1.
Front Oncol. 2020 Feb 14;9:1576. doi: 10.3389/fonc.2019.01576. eCollection 2019.
Senolytics (DQ) Mitigates Radiation Ulcers by Removing Senescent Cells.
Abstract
Radiation ulcers are a prevalent toxic side effect in patients receiving radiation therapy. At present, there is still no effective treatment for the complication. Senescent cells accumulate after radiation exposure, which can induce cell and tissue dysfunction. Here we demonstrate increased expression of p16 (a senescence biomarker) in human radiation ulcers after radiotherapy and radiation-induced persistent cell senescence in animal ulcer models. Furthermore, senescent cells secreted the senescence-associated secretory phenotype (SASP) and induced cell senescence in adjacent cells, which was alleviated by JAK inhibition. In addition, the clearance of senescent cells following treatment with a senolytics cocktail, Dasatinib plus Quercetin (DQ), mitigated radiation ulcers. Finally, DQ induced tumor cell apoptosis and enhanced radiosensitivity in representative CAL-27 and MCF-7 cell lines. Our results demonstrate that cell senescence is involved in the development of radiation ulcers and that elimination of senescent cells might be a viable strategy for patients with this condition.
Copyright © 2020 Wang, Wang, Huang, Zhou, Sheng, Jiang, Wang, Luo, Luo and Shi.
KEYWORDS:
SASP; apoptosis; oral mucositis; radiation ulcer; senescence; skin ulcer
2.
Front Oncol. 2020 Feb 4;9:1571. doi: 10.3389/fonc.2019.01571. eCollection 2019.
Magnetic Resonance vs. Intraoral Ultrasonography in the Preoperative Assessment of Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis.
Marchi F1, Filauro M1,2, Iandelli A1, Carobbio ALC1, Mazzola F1, Santori G3, Parrinello G1, Canevari FRM1,3, Piazza C4, Peretti G1,3.
Abstract
Background: Preoperative assessment is critical to decide the most adequate surgical strategy for oral squamous cell carcinoma (SCC). Magnetic resonance (MR) and intraoral ultrasonography (US) have been reported to be of great value for preoperative estimation of depth of invasion (DOI) and/or tumor thickness (TT). This review aims to analyze the accuracy of MR and intraoral US in determining DOI/TT in oral SCC, by assuming histological evaluation as the reference method. Methods: The procedure was conducted following the modified 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We performed a systematic search of papers on PubMed, Scopus, Web of Science, and Cochrane Library databases until July 31st, 2019. For quantitative synthesis, we included nine studies (487 patients) focused on MR, and 12 (520 patients) focused on intraoral US. The Pearson correlation coefficient (r) between DOI/TT evaluated with MR or intraoral US was assumed as effect size. A meta-analysis (MA) for each study group (MR and US) was performed by using the random-effects models with the DerSimonian-Laird estimator and r-to-z transformation. Results: In the MA for MR studies, a high heterogeneity was found (I 2 = 94.84%; Q = 154.915, P < 0.001). No significant risk of bias occurred by evaluating funnel plot asymmetry (P = 0.563). The pooled (overall) r of the MR studies was 0.87 (95% CI from 0.82 to 0.92), whereas the pooled r-to-z transformed was 1.44 (95% CI from 1.02 to 1.85). In the MA for US studies a high heterogeneity was found (I 2 = 93.56%; Q = 170.884, P < 0.001). However, no significant risk of bias occurred (P = 0.779). The pooled r of the US studies was 0.96 (95% CI from 0.94 to 0.97), whereas the pooled r-to-z transformed was 1.76 (95% CI from 1.39 to 2.13). These outputs were confirmed in additional MA performed by enrolling only MR (n = 8) and US (n = 11) studies that evaluated TT. Conclusions: MR and intraoral US seem to be promising approaches for preoperative assessment of DOI/TT in oral SCC. Remarkably, a higher pooled r and r-to-z transformed were observed in the intraoral US studies, suggesting that this approach could be more closely related to histopathological findings.
Copyright © 2020 Marchi, Filauro, Iandelli, Carobbio, Mazzola, Santori, Parrinello, Canevari, Piazza and Peretti.
KEYWORDS:
depth of invasion (DOI); magnetic resonance imaging (MRI); oral cavity; squamous cell cancer (SCC); tumor thickness; ultrasound
3.
Front Oncol. 2020 Feb 7;9:1567. doi: 10.3389/fonc.2019.01567. eCollection 2019.
THBS1 Is a Novel Serum Prognostic Factors of Acute Myeloid Leukemia.
Zhu L1,2, Li Q1,2, Wang X1,2, Liao J1,2, Zhang W1,2, Gao L1,2, Liu Y1,2, Zhang C1,2, Zhang X1,2, Rao J1,2, Kong P1,2.
Abstract
Dysregulation of cytokines and growth factors is a general feature of tumor microenvironment, and unraveling the expression spectrum of cytokine and growth factor in niche is of utmost importance. Here, we evaluated cytokine profiling of bone marrow serum samples in AML patients and healthy controls. Protein expression profiling of serum from nine AML patients and five healthy controls was obtained using a biotinylated antibody chip. A total of 507 cytokines and growth factors were analyzed. Compared with healthy people, AML patients expressed 31 signature proteins, among which, 27 were significantly higher expressed and 4 proteins were lower. When patients were divided into favorable and poor prognosis, 12 signature proteins were significantly differentially expressed between these two groups. Furthermore, in order to identify the accuracy of cytokine expression profiles, we verified and analyzed the expression of THBS1 (Thrombospondin 1) in 116 patients and 9 healthy people. We found that THBS1 was lowly expressed in AML patients, which might be induced by promoter methylation, and patients with low THBS1 possessed shorter survivor time. Our data indicated that we successfully unveil differentially expressed proteins in AML patients using a biotinylated antibody chip; among them, THBS1 may be a potential therapeutic target for AML patients' treatment.
Copyright © 2020 Zhu, Li, Wang, Liao, Zhang, Gao, Liu, Zhang, Zhang, Rao and Kong.
KEYWORDS:
Acute myeloid leukemia; THBS1; promoter methylation; protein microarray; serum protein markers
4.
Front Oncol. 2020 Feb 5;9:1561. doi: 10.3389/fonc.2019.01561. eCollection 2019.
When the Loss Costs Too Much: A Systematic Review and Meta-Analysis of Sarcopenia in Head and Neck Cancer.
Abstract
Purpose: Whether or not skeletal muscle mass (SMM) depletion, known as sarcopenia, has significant negative effects on the prognosis of patients with head and neck cancer (HNC) is both new and controversial. In this meta-analysis, we aimed to determine the prognostic significance of sarcopenia in HNC. Methods: We searched PubMed, the Cochrane Library, Embase, and Web of Science, which contain trial registries and meeting proceedings, to identify related published or unpublished studies. We used the Newcastle-Ottawa Scale (NOS) to appraise the risk of bias of the included retrospective studies. Pooled hazard ratios (HR) and the I 2 statistic were estimated for the impact of sarcopenia on overall survival (OS) and relapse-free survival (RFS). Results: We analyzed data from 11 studies involving 2,483 patients (39.4% on average of whom had sarcopenia). Based on the univariate analysis data, the sarcopenia group had significantly poorer OS compared to the non-sarcopenia group [HR = 1.97, 95% confidence interval (CI): 1.71-2.26, I 2 = 0%]. In the cutoff value subgroup, group 1, defined as skeletal muscle index (SMI) of 38.5 cm2/m2 for women and 52.4 cm2/m2 for men (HR = 2.41, 95% CI: 1.72-3.38, I 2 = 0%), had much poorer OS. In the race subgroup, the results were consistent between the Asia (HR = 2.11, 95% CI: 1.59-2.81) and non-Asia group (HR = 1.92, 95% CI: 1.64-2.25). The sarcopenia group also had significantly poorer RFS (HR = 1.74, 95% CI: 1.43-2.12, I 2 = 0%). Conclusions: Presence of pre-treatment sarcopenia has a significant negative impact on OS and RFS in HNC compared with its absence. Further well-conducted studies with detailed stratification are needed to complement our findings.
Copyright © 2020 Hua, Liu, Liao, Wen, Long, Lu, Guo and Lin.
KEYWORDS:
head and neck cancer; meta-analysis; prognostic factor; sarcopenia; skeletal muscle mass (SMM)
5.
Front Oncol. 2020 Feb 5;9:1555. doi: 10.3389/fonc.2019.01555. eCollection 2019.
Identification of Therapeutic Targets and Prognostic Biomarkers Among CXC Chemokines in the Renal Cell Carcinoma Microenvironment.
Abstract
Background: Renal cell carcinoma (RCC) is one of the most common malignances with an ever-increasing incidence and high mortality. Cross-talk between cancer cells and interstitial cells exerts significant effects on neoplasia and tumor development and is modulated in part by chemokines. CXC chemokines in the tumor microenvironment can modulate immune cell trafficking and regulate tumor cell activities, thus exerting anti-tumor immunological effects and affecting patient outcomes; however, the expression and prognostic values of CXC chemokines in RCC have not been clarified. Methods: ONCOMINE, GEPIA, UALCAN, cBioPortal, GeneMANIA, DAVID 6.8, Metascape, TRRUST, LinkedOmics, and TIMER were utilized in this study. Results: The transcriptional levels of CXCL1/2/5/6/9/10/11/16 in RCC tissues were significantly elevated while the transcriptional levels of CXCL3/7/12/13 were significantly reduced. A significant correlation was found between the expression of CXC1/5/9/10/11/13 and the pathological stage of RCC patients. RCC patients with low transcriptional levels of CXCL1/2/3/5/13 were associated with a significantly better prognosis. The functions of differentially expressed CXC chemokines are primarily related to the chemokine signaling pathway, cytokine-cytokine receptor interactions, and the ILK signaling pathway. Our data suggest that RELA, NFKB1, and SP1 are key transcription factors for CXC chemokines, and the SRC family of tyrosine kinases (LCK, LYN, and FYN), mitogen-activated protein kinases (MAPK1 and MAPK3), and CSNK1D are CXC chemokine targets. We found significant correlations among the expression of CXC chemokines and the infiltration of six types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells). Conclusions: Our results may provide novel insights for the selection of immunotherapeutic targets and prognostic biomarkers for renal cell carcinoma.
Copyright © 2020 Zeng, Sun, Li, Li, Li and Liang.
KEYWORDS:
bioinformatics analysis; biomarker; chemokine; renal cell carcinoma; tumor microenvironment
6.
Front Oncol. 2020 Feb 5;9:1552. doi: 10.3389/fonc.2019.01552. eCollection 2019.
Resection of Early-Stage Second Primary Non-small Cell Lung Cancer After Small Cell Lung Cancer: A Population-Based Study.
Zhang R1,2,3, Cai L1,4, Wang G1,2, Wen Y1,2, Wang F1,5, Zhou N1,6, Zhang X1,7, Huang Z1,2, Yu X8, Xi K9, Yang L1,2, Zhao D1,2, Lin Y1,2, Zhang L1,2.
Abstract
Introduction: A certain number of small cell lung cancer (SCLC) patients become long-term survivors after treatment, and they are at high risk to develop a second primary malignancy, including non-small cell lung cancer. However, the optimal management of early-stage second primary non-small cell lung cancer (SPLC) after SCLC remains unknown. This study aims to evaluate the survival benefits of surgery in these patients. Methods: Patients with early-stage SPLC after SCLC were identified from the Surveillance, Epidemiology, and End Results database. Patients were balanced with propensity score matching (PSM). Overall survival (OS) and lung cancer-specific survival (CSS) were compared between non-surgery group and surgery group with the Kaplan-Meier method and Cox multivariate regressions. Results: A total of 228 patients with early-stage SPLC after SCLC were identified. Surgery was associated with significantly improved OS and CSS in the multivariate Cox regression analysis (OS, 5-year survival: 41.2 vs. 11.6%, HR: 0.42, 95% CI: 0.31-0.59, P < 0.01; CSS, 5-year survival: 46.8 vs. 24.3%, HR: 0.53, 95% CI: 0.37-0.75, P < 0.01). However, no statistically significant survival difference was found between sublobar resection and lobectomy (OS, 5-year survival: 41.0 vs. 45.3%, P = 0.73; CSS, 5-year survival: 43.5 vs. 54.1%, P = 0.49). After 1:1 PSM, 162 patients were selected for further analysis, and surgery continued to demonstrate superior survival (OS, 5-year survival: 44.2 vs. 7.2%, HR: 0.48, 95% CI: 0.33-0.70, P < 0.01; CSS, 5-year survival: 48.0 vs. 20.6%, HR: 0.44, 95% CI: 0.42-0.97, P = 0.03). Conclusion: The resection of early-stage SPLC after SCLC led to significantly improved OS and CSS and therefore should be considered whenever possible. Nevertheless, further randomized controlled trials are warranted to investigate the safety and effect of surgery in these patients.
Copyright © 2020 Zhang, Cai, Wang, Wen, Wang, Zhou, Zhang, Huang, Yu, Xi, Yang, Zhao, Lin and Zhang.
KEYWORDS:
SEER database; non-small cell lung cancer; second primary lung cancer; small cell lung cancer; surgery; survival
7.
Front Oncol. 2020 Feb 14;9:1551. doi: 10.3389/fonc.2019.01551. eCollection 2019.
Post-mastectomy Radiotherapy in T1-2 Breast Cancer Patients With One to Three Lymph Node Metastases: A Propensity Score Matching Analysis.
Abstract
Background and Objectives: Whether post-mastectomy radiotherapy (PMRT) could improve prognosis for T1-2 breast cancer patients with one to three lymph node metastases remains controversial. The present study aimed to determine the significance of PMRT in patients with T1-2N1M0 breast cancer. Methods: Data of 45,646 patients from the Surveillance, Epidemiology, and End Results (SEER) database were analyzed; 12,585 matched patients were divided into a PMRT group and non-radiotherapy group (no-PMRT), respectively, using the propensity score matching method. Univariate and multivariate analyses were performed to determine the prognostic factors of breast cancer, and subgroup analysis was performed according to the number of lymph node metastases. Results: With the median follow-up of 62 months, 5-year cancer-specific survival was 91.48% in the PMRT group and 91.88% in the no-PMRT group (P = 0.405). PMRT did not improve the breast cancer-specific survival (BCSS) in patients with stage T1-2N1M0 (HR = 0.99, 95% CI = 0.92-1.06, P = 0.715). In subgroup analysis, radiotherapy improved the BCSS in patients with three nodes positive, with the 5-year BCSS at 88.5% in the radiation group and 86.6% in the no-radiation group (HR = 0.78, 95% CI = 0.65-0.90, P < 0.001). In patients with two nodes positive, 5-year BCSS was 90.3% in the PMRT group and 89.5% in the no-PMRT group, with no significant difference between the two groups (HR = 0.96, 95% CI = 0.85-1.09, P = 0.552). In patients with one node positive, 5-year BCSS was higher in the no-PMRT group (92.1%) than that in the PMRT group (90.8%); radiotherapy increased the cancer-related death compared with those who did not receive it (HR = 1.21, 95% CI = 1.08-1.36, P = 0.002). Conclusion: The benefit of PMRT in T1-2N1M0 patients was obviously different, and the recommendation of PMRT for this population should be individualized. PMRT should be considered for patients with three nodes positive, should be suggested cautiously in those with two nodes positive, and could be omitted in those with one node positive.
Copyright © 2020 Chen, Huang, Leng, Yang, Li, Yang and Hou.
KEYWORDS:
Epidemiology; Surveillance; and End Results (SEER) Program; breast neoplasms; lymph node; prognosis; radiotherapy
8.
Front Oncol. 2020 Feb 7;9:1531. doi: 10.3389/fonc.2019.01531. eCollection 2019.
Comprehensive Molecular Profiling for Relapsed/Refractory Pediatric Burkitt Lymphomas-Retrospective Analysis of Three Real-Life Clinical Cases-Addressing Issues on Randomization and Customization at the Bedside.
Polaskova K1,2, Merta T1,2, Martincekova A1,2, Zapletalova D1,2, Kyr M1,2, Mazanek P1, Krenova Z1, Mudry P1, Jezova M3, Tuma J4, Skotakova J5, Cervinkova I5, Valik D6,7, Zdrazilova-Dubska L6,7, Noskova H8, Pal K8, Slaby O8, Fabian P9, Kozakova S2,7, Neradil J2,10, Veselska R2,10, Kanderova V11, Hrusak O11, Freiberger T8,12,13, Klement GL1,14, Sterba J1,2,7.
Abstract
In order to identify reasons for treatment failures when using targeted therapies, we have analyzed the comprehensive molecular profiles of three relapsed, poor-prognosis Burkitt lymphoma cases. All three cases had resembling clinical presentation and histology and all three patients relapsed, but their outcomes differed significantly. The samples of their tumor tissue were analyzed using whole-exome sequencing, gene expression profiling, phosphoproteomic assays, and single-cell phosphoflow cytometry. These results explain different treatment responses of the three histologically identical but molecularly different tumors. Our findings support a personalized approach for patient with high risk, refractory, and rare diseases and may contribute to personalized and customized treatment efforts for patients with limited treatment options like relapsed/refractory Burkitt lymphoma.
SUMMARY:
The main aim of this study is to analyze three relapsed Burkitt lymphoma patients using a comprehensive molecular profiling, in order to explain their different outcomes and to propose a biomarker-based targeted treatment. In cases 1 and 3, the tumor tissue and the host were analyzed prospectively and appropriate target for the treatment was successfully implemented; however, in case 2, analyses become available only retrospectively and his empirically based rescue treatment did not hit the right target of his disease.
Copyright © 2020 Polaskova, Merta, Martincekova, Zapletalova, Kyr, Mazanek, Krenova, Mudry, Jezova, Tuma, Skotakova, Cervinkova, Valik, Zdrazilova-Dubska, Noskova, Pal, Slaby, Fabian, Kozakova, Neradil, Veselska, Kanderova, Hrusak, Freiberger, Klement and Sterba.
KEYWORDS:
Burkitt lymphoma; pediatric oncology; precision medicine; targeted therapy; theranostics
9.
Front Oncol. 2020 Feb 13;9:1423. doi: 10.3389/fonc.2019.01423. eCollection 2019.
PELP1 Suppression Inhibits Gastric Cancer Through Downregulation of c-Src-PI3K-ERK Pathway.
Abstract
Background: Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), a co-activator of estrogen receptors alpha, was confirmed to be directly associated with the oncogenic process of multiple cancers, especially hormone-dependent cancers. The purpose of our research was to explore the biological function, clinical significance, and therapeutic targeted value of PELP1 in gastric cancer (GC). Methods: The expression status of PELP1 in GC cell lines or tissues was analyzed through bioinformatics data mining. Thirty-six GC tissue chip was applied to demonstrate the results of bioinformatics data mining assayed by immunohistochemical method. The expression status of PELP1 in GC cell lines was also analyzed using western blot. Correlation analysis between PELP1 expression and clinicopathological parameter was performed. Kaplan-Meier survival analysis was applied to analyze the relationship between PELP1 expression and total survival time. Three pairs of siRNA were designed to silence the expression of PELP1 in GC. After PELP1 was silenced by siRNA or activated by saRNA, the growth, plate colony formation, migration and invasion ability of the GC cell or normal gastric epithelium cell line was tested in vitro. Cell cycle was tested by flow cytometry. Nude mice xenograft experiment was performed after PELP1 was silenced. The downstream molecular pathway regulated by PELP1 was explored. Molecular docking tool was applied to combine chlorpromazine with PELP1. The inhibitory effect of chlorpromazine in GC was assayed, then it was tested whether PELP1 was a therapeutic target of chlorpromazine in GC. Results: PELP1 expression was elevated in GC cell lines and clinical GC tissue samples. PELP1 silence by siRNA compromised the malignant traits of GC. PELP1 expression positively correlated with tumor invasion depth, lymph node metastasis, tissue grade, TNM stage, but had no correlation with patient age, sex, tumor size, and tumor numbers. Kaplan-Meier survival analysis revealed high PELP1 expression had a shorter survival period in GC patients after follow-up. Q-PCR and western blot revealed PELP1 suppression in GC decreased expression of the c-Src-PI3K-ERK pathway. It was also implied that chlorpromazine (CPZ) can inhibit the malignant traits of GC and downregulate the expression of PELP1. Conclusions: In a word, PELP1 is an oncogene in gastric cancer and c-Src-PI3K-ERK pathway activation may be responsible for its tumorigenesis, PELP1 may be a potential therapeutic target of chlorpromazine in GC.
Copyright © 2020 Yan, Sun, Wu, Wu, Hu, Sun, Liu, Ma, Liu, Xiao, Liu and Ning.
KEYWORDS:
PELP1; c-Src-PI3K-ERK pathway; chlorpromazine; gastric cancer; master gene; oncogene; therapeutic target
10.
Front Oncol. 2020 Feb 6;9:1061. doi: 10.3389/fonc.2019.01061. eCollection 2019.
Editorial: Current Perspectives, Challenges and Advances in Cell Based Therapies.
KEYWORDS:
CAR (chimeric antigen receptor) T cells; NK cell; cell based therapy; immunotherapy; tumor micoenvironment
11.
Front Oncol. 2020 Feb 14;10:144. doi: 10.3389/fonc.2020.00144. eCollection 2020.
LRRC4 Suppresses E-Cadherin-Dependent Collective Cell Invasion and Metastasis in Epithelial Ovarian Cancer.
Zhao C1,2,3,4,5, She X6, Zhang Y1,2,3,4, Liu C1,2,3,4, Li P1,2,3,4, Chen S1, Sai B1,2,3,4, Li Y6, Feng J1,2,3,4, Liu J1, Sun Y1, Xiao S7, Li L8, Wu M1,2,3,4.
Abstract
Epithelial ovarian cancer (EOC) is the most malignant gynecological carcinoma and is of a high incidence of death due to detection at late stages when metastasis already occurs. However, the mechanism underlying metastasis of EOC remains unclear. Analysis of the open database and experiments with immunochemistry showed that LRRC4 is lowly expressed in high-grade serous ovarian cancer (HGSC) cells and during EOC metastasis. The 3D cell culture system and the orthotopic ovarian xenograft model infected with LRRC4-containing adeno-associated virus serotype 9 (AAV9) were used to confirm collective invasion and metastasis of cells in vitro and in vivo. Phos-tag SDS-PAGE was used to detect the phosphorylation of LRRC4 and PIK3R1. A number of experiments with methods such as co-immunoprecipitation and immunoblotting were performed to explore the mechanism for the actions of LRRC4 and PIK3R1 in EOC metastasis. An inverse correlation between LRRC4 and E-cadherin expression was detected in the regions of invasion in primary EOC tissues and metastatic ascites. LRRC4 binds to the cSH2 domain of PIK3R1 and inhibits the activity of PIK3R1, without disrupting the physical interactions between PIK3R1 and PIK3CA. LRRC4 inhibits EOC metastasis by targeting E-cadherin-dependent collective cell invasion and does so by inhibiting the PIK3R1-mediated AKT/GSK3β/β-catenin signaling pathway. LRRC4 functions as a tumor suppressor gene to inhibit EOC collective invasion and metastasis in vitro and in vivo and does so by directly binding to the cSH2 domain of PIK3R1 to exert its regulatory function. Our findings provide a potential novel approach for metastasis prognosis and a new strategy for the treatment of EOC.
Copyright © 2020 Zhao, She, Zhang, Liu, Li, Chen, Sai, Li, Feng, Liu, Sun, Xiao, Li and Wu.
KEYWORDS:
E-cadherin; LRRC4; PIK3R1; collective invasion and metastasis; epithelial ovarian cancer
12.
Front Oncol. 2020 Feb 12;10:142. doi: 10.3389/fonc.2020.00142. eCollection 2020.
Tissue-Plasma TMB Comparison and Plasma TMB Monitoring in Patients With Metastatic Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitors.
Abstract
Immuno-oncology is an ever growing field that has seen important progress across the spectrum of cancers. Responses can be deep and durable. However, as only a minority of patients respond to checkpoint inhibition, predictive biomarkers are needed. Cancer is a genetic disease arising from the accumulation of somatic mutations in the DNA of affected cells. Tumor mutational burden (TMB), represents the number of somatic mutations in a tumor that form neoantigens, responsible for the immunogenicity of tumors. Randomized controlled trials have so far failed to show a survival benefit when stratifying patients by tissue TMB. TMB has also been evaluated in plasma (PTMB). PTMB is anticipated to represent the biology of the entire cancer, whereas obtaining tissue of an amenable primary or a metastatic lesion may be prone to sampling bias because of tumor heterogeneity. For this reason, we are evaluating the correlation between TMB and PTMB, and prospectively evaluating the impact of these biomarkers on clinical outcomes. We also discuss the technical difficulties inherent to performing and comparing these analyses. Furthermore, we evaluate the correlation between the evolution of PTMB during an immunotherapy treatment and response at 3 and 6 months, as we believe PTMB may be a dynamic biomarker. In this paper, we present results from the first 4 patients in this project.
Copyright © 2020 Friedlaender, Nouspikel, Christinat, Ho, McKee and Addeo.
KEYWORDS:
CtDNA; NSCLC; TMB; biomarker; immune check inhibitor (ICI)
13.
Front Oncol. 2020 Feb 12;10:140. doi: 10.3389/fonc.2020.00140. eCollection 2020.
Best Practice in Surgical Treatment of Malignant Head and Neck Tumors.
Abstract
Purpose of review: Defining the best practice of surgical care for patients affected by malignant head and neck tumors is of great importance. In this review we aim to describe the evolution of "best practice" guidelines in the context of quality-of-care measures and discuss current evidence on "best practice" for the surgical treatment of cancers of the sino-nasal tract, skull base, aero-digestive tract, and the neck. Recent findings: Current evidence based on certain structure and outcome indicators, but mostly based on process indicators already helps defining the framework of "Best practice" for head and neck cancer surgery. However, many aspects of surgical treatment still require in-depth research. Summary: While a framework of "Best practice" strategies already exists for the conduction of the surgical treatment of head and neck cancers, many questions still require additional research in particular in case of rare histologies in the head and neck region.
Copyright © 2020 Simon, Nicolai, Paderno and Dietz.
KEYWORDS:
best practice; head and neck cancer; paranasal sinus; quality assurance; skull base; surgery
14.
Front Oncol. 2020 Feb 14;10:139. doi: 10.3389/fonc.2020.00139. eCollection 2020.
von Hippel-Lindau Syndrome: Genetic Study of Case With a Rare Pathogenic Variant With Optic Nerve Hemangioblastoma, a Rare Phenotypic Expression.
Abstract
von Hippel-Lindau syndrome (VHLS) is a rare, autosomal dominant genetic disease with high penetrance and variable phenotypic expression caused by variants in the VHL gene. VHLS is associated with the presence of vascular tumors, often hemangioblastoma of the central nervous system, retina, or spinal cord and, less frequently, pancreatic cystic neoplasm, pancreatic neuroendocrine tumor, clear cell carcinoma of the kidney, endolymphatic sac tumor, pheochromocytoma, and paraganglioma. The authors report a case of a patient with VHLS with a rare pathogenic variant in the VHL gene and with an optic nerve hemangioblastoma, a rare phenotypic expression. Case report: A 49-year-old woman was diagnosed with cystic neoplasm of the pancreas, renal cell carcinoma of the right kidney, and hemangioblastoma of the left optic nerve. The patient's family history revealed siblings with VHLS manifestations. The index case was her mother who died at age 63 of clear cell renal carcinoma. The information was obtained by consulting the patient's medical register and by interviews with the patient and her relatives. The presence of left optic nerve hemangioblastoma was suggested by CT scan of the skull and orbit. The sequencing of the VHL gene was performed in the peripheral blood by the polymerase chain reaction (PCR) technique, and the duplication and deletion research was performed using the multiplex ligation-dependent probe amplification (MPLA) technique. The presence of a rare pathogenic variant c.263G> A (p.Trp88Ter) was observed in heterozygosity in the VHL gene that determined a premature stop codon. CT scan of the skull and orbits suggested the presence of HB in the optic nerve of the left eye. The results of the CT scan of the skull and orbits show thickening with tortuosity of the left optic nerve, with a small area of nodular enhancement. The right optic nerve had a conserved aspect. Conclusion: This is the fourth case described of this rare pathogenic variant of the VHL gene, according to the Human Gene Mutation Database and VHLdb database records and with an optic nerve hemangioblastoma of the optic nerve, a very rare phenotypic expression of the VHLS.
Copyright © 2020 Boratto, Cardoso, Priolli, Botelho, Goldenberg, Bianco and Waisberg.
KEYWORDS:
VHL gene; brain neoplasms; hemangioblastoma; optic nerve neoplasms; renal carcinoma; von Hippel-Lindau syndrome
15.
Front Oncol. 2020 Feb 14;10:136. doi: 10.3389/fonc.2020.00136. eCollection 2020.
Dosimetric Optimization and Commissioning of a High Field Inline MRI-Linac.
Abstract
Purpose: Unique characteristics of MRI-linac systems and mutual interactions between their components pose specific challenges for their commissioning and quality assurance. The Australian MRI-linac is a prototype system which explores the inline orientation, with radiation beam parallel to the main magnetic field. The aim of this work was to commission the radiation-related aspects of this system for its application in clinical treatments. Methods: Physical alignment of the radiation beam to the magnetic field was fine-tuned and magnetic shielding of the radiation head was designed to achieve optimal beam characteristics. These steps were guided by investigative measurements of the beam properties. Subsequently, machine performance was benchmarked against the requirements of the IEC60976/77 standards. Finally, the geometric and dosimetric data was acquired, following the AAPM Task Group 106 recommendations, to characterize the beam for modeling in the treatment planning system and with Monte Carlo simulations. The magnetic field effects on the dose deposition and on the detector response have been taken into account and issues specific to the inline design have been highlighted. Results: Alignment of the radiation beam axis and the imaging isocentre within 2 mm tolerance was obtained. The system was commissioned at two source-to-isocentre distances (SIDs): 2.4 and 1.8 m. Reproducibility and proportionality of the dose monitoring system met IEC criteria at the larger SID but slightly exceeded it at the shorter SID. Profile symmetry remained under 103% for the fields up to ~34 × 34 and 21 × 21 cm2 at the larger and shorter SID, respectively. No penumbra asymmetry, characteristic for transverse systems, was observed. The electron focusing effect, which results in high entrance doses on central axis, was quantified and methods to minimize it have been investigated. Conclusion: Methods were developed and employed to investigate and quantify the dosimetric properties of an inline MRI-Linac system. The Australian MRI-linac system has been fine-tuned in terms of beam properties and commissioned, constituting a key step toward the application of inline MRI-linacs for patient treatments.
Copyright © 2020 Jelen, Dong, Begg, Roberts, Whelan, Keall and Liney.
KEYWORDS:
MRI-linac; beam characterization; commissioning; dosimetry; magnetic field
16.
Front Oncol. 2020 Feb 11;10:134. doi: 10.3389/fonc.2020.00134. eCollection 2020.
The Rare Variant rs35356162 in UHRF1BP1 Increases Bladder Cancer Risk in Han Chinese Population.
Abstract
Background: Seventeen loci have been found to be associated with bladder cancer risk by genome-wide association studies (GWAS) in European population. However, little is known about contribution of low-frequency and rare variants to bladder cancer susceptibility, especially in Eastern population. Methods: We performed a three-stage case-control study including 3,399 bladder cancer patients and 4,647 controls to identify low-frequency and rare variants associated with bladder cancer risk in Han Chinese. We examined exome-array data in 1,019 bladder cancer patients and 1,008 controls in discovery stage. Two replication stages were included to validate variants identified. Bonferroni adjustment was performed to define statistical significance. Logistic regression was conducted to evaluate single marker association with bladder cancer risk. We used SKAT-O method to perform gene level-based analysis. We also conduct additional experiments to explore the underlying mechanism of filtered gene(s). Results: We identified a novel rare coding variant (rs35356162 in UHRF1BP1: G > T, OR = 4.332, P = 3.62E-07 < 7.93E-07, Bonferroni cutoff) that increased bladder cancer risk in Han Chinese. Gene-level analysis showed a significant association of UHRF1BP1 (P = 4.47E-03) with bladder cancer risk. Experiments indicated down-regulation of UHRF1BP1 promoted migration and invasion through epithelial-mesenchymal transition in bladder cancer cell lines. Conclusion: The rare variant of UHRF1BP1, rs35356162, increases bladder cancer risk in Han Chinese and UHRF1BP1 might act as a tumor suppressor in bladder cancer development and progression. Summary: Little is known about potential contribution of low-frequency and rare variants to bladder cancer susceptibility. We performed a three-stage case-control study and identified a new rare variant, rs35356162 in UHRF1BP1, which increased bladder cancer risk in Han Chinese.
Copyright © 2020 Wu, Wang, Chen, Xu, Zhang, Gu, Ding, Wei, Zhu and Ye.
KEYWORDS:
Chinese; UHRF1BP1; bladder cancer; exome array; single nucleotide variant
17.
Front Oncol. 2020 Feb 14;10:128. doi: 10.3389/fonc.2020.00128. eCollection 2020.
Combination Therapy With Charged Particles and Molecular Targeting: A Promising Avenue to Overcome Radioresistance.
Abstract
Radiotherapy plays a central role in the treatment of cancer patients. Over the past decades, remarkable technological progress has been made in the field of conventional radiotherapy. In addition, the use of charged particles (e.g., protons and carbon ions) makes it possible to further improve dose deposition to the tumor, while sparing the surrounding healthy tissues. Despite these improvements, radioresistance and tumor recurrence are still observed. Although the mechanisms underlying resistance to conventional radiotherapy are well-studied, scientific evidence on the impact of charged particle therapy on cancer cell radioresistance is restricted. The purpose of this review is to discuss the potential role that charged particles could play to overcome radioresistance. This review will focus on hypoxia, cancer stem cells, and specific signaling pathways of EGFR, NFκB, and Hedgehog as well as DNA damage signaling involving PARP, as mechanisms of radioresistance for which pharmacological targets have been identified. Finally, new lines of future research will be proposed, with a focus on novel molecular inhibitors that could be used in combination with charged particle therapy as a novel treatment option for radioresistant tumors.
Copyright © 2020 Konings, Vandevoorde, Baselet, Baatout and Moreels.
KEYWORDS:
X-rays; carbon ion therapy; combination treatment; molecular targeted drugs; particle therapy; proton therapy; radioresistance; radiosensitization
18.
Front Oncol. 2020 Feb 13;10:127. doi: 10.3389/fonc.2020.00127. eCollection 2020.
DNA-PK Inhibitor, M3814, as a New Combination Partner of Mylotarg in the Treatment of Acute Myeloid Leukemia.
Abstract
Despite significant advances in the treatment of acute myeloid leukemia (AML) the long-term prognosis remains relatively poor and there is an urgent need for improved therapies with increased potency and tumor selectivity. Mylotarg is the first AML-targeting drug from a new generation of antibody drug conjugate (ADC) therapies aiming at the acute leukemia cell compartment with increased specificity. This agent targets leukemia cells for apoptosis with a cytotoxic payload, calicheamicin, carried by a CD33-specific antibody. Calicheamicin induces DNA double strand breaks (DSB) which, if left unrepaired, lead to cell cycle arrest and apoptosis in cancer cells. However, repair of DSB by the non-homologous end joining pathway driven by DNA-dependent protein kinase (DNA-PK) can reduce the efficacy of calicheamicin. M3814 is a novel, potent and selective inhibitor of DNA-PK. This compound effectively blocks DSB repair, strongly potentiates the antitumor activity of ionizing radiation and DSB-inducing chemotherapeutics and is currently under clinical investigation. Suppressing DSB repair with M3814 synergistically enhanced the apoptotic activity of calicheamicin in cultured AML cells. Combination of M3814 with Mylotarg in two AML xenograft models, MV4-11 and HL-60, demonstrated increased efficacy and significantly improved survival benefit without elevated body weight loss. Our results support a new application for pharmacological DNA-PK inhibitors as enhancers of Mylotarg and a potential new combination treatment option for AML patients.
Copyright © 2020 Carr, Zimmermann, Chiu, Zenke, Blaukat and Vassilev.
KEYWORDS:
ADC-antibody drug conjugate; AML-acute myeloid leukemia; DNA-PK; DSB-double-strand break; therapy
19.
Front Oncol. 2020 Feb 12;10:125. doi: 10.3389/fonc.2020.00125. eCollection 2020.
Collagen Kinase Receptors as Potential Therapeutic Targets in Metastatic Colon Cancer.
Abstract
Colorectal cancer (CRC) is one of the leading causes of tumor-related death worldwide. While surgery can cure patients with early stage CRC, the 5-year survival rate is only 10% for patients with metastatic disease. Therefore, new anti-metastatic therapies are needed for this cancer. Metastatic spread defines the dissemination of cancer cells with tumor-initiating capacities from the primary tumor and their colonization of distinct organs, mainly the liver, for secondary tumor formation. Although the underlying mechanisms are not fully understood, components of the tumor microenvironment have gained strong interest. Among the known metastatic-promoting factors, collagens are extracellular matrix components that are deposited within the tumor, the tumor microenvironment, and at metastatic site(s), and are recognized to play essential roles during metastasis development. Here, we review recent findings on the metastatic role of the collagen receptors Discoidin Domain Receptors 1 and 2 (DDR1 and DDR2) in CRC and discuss the therapeutic value of targeting these receptor tyrosine kinases in this cancer.
Copyright © 2020 Lafitte, Sirvent and Roche.
KEYWORDS:
collagen; colorectal cancer; extracellular matrix; metastasis; receptor; targeted therapy; tumor microenvironment; tyrosine kinase
20.
Front Oncol. 2020 Feb 11;10:124. doi: 10.3389/fonc.2020.00124. eCollection 2020.
Hypofractionated Radiotherapy Dose Scheme and Application of New Techniques Are Associated to a Lower Incidence of Radiation Pneumonitis in Breast Cancer Patients.
Abstract
Purpose: Radiation pneumonitis (RP) is one of the most severe toxicities experienced by patients with breast cancer after radiotherapy (RT). RT fractionation schemes and techniques for breast cancer have undergone numerous changes over the past decades. This study aimed to investigate the incidence of RP as a function of such changes in patients with breast cancer undergoing RT and to identify dosimetric markers that predict the risk of this adverse event. Methods and Materials: We identified 1,847 women with breast cancer who received adjuvant RT at our institution between 2015 and 2017. The RT technique was individually tailored based on each patient's clinicopathological features. Deep inspiration breath hold technique or prone positioning were used for patients who underwent left whole-breast irradiation for cardiac sparing, while those requiring regional lymph node irradiation underwent volumetric-modulated arc therapy (VMAT). Results: Of 1,847 patients who received RT, 21.2% received the conventional dose scheme, while 78.8% received the hypofractionated dose scheme (mostly 40 Gy in 15 fractions). The median follow-up period was 14.5 months, and the overall RP rate was 2.1%. The irradiated organ at risk was corrected concerning biologically equivalent dose. The ipsilateral lung V30 in equivalent dose in 2 Gy (EQD2) was the most significant dosimetric factor associated with RP development. Administering RT using VMAT, and hypofractionated dose scheme significantly reduced ipsilateral lung V30. Conclusions: Application of new RT techniques and hypofractionated scheme significantly reduce the ipsilateral lung dose. Our data demonstrated that ipsilateral lung V30 in EQD2 is the most relevant dosimetric predictor of RP in patients with breast cancer.
Copyright © 2020 Lee, Chang, Kim, Keum, Suh and Kim.
KEYWORDS:
breast cancer; hypofractionation; lung dosimetry; radiation pneumonitis; radiotherapy
21.
Front Oncol. 2020 Feb 12;10:123. doi: 10.3389/fonc.2020.00123. eCollection 2020.
The Methods of Lymph Node Examination Make a Difference to Node Staging and Detection of N3b Node Status for Gastric Cancer.
Chen X1, Chen Y1, Hu Y1, Lin T1, Luo J1, Li T1, Li T1, Huang H1, Zhu Y1, Li T1, Chen H1, Liu H1, Li G1, Yu J1.
Abstract
Background: The number of retrieved lymph nodes (RLNs) affects the likelihood of detecting metastatic lymph nodes (MLNs) for gastric cancer (GC), but the retrieval of LNs is not satisfactory worldwide. There is no standard for LN examination. Methods: We retrospectively analyzed 2,163 patients diagnosed with GC who underwent surgery at Nanfang Hospital between October 2004 and September 2016. According to the methods of LN examination, patients were classified into two groups: LN detection by pathologists (pathologist group) and LN examination by surgicopathologic team (surgicopathologist group). The relationship between RLNs and LN staging accuracy as well as the factors influencing the detection of MLNs were evaluated. Results: There were 472 males in pathologist group and 467 males in surgicopathologist group. The number of RLNs and MLNs in surgicopathologist group was significantly higher than that in pathologist group (RLNs: 53.8 ± 20.9 vs. 18.8 ± 11.5, p < 0.001; MLNs: 5.6 ± 9.8 vs. 3.9 ± 5.7, p < 0.001). Notably, the detection of N3b node status was significantly improved in surgicopathologist group [83 (11.9%) vs. 34 (4.8%), p < 0.001]. Additionally, the detection rate of N3b status gradually increased from 0 in patients with 1-16 RLNs to 16.6% in patients with more than 49 RLNs. The MLNs detected increased gradually from 2.3 ± 3.0 in patients with 1-16 RLNs to 7.3 ± 11.7 in patients with more than 49 RLNs. Univariate and multivariate analyses indicated that LN examination by surgicopathologic team, more advanced pT, tumor size ≥5 cm and combined organ(s) resection were related to detecting more MLNs. Conclusions: The retrieval of nodes immediately postoperatively by the surgicopathologic team could significantly improve the number of RLNs, detect more MLNs, and screen more patients with N3b node status.
Copyright © 2020 Chen, Chen, Hu, Lin, Luo, Li, Li, Huang, Zhu, Li, Chen, Liu, Li and Yu.
KEYWORDS:
N3b; examination; gastric cancer; lymph node; node staging
22.
Front Oncol. 2020 Feb 11;10:122. doi: 10.3389/fonc.2020.00122. eCollection 2020.
Performance of a 6D Treatment Chair for Patient Positioning in an Upright Posture for Fixed Ion Beam Lines.
Abstract
Purpose: To evaluate the mechanical accuracy and the robustness of position alignment under x-ray-based image guidance of a treatment chair with six degrees of freedom (6DTC) which was developed for patient treatment in an upright posture at fixed horizontal beam lines in particle (proton, carbon ion, or others) radiotherapy facilities. Method and Material: The positional accuracy including translational and axial rotational accuracy of the 6DTC was evaluated by using a Vicon Motion Capture System (VMCS). Stability of the chair rotation isocenter was determined by a CCD camera with an in-house developed software. The tests were carried out to examine two key motion components of the 6DTC: a floor/rail-mount 360°-rotating platform and a 6-degree-of-freedom (6DOF) platform. The measurement results were compared to that of a commercial clinical robot couch. The accuracy of position alignment, simulating the actual clinical protocol, through an Image-guided Radiation Therapy (IGRT) system was studied at the pre-treatment position and beam specific treatment position. Results: The translational accuracy was 0.12 mm (SD 0.07 mm) for the 6DOF platform. The rotational accuracy was 0.04° (SD 0.03°) and 0.02° (SD 0.02°) for the 6DOF platform and the 360° -rotating platform, respectively. The displacement between the chair rotation center and the room isocenter center was no more than 0.18 mm in all three rotational axes. Combined with an x-ray-based IGRT system, the treatment alignment test with a rigid phantom yielded a total positional accuracy of 0.23 mm (SD 0.17 mm) and 0.14° (SD 0.14°) at treatment position. Conclusions: On the basis of the rigid phantom study, the 6DTC showed comparable accuracy to the robot treatment couch. Combining with the IGRT, the 6DTC can provide position alignment with submillimeter accuracy for rigid phantom in upright posture.
Copyright © 2020 Sheng, Sun, Wang, Stuart, Kong, Gao, You and Wu.
KEYWORDS:
6D treatment chair; fixed beam line; ion radiotherapy; mechanic accuracy; position alignment; sitting posture; upright posture
23.
Front Oncol. 2020 Feb 11;10:121. doi: 10.3389/fonc.2020.00121. eCollection 2020.
Improved Prediction of Aqueous Solubility of Novel Compounds by Going Deeper With Deep Learning.
Abstract
Aqueous solubility is an important physicochemical property of compounds in anti-cancer drug discovery. Artificial intelligence solubility prediction tools have scored impressive performances by employing regression, machine learning, and deep learning methods. The reported performances vary significantly partly because of the different datasets used. Solubility prediction on novel compounds needs to be improved, which may be achieved by going deeper with deep learning. We constructed deeper-net models of ~20-layer modified ResNet convolutional neural network architecture, which were trained and tested with 9,943 compounds encoded by molecular fingerprints. Retrospectively tested by 62 recently-published novel compounds, one deeper-net model outperformed four established tools, shallow-net models, and four human experts. Deeper-net models also outperformed others in predicting the solubility values of a series of novel compounds newly-synthesized for anti-cancer drug discovery. Solubility prediction may be improved by going deeper with deep learning. Our deeper-net models are accessible at http://www.npbdb.net/solubility/index.jsp.
Copyright © 2020 Cui, Lu, Ni, Zeng, Tan, Chen and Zhao.
KEYWORDS:
anti-cancer drug discovery; aqueous solubility; artificial intelligence; chemical; compounds; deep learning
24.
Front Oncol. 2020 Feb 12;10:120. doi: 10.3389/fonc.2020.00120. eCollection 2020.
Microbiome and Breast Cancer: New Role for an Ancient Population.
Abstract
There are many risk factors associated with breast cancer (BC) such as the familial history of BC, using hormone replacement therapy, obesity, personal habits, and other clinical factors; however, not all BC cases are attributed to these risk factors. Recent researches show a correlation between patient microbiome and BC suggested as a new risk factor. The present review article aimed at evaluating the role of the microbiome as a risk factor in the occurrence of BC, investigating the proposed mechanisms of interaction between the microbiome and human genes involved in BC, and assessing the impact of the altered composition of breast, gut, and milk microbiome in the physiological status of normal breast as well as cancerous or non-cancerous breast lesions. The study also evaluated the growing evidence that these altered populations may hinder chemotherapeutic treatment. The role of microbiome in the development and maintenance of inflammation, estrogen metabolism, and epigenetic alterations was properly investigated. Finally, clinical and therapeutic applications of the microbiome- e.g., probiotics, microbiome genome modulation, and engineered microbiome enzymes in the management of BC were reviewed.
Copyright © 2020 Eslami-S, Majidzadeh-A, Halvaei, Babapirali and Esmaeili.
KEYWORDS:
estrogen metabolism; gene-based therapy; microbiome chemotherapies; microbiome immunotherapy; microbiome radiotherapy; milk microbiome; probiotic therapy
25.
Front Oncol. 2020 Feb 14;10:119. doi: 10.3389/fonc.2020.00119. eCollection 2020.
Evaluation of the National Comprehensive Cancer Network and European Society for Medical Oncology Nasopharyngeal Carcinoma Surveillance Guidelines.
Abstract
Purpose: The National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) provide surveillance guidelines for nasopharyngeal carcinoma (NPC). We evaluated the ability of these guidelines to capture disease recurrence. Materials and methods: All 749 NPC patients were stratified for analysis by T and N stage. We evaluated the guidelines by calculating the percentage of relapses detected when following the 2018 NCCN, 2015 NCCN, and 2012 ESMO surveillance guidelines, and related surveillance costs were compared. Results: At a median follow-up of 100.8 months, 168 patients (22.4%) had experienced recurrence. Nineteen recurrences (11.3%) were detected using the 2018 NCCN, 53 (31.5%) using the 2015 NCCN and 46 (27.4%) using the ESMO guidelines. To capture 95% recurrences, surveillance would be required for 85.57 months for T1/2, 67.45 months for T3/4, 83.57 months for N0/1, and 55.80 months for N2/3 disease. In T1/2 disease, Medicare surveillance costs per patient were US$1642.66 using 2018 NCCN or ESMO and US$2179.81 using 2015 NCCN. Costs per recurrence detected were US$42,578.64, 62,088.70, and 73,329.76 using 2018 NCCN, 2015 NCCN, and ESMO, respectively. Conclusions: If strictly followed, the NCCN and ESMO guidelines will miss more than two-thirds recurrences. Improved surveillance algorithms to balance patient benefit against costs are needed.
Copyright © 2020 Zhou, Lv, Tang, Mao, Guo, Ma and Sun.
KEYWORDS:
European Society for Medical Oncology; guidelines; nasopharyngeal carcinoma; national comprehensive cancer network; surveillance
26.
Front Oncol. 2020 Feb 12;10:118. doi: 10.3389/fonc.2020.00118. eCollection 2020.
Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer.
Perrone E1,2, Lopez S1,3, Zeybek B1, Bellone S1, Bonazzoli E1, Pelligra S1, Zammataro L1, Manzano A1, Manara P1, Bianchi A1, Buza N4, Tymon-Rosario J1, Altwerger G1, Han C1, Menderes G1, Ratner E1, Silasi DA1, Azodi M1, Hui P4, Schwartz PE1, Scambia G3, Santin AD1.
Abstract
Background: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast-antigen-2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver SN-38, the active metabolite of irinotecan. This study aimed to evaluate Trop-2 expression in EOC tissues and the preclinical activity of SG against primary EOC cell lines and xenografts. Methods: Trop-2 expression was assessed in 90 formalin-fixed-paraffin-embedded tumors and nine primary tumor cell lines by immunohistochemistry (IHC) and flow cytometry, respectively. Trop-2 expression and cell viability after exposure to SG in primary tumor cell lines, non-targeting control ADC, and SG-parental antibody hRS7 were evaluated using flow-cytometry-based-assays. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2- EOC cell lines was tested in vitro using 4 h Chromium-release-assays. In vivo activity of SG was evaluated against Trop-2+ EOC xenografts. Results: Moderate-to-strong staining was seen in 47% (42/90) of ovarian tumors by IHC while 89% (8/9) of the primary EOC cell lines overexpressed Trop-2 by flow cytometry. EOC Trop-2+ were significantly more sensitive to SG compared to control ADC (p < 0.05). Both SG and hRS7 mediated high ADCC activity against Trop-2+ cell lines. SG also induced significant bystander killing of Trop-2- tumor cells admixed with Trop-2+ EOC cells. In in vivo experiments SG treatment demonstrated impressive anti-tumor activity against chemotherapy-resistant EOC xenografts. Conclusion: SG demonstrates remarkable preclinical activity against biologically aggressive and chemotherapy-resistant EOC cell lines and a significant bystander effect against EOC cell lines with heterogenous Trop-2 expression. Clinical trials are warranted.
Copyright © 2020 Perrone, Lopez, Zeybek, Bellone, Bonazzoli, Pelligra, Zammataro, Manzano, Manara, Bianchi, Buza, Tymon-Rosario, Altwerger, Han, Menderes, Ratner, Silasi, Azodi, Hui, Schwartz, Scambia and Santin.
KEYWORDS:
Trop-2; antibody drug conjugate (ADC); ovarian carcinoma; sacituzumab govitecan; target therapy
27.
Front Oncol. 2020 Feb 11;10:117. doi: 10.3389/fonc.2020.00117. eCollection 2020.
From the Clinic to the Bench and Back Again in One Dog Year: How a Cross-Species Pipeline to Identify New Treatments for Sarcoma Illuminates the Path Forward in Precision Medicine.
Rao SR1, Somarelli JA2,3, Altunel E2, Selmic LE4, Byrum M4, Sheth MU5, Cheng S2, Ware KE2, Kim SY6, Prinz JA7, Devos N7, Corcoran DL7, Moseley A7, Soderblom E7, Hsu SD2,3, Eward WC1,3.
Abstract
Cancer drug discovery is an inefficient process, with more than 90% of newly-discovered therapies failing to gain regulatory approval. Patient-derived models of cancer offer a promising new approach to identify new treatments; however, for rare cancers, such as sarcomas, access to patient samples is limited, which precludes development of patient-derived models. To address the limited access to patient samples, we have turned to pet dogs with naturally-occurring sarcomas. Although sarcomas make up <1% of all human cancers, sarcomas represent 15% of cancers in dogs. Because dogs have similar immune systems, an accelerated pace of cancer progression, and a shared environment with humans, studying pet dogs with cancer is ideal for bridging gaps between mouse models and human cancers. Here, we present our cross-species personalized medicine pipeline to identify new therapies for sarcomas. We explore this process through the focused study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. Using our pipeline we identified proteasome inhibitors as a potential therapy for Teddy. Teddy was treated with bortezomib and showed a varied response across tumors. Whole exome sequencing revealed substantial genetic heterogeneity across Teddy's recurrent tumors and metastases, suggesting that intra-patient heterogeneity and tumoral adaptation were responsible for the heterogeneous clinical response. Ubiquitin proteomics coupled with exome sequencing revealed multiple candidate driver mutations in proteins related to the proteasome pathway. Together, our results demonstrate how the comparative study of canine sarcomas offers important insights into the development of personalized medicine approaches that can lead to new treatments for sarcomas in both humans and canines.
Copyright © 2020 Rao, Somarelli, Altunel, Selmic, Byrum, Sheth, Cheng, Ware, Kim, Prinz, Devos, Corcoran, Moseley, Soderblom, Hsu and Eward.
KEYWORDS:
cancer therapy; comparative oncology; precision medicine; tumor evolution; tumor heterogeneity
28.
Front Oncol. 2020 Feb 11;10:116. doi: 10.3389/fonc.2020.00116. eCollection 2020.
Penicilazaphilone C, a New Azaphilone, Induces Apoptosis in Gastric Cancer by Blocking the Notch Signaling Pathway.
Abstract
Penicilazaphilone C (PAC) is a novel azaphilonidal derivative isolated by our group that demonstrates good anticancer activities. Considering that its molecular mechanisms remain largely unknown, here we explore the molecular mechanisms of the anticancer activities of PAC against gastric cancer. The in vitro effects of PAC on cell growth, proliferation, and apoptosis were evaluated by MTT, BrdU, MTS, colony formation assays, Hoechst 33258 staining, and flow cytometry. Related proteins were examined by western blotting. Notch receptor expression was analyzed by RT-PCR. In vivo antitumor activities of PAC were observed in a nude mouse model. We found that compared to the controls, PAC treatment suppressed cell proliferation and promoted apoptosis in MGC-803 and SGC-7901 cells, and the Notch/PTEN/AKT axis was involved in the activating PAC-induced apoptosis. PAC treatment led to decreased levels of Notch (NTM), NICD, pPTEN, and pAKT compared to controls. PAC-induced inhibition of Notch-related protein expression levels and the resulting apoptosis were reversed by overexpression of Notch1 (NTM) or/and Notch2 (NTM). Moreover, PAC treatment clearly inhibited tumor growth in mice both bearing tumors derived from both MGC-803 and SGC-7901 cells. This work reveals that PAC induces the apoptosis by suppressing activation of Notch receptor proteolytic cleavage and subsequently blocking the PTEN/AKT signaling axis in gastric cancer cells. Thus, PAC is a potential alternative agent for the treatment of gastric cancer.
Copyright © 2020 Wang, Zhao, Hu, Xu, Lin and Zhou.
KEYWORDS:
apoptosis; gastric cancer; molecular mechanism; notch signaling pathway; penicilazaphilone C
29.
Front Oncol. 2020 Feb 7;10:114. doi: 10.3389/fonc.2020.00114. eCollection 2020.
PARP Inhibitors in Prostate and Urothelial Cancers.
Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors targeting DNA repair gene mutations have shown significant clinical benefit in patients with ovarian and breast cancers. In metastatic prostate cancers, the prevalence of DNA repair gene mutations is up to 20%, and early phase studies have shown clinical activity of PARP inhibitors. Numerous clinical trials with either PARP monotherapy or in combination with other therapeutic agents are ongoing in prostate cancer. In this comprehensive review, we provide the rationale, efficacy, and safety data of PARP inhibitors in prostate as well as urothelial cancers.
Copyright © 2020 Garje, Vaddepally and Zakharia.
KEYWORDS:
DNA damage repair genes; PARP inhibitor; precision oncology; prosate cancer; urothelial cancer (UC)
30.
Front Oncol. 2020 Feb 13;10:113. doi: 10.3389/fonc.2020.00113. eCollection 2020.
Clonal Hematopoiesis From Next Generation Sequencing of Plasma From a Patient With Lung Adenocarcinoma: A Case Report.
Ito M1, Fujiwara Y1,2,3, Kubo T4, Matsushita H5, Kumamoto T6, Suzuki T7, Sunami K5, Yamamoto N1,2, Kohno T4,8.
Abstract
Reliable and accurate next generation sequencing (NGS) technologies are important in precision medicine. Analysis using currently available NGS genomic tests is conducted on cancer-derived DNA collected from tumor tissue, blood, or both. Clonal hematopoiesis (CH) produces a detectable somatic clonal mutation that is commonly associated with clonal expansion of hematopoietic cells with age and genomic analysis of blood samples can be used to detect CH. A 74-year-old Korean male had lung adenocarcinoma with a metastasis to the left scapula. He underwent palliative radiotherapy to the left scapula and received multi-line chemotherapies. After disease progression, he underwent re-biopsy of the metastatic tumor tissue from lung cancer and concomitant blood sampling. NGS genomic testing revealed no significant genomic mutation in the tumor tissue DNA but showed the TP53 mutation C135Y in peripheral blood DNA. To investigate the discordance between the genotyping results in tumor tissue and blood, we tested for the TP53 mutation using a target sequencing test in blood and normal oral mucosa. The TP53 mutation C135Y was only detected in the blood sample, confirming the presence of TP53-mutated CH. We should be aware of different characteristics in NGS genomic testing including sample type such as tumor, blood, or paired specimens. Performing genomic testing on paired tumor and blood samples is effective for discriminating mutations derived from CH from germline mutations and somatic mutations in tumor cells.
Copyright © 2020 Ito, Fujiwara, Kubo, Matsushita, Kumamoto, Suzuki, Sunami, Yamamoto and Kohno.
KEYWORDS:
TP53 mutation; cell-free DNA; clonal hematopoiesis; next generation sequencing; precision medicine
31.
Front Oncol. 2020 Feb 11;10:111. doi: 10.3389/fonc.2020.00111. eCollection 2020.
Feasibility of Bioimpedance Analysis to Assess the Outcome of Complex Decongestive Therapy in Cancer Treatment-Related Lymphedema.
Abstract
Background: Cancer treatment-related lymphedema (CTRL) affects patients physically, psychologically and emotionally, and remains a significant quality of life issue among patients with cancer. Reliable methods to measure changes in lymphedema are required for early detection, acute intensive treatment, and long-term management. Here, we evaluated the use of bioimpedance analysis (BIA) as a tool to measure lymphedema before and after treatment. Patients and Methods: Patients with CTRL who were admitted to a secondary university hospital between October 2017 and July 2018 for complex decongestive therapy (CDT) were eligible for this prospective cohort study. Circumferential measure (CM) and BIA were used to evaluate lymphedema at admission (initial) and before discharge (follow-up, FU). Volume was calculated from the CM using the truncated cone formula. The inter-limb ratios (ILRs) of the circumference, volume, and impedance were also calculated as the unaffected limb to affected limb. Each parameter before and after treatment and correlations between parameters also were analyzed. Results: A total of 29 patients (12 upper- and 17 lower-extremity CTRL) completed were included in this analysis. Absolute value and the ILRs of circumference, volume or impedance, and extracellular water/total body water (ECW/TBW) were significantly improved at FU (p < 0.01, p < 0.05). The initial and FU absolute values, ILRs, ECW/TBW correlated significantly with each other (p < 0.01, p < 0.05). The cutoff values of ECW/TBW for moderate and severe degree of CTRL were 0.3855 and 0.3955, respectively. The changes of ILRs between initial and FU assessments were significantly different among three groups according to lymphedema severity (p < 0.01, p < 0.05). Conclusions: BIA data correlates significantly with clinical measurement, and therefore can be a practical tool in monitoring outcome measure after lymphedema treatment. In addition, BIA is more sensitive to subtle changes in lymphedema, and therefore can be useful for the long-term maintenance of lymphedema.
Copyright © 2020 Cho, Han, Lee, Park, Lee and IM.
KEYWORDS:
bioimpedance analysis; breast cancer; cancer treatment-related lymphedema; complex decongestive therapy; gynecologic cancer
32.
Front Oncol. 2020 Feb 11;10:110. doi: 10.3389/fonc.2020.00110. eCollection 2020.
Hepatic Resection Is Associated With Improved Long-Term Survival Compared to Radio-Frequency Ablation in Patients With Multifocal Hepatocellular Carcinoma.
Abstract
Background: The prognosis of patients with hepatocellular carcinoma (HCC) is of major public health interest. However, studies comparing hepatic resection (HR) and radio-frequency ablation (RFA) applied to multifocal HCC are limited. This study aimed to compare the efficacies of HR and RFA in patients with multifocal HCC. Methods: We retrospectively analyzed a cohort from the Surveillance, Epidemiology, and End Results database between 2004 and 2015. Disease-specific survival and overall survival rates were assessed before and after propensity score matching (PSM). Results: In total, 2,201 patients with multifocal HCC treated with HR (n = 1,095) or RFA (n = 1,106) were included; 1,096 patients were identified after nearest-neighbor PSM at a ratio of 1:1 (HR: n = 548; RFA: n = 548). In the multivariate Cox regression model, HR was associated with significantly improved disease-specific survival [before PSM: hazard ratio 0.67, 95% confidence interval (CI) 0.57-0.79, p < 0.001; after PSM: hazard ratio 0.69, 95% CI 0.58-0.82, p < 0.001] and overall survival (before PSM: hazard ratio 0.67, 95% CI 0.58-0.78, p < 0.001; after PSM: hazard ratio 0.69, 95% CI 0.59-0.80, p < 0.001) compared to RFA in patients with multifocal HCC. In the survival curve analysis, the disease-specific survival of the HR group was similar to that of the RFA group before PSM (p = 0.936, log-rank test) but was significantly longer after PSM (p < 0.001) in all patients. Multivariate analyses revealed that differentiation grade, alpha-fetoprotein, tumor size, and tumor extension were independent predictors of poor prognosis in patients with multifocal HCC. Conclusions: The long-term survival rate of HR is better than that of RFA in patients with multifocal HCC. HR may serve as a first-line treatment for patients with multifocal HCC. The presence of large tumors and vascular invasion are not contraindications for HR.
Copyright © 2020 Yue and Zhou.
KEYWORDS:
hepatic resection; hepatocellular carcinoma; liver cancer; multifocal tumor; radio-frequency ablation
33.
Front Oncol. 2020 Feb 7;10:109. doi: 10.3389/fonc.2020.00109. eCollection 2020.
The Generation and Identity of Human Myeloid-Derived Suppressor Cells.
Abstract
Myeloid-derived suppressor cells (MDSCs) are cells of myeloid lineage with a potent immunosuppressive capacity. They are present in cancer patients as well as in patients with severe inflammatory conditions and infections. MDSCs exist as two main subtypes, the granulocytic (G-MDSCs) and the monocytic (Mo-MDSCs) type, as defined by their surface phenotype and functions. While the functions of MDSCs have been investigated in depth, the origin of human MDSCs is less characterized and even controversial. In this review, we recapitulate theories on how MDSCs are generated in mice, and whether this knowledge is translatable into human MDSC biology, as well as on problems of defining MDSCs by their immature cell surface phenotype in relation to the plasticity of myeloid cells. Finally, the challenge of pharmacological targeting of MDSCs in the future is envisioned.
Copyright © 2020 Bergenfelz and Leandersson.
KEYWORDS:
activation; cancer; development; differentiation; infection; maturation; myeloid-derived suppressor cell; tolerance
34.
Front Oncol. 2020 Feb 13;10:107. doi: 10.3389/fonc.2020.00107. eCollection 2020.
miR-20a-5p/TGFBR2 Axis Affects Pro-inflammatory Macrophages and Aggravates Liver Fibrosis.
Abstract
Combined inhibition of programmed death-ligand 1 (PD-L1) and transforming growth factor-β (TGF-β) displayed additive anti-tumor response in a subgroup of cancer patients, highlighting the importance of understanding the multifaceted roles of TGF-β in immunity and fibrosis. In the present research, we show that TGF-β signaling pathway, controlled by miR-20a-5p and transforming growth factor-β receptor 2 (TGFBR2), alters the inflammation and fibrosis processes in liver. We performed integrated analysis of differently expressed miRNA (DEM) associated with liver fibrosis and screened miR-20a-5p out as a key regulator in inflammation-driven liver fibrosis. We subsequently conducted Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the genes targeted by miR-20a-5p. And the result showed that 12 target genes were significantly enriched in TGF-β signaling pathway. Further study showed that miR-20a-5p was down-regulated and involved in inflammation during liver fibrosis in human and mouse samples, indicating that miR-20a-5p and inflammation are functionally linked during liver fibrosis progression. To uncover the underlying pro-inflammatory mechanism of miR-20a-5p in liver fibrosis, we selected and verified TGFBR2, which is a key functional receptor in TGF-β signaling pathway, as a direct target gene of miR-20a-5p. The downregulation of miR-20a-5p in liver fibrosis resulted in TGFBR2-activated TGF-β signaling pathway, followed by the activation of macrophage and extracellular matrix (ECM) production by hepatic stellate cell (HSC). Our results identify the miR-20a-5p/TGFBR2 axis as a key regulator of TGF-β signaling, and highlight the critical role of miR-20a-5p in the development of liver fibrosis.
Copyright © 2020 Fu, Qie, Fu, Chen, Jin and Ding.
KEYWORDS:
TGF-β signaling pathway; TGFBR2; inflammation; liver fibrosis; miR-20a-5p
35.
Front Oncol. 2020 Feb 7;10:106. doi: 10.3389/fonc.2020.00106. eCollection 2020.
Editorial: Cancer Epidemiology in China: What We Have Learnt So Far?
KEYWORDS:
China; cancer epidemiology; cancer incidence; cancer mortality; cancer survival; cohort
36.
Front Oncol. 2020 Feb 7;10:105. doi: 10.3389/fonc.2020.00105. eCollection 2020.
Manipulating microRNAs for the Treatment of Malignant Pleural Mesothelioma: Past, Present and Future.
Abstract
microRNAs (miRNAs) are an important class of non-coding RNA that post-transcriptionally regulate the expression of most protein-coding genes. Their aberrant expression in tumors contributes to each of the hallmarks of cancer. In malignant pleural mesothelioma (MPM), in common with other tumor types, changes in miRNA expression are characterized by a global downregulation, although elevated levels of some miRNAs are also found. While an increasing number of miRNAs exhibit altered expression in MPM, relatively few have been functionally characterized. Of a growing number with tumor suppressor activity in vitro, miR-16, miR-193a, and miR-215 were also shown to have tumor suppressor activity in vivo. In the case of miR-16, the significant inhibitory effects on tumor growth following targeted delivery of miR-16-based mimics in a xenograft model was the basis for a successful phase I clinical trial. More recently overexpressed miRNAs with oncogenic activity have been described. Many of these changes in miRNA expression are related to the characteristic loss of tumor suppressor pathways in MPM tumors. In this review we will highlight the studies providing evidence for therapeutic effects of modulating microRNA levels in MPM, and discuss these results in the context of emerging approaches to miRNA-based therapy.
Copyright © 2020 Reid, Johnson and van Zandwijk.
KEYWORDS:
drug delivery; drug formulation; extracellular vesicles; malignant pleural mesothelioma; microRNA; oncomiR; tumor suppressor miRNA
37.
Front Oncol. 2020 Feb 5;10:104. doi: 10.3389/fonc.2020.00104. eCollection 2020.
Heterozygous p53-R280T Mutation Enhances the Oncogenicity of NPC Cells Through Activating PI3K-Akt Signaling Pathway.
Abstract
A heterozygous point mutation of p53 gene at codon 280 from AGA to ACA (R280T) frequently occurs in nasopharyngeal carcinoma (NPC) cell lines, and about 10% NPC tissues. However, the role of this mutation in the pathogenesis of NPC remains unclear. In this study, we generated p53 knockout (KO) NPC cell lines from CNE2 cells carrying heterozygous p53 R280T (p53-R280T) mutation and C666-1 cells carrying wild-type p53 by CRISPR-Cas9 gene editing system, and found that KO of heterozygous p53-R280T significantly decreased NPC cell proliferation and increased NPC cell apoptosis, whereas KO of wild-type p53 had opposite effects on NPC cell proliferation and apoptosis. Moreover, KO of heterozygous p53-R280T inhibited the anchorage-independent growth and in vivo tumorigenicity of NPC cells. mRNA sequencing of heterozygous p53-R280T KO and control CNE2 cells revealed that heterozygous p53-R280T mutation activated PI3K-Akt signaling pathway. Moreover, blocking of PI3K-Akt signaling pathway abolished heterozygous p53-R280T mutation-promoting NPC cell proliferation and survival. Our data indicate that p53 with heterozygous R280T mutation functions as an oncogene, and promotes the oncogenicity of NPC cells by activating PI3K-Akt signaling pathway.
Copyright © 2020 Qin, Li, Yi, Lu, Huang, Rong, Tang and Xiao.
KEYWORDS:
Akt; R280T mutation; nasopharyngeal carcinoma; oncogenicity; p53
38.
Front Oncol. 2020 Feb 11;10:103. doi: 10.3389/fonc.2020.00103. eCollection 2020.
A Cost-Effectiveness and Quality of Life Analysis of Different Approaches to the Management and Treatment of Localized Prostate Cancer.
Abstract
The aim of this study was to compare the cost-effectiveness and quality-adjusted life years (QALYs) of active monitoring (AM), radical prostatectomy (PR), and external-beam radiotherapy with neoadjuvant hormone therapy (RT) for localized prostate cancer. Microsimulations of radical prostatectomy, 3D-conformal radiotherapy, or active monitoring were performed using Medicare reimbursement schedules and clinical trial results for a target population of men aged 50-69 years with newly diagnosed localized prostate cancer (T1-T2, NX, M0) over a time horizon of 10 years. Quality-adjusted life years (QALYs) and costs were assessed and sensitivity analyses performed. Monte Carlo simulations revealed that the mean cost for AM, PR, and RT were $15,654, $18,791, and $30,378, respectively, and QALYs were 6.96, 7.44, and 7.9 years, respectively. The incremental cost-effectiveness ratio (ICER) was $6,548 for PR over AM and $68,339 for RT over PR. Results were sensitive to the number of years of follow-up and procedure cost. With relaxed assumptions for AM, the ICER of PR and RT met the societal willingness to pay (WTP) threshold of $50,000 per QALY. Compared with AM, PR was highly cost-effective. RT and PR for localized prostate cancer can be cost-effective, but RT must offer increased QALYs or decreased procedural costs to be cost-effective compared to PR. Newer and cheaper radiotherapy strategies like stereotactic body radiotherapy may play a crucial role in future early prostate cancer management.
Copyright © 2020 Harat, Harat and Martinson.
KEYWORDS:
QALY; active monitoring; cost-effectiveness analysis; prostate cancer; prostatectomy; radiotherapy
39.
Front Oncol. 2020 Feb 7;10:102. doi: 10.3389/fonc.2020.00102. eCollection 2020.
Traditional Classification and Novel Subtyping Systems for Bladder Cancer.
Abstract
Bladder cancer is the most common tumor in the urinary system, with approximately 420,000 new cases and 160,000 deaths per year. The European Organization for Research and Treatment of Cancer (EOTRC) classifies non-muscular invasive bladder cancer (NMIBC) into low-risk, medium-risk and high-risk groups based on a comprehensive analysis of NMIBC pathological parameters and the risk of recurrence and progression to muscular invasive bladder cancer (MIBC). Traditional classification systems are based on pathologic grading, staging systems, and clinical prognosis. However, the pathological parameters of the tumor cannot fully reflect the "intrinsic characteristics" of bladder cancer, and tumors with a similar pathology exhibit different biological behaviors. Furthermore, although the traditional classification system cannot accurately predict the risk of recurrence or the progression of bladder cancer patients (BCs) individually, this method is widely used in clinical practice because of its convenient operation. With the development of sequencing and other technologies, the genetics-based molecular subtyping of bladder cancer has become increasingly studied. Compared with the traditional classification system, it provides more abundant tumor biological information and is expected to assist or even replace the traditional typing system in the future.
Copyright © 2020 Zhu, Yu, Yang, Wu and Cheng.
KEYWORDS:
EOTRC; bladder cancer; clinical prognosis; molecular subtypes; multiomics
40.
Front Oncol. 2020 Feb 11;10:101. doi: 10.3389/fonc.2020.00101. eCollection 2020.
Preclinical Models of Malignant Mesothelioma.
Abstract
Rodent models of malignant mesothelioma help facilitate the understanding of the biology of this highly lethal cancer and to develop and test new interventions. Introducing the same genetic lesions as found in human mesothelioma in mice results in tumors that show close resemblance with the human disease counterpart. This includes the extensive inflammatory responses that characterize human malignant mesothelioma. The relatively fast development of mesothelioma in mice when the appropriate combination of lesions is introduced, with or without exposure to asbestos, make the autochthonous models particularly useful for testing new treatment strategies in an immunocompetent setting, whereas Patient-Derived Xenograft models are particularly useful to assess effects of inter- and intra-tumor heterogeneity and human-specific features of mesothelioma. It is to be expected that new insights obtained by studying these experimental systems will lead to new more effective treatments for this devastating disease.
Copyright © 2020 Testa and Berns.
KEYWORDS:
conditional tumor suppressor gene knockout/oncogene mouse models; genetic driver lesions; in vivo asbestos carcinogenesis; malignant mesothelioma; mesothelioma inflammatory phenotype; patient-derived xenograft models of mesothelioma; preclinical rodent models
41.
Front Oncol. 2020 Feb 11;10:99. doi: 10.3389/fonc.2020.00099. eCollection 2020.
Intracranial Metastases Originating From Pediatric Primary Spinal Cord Glioblastoma Multiforme: A Case Report and Literature Review.
Abstract
Primary spinal cord glioblastoma multiforme (scGBM) is an uncommon entity in pediatrics, and intracranial metastasis originating in spinal cord gliomas is very rare. A 7-year-old female presented with weakness in the limbs, paralysis of the lower limbs and incontinence. The initial MRI of the spinal cord revealed expansion and abnormal signals from T2 to T5. She was initially diagnosed with Neuromyelitis optica spectrum disorders and treated with high-dose glucocorticoid and gamma globulin. Four months later, her symptoms worsened and follow-up imaging showed multiple intracranial mass lesions. We performed a subtotal resection of the right thalamic basal ganglia tumor and gross total resection of the right frontal lobe tumor under microscopic examination. Histopathology revealed scGBM with intracranial metastasis and the molecular pathology diagnosis suggested H3K27M mutant diffuse midline glioma WHO grade IV, which had previously been misdiagnosed as a Neuromyelitis optica spectrum disorders. We review the literature of intracranial metastases originating from pediatric primary spinal cord glioblastoma multiforme and summarize possible methods of differentiation, including changes in muscle strength or tone, intramedullary heterogeneously enhancing solitary mass lesions and cord expansion in MRI. Finally, we emphasize that in unexpected radiological changes or disadvantageous response to the treatment, a biopsy to achieve a pathological diagnosis is necessary to discard other diseases, especially neoplasms.
Copyright © 2020 Song, Xu, Gao, Hu and Guo.
KEYWORDS:
case report; intracranial metastases; literature review; pediatric; spinal cord glioblastoma
42.
Front Oncol. 2020 Feb 11;10:97. doi: 10.3389/fonc.2020.00097. eCollection 2020.
Targeting Metabolic Deregulation Landscapes in Breast Cancer Subtypes.
Abstract
Metabolic deregulation is an emergent hallmark of cancer. Altered patterns of metabolic pathways result in exacerbated synthesis of macromolecules, increased proliferation, and resistance to treatment via alteration of drug processing. In addition, molecular heterogeneity creates a barrier to therapeutic options. In breast cancer, this broad variation in molecular metabolism constitutes, simultaneously, a source of prognostic and therapeutic challenges and a doorway to novel interventions. In this work, we investigated the metabolic deregulation landscapes in breast cancer molecular subtypes. Such landscapes are the regulatory signatures behind subtype-specific metabolic features. n = 735 breast cancer samples of the Luminal A, Luminal B, Her2+, and Basal subtypes, as well as n = 113 healthy breast tissue samples were analyzed. By means of a single-sample-based algorithm, deregulation for all metabolic pathways in every sample was determined. Deregulation levels match almost perfectly with the molecular classification, indicating that metabolic anomalies are closely associated with gene-expression signatures. Luminal B tumors are the most deregulated but are also the ones with higher within-subtype variance. We argued that this variation may underlie the fact that Luminal B tumors usually present the worst prognosis, a high rate of recurrence, and the lowest response to treatment in the long term. Finally, we designed a therapeutic scheme to regulate purine metabolism in breast cancer, independently of the molecular subtype. This scheme is founded on a computational tool that provides a set of FDA-approved drugs to target pathway-specific differentially expressed genes. By providing metabolic deregulation patterns at the single-sample level in breast cancer subtypes, we have been able to further characterize tumor behavior. This approach, together with targeted therapy, may open novel avenues for the design of personalized diagnostic, prognostic, and therapeutic strategies.
Copyright © 2020 Serrano-Carbajal, Espinal-Enríquez and Hernández-Lemus.
KEYWORDS:
breast cancer subtypes; cancer metabolism; pathway deregulation; purine metabolism; steroid and fatty acid metabolism; therapeutic targets
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