA cohort and our cohort. Silencing of SEMA3C suppressed cervical cancer cell proliferation, colony formation ability, and the activation of the p-ERK signaling pathway in vitro. SEMA3C depletion inhibited tumor growth in vitro. GSEA also showed that the epithelial mesenchymal transition (EMT), TGFβ signaling pathway, angiogenesis, and extracellular matrix (ECM) receptor interactions are associated with a high SEMA3C expression phenotype. Conclusion: SEMA3C is correlated with poor prognosis of cervical cancer patients and promotes tumor growth via the activation of the p-ERK pathway.

Copyright © 2019 Liu, Shuai, Luo and Zhang.

KEYWORDS:
GSEA; SEMA3C; TCGA; cervical cancer; p-ERK signaling pathway

PMID: 31649890 PMCID: PMC6794562 DOI: 10.3389/fonc.2019.01035
Similar articles
Select item 31649889
4.
Front Oncol. 2019 Oct 9;9:1033. doi: 10.3389/fonc.2019.01033. eCollection 2019.
Vitiligo Adverse Event Observed in a Patient With Durable Complete Response After Nivolumab for Metastatic Renal Cell Carcinoma.
Billon E1, Walz J2, Brunelle S3, Thomassin J4, Salem N5, Guerin M1, Vicier C1, Dermeche S1, Albiges L6, Tantot F7, Nenan S7, Pignot G2, Gravis G1,8.
Author information
1
Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France.
2
Department of Urology, Institut Paoli-Calmettes, Marseille, France.
3
Department of Radiology, Institut Paoli-Calmettes, Marseille, France.
4
Department of Biopathology, Institut Paoli-Calmettes, Marseille, France.
5
Department of Radiotherapy, Institut Paoli-Calmettes, Marseille, France.
6
Department of Cancer Medicine, Gustave Roussy, Villejuif, France.
7
Research Department, UNICANCER, Paris, France.
8
Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068; CNRS UMR7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France.
Abstract
Background: Renal cell carcinoma is the third most prevalent urological cancer worldwide and about 30% of patients present with metastatic disease at the time of diagnosis. Systemic treatments for metastatic renal cell carcinoma have improved recently. Vascular endothelial growth factor targeting therapies were the previous standard of care. However, immune checkpoint inhibitors used in second line therapy have now been shown to improve patient survival. We report a case of metastatic renal cell carcinoma with nivolumab as a second-line therapy after progression with tyrosine kinase inhibitor therapy. Unusual adverse events in metastatic renal cell carcinoma, such as vitiligo, were observed in this patient who developed a remarkable documented pathological complete response to his renal tumor. Case presentation: A 60-year-old caucasian male was diagnosed with a pulmonary metastatic clear cell renal cell carcinoma. Sunitinib was used as first line treatment without success. He received nivolumab in second-line treatment. He developed several immune-related adverse events, most notably vitiligo. The patient had a radiological complete response on metastatic sites, with a significant decrease of renal tumor volume and underwent cytoreductive nephrectomy after 2 years of treatment, confirming the pathological complete response. The patient remains disease-free for 10 months without further systemic therapy after nivolumab discontinuation. Conclusions: Pathological complete response with nivolumab in metastatic renal cell carcinoma is rare. This case further highlights the potentially predictive role of immune-related adverse events during nivolumab therapy for metastatic renal cell carcinoma and raises questions concerning the role of nephrectomy after immune checkpoint inhibitor therapy. Further studies are needed to better identify predictive factors for treatment response to immunotherapy in metastatic renal cell carcinoma, and to better understand the role of nephrectomy after nivolumab treatment.

Copyright © 2019 Billon, Walz, Brunelle, Thomassin, Salem, Guerin, Vicier, Dermeche, Albiges, Tantot, Nenan, Pignot and Gravis.

KEYWORDS:
complete response; immune adverse events; immunotherapy; nephrectomy; nivolumab; renal cell carcinoma; thyroid dysfunction; vitiligo

PMID: 31649889 PMCID: PMC6795279 DOI: 10.3389/fonc.2019.01033
Similar articles
Publication type
Select item 31649888
5.
Front Oncol. 2019 Oct 9;9:1032. doi: 10.3389/fonc.2019.01032. eCollection 2019.
Atorvastatin Exerts Antileukemia Activity via Inhibiting Mevalonate-YAP Axis in K562 and HL60 Cells.
Zhang L1, Chen T1, Dou Y1, Zhang S1,2, Liu H2, Khishignyam T1, Li X1, Zuo D3, Zhang Z1, Jin M1, Wang R1, Qiu Y1, Zhong Y2, Kong D1,4.
Author information
1
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China.
2
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
3
Tianjin Medical University Cancer Hospital, Tianjin, China.
4
School of Medicine, Tianjin Tianshi College, Tianyuan University, Tianjin, China.
Abstract
Novel therapeutic strategies are still urgently expected for leukemia despite undisputed success of various targeted therapeutics. The antileukemia activity of Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on human leukemia cells was investigated. Atorvastatin inhibited K562 and HL60 cell proliferation, induced G2/M cell cycle arrest in K562 cells by down-regulating cyclinB1 and cdc2, but G0/G1 arrest in HL60 cells by up-regulating p27 and down-regulating cyclinD1 and p-pRb. Atorvastatin also induced apoptosis in both cell lines, in which the reactive oxygen species (ROS)-related mitochondrial apoptotic signaling might be involved, with increase of ROS and Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (MMP), release of cytochrome C into cytosol, and activation of Bax/Caspase-9/Caspase-3/PARP pathway. Inhibition of YAP nuclear localization and activation by Atorvastatin was reversed by the addition of mevalonate, GGPP, or FPP. Further, the effects on cell cycle arrest- and apoptosis- related proteins by Atorvastatin were alleviated by addition of mevalonate, suggesting the antileukemia effect of Atorvastatin might be through mevalonate-YAP axis in K562 and HL60 cells. Our results suggest that Atorvastatin might be used for leukemia therapy while evidence of clinical efficacy is required.

Copyright © 2019 Zhang, Chen, Dou, Zhang, Liu, Khishignyam, Li, Zuo, Zhang, Jin, Wang, Qiu, Zhong and Kong.

KEYWORDS:
Atorvastatin; anti-leukemia; apoptosis; cell cycle; mevalonate-YAP axis

PMID: 31649888 PMCID: PMC6794561 DOI: 10.3389/fonc.2019.01032
Similar articles
Select item 31649887
6.
Front Oncol. 2019 Oct 10;9:1031. doi: 10.3389/fonc.2019.01031. eCollection 2019.
Circulating Tumor Biomarkers in Meningiomas Reveal a Signature of Equilibrium Between Tumor Growth and Immune Modulation.
Erkan EP1, Ströbel T2, Dorfer C3, Sonntagbauer M4, Weinhäusel A4, Saydam N5, Saydam O6.
Author information
1
Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
2
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
3
Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
4
Austrian Institute of Technology, Molecular Diagnostics Center for Health and Bioresources, Vienna, Austria.
5
Department of Biochemistry, Molecular Biology, and Biophysics, Medical School, University of Minnesota, Minneapolis, MN, United States.
6
Division of Hematology and Oncology, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN, United States.
Abstract
Meningiomas are primary central nervous system (CNS) tumors that originate from the arachnoid cells of the meninges. Recurrence occurs in higher grade meningiomas and a small subset of Grade I meningiomas with benign histology. Currently, there are no established circulating tumor markers which can be used for diagnostic and prognostic purposes in a non-invasive way for meningiomas. Here, we aimed to identify potential biomarkers of meningioma in patient sera. For this purpose, we collected preoperative (n = 30) serum samples from the meningioma patients classified as Grade I (n = 23), Grade II (n = 4), or Grade III (n = 3). We used a high-throughput, multiplex immunoassay cancer panel comprising of 92 cancer-related protein biomarkers to explore the serum protein profiles of meningioma patients. We detected 14 differentially expressed proteins in the sera of the Grade I meningioma patients in comparison to the age- and gender-matched control subjects (n = 12). Compared to the control group, Grade I meningioma patients showed increased serum levels of amphiregulin (AREG), CCL24, CD69, prolactin, EGF, HB-EGF, caspase-3, and decreased levels of VEGFD, TGF-α, E-Selectin, BAFF, IL-12, CCL9, and GH. For validation studies, we utilized an independent set of meningioma tumor tissue samples (Grade I, n = 20; Grade II, n = 10; Grade III, n = 6), and found that the expressions of amphiregulin and Caspase3 are significantly increased in all grades of meningiomas either at the transcriptional or protein level, respectively. In contrast, the gene expression of VEGF-D was significantly lower in Grade I meningioma tissue samples. Taken together, our study identifies a meningioma-specific protein signature in blood circulation of meningioma patients and highlights the importance of equilibrium between tumor-promoting factors and anti-tumor immunity.

Copyright © 2019 Erkan, Ströbel, Dorfer, Sonntagbauer, Weinhäusel, Saydam and Saydam.

KEYWORDS:
CNS tumors; biomarker; high-throughput immunoassay cancer panel; meningioma; proximity extension assay; serum biomarker

PMID: 31649887 PMCID: PMC6795693 DOI: 10.3389/fonc.2019.01031
Similar articles
Select item 31649886
7.
Front Oncol. 2019 Oct 9;9:1029. doi: 10.3389/fonc.2019.01029. eCollection 2019.
MicroRNA and mRNA Interaction Network Regulates the Malignant Transformation of Human Bronchial Epithelial Cells Induced by Cigarette Smoke.
Wang J1, Yu XF1, Ouyang N1, Zhao S1, Yao H1, Guan X1, Tong J1, Chen T1, Li JX1.
Author information
1
Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, China.
Abstract
This study analyzes the correlation and interaction of miRNAs and mRNAs and their biological function in the malignant transformation of BEAS-2B cells induced by cigarette smoke (CS). Normal human bronchial epithelial cells (BEAS-2B) were continuously exposed to CS for 30 passages (S30) to establish an in vitro cell model of malignant transformation. The transformed cells were validated by scratch wound healing assay, transwell migration assay, colony formation and tumorigenicity assay. The miRNA and mRNA sequencing analysis were performed to identify differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) between normal BEAS-2B and S30 cells. The miRNA-seq data of lung cancer with corresponding clinical data obtained from TCGA was used to further identify lung cancer-related DEMs and their correlations with smoking history. The target genes of these DEMs were predicted using the miRDB database, and their functions were analyzed using the online tool "Metascape." It was found that the migration ability, colony formation rate and tumorigenicity of S30 cells enhanced. A total of 42 miRNAs and 753 mRNAs were dysregulated in S30 cells. The change of expression of top five DEGs and DEMs were consistent with our sequencing results. Among these DEMs, eight miRNAs were found dysregulated in lung cancer tissues based on TCGA data. In these eight miRNAs, six of them including miR-96-5p, miR-93-5p, miR-106-5p, miR-190a-5p, miR-195-5p, and miR-1-3p, were found to be associated with smoking history. Several DEGs, including THBS1, FN1, PIK3R1, CSF1, CORO2B, and PREX1, were involved in many biological processes by enrichment analysis of miRNA and mRNA interaction. We identified the negatively regulated miRNA-mRNA pairs in the CS-induced lung cancer, which were implicated in several cancer-related (especially EMT-related) biological process and KEGG pathways in the malignant transformation progress of lung cells induced by CS. Our result demonstrated the dysregulation of miRNA-mRNA profiles in cigarette smoke-induced malignant transformed cells, suggesting that these miRNAs might contribute to cigarette smoke-induced lung cancer. These genes may serve as biomarkers for predicting lung cancer pathogenesis and progression. They can also be targets of novel anticancer drug development.

Copyright © 2019 Wang, Yu, Ouyang, Zhao, Yao, Guan, Tong, Chen and Li.

KEYWORDS:
BEAS-2B; The Cancer Genome Atlas; cigarette smoke; lung cancer; miRNA-mRNA network

PMID: 31649886 PMCID: PMC6794608 DOI: 10.3389/fonc.2019.01029
Similar articles
Select item 31649885
8.
Front Oncol. 2019 Oct 10;9:1028. doi: 10.3389/fonc.2019.01028. eCollection 2019.
Clinical Outcome Assessments Toolbox for Radiopharmaceuticals.
Kunos CA1, Capala J2, Dicker AP3, Movsas B4, Ivy SP1, Minasian LM5.
Author information
1
Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, United States.
2
Radiation Research Program, National Cancer Institute, Bethesda, MD, United States.
3
Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States.
4
Henry Ford Hospital, Detroit, MI, United States.
5
Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, United States.
Abstract
For nearly 40 years, the U.S. National Cancer Institute (NCI) has funded health-related quality-of-life (HRQOL) and symptom management in oncology clinical trials as a method for including a cancer patient's experience during and after treatment. The NCI's planned scope for HRQOL, symptom and patient-reported outcomes management research is explained as it pertains to radiopharmaceutical clinical development. An effort already underway to support protocol authoring via an NCI Cancer Therapy Evaluation Program (CTEP) Centralized Protocol Writing Service (CPWS) is described as this service aids incorporation of HRQOL, symptom and patient-reported outcomes management research into sponsored protocols.

Copyright © 2019 Kunos, Capala, Dicker, Movsas, Ivy and Minasian.

KEYWORDS:
cancer; clinical outcome assessment; digital device usage; patient reported outcome (PRO); radiopharmaceutical; radiotherapy; radiotherapy adverse effects

PMID: 31649885 PMCID: PMC6795707 DOI: 10.3389/fonc.2019.01028
Similar articles
Select item 31649884
9.
Front Oncol. 2019 Oct 9;9:1027. doi: 10.3389/fonc.2019.01027. eCollection 2019.
Targeting the GFI1/1B-CoREST Complex in Acute Myeloid Leukemia.
van Bergen MGJM1, van der Reijden BA1.
Author information
1
Laboratory of Hematology, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
Abstract
One of the hallmarks of acute myeloid leukemia (AML) is a block in cellular differentiation. Recent studies have shown that small molecules targeting Lysine Specific Demethylase 1A (KDM1A) may force the malignant cells to terminally differentiate. KDM1A is a core component of the chromatin binding CoREST complex. Together with histone deacetylases CoREST regulates gene expression by histone 3 demethylation and deacetylation. The transcription factors GFI1 and GFI1B (for growth factor independence) are major interaction partners of KDM1A and recruit the CoREST complex to chromatin in myeloid cells. Recent studies show that the small molecules that target KDM1A disrupt the GFI1/1B-CoREST interaction and that this is key to inducing terminal differentiation of leukemia cells.

Copyright © 2019 van Bergen and van der Reijden.

KEYWORDS:
CoREST; GFI1; GFI1B; HDAC1/2; KDM1A/LSD1 inhibitors; RCOR; acute myeloid leukemia; histone modifications

PMID: 31649884 PMCID: PMC6794713 DOI: 10.3389/fonc.2019.01027
Similar articles
Publication type
Select item 31649883
10.
Front Oncol. 2019 Oct 9;9:1025. doi: 10.3389/fonc.2019.01025. eCollection 2019.
Immunomodulation in Cutaneous T Cell Lymphoma.
Ferranti M1, Tadiotto Cicogna G1, Russo I1, Alaibac M1.
Author information
1
Unit of Dermatology, University of Padua, Padua, Italy.
KEYWORDS:
CD30 cutaneous T-cell lymphoma; HIV; cutaneous T-cell lymphoma; immunosuppression; mycosis fungoides

PMID: 31649883 PMCID: PMC6794804 DOI: 10.3389/fonc.2019.01025
Similar articles
Select item 31649882
11.
Front Oncol. 2019 Oct 9;9:1023. doi: 10.3389/fonc.2019.01023. eCollection 2019.
Cranial Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumors: A Retrospective Study Focused on Prognostic Factors and Long-Term Outcomes.
Chen J1, Cheng R2, Fan F3, Zheng Y3, Li Y3, Chen Y3, Wang Y3.
Author information
1
Department of Neurosurgery, Xianning Center Hospital, Xianning, China.
2
Department of Dermatology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
3
Department of Neurosurgery, Tongji Medical School, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
Abstract
Purpose: Cranial Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumors (pPNETs) are rarely reported because of their extremely low incidence, and the current understanding of these tumors is poor. The purpose of this study was to illustrate the clinical, radiological, and pathological features of cranial ES/pPNETs and to discuss prognostic factors by survival analysis. Methods: A total of 31 patients who were pathologically diagnosed with cranial ES/pPNETs between 2000 and 2019 were enrolled in this study. To identify which parameters were associated with higher progression-free survival (PFS) and overall survival (OS) rates, univariate and multivariate analyses were performed. Results: The mean follow-up period was 24.8 months (range, 1-109 months). Eighteen (58.1%) patients had local recurrence and seven (22.6%) patients had distant metastasis. The results of the univariate analysis suggest that the extent of resection and adjuvant radiotherapy are potential prognostic factors for PFS and OS. Adjuvant chemotherapy was associated with OS (P = 0.027) but not with PFS (P = 0.053). The multivariate analysis revealed that the extent of resection and adjuvant radiotherapy were independent prognostic factors for both PFS and OS. In addition, metastasis was an adverse prognostic factor for OS. Conclusions: Surgical management plays a crucial role in the treatment of cranial ES/pPNETs, and gross total resection should be striven for whenever possible. Post-operative radiotherapy is highly recommended to improve PFS and OS. This study also confirms that metastasis is an adverse prognostic factor for cranial ES/pPNETs.

Copyright © 2019 Chen, Cheng, Fan, Zheng, Li, Chen and Wang.

KEYWORDS:
Ewing sarcoma; cranial; primitive neuroectodermal tumors; prognostic factor; survival

PMID: 31649882 PMCID: PMC6794714 DOI: 10.3389/fonc.2019.01023
Similar articles
Select item 31649881
12.
Front Oncol. 2019 Oct 9;9:1020. doi: 10.3389/fonc.2019.01020. eCollection 2019.
Single Purse-String Suture for Reinforcement of Duodenal Stump During Laparoscopic Radical Gastrectomy for Gastric Cancer.
He H1, Li H1, Ye B1, Liu F1.
Author information
1
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Abstract
Background: Duodenal stump leakage (DSL) is a serious surgical complication after radical gastrectomy with Roux-en-Y or BillrothII reconstruction. This study was designed to evaluate the effectiveness of laparoscopic single purse-string suture for reinforcement of duodenal stump. Methods: A total of 183 patients harboring gastric adenocarcinoma following laparoscopic radical gastrectomy with Roux-en-Y or BillrothIIreconstruction and single purse-string suture for reinforcement of duodenal stump were retrospectively enrolled from Zhongshan Hospital of Fudan University (Shanghai, China) between January 2014 and December 2016. Operative variables and short-term complications were documented and analyzed. Clavien-Dindo classification system was used to identify surgical complications. Results: Among 183 patients, 108 (59.02%) patients received distal gastrectomy and 75 (40.98%) received total gastrectomy. 88 (48.09%) patients underwent Roux-en-Y reconstruction and 95 (51.91%) patients underwent Billroth-II reconstruction. The mean time of laparoscopic single purse-string suture was 5.01 ± 1.33 min (range from 3.6 to 10.2 min). Postoperative early complication occurred in 26 cases of the patients. There were 4 cases of system-related complications (2.19%), including 3 cases of pulmonary infection (1.64%) and 1 cases of cardiovascular event (0.55%); and 22 cases of surgery-related complications (12.02%), including 6 cases of intra-abdominal infection (3.28%), 4 cases of pancreatic leakage (2.19%), 4 cases of wound complications (2.19%), 3 cases of gastroparesis (1.64%), 2 cases of intra-abdominal bleeding (1.09%), 2 cases of ileus (1.09%), 1 cases of lymphatic leakage (0.55%), and no duodenal stump leakage. Conclusion: Reinforcement on duodenal stump using laparoscopic single purse-string suture during laparoscopic radical gastrectomy is simple and effective and could avoid the incidence of duodenal stump leakage to some extent.

Copyright © 2019 He, Li, Ye and Liu.

KEYWORDS:
duodenal stump leakage; gastric cancer; laparoscopic radical gastrectomy; laparoscopic single purse-string suture; reinforcement

PMID: 31649881 PMCID: PMC6794805 DOI: 10.3389/fonc.2019.01020
Similar articles
Select item 31649880
13.
Front Oncol. 2019 Oct 9;9:1018. doi: 10.3389/fonc.2019.01018. eCollection 2019.
Unfavorable Outcome of Neuroblastoma in Patients With 2p Gain.
Szewczyk K1, Wieczorek A2,3, Młynarski W4, Janczar S4, Woszczyk M5, Gamrot Z5, Chaber R6, Wysocki M7, Pogorzała M7, Bik-Multanowski M1, Balwierz W2,3.
Author information
1
Department of Medical Genetics, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.
2
Department of Pediatrics Oncology and Hematology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.
3
Department of Pediatric Oncology and Hematology, University Children's Hospital of Krakow, Krakow, Poland.
4
Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland.
5
Unit of Pediatric Oncology and Hematology, City Hospital, Chorzow, Poland.
6
Clinic of Pediatric Oncology and Hematology, Faculty of Medicine, University of Rzeszow, Rzeszow, Poland.
7
Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
Abstract
Background: Amplification of the MYCN oncogene is the most unfavorable genetic factor in neuroblastoma patients. However, knowledge about the clinical impact of low-level multiplication of MYCN is still insufficient. Therefore, we aimed to investigate the disease course in patients with different copy number status of MYCN. Materials and Methods: We examined 105 children diagnosed with neuroblastoma from 2010 to 2018 in five pediatric oncology centers in Poland. We determined the MYCN status at diagnosis by the interphase FISH examination and assessed the clinical outcome in patients. Results: A total of 35% of tumors presented with chromosome 2 numerical changes, 20% had MYCN amplification and 16% revealed 2p gain. Unexpectedly, we observed very low overall survival and event free survival (EFS) rates in neuroblastomas with 2p gain, which were comparable with patients with MYCN amplification. Conclusions: The 2p gain alteration should be reported as a strong unfavorable prognostic marker in neuroblastoma patients.

Copyright © 2019 Szewczyk, Wieczorek, Młynarski, Janczar, Woszczyk, Gamrot, Chaber, Wysocki, Pogorzała, Bik-Multanowski and Balwierz.

KEYWORDS:
2p gain; MYCN amplification; MYCN gain; neuroblastoma; structural chromosomal aberrations

PMID: 31649880 PMCID: PMC6794702 DOI: 10.3389/fonc.2019.01018
Similar articles
Select item 31649879
14.
Front Oncol. 2019 Oct 9;9:1010. doi: 10.3389/fonc.2019.01010. eCollection 2019.
Super-Resolution 1H Magnetic Resonance Spectroscopic Imaging Utilizing Deep Learning.
Iqbal Z1, Nguyen D1, Hangel G2, Motyka S2, Bogner W2, Jiang S1.
Author information
1
Medical Artificial Intelligence and Automation Laboratory, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, United States.
2
Christian Doppler Laboratory for Clinical Molecular MR Imaging, Department of Biomedical Imaging and Image-guided Therapy, High Field MR Center, Medical University of Vienna, Vienna, Austria.
Abstract
Magnetic resonance spectroscopic imaging (SI) is a unique imaging technique that provides biochemical information from in vivo tissues. The 1H spectra acquired from several spatial regions are quantified to yield metabolite concentrations reflective of tissue metabolism. However, since these metabolites are found in tissues at very low concentrations, SI is often acquired with limited spatial resolution. In this work, we test the hypothesis that deep learning is able to upscale low resolution SI, together with the T1-weighted (T1w) image, to reconstruct high resolution SI. We report on a novel densely connected UNet (D-UNet) architecture capable of producing super-resolution spectroscopic images. The inputs for the D-UNet are the T1w image and the low resolution SI image while the output is the high resolution SI. The results of the D-UNet are compared both qualitatively and quantitatively to simulated and in vivo high resolution SI. It is found that this deep learning approach can produce high quality spectroscopic images and reconstruct entire 1H spectra from low resolution acquisitions, which can greatly advance the current SI workflow.

Copyright © 2019 Iqbal, Nguyen, Hangel, Motyka, Bogner and Jiang.

KEYWORDS:
artificial intelligence; deep learning (DL); magnetic resonance spectroscopic imaging (SI); magnetic resonance spectroscopy (1H MRS); super-resolution

PMID: 31649879 PMCID: PMC6794570 DOI: 10.3389/fonc.2019.01010
Similar articles
Select item 31649878
15.
Front Oncol. 2019 Oct 10;9:1009. doi: 10.3389/fonc.2019.01009. eCollection 2019.
Altering DNA Repair to Improve Radiation Therapy: Specific and Multiple Pathway Targeting.
Biau J1,2,3,4,5,6, Chautard E5,7, Verrelle P1,6,8,9, Dutreix M1,2,3,4.
Author information
1
Institut Curie, PSL Research University, Centre de Recherche, Paris, France.
2
UMR3347, CNRS, Orsay, France.
3
U1021, INSERM, Orsay, France.
4
Université Paris Sud, Orsay, France.
5
Université Clermont Auvergne, INSERM, U1240 IMoST, Clermont Ferrand, France.
6
Radiotherapy Department, Université Clermont Auvergne, Centre Jean Perrin, Clermont-Ferrand, France.
7
Pathology Department, Université Clermont Auvergne, Centre Jean Perrin, Clermont-Ferrand, France.
8
U1196, INSERM, UMR9187, CNRS, Orsay, France.
9
Radiotherapy Department, Institut Curie Hospital, Paris, France.
Abstract
Radiation therapy (RT) is widely used in cancer care strategies. Its effectiveness relies mainly on its ability to cause lethal damage to the DNA of cancer cells. However, some cancers have shown to be particularly radioresistant partly because of efficient and redundant DNA repair capacities. Therefore, RT efficacy might be enhanced by using drugs that can disrupt cancer cells' DNA repair machinery. Here we review the recent advances in the development of novel inhibitors of DNA repair pathways in combination with RT. A large number of these compounds are the subject of preclinical/clinical studies and target key enzymes involved in one or more DNA repair pathways. A totally different strategy consists of mimicking DNA double-strand breaks via small interfering DNA (siDNA) to bait the whole DNA repair machinery, leading to its global inhibition.

Copyright © 2019 Biau, Chautard, Verrelle and Dutreix.

KEYWORDS:
DNA damage; inhibition; radioresistance; radiotherapy; repair systems

PMID: 31649878 PMCID: PMC6795692 DOI: 10.3389/fonc.2019.01009
Similar articles
Publication type
Select item 31649877
16.
Front Oncol. 2019 Oct 9;9:1007. doi: 10.3389/fonc.2019.01007. eCollection 2019.
Multiplanar MRI-Based Predictive Model for Preoperative Assessment of Lymph Node Metastasis in Endometrial Cancer.
Xu X1, Li H2,3,4, Wang S2,3, Fang M2,3, Zhong L2,3, Fan W1, Dong D2,3, Tian J2,5, Zhao X1.
Author information
1
Department of Diagnostic Imaging, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
2
CAS Key Lab of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
3
School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, China.
4
School of Automation, Harbin University of Science and Technology, Harbin, China.
5
Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medicine, Beihang University, Beijing, China.
Abstract
Introduction: Assessment of lymph node metastasis (LNM) is crucial for treatment decision and prognosis prediction for endometrial cancer (EC). However, the sensitivity of the routinely used magnetic resonance imaging (MRI) is low in assessing normal-sized LNM (diameter, 0-0.8 cm). We aimed to develop a predictive model based on magnetic resonance (MR) images and clinical parameters to predict LNM in normal-sized lymph nodes (LNs). Materials and Methods: A total of 200 retrospective patients were enrolled and divided into a training cohort (n = 140) and a test cohort (n = 60). All patients underwent preoperative MRI and had pathological result of LNM status. In total, 4,179 radiomic features were extracted. Four models including a clinical model, a radiomic model, and two combined models were built. Area under the receiver operating characteristic (ROC) curves (AUC) and calibration curves were used to assess these models. Subgroup analysis was performed according to LN size. All patients underwent surgical staging and had pathological results. Results: All of the four models showed predictive ability in LNM. One of the combined models, ModelCR1, consisting of radiomic features, LN size, and cancer antigen 125, showed the best discrimination ability on the training cohort [AUC, 0.892; 95% confidence interval [CI], 0.834-0.951] and test cohort (AUC, 0.883; 95% CI, 0.786-0.980). The subgroup analysis showed that this model also indicated good predictive ability in normal-sized LNs (0.3-0.8 cm group, accuracy = 0.846; <0.3 cm group, accuracy = 0.849). Furthermore, compared with the routinely preoperative MR report, the sensitivity and accuracy of this model had a great improvement. Conclusions: A predictive model was proposed based on MR radiomic features and clinical parameters for LNM in EC. The model had a good discrimination ability, especially for normal-sized LNs.

Copyright © 2019 Xu, Li, Wang, Fang, Zhong, Fan, Dong, Tian and Zhao.

KEYWORDS:
endometrial cancer; lymph node; magnetic resonance imaging; metastasis; radiomics

PMID: 31649877 PMCID: PMC6794606 DOI: 10.3389/fonc.2019.01007
Similar articles
Select item 31649876
17.
Front Oncol. 2019 Oct 9;9:1006. doi: 10.3389/fonc.2019.01006. eCollection 2019.
Head and Neck Cancer in Belgium: Quality of Diagnostic Management and Variability Across Belgian Hospitals Between 2009 and 2014.
Leroy R1, De Gendt C2, Stordeur S1, Schillemans V2, Verleye L1, Silversmit G2, Van Eycken E2, Savoye I1, Grégoire V3, Nuyts S4, Vermorken J5,6.
Author information
1
Belgian Health Care Knowledge Centre (KCE), Brussels, Belgium.
2
Belgian Cancer Registry, Brussels, Belgium.
3
Centre Léon Bérard, Lyon, France.
4
Department of Radiotherapy-Oncology, University Hospitals Leuven, University of Leuven, KU Leuven, Leuven, Belgium.
5
Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium.
6
Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
Abstract
Aims: The study assessed the quality of diagnosis and staging offered to patients with a head and neck squamous cell carcinoma (HNSCC) and the variability across Belgian hospitals. Methods: In total, 9,245 patients diagnosed with HNSCC between 2009 and 2014, were identified in the population-based Belgian Cancer Registry (BCR). The BCR data were coupled with other databases providing information on diagnostic and therapeutic procedures reimbursed by the compulsory health insurance, vital status data, and comorbidities. The use of diagnosis and staging procedures was assessed by four quality indicators (QI) (i.e., use of dedicated head and neck imaging studies, use of PET-CT, TNM reporting and interval between diagnosis and start of treatment), for which a target was defined before the analysis. The association between the binary QIs and observed survival was assessed using Cox proportional hazard models adjusted for potential confounders. Results: Overall, 82.5% of patients received staging by MRI and/or CT of the head and neck region before the start of treatment. In 47.6% of stage III-IV patients eligible for treatment with curative intent, a whole-body FDG-PET(/CT) was performed. The proportion of patients whose cTNM and pTNM stage was reported to the BCR was 80.5 and 78.4%, respectively. The median interval from diagnosis to first treatment with curative intent was 32 days (IQR: 19-46). For none of these QIs the pre-set targets were reached and a substantial variability between centers was observed for all quality indicators. No binary QI was significantly associated with observed survival. Conclusions: The four quality indicators related to diagnosis and staging in HNSCC all showed substantial room for improvement. For none of them the pre-set targets were met at the national level and the variability between centers was substantial. Each Belgian hospital received an individual feedback report in order to stimulate reflection and quality improvement processes.

Copyright © 2019 Leroy, De Gendt, Stordeur, Schillemans, Verleye, Silversmit, Van Eycken, Savoye, Grégoire, Nuyts and Vermorken.

KEYWORDS:
diagnosis; head and neck cancer; quality indicators; quality of care; squamous cell carcinoma; staging; variability in care

PMID: 31649876 PMCID: PMC6794682 DOI: 10.3389/fonc.2019.01006
Similar articles
Select item 31649875
18.
Front Oncol. 2019 Oct 9;9:1004. doi: 10.3389/fonc.2019.01004. eCollection 2019.
Chemotherapy-Induced Tumor Cell Death at the Crossroads Between Immunogenicity and Immunotolerance: Focus on Acute Myeloid Leukemia.
Ocadlikova D1, Lecciso M1, Isidori A2, Loscocco F2, Visani G2, Amadori S3, Cavo M1, Curti A1.
Author information
1
Department of Hematology and Oncology, University Hospital S.Orsola-Malpighi, Institute of Hematology "L. and A. Seràgnoli", Bologna, Italy.
2
Hematology and Stem Cell Transplant Center, AORMN Hospital, Pesaro, Italy.
3
Department of Medicine, Institute of Hematology, University Hospital Tor Vergata, Rome, Italy.
Abstract
In solid tumors and hematological malignancies, including acute myeloid leukemia, some chemotherapeutic agents, such as anthracyclines, have proven to activate an immune response via dendritic cell-based cross-priming of anti-tumor T lymphocytes. This process, known as immunogenic cell death, is characterized by a variety of tumor cell modifications, i.e., cell surface translocation of calreticulin, extracellular release of adenosine triphosphate and pro-inflammatory factors, such as high mobility group box 1 proteins. However, in addition to with immunogenic cell death, chemotherapy is known to induce inflammatory modifications within the tumor microenvironment, which may also elicit immunosuppressive pathways. In particular, DCs may be driven to acquire tolerogenic features, such as the overexpression of indoleamine 2,3-dioxygensase 1, which may ultimately hamper anti-tumor T-cells via the induction of T regulatory cells. The aim of this review is to summarize the current knowledge about the mechanisms and effects by which chemotherapy results in both activation and suppression of anti-tumor immune response. Indeed, a better understanding of the whole process underlying chemotherapy-induced alterations of the immunological tumor microenvironment has important clinical implications to fully exploit the immunogenic potential of anti-leukemia agents and tune their application.

Copyright © 2019 Ocadlikova, Lecciso, Isidori, Loscocco, Visani, Amadori, Cavo and Curti.

KEYWORDS:
T regulatory cells; acute myeloid leukemia; dendritic cells; immunogenic cell death; immunosuppression

PMID: 31649875 PMCID: PMC6794495 DOI: 10.3389/fonc.2019.01004
Similar articles
Publication type
Select item 31649874
19.
Front Oncol. 2019 Oct 9;9:995. doi: 10.3389/fonc.2019.00995. eCollection 2019.
Prognostic Value of Peripheral Inflammatory Markers in Preoperative Mucosal Melanoma: A Multicenter Retrospective Study.
Wang Y1,2, Zhang H3, Yang Y1,2, Zhang T1,2, Ma X1,4.
Author information
1
Department of Biotherapy, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
2
West China School of Medicine, Sichuan University, Chengdu, China.
3
Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China.
4
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Abstract
Background: Peripheral neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) have been widely reported prognostic predictors for many cancers. However, data predicting prognosis on mucosal melanoma is currently limited. This study aimed to identify the value of these inflammatory markers in predicting prognosis in preoperative mucosal melanoma. Methods: In this multicenter retrospective study, we assessed patients with preoperative mucosal melanoma for 7 years. Connection between baseline inflammatory markers (NLR, PLR, and LMR) and overall survival (OS) and progression-free survival (PFS) was analyzed by Kaplan-Meier curve with a log-rank test. Then, NLR, PLR, and LMR, along with characteristics of patients, were included in the univariate and multivariate Cox hazards regression model to examine the correlation with OS and PFS. The optimal cutoff value of these inflammatory markers was stratified by receiver operating characteristic (ROC) curve. Results: Patients with baseline NLR > 3.07, PLR > 118.70, or LMR ≤ 7.38 had significantly poorer OS and PFS according to Kaplan-Meier curve with a log-rank test. Univariate analysis indicated that surgery, alkaline phosphatase (ALP), NLR, PLR, and LMR were statistically connected to both OS and PFS. In multivariate analysis, LMR (hazard ratio [HR] = 0.113; 95% CI: 0.017-0.772; P = 0.026) and surgery (HR = 0.166; 95% CI: 0.033-0.846; P = 0.031) maintained significant relevance with OS. Conclusions: This research revealed that a higher NLR and PLR and a lower LMR than the cutoff point was associated with a worse prognosis of preoperative mucosal melanoma. Thus, we assumed that NLR, PLR, and especially LMR were potential prognostic predictors of preoperative mucosal melanoma.

Copyright © 2019 Wang, Zhang, Yang, Zhang and Ma.

KEYWORDS:
LMR; NLR; PLR; mucosal melanoma; prognosis

PMID: 31649874 PMCID: PMC6795127 DOI: 10.3389/fonc.2019.00995
Similar articles
Select item 31649873
20.
Front Oncol. 2019 Oct 9;9:957. doi: 10.3389/fonc.2019.00957. eCollection 2019.
ACAT1 and Metabolism-Related Pathways Are Essential for the Progression of Clear Cell Renal Cell Carcinoma (ccRCC), as Determined by Co-expression Network Analysis.
Chen L1, Peng T1, Luo Y1, Zhou F1, Wang G2,3, Qian K2,3, Xiao Y1,2,3, Wang X1,3.
Author information
1
Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
2
Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.
3
Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
Abstract
Kidney cancer ranks as one of the top 10 causes of cancer death; this cancer is difficult to detect, difficult to treat, and poorly understood. The most common subtype of kidney cancer is clear cell renal cell carcinoma (ccRCC) and its progression is influenced by complex gene interactions. Few clinical studies have investigated the molecular markers associated with the progression of ccRCC. In this study, we collected microarray profiles of 72 ccRCCs and matched normal samples to identify differentially expressed genes (DEGs). Then a weighted gene co-expression network analysis (WGCNA) was conducted to identify co-expressed gene modules. By relating all co-expressed modules to clinical features, we found that the brown module and Fuhrman grade had the highest correlation (r = -0.8, p = 1e-09). Thus, the brown module was regarded as a clinically significant module and subsequently analyzed. Functional annotation showed that the brown module focused on metabolism-related biological processes and pathways, such as fatty acid oxidation and amino acid metabolism. We then performed a protein-protein interaction (PPI) network to identify the hub nodes in the brown module. It is worth noting that only one candidate, acetyl-CoA acetyltransferase (ACAT1), was considered to be the final target most relevant to the Fuhrman grade of ccRCC, by applying the intersection of hub genes in the co-expressed network and the PPI network. ACAT1 was subsequently validated using another two external microarray datasets and the TCGA dataset. Intriguingly, validation results indicated that ACAT1 was negatively correlated with four grades of ccRCC, which was also consistent with our results from qRT-PCR analysis and immunohistochemistry staining of clinical samples. Overexpression of ACAT1 inhibited the proliferation and migration of human ccRCC cells in vitro. In addition, the Kaplan-Meier survival curve showed that patients with a lower expression of ACAT1 showed a significantly lower overall survival rate and disease-free survival rate, indicating that ACAT1 could act as a prognostic and recurrence/progression biomarker of ccRCC. In summary, we found and confirmed that ACAT1 might help to identify the progression of ccRCC, which might have important clinical implications for enhancing risk stratification, therapeutic decision, and prognosis prediction in ccRCC patients.

Copyright © 2019 Chen, Peng, Luo, Zhou, Wang, Qian, Xiao and Wang.

KEYWORDS:
ACAT1; Fuhrman grade; clear cell renal cell carcinoma (ccRCC); survival prognosis; weighted gene co-expression network analysis (WGCNA)

PMID: 31649873 PMCID: PMC6795108 DOI: 10.3389/fonc.2019.00957