1
Review Front Oncol
. 2020 Apr 28;10:570. doi: 10.3389/fonc.2020.00570. eCollection 2020.
Therapeutic Potential of Combining PARP Inhibitor and Immunotherapy in Solid Tumors
Praveen Vikas 1 2, Nicholas Borcherding 2 3 4 5, Adithya Chennamadhavuni 1 2, Rohan Garje 1 2
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PMID: 32457830 PMCID: PMC7228136 DOI: 10.3389/fonc.2020.00570
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Abstract
Immunotherapy has revolutionized the treatment of both hematological malignancies and solid tumors. The use of immunotherapy has improved outcome for patients with cancer across multiple tumor types, including lung, melanoma, ovarian, genitourinary, and more recently breast cancer with durable responses seen even in patients with widespread metastatic disease. Despite the promising results, immunotherapy still helps only a subset of patients due to overall low response rates. Moreover, the response to immunotherapy is highly cancer specific and results have not been as promising in cancers that are considered less immunogenic. The strategies to improve immunotherapy responses have focused on biomarker selection, like PD-L1 status, and usage of combinatorial agents, such as chemotherapy, targeted therapy, and radiotherapy. Of particular interest, DNA-damaging agents have the potential to enhance the response to immunotherapy by promoting neoantigen release, increasing tumor mutational burden, and enhancing PD-L1 expression. Poly-ADP-ribose polymerase (PARP) inhibitors are one such class of drugs that has shown synergy with immunotherapy in preclinical and early clinical studies. PARP-based therapies work through the inhibition of single-strand DNA repair leading to DNA damage, increased tumor mutational burden, making the tumor a more attractive target for immunotherapy. Of the solid tumors reviewed, breast, ovarian, and prostate cancers have demonstrated efficacy in the combination of PARP inhibition and immunotherapy, predominately in BRCA-mutated tumors. However, initial investigations into wildtype BRCA and gastrointestinal tumors have shown moderate overall response or disease control rates, dependent on the tumor type. In contrast, although a number of clinical trials underway, there is a paucity of published results for the use of the combination in lung or urothelial cancers. Overall this article focuses on the promise of combinatorial PARP inhibition and immunotherapy to improve patient outcomes in solid tumors, summarizing both early results and looking toward ongoing trials.

Keywords: PARP inhibitor; breast cancer; combination therapy; gastrointestinal cancers; gynecologic cancer; immunotherapy; prostate cancer; solid tumors.

Copyright © 2020 Vikas, Borcherding, Chennamadhavuni and Garje.

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2
Review Front Oncol
. 2020 May 8;10:506. doi: 10.3389/fonc.2020.00506. eCollection 2020.
Biological Difference Between Epstein-Barr Virus Positive and Negative Post-transplant Lymphoproliferative Disorders and Their Clinical Impact
Valeria Ferla 1, Francesca Gaia Rossi 1, Maria Cecilia Goldaniga 1, Luca Baldini 1 2
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PMID: 32457824 PMCID: PMC7225286 DOI: 10.3389/fonc.2020.00506
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Abstract
Epstein-Barr virus (EBV) infection is correlated with several lymphoproliferative disorders, including Hodgkin disease, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and post-transplant lymphoproliferative disorder (PTLD). The oncogenic EBV is present in 80% of PTLD. EBV infection influences immune response and has a causative role in the oncogenic transformation of lymphocytes. The development of PTLD is the consequence of an imbalance between immunosurveillance and immunosuppression. Different approaches have been proposed to treat this disorder, including suppression of the EBV viral load, reduction of immune suppression, and malignant clone destruction. In some cases, upfront chemotherapy offers better and durable clinical responses. In this work, we elucidate the clinicopathological and molecular-genetic characteristics of PTLD to clarify the biological differences of EBV(+) and EBV(-) PTLD. Gene expression profiling, next-generation sequencing, and microRNA profiles have recently provided many data that explore PTLD pathogenic mechanisms and identify potential therapeutic targets. This article aims to explore new insights into clinical behavior and pathogenesis of EBV(-)/(+) PTLD with the hope to support future therapeutic studies.

Keywords: Epstein–Barr virus; gene expression profile; microRNA; next-generation sequencing; post-transplant lymphoproliferative disorders; tumor microenvironment.

Copyright © 2020 Ferla, Rossi, Goldaniga and Baldini.

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3
Front Oncol
. 2020 May 14;10:750. doi: 10.3389/fonc.2020.00750. eCollection 2020.
Incidence, Prognostic Factors and Survival Outcome in Patients With Primary Hepatic Lymphoma
Shi-Long Zhang 1, Chen Chen 2, Qian-Wen Rao 1, Zhe Guo 3, Xin Wang 4, Zhi-Ming Wang 5 6, Li-Shun Wang 1
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PMID: 32477954 PMCID: PMC7239999 DOI: 10.3389/fonc.2020.00750
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Abstract
Aim: The objective of our study was to investigate the epidemiologic characteristics, prognostic factors and survival in patients with primary hepatic lymphoma (PHL). Methods: PHL patients diagnosed between 1983 and 2015 were identified from the SEER database. The temporal trend in PHL incidence was assessed using joinpoint regression software. Overall survival(OS) and disease-specific survival (DSS) was evaluated using the Kaplan-Meier method and log-rank test. Univariate and multivariate Cox regression analysis was performed to identify the independent prognostic factors for OS and DSS. Nomograms to predict survival possibilities were constructed based on the identified independent prognostic factors. Results: A total of 1,182 patients were identified with PHL. The mean age was 61.7 ± 17.1 years with a male to female of 1.6:1. Diffuse large B-cell lymphoma (59.8%) was the most common histological subtype. The incidence of PHL steadily increasing by an annual percentage change (APC) of 2.6% (95% CI 2.0-3.2, P < 0.05). The 1-, 5-, and 10-year OS rates were 50.85, 39.6, and 30.4%, respectively, and the corresponding DSS rates were 55.3, 47.9, and 43.3%, respectively. Multivariate Cox regression analysis revealed that age, sex, race, marital status, histological subtype, surgery, and chemotherapy were independent prognostic factors for survival. Nomograms specifically for DLBCL were constructed to predict 1-, 5-, and 10-year OS and DSS possibility, respectively. The concordance index (C-index) and calibration plots showed the established nomograms had robust and accurate performance. Conclusion: PHL were rare but the incidence has been steadily increasing over the past four decades. Survival has improved in recent years. Surgery or chemotherapy could provide better OS and DSS. The established nomograms specifically for DLBCL were robust and accurate in predicting 1-, 5-, and 10-year OS and DSS.

Keywords: SEER; incidence; nomogram; primary hepatic lymphoma; prognosis; treatment.

Copyright © 2020 Zhang, Chen, Rao, Guo, Wang, Wang and Wang.

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4
Review Front Oncol
. 2020 May 12;10:554. doi: 10.3389/fonc.2020.00554. eCollection 2020.
Unresolved Complexity in the Gene Regulatory Network Underlying EMT
Deborah P Lavin 1, Vijay K Tiwari 1
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PMID: 32477926 PMCID: PMC7235173 DOI: 10.3389/fonc.2020.00554
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Abstract
Epithelial to mesenchymal transition (EMT) is the process whereby a polarized epithelial cell ceases to maintain cell-cell contacts, loses expression of characteristic epithelial cell markers, and acquires mesenchymal cell markers and properties such as motility, contractile ability, and invasiveness. A complex process that occurs during development and many disease states, EMT involves a plethora of transcription factors (TFs) and signaling pathways. Whilst great advances have been made in both our understanding of the progressive cell-fate changes during EMT and the gene regulatory networks that drive this process, there are still gaps in our knowledge. Epigenetic modifications are dynamic, chromatin modifying enzymes are vast and varied, transcription factors are pleiotropic, and signaling pathways are multifaceted and rarely act alone. Therefore, it is of great importance that we decipher and understand each intricate step of the process and how these players at different levels crosstalk with each other to successfully orchestrate EMT. A delicate balance and fine-tuned cooperation of gene regulatory mechanisms is required for EMT to occur successfully, and until we resolve the unknowns in this network, we cannot hope to develop effective therapies against diseases that involve aberrant EMT such as cancer. In this review, we focus on data that challenge these unknown entities underlying EMT, starting with EMT stimuli followed by intracellular signaling through to epigenetic mechanisms and chromatin remodeling.

Keywords: EMT; cancer; chromatin; epigenetics; gene regulation; signaling; transcription factors.

Copyright © 2020 Lavin and Tiwari.

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5
Review Front Oncol
. 2020 May 12;10:765. doi: 10.3389/fonc.2020.00765. eCollection 2020.
Update on Biology of Cutaneous T-Cell Lymphoma
Zaw H Phyo 1, Satish Shanbhag 2, Sima Rozati 3
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PMID: 32477957 PMCID: PMC7235328 DOI: 10.3389/fonc.2020.00765
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Abstract
Cutaneous T cell lymphomas (CTCL) comprise of a heterogeneous group of non-Hodgkin lymphomas derived from skin-homing T cells. Variation in clinical presentation and lack of definitive molecular markers make diagnosis especially challenging. The biology of CTCL remains elusive and clear links between genetic aberrations and epigenetic modifications that would result in clonal T cell expansion have not yet been identified. Nevertheless, in recent years, next generation sequencing (NGS) has enabled a much deeper understanding of the genomic landscape of CTCL by uncovering aberrant genetic pathways and epigenetic dysregulations. Additionally, single cell profiling is rapidly advancing our understanding of patients-specific tumor landscape and its interaction with the surrounding microenvironment. These studies have paved the road for future investigations that will explore the functional relevance of genetic alterations in the progression of disease. The ultimate goal of elucidating the pathogenesis of CTCL is to establish effective therapeutic targets with more durable clinical response and treat relapsing and refractory CTCL.

Keywords: cutaneous T cell lymphoma (CTCL); mycosis fungoides; next generation sequencing; precision medicine; sezary syndrome; single cell profiling; tumor microenvironment.

Copyright © 2020 Phyo, Shanbhag and Rozati.

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6
Review Front Oncol
. 2020 May 7;10:724. doi: 10.3389/fonc.2020.00724. eCollection 2020.
Extracellular Vesicles in Renal Cell Carcinoma: Multifaceted Roles and Potential Applications Identified by Experimental and Computational Methods
Zhiyuan Qin 1, Qingwen Xu 1, Haihong Hu 1, Lushan Yu 1, Su Zeng 1
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PMID: 32457844 PMCID: PMC7221139 DOI: 10.3389/fonc.2020.00724
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Abstract
Renal cell carcinoma (RCC) is the most common type of kidney cancer. Increasingly evidences indicate that extracellular vesicles (EVs) orchestrate multiple processes in tumorigenesis, metastasis, immune evasion, and drug response of RCC. EVs are lipid membrane-bound vesicles in nanometer size and secreted by almost all cell types into the extracellular milieu. A myriad of bioactive molecules such as RNA, DNA, protein, and lipid are able to be delivered via EVs for the intercellular communication. Hence, the abundant content of EVs is appealing reservoir for biomarker identification through computational analysis and experimental validation. EVs with excellent biocompatibility and biodistribution are natural platforms that can be engineered to offer achievable drug delivery strategies for RCC therapies. Moreover, the multifaceted roles of EVs in RCC progression also provide substantial targets and facilitate EVs-based drug discovery, which will be accelerated by using artificial intelligence approaches. In this review, we summarized the vital roles of EVs in occurrence, metastasis, immune evasion, and drug resistance of RCC. Furthermore, we also recapitulated and prospected the EVs-based potential applications in RCC, including biomarker identification, drug vehicle development as well as drug target discovery.

Keywords: artificial intelligence; biomarkers; drug targets; drug vehicles; exosomes; extracellular vesicles; machine learning; renal cell carcinoma.

Copyright © 2020 Qin, Xu, Hu, Yu and Zeng.

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7
Front Oncol
. 2020 May 7;10:687. doi: 10.3389/fonc.2020.00687. eCollection 2020.
TGFβ Signaling Increases Net Acid Extrusion, Proliferation and Invasion in Panc-1 Pancreatic Cancer Cells: SMAD4 Dependence and Link to Merlin/NF2 Signaling
Raj R Malinda 1, Katrine Zeeberg 1, Patricia C Sharku 1, Mette Q Ludwig 1, Lotte B Pedersen 1, Søren T Christensen 1, Stine F Pedersen 1
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PMID: 32457840 PMCID: PMC7221161 DOI: 10.3389/fonc.2020.00687
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related death, with a 5-year survival of <10% and severely limited treatment options. PDAC hallmarks include profound metabolic acid production and aggressive local proliferation and invasiveness. This phenotype is supported by upregulated net acid extrusion and epithelial-to-mesenchymal transition (EMT), the latter typically induced by aberrant transforming growth factor-β (TGFβ) signaling. It is, however, unknown whether TGFβ-induced EMT and upregulation of acid extrusion are causally related. Here, we show that mRNA and protein expression of the net acid extruding transporters Na+/H+ exchanger 1 (NHE1, SLC9A1) and Na+, HCO
−
3
 cotransporter 1 (NBCn1, SLC4A7) are increased in a panel of human PDAC cell lines compared to immortalized human pancreatic ductal epithelial (HPDE) cells. Treatment of Panc-1 cells (which express SMAD4, required for canonical TGFβ signaling) with TGFβ-1 for 48 h elicited classical EMT with down- and upregulation of epithelial and mesenchymal markers, respectively, in a manner inhibited by SMAD4 knockdown. Accordingly, less pronounced EMT was induced in BxPC-3 cells, which do not express SMAD4. TGFβ-1 treatment elicited a SMAD4-dependent increase in NHE1 expression, and a smaller, SMAD4-independent increase in NBCn1 in Panc-1 cells. Consistent with this, TGFβ-1 treatment led to elevated intracellular pH and increased net acid extrusion capacity in Panc-1 cells, but not in BxPC-3 cells, in an NHE1-dependent manner. Proliferation was increased in Panc-1 cells and decreased in BxPC-3 cells, upon TGFβ-1 treatment, and this, as well as EMT per se, was unaffected by NHE1- or NBCn1 inhibition. TGFβ-1-induced EMT was associated with a 4-fold increase in Panc-1 cell invasiveness, which further increased ~10-fold upon knockdown of the tumor suppressor Merlin (Neurofibromatosis type 2). Knockdown of NHE1 or NBCn1 abolished Merlin-induced invasiveness, but not that induced by TGFβ-1 alone. In conclusion, NHE1 and NBCn1 expression and NHE-dependent acid extrusion are upregulated during TGFβ-1-induced EMT of Panc-1 cells. NHE1 upregulation is SMAD4-dependent, and SMAD4-deficient BxPC-3 cells show no change in pHi regulation. NHE1 and NBCn1 are not required for EMT per se or EMT-associated proliferation changes, but are essential for the potentiation of invasiveness induced by Merlin knockdown.

Keywords: Merlin; NBCn1; NHE1; PDAC; SLC4A7; SLC9A1; invasion; proliferation.

Copyright © 2020 Malinda, Zeeberg, Sharku, Ludwig, Pedersen, Christensen and Pedersen.

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8
Front Oncol
. 2020 May 8;10:512. doi: 10.3389/fonc.2020.00512. eCollection 2020.
Measuring Intratumoral Heterogeneity of Immune Repertoires
Diana Vladimirovna Yuzhakova 1, Lilia N Volchkova 1, Mikhail Valerievich Pogorelyy 2 3, Ekaterina O Serebrovskaya 2 3, Irina A Shagina 2 3, Ekaterina A Bryushkova 3 4, Tatiana O Nakonechnaya 1 2 3, Anna V Izosimova 1, Daria S Zavyalova 1, Maria M Karabut 1, Mark Izraelson 1 2 3, Igor V Samoylenko 5, Vladimir E Zagainov 1 6, Dmitriy M Chudakov 1 2 3 7 8, Elena V Zagaynova 1, George Vladimirovich Sharonov 1 2 3
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PMID: 32457825 PMCID: PMC7227437 DOI: 10.3389/fonc.2020.00512
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Abstract
There is considerable clinical and fundamental value in measuring the clonal heterogeneity of T and B cell expansions in tumors and tumor-associated lymphoid structures-along with the associated heterogeneity of the tumor neoantigen landscape-but such analyses remain challenging to perform. Here, we propose a straightforward approach to analyze the heterogeneity of immune repertoires between different tissue sections in a quantitative and controlled way, based on a beta-binomial noise model trained on control replicates obtained at the level of single-cell suspensions. This approach allows to identify local clonal expansions with high accuracy. We reveal in situ proliferation of clonal T cells in a mouse model of melanoma, and analyze heterogeneity of immunoglobulin repertoires between sections of a metastatically-infiltrated lymph node in human melanoma and primary human colon tumor. On the latter example, we demonstrate the importance of training the noise model on datasets with depth and content that is comparable to the samples being studied. Altogether, we describe here the crucial basic instrumentarium needed to facilitate proper experimental setup planning in the rapidly evolving field of intratumoral immune repertoires, from the wet lab to bioinformatics analysis.

Keywords: TCR repertoire; clonal expansions; immunoglobulin repertoire; tumour clonality; tumour heterogeneity.

Copyright © 2020 Yuzhakova, Volchkova, Pogorelyy, Serebrovskaya, Shagina, Bryushkova, Nakonechnaya, Izosimova, Zavyalova, Karabut, Izraelson, Samoylenko, Zagainov, Chudakov, Zagaynova and Sharonov.

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9
Front Oncol
. 2020 May 7;10:572. doi: 10.3389/fonc.2020.00572. eCollection 2020.
Feasibility of Automated Volumetric Assessment of Large Hepatocellular Carcinomas' Responses to Transarterial Chemoembolization
Ahmed W Moawad 1, David Fuentes 1, Ahmed M Khalaf 2, Katherine J Blair 2, Janio Szklaruk 2, Aliya Qayyum 2, John D Hazle 1, Khaled M Elsayes 2
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PMID: 32457831 PMCID: PMC7221016 DOI: 10.3389/fonc.2020.00572
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Abstract
Background: Hepatocellular carcinoma (HCC) is the most common liver malignancy and the leading cause of death in patients with cirrhosis. Various treatments for HCC are available, including transarterial chemoembolization (TACE), which is the commonest intervention performed in HCC. Radiologic tumor response following TACE is an important prognostic factor for patients with HCC. We hypothesized that, for large HCC tumors, assessment of treatment response made with automated volumetric response evaluation criteria in solid tumors (RECIST) might correlate with the assessment made with the more time- and labor-intensive unidimensional modified RECIST (mRECIST) and manual volumetric RECIST (M-vRECIST) criteria. Accordingly, we undertook this retrospective study to compare automated volumetric RECIST (A-vRECIST) with M-vRECIST and mRESIST for the assessment of large HCC tumors' responses to TACE. Methods:We selected 42 pairs of contrast-enhanced computed tomography (CT) images of large HCCs. Images were taken before and after TACE, and in each of the images, the HCC was segmented using both a manual contouring tool and a convolutional neural network. Three experienced radiologists assessed tumor response to TACE using mRECIST criteria. The intra-class correlation coefficient was used to assess inter-reader reliability in the mRECIST measurements, while the Pearson correlation coefficient was used to assess correlation between the volumetric and mRECIST measurements. Results:Volumetric tumor assessment using automated and manual segmentation tools showed good correlation with mRECIST measurements. For A-vRECIST and M-vRECIST, respectively, r = 0.597 vs. 0.622 in the baseline studies; 0.648 vs. 0.748 in the follow-up studies; and 0.774 vs. 0.766 in the response assessment (P < 0.001 for all). The A-vRECIST evaluation showed high correlation with the M-vRECIST evaluation (r = 0.967, 0.937, and 0.826 in baseline studies, follow-up studies, and response assessment, respectively, P < 0.001 for all). Conclusion:Volumetric RECIST measurements are likely to provide an early marker for TACE monitoring, and automated measurements made with a convolutional neural network may be good substitutes for manual volumetric measurements.

Keywords: TACE; automated segmentation; hepatocellular carcinoma; tumor response; volumetric RECIST.

Copyright © 2020 Moawad, Fuentes, Khalaf, Blair, Szklaruk, Qayyum, Hazle and Elsayes.

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10
Front Oncol
. 2020 May 7;10:606. doi: 10.3389/fonc.2020.00606. eCollection 2020.
Efficacy and Safety of Intraoperative Lumbar Drain in Endoscopic Skull Base Tumor Resection: A Meta-Analysis
Xiaoming Guo 1, Yueli Zhu 2, Yuan Hong 1
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PMID: 32457833 PMCID: PMC7221155 DOI: 10.3389/fonc.2020.00606
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Abstract
Objectives: This study aims to evaluate the efficacy and safety of lumbar drainage (LD) in preventing cerebrospinal fluid (CSF) leaks after endoscopic skull base tumor resection. Methods: A systematic online search was conducted using PubMed, Embase, Scopus, Web of Science, and Cochrane Library from January 2006 to July 2019. Data analyses were performed by the Cochrane Collaboration's Review Manager 5.3 software. Results: Eight studies, including two randomized controlled trials and six observational studies, met the inclusion criteria. No significant difference was found in the post-operative CSF leak rate between the LD group and the non-LD group [odds ratio (OR), 0.80; 95%CI, 0.37-1.74; I 2 = 37%; P = 0.57). Subgroup analysis of the intraoperative high-flow leaks, including 4 studies and 313 patients, showed that LD was associated with reduced likelihood of post-operative CSF leak (OR, 0.37; 95%CI, 0.17-0.83; I 2 = 0%; P = 0.02). The placement of LD was related to increased risk of headache compared with non-LD use, and no significant difference was found in the occurrence of deep vein thromboses and pulmonary emboli between two groups. Conclusion: LD is not recommended in all patients undergoing endoscopic skull base tumor resection. However, for patients with intraoperative high-flow leaks, LD is effective and safe in reducing risk of CSF leak.

Keywords: cerebrospinal fluid leak; endoscopic endonasal surgery; lumbar drainage; pituitary; skull base tumor.

Copyright © 2020 Guo, Zhu and Hong.

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11
Review Front Oncol
. 2020 May 13;10:744. doi: 10.3389/fonc.2020.00744. eCollection 2020.
The Autonomic Regulation of Tumor Growth and the Missing Links
Maricris Bautista 1 2, Anand Krishnan 1 2
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PMID: 32477953 PMCID: PMC7237572 DOI: 10.3389/fonc.2020.00744
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Abstract
Accumulating evidence now indicates that peripheral nerves and solid tumors mutually support the growth of each other. Tumor-derived molecular cues guide nerve infiltration to the tumor milieu, while the tumor-infiltrating nerves provide molecular support to promote tumor growth and dissemination. In this mini-review, we discuss the unique roles of sympathetic and parasympathetic nerves in promoting tumor growth and metastasis. The contribution of adrenergic and cholinergic signals, the specific receptors involved, and the downstream molecular links in both cancer cells and stromal cells are discussed for their intrinsic capacity to modulate tumor growth. We identified unappreciated niche areas in the field, an investigation of which are critical to filling the knowledge gap in understanding the biology of neuromodulation of cancers.

Keywords: acetylcholine; metastasis; nerve-dependence of cancers; nerve-tumor crosstalk; nerve-tumor interface; neurotrophic factors; norepinephrine.

Copyright © 2020 Bautista and Krishnan.

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12
Front Oncol
. 2020 May 12;10:708. doi: 10.3389/fonc.2020.00708. eCollection 2020.
Do 21-Gene Recurrence Score Influence Chemotherapy Decisions in T1bN0 Breast Cancer Patients?
Jing Yu 1, Jiayi Wu 1, Ou Huang 1, Jianrong He 1, Zhu Li 1, Weiguo Chen 1, Yafen Li 1, Xiaosong Chen 1, Kunwei Shen 1
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PMID: 32477946 PMCID: PMC7236800 DOI: 10.3389/fonc.2020.00708
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Abstract
Purpose: Hormone receptor (HR)-positive breast cancer patients with tumor size ≤1.0 cm and negative node have favorable outcomes. The 21-gene Recurrence Score (RS) could predict response to chemotherapy for HR+ breast cancer, but its role in T1bN0 disease is challenging. Methods: T1bN0 breast cancer patients diagnosed between January 2014 and June 2019 with RS results were included and categorized as Low- (RS < 18), Intermediate- (RS 18-30), or High-risk (RS > 30) groups. Univariate and multivariate analysis were used to assess factors associated with RS distribution and chemotherapy recommendation. Chemotherapy decisions change and patient adherence after 21-gene RS testing were also evaluated. Results: Among 237 patients with T1bN0 tumors, proportions of Low-, Intermediate-, and High-risk RS were 19.8, 63.3, and 16.9%, respectively. Multivariate analysis found that ER expression (P = 0.011), PR expression (P < 0.001), and Ki-67 index (P = 0.001) were independently associated with RS distribution. Adjuvant chemotherapy was recommended for 31.6% of patients, which was more frequently given to patients with higher tumor grade [Odds ratio (OR) = 2.99 for grade II, OR = 59.19 for grade III, P = 0.006], lymph vascular invasion (OR = 8.22, P = 0.032), Luminal-B subtype (OR = 5.68, P < 0.001), and Intermediate-to High-risk RS (OR = 10.01 for Intermediate-risk, OR = 192.42 for High-risk, P < 0.001). Chemotherapy decision change was found in 18.6% of patients, mainly in those with Intermediate- to High-risk RS tumor with the majority from no-chemotherapy to chemotherapy. The treatment compliance rate after the 21-gene RS testing with MDT was 95.4%. Conclusion: RS category was related to ER, PR, and Ki-67 expression, which was recognized as an independent factor of chemotherapy recommendation in T1bN0 breast cancer. The 21-gene RS testing would lead to a chemotherapy decision change rate of 18.6% as well as a high treatment adherence, which can be applied in T1bN0 patients.

Keywords: 21-gene recurrence score; T1bN0 tumors; breast cancer; chemotherapy decisions; treatment adherence.

Copyright © 2020 Yu, Wu, Huang, He, Li, Chen, Li, Chen and Shen.

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Front Oncol
. 2020 May 7;10:678. doi: 10.3389/fonc.2020.00678. eCollection 2020.
Use of Baseline 18 F-FDG PET/CT to Identify Initial Sub-Volumes Associated With Local Failure After Concomitant Chemoradiotherapy in Locally Advanced Cervical Cancer
François Lucia 1 2, Omar Miranda 1, Ronan Abgral 3, Vincent Bourbonne 1 2, Gurvan Dissaux 1 2, Olivier Pradier 1 2, Mathieu Hatt 2, Ulrike Schick 1 2
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PMID: 32457839 PMCID: PMC7221149 DOI: 10.3389/fonc.2020.00678
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Abstract
Introduction: Locally advanced cervical cancer (CC) patients treated by chemoradiotherapy (CRT) have a significant local recurrence rate. The objective of this work was to assess the overlap between the initial high-uptake sub-volume (V1) on baseline 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scans and the metabolic relapse (V2) sites after CRT in locally advanced CC. Methods: PET/CT performed before treatment and at relapse in 21 patients diagnosed with LACC and treated with CRT were retrospectively analyzed. CT images at the time of recurrence were registered to baseline CT using the 3D Slicer TM Expert Automated Registration module. The corresponding PET images were then registered using the corresponding transform. The fuzzy locally adaptive Bayesian (FLAB) algorithm was implemented using 3 classes (one for the background and the other two for tumor) in PET1 to simultaneously define an overall tumor volume and the sub-volume V1. In PET2, FLAB was implemented using 2 classes (one for background, one for tumor), in order to define V2. Four indices were used to determine the overlap between V1 and V2 (Dice coefficients, overlap fraction, X = (V1nV2)/V1 and Y = (V1nV2)/V2). Results: The mean (±standard deviation) follow-up was 26 ± 11 months. The measured overlaps between V1 and V2 were moderate to good according to the four metrics, with 0.62-0.81 (0.72 ± 0.05), 0.72-1.00 (0.85 ± 0.10), 0.55-1.00 (0.73 ± 0.16) and 0.50-1.00 (0.76 ± 0.12) for Dice, overlap fraction, X and Y, respectively. Conclusion: In our study, the overlaps between the initial high-uptake sub-volume and the recurrent metabolic volume showed moderate to good concordance. These results now need to be confirmed in a larger cohort using a more standardized patient repositioning procedure for sequential PET/CT imaging, as there is potential for RT dose escalation exploiting the pre-treatment PET high-uptake sub-volume.

Keywords: PET/CT; cervical cancer; chemoradiotherapy; hotspots; personalized targeted treatment.

Copyright © 2020 Lucia, Miranda, Abgral, Bourbonne, Dissaux, Pradier, Hatt and Schick.

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14
Front Oncol
. 2020 May 14;10:647. doi: 10.3389/fonc.2020.00647. eCollection 2020.
Oncologic and Reproductive Outcomes of Uterine Smooth Muscle Tumor of Uncertain Malignant Potential: A Single Center Retrospective Study of 67 Cases
Lanqing Huo 1, Dan Wang 1, Wenze Wang 2, Dongyan Cao 1, Jiaxin Yang 1, Ming Wu 1, Junjun Yang 1, Yang Xiang 1
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PMID: 32477938 PMCID: PMC7240040 DOI: 10.3389/fonc.2020.00647
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Abstract
Background: The term "uterine smooth muscle tumor of uncertain malignant potential" (STUMP) indicates a rare tumor that cannot be classified as a benign leiomyoma or malignant leiomyosarcoma. In this study, we assessed the clinical characteristics, fertility, and oncologic outcomes of patients diagnosed as STUMP in 14 years. In addition, we analyzed the risk factors for recurrence in patients with STUMP. Methods: Medical records of STUMP patients at Peking Union Medical College Hospital (PUMCH) between January 2005 and June 2019 were reviewed and analyzed. Disease-free survival, age of diagnosis, tumor size, surgical procedure, pathology and immunohistochemistry, clinical characteristics, recurrence rate, and reproductive outcomes in the follow-up period were assessed. Univariate and multivariate analyses were performed to determine the prognostic factors. Results: The median age was 42 years old (range: 21-63). Total hysterectomy with or without bilateral salpingo-oophorectomy was performed in 29/67 cases (43.3%), and myomectomy was performed in 38/67 cases (56.7%). Ten patients experienced recurrences, and all but two recurrences occurred within 5 years after the initial surgery. Only two of these recurrences were leiomyosarcoma. There were no deaths in the median follow-up period of 48.4 (range 2.6-170.2) months. There were no remarkable differences in location of tumor between the myomectomy and hysterectomy groups, but the patients in the myomectomy group were younger than those in the hysterectomy group. In univariate and multivariate analysis, mitosis on pathology was the only independent risk factor for recurrence. Expression of Ki-67, p53, and p16 was significantly higher in patients with recurrence. Seven of the 35 patients who attempted to conceive had successful pregnancies. Conclusions: The prognosis of STUMP was favorable and tumors with more than 10 mitoses per 10 high power field should be monitored closely. The surgical procedure was not an independent risk factor of recurrence, and myomectomy may be an acceptable option for patients wishing to preserve fertility.

Keywords: recurrence; reproductive outcomes; smooth muscle tumor; surgical procedure; uncertain malignant potential.

Copyright © 2020 Huo, Wang, Wang, Cao, Yang, Wu, Yang and Xiang.

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15
Front Oncol
. 2020 May 7;10:551. doi: 10.3389/fonc.2020.00551. eCollection 2020.
Repeatability of Quantitative Imaging Features in Prostate Magnetic Resonance Imaging
Hong Lu 1 2, Nestor A Parra 2, Jin Qi 2, Kenneth Gage 3, Qian Li 1, Shuxuan Fan 1 2, Sebastian Feuerlein 3, Julio Pow-Sang 4, Robert Gillies 2 3, Jung W Choi 3, Yoganand Balagurunathan 3 4 5
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PMID: 32457827 PMCID: PMC7221156 DOI: 10.3389/fonc.2020.00551
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Abstract
Background: Multiparametric magnetic resonance imaging (mpMRI) has emerged as a non-invasive modality to diagnose and monitor prostate cancer. Quantitative metrics on the regions of abnormality have shown to be useful descriptors to discriminate clinically significant cancers. In this study, we evaluate the reproducibility of quantitative imaging features using repeated mpMRI on the same patients. Methods: We retrospectively obtained the deidentified records of patients, who underwent two mpMRI scans within 2 weeks of the first baseline scan. The patient records were obtained as deidentified data (including imaging), obtained through the TCIA (The Cancer Imaging Archive) repository and analyzed in our institution with an institutional review board-approved Health Insurance Portability and Accountability Act-compliant retrospective study protocol. Indicated biopsied regions were used as a marker for our study radiologists to delineate the regions of interest. We extracted 307 quantitative features in each mpMRI modality [T2-weighted MR sequence image (T2w) and apparent diffusion coefficient (ADC) with b values of 0 and 1,400 mm/s2] across the two sequential scans. Concordance correlation coefficients (CCCs) were computed on the features extracted from sequential scans. Redundant features were removed by computing the coefficient of determination (R 2) among them and replaced with a feature that had the highest dynamic range within intercorrelated groups. Results: We have assessed the reproducibility of quantitative imaging features among sequential scans and found that habitat region characterization improves repeatability in ADC maps. There were 19 T2w features and two ADC features in radiologist drawn regions (native raw image), compared to 18 T2w and 15 ADC features in habitat regions (sphere), which were reproducible (CCC ≥0.65) and non-redundant (R 2 ≥ 0.99). We also found that z-transformation of the images prior to feature extraction reduced the number of reproducible features with no detrimental effect. Conclusion: We have shown that there are quantitative imaging features that are reproducible across sequential prostate mpMRI acquisition at a preset level of filters. We also found that a habitat approach improves feature repeatability in ADC. A validated set of reproducible image features in mpMRI will allow us to develop clinically useful disease risk stratification, enabling the possibility of using imaging as a surrogate to invasive biopsies.

Keywords: mpMRI; prostate TRUS-MRI; prostate cancer; radiomics; repeatable MRI features; test–retest in mpMRI.

Copyright © 2020 Lu, Parra, Qi, Gage, Li, Fan, Feuerlein, Pow-Sang, Gillies, Choi and Balagurunathan.

30 references4 figures
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Front Oncol
. 2020 May 8;10:627. doi: 10.3389/fonc.2020.00627. eCollection 2020.
High Levels of HIST1H2BK in Low-Grade Glioma Predicts Poor Prognosis: A Study Using CGGA and TCGA Data
Weidong Liu 1, Zhentao Xu 1, Jie Zhou 2, Shuang Xing 2, Zhiqiang Li 3, Xu Gao 4, Shiyu Feng 5, Yilei Xiao 1
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PMID: 32457836 PMCID: PMC7225299 DOI: 10.3389/fonc.2020.00627
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Abstract
A number of biomarkers have been identified for various cancers. However, biomarkers associated with glioma remain largely to be explored. In the current study, we investigated the relationship between the expression and prognostic value of the HIST1H2BK gene in glioma. Sequential data filtering (survival analysis, independent prognostic analysis, ROC curve analysis, and clinical correlation analysis) was performed, which resulted in identification of the association between the HIST1H2BK gene and glioma. Then, the HIST1H2BK gene was analyzed using bioinformatics (Kaplan-Meier survival analysis, univariate Cox analysis, multivariate Cox analysis, and ROC curve analysis). The results showed that low expression of HIST1H2BK was associated with better prognosis, and high expression of HIST1H2BK was associated with poor prognosis. In addition, HIST1H2BK was an independent prognostic indicator for patients with glioma. We also evaluated the association between HIST1H2BK and clinical characteristics. Furthermore, gene set enrichment analysis (GSEA) and analysis of immune infiltration were performed. The results showed that HIST1H2BK was associated with intensity of immune infiltration in glioma. Finally, co-expression analysis was performed. The results showed that HIST1H2BK was positively correlated with HIST1H2AG, HIST2H2AA4, HIST1H2BJ, HIST2H2BE, and HIST1H2AC, and negatively correlated with PDZD4, CRY2, GABBR1, rp5-1119a7.17, and KCNJ11. This study showed that upregulation of HIST1H2BK in low-grade glioma (LGG) tissue was an indicator of poor prognosis. Moreover, this study demonstrated that HIST1H2BK may be a promising biomarker for the treatment of LGG.

Keywords: CGGA; HIST1H2BK; TCGA; glioma; prognosis.

Copyright © 2020 Liu, Xu, Zhou, Xing, Li, Gao, Feng and Xiao.

43 references8 figures
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Front Oncol
. 2020 May 12;10:455. doi: 10.3389/fonc.2020.00455. eCollection 2020.
The Reliability and Validity of Quality of Life Questionnaire Upper Limb Lymphedema (ULL-27) Turkish Patient With Breast Cancer Related Lymphedema
Ayşe Kayali Vatansever 1, Tuğba Yavuzşen 2, Didem Karadibak 3
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PMID: 32477925 PMCID: PMC7235329 DOI: 10.3389/fonc.2020.00455
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Abstract
Purpose: Breast cancer is the most common cancer amongst women both in Turkey and in the world. Lymphedema, which negatively affects the quality of life, is one of the most prevalent problems reported by breast cancer survivors. Upper Limb Lymphedama 27 (ULL-27) questionnaire is a valid and reliable tool that assesses the quality of life in patients with breast cancer-related lymphedema. Until now, a Turkish-language version was lacking. The aim of this study was to perform a cross-cultural validation and reliability of the Turkish version of the ULL-27 questionnaire. Methods: This cross-sectional study involved forward- backward translation, and cross-cultural adaptation. 81 women (mean age and body mass index 54.96 ± 11.35 years and 29.50 ± 5.74 kg/m2) who had breast cancer related-upper extremity lymphedema were evaluated using the ULL-27 Quality of life questionnaire-Turkish version. Assessment of limb size was quantified by using circumferential limb measurements. European Organization for Research and Treatment of Cancer (EORTC) 30-item Quality of Life Questionnaire and Quality of Life Questionnaire breast cancer-23 (QLQ-BR23) were analyzed by Pearson's correlation analysis with the ULL-27 Turkish Version to indicate the convergent validity. Cronbach's alpha (internal consistency) and exploratory factor analysis were used to assess the questionnaire's reliability. Results: The mean of lymphedema duration and severity were 23.12 ± 30.88 months. Mild lymphedema was reported in 42% (34 people) of the cases included in the study. It was observed that 33.3% (27 people) had moderate lymphedema and 24.7% (20 people) had severe lymphedema. The alpha coefficient (internal consistency) for the Turkish ULL-27 total score was high (alpha = 0.93). Content validity was good because all questions were understandable for all participants (The alpha coefficient for the subgroups of the scale of physical, psychological, social scores, were 0.90, 0.87, and 0.75, respectively). External construct validity was highly confirmed by expected correlations with comparator scales, EORTC-30, and QLQ-BR23 (p < 0.01). Conclusions: The Turkish version of the ULL-27 Questionnaire is a valid and reliable tool for evaluating QoL in women with upper limb lymphedema related to breast cancer.

Keywords: ULL-27 quality of life questionnaire; breast cancer; eortc30; lymphedema; quality of life.

Copyright © 2020 Kayali Vatansever, Yavuzşen and Karadibak.

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18
Front Oncol
. 2020 May 14;10:774. doi: 10.3389/fonc.2020.00774. eCollection 2020.
Syndecan-1-Dependent Regulation of Heparanase Affects Invasiveness, Stem Cell Properties, and Therapeutic Resistance of Caco2 Colon Cancer Cells
Sampath Kumar Katakam 1, Paride Pelucchi 2, Cinzia Cocola 2, Rolland Reinbold 2, Israel Vlodavsky 3, Burkhard Greve 4, Martin Götte 1
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PMID: 32477959 PMCID: PMC7240066 DOI: 10.3389/fonc.2020.00774
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Abstract
The heparan sulfate proteoglycan Syndecan-1 binds cytokines, morphogens and extracellular matrix components, regulating cancer stem cell properties and invasiveness. Syndecan-1 is modulated by the heparan sulfate-degrading enzyme heparanase, but the underlying regulatory mechanisms are only poorly understood. In colon cancer pathogenesis, complex changes occur in the expression pattern of Syndecan-1 and heparanase during progression from well-differentiated to undifferentiated tumors. Loss of Syndecan-1 and increased expression of heparanase are associated with a change in phenotypic plasticity and an increase in invasiveness, metastasis and dedifferentiation. Here we investigated the regulatory and functional interplay of Syndecan-1 and heparanase employing siRNA-mediated silencing and plasmid-based overexpression approaches in the human colon cancer cell line Caco2. Heparanase expression and activity were upregulated in Syndecan-1 depleted cells. This increase was linked to an upregulation of the transcription factor Egr1, which regulates heparanase at the promoter level. Inhibitor experiments demonstrated an impact of focal adhesion kinase, Wnt and ROCK-dependent signaling on this process. siRNA-depletion of Syndecan-1, and upregulation of heparanase increased the colon cancer stem cell phenotype based on sphere formation assays and phenotypic marker analysis (Side-population, NANOG, KLF4, NOTCH, Wnt, and TCF4 expression). Syndecan-1 depletion increased invasiveness of Caco2 cells in vitro in a heparanase-dependent manner. Finally, upregulated expression of heparanase resulted in increased resistance to radiotherapy, whereas high expression of enzymatically inactive heparanase promoted chemoresistance to paclitaxel and cisplatin. Our findings provide a new avenue to target a stemness-associated signaling axis as a therapeutic strategy to reduce metastatic spread and cancer recurrence.

Keywords: cancer stem cells; colon cancer; heparan sulfate; heparanase; proteoglycan; syndecan.

Copyright © 2020 Katakam, Pelucchi, Cocola, Reinbold, Vlodavsky, Greve and Götte.

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19
Front Oncol
. 2020 May 7;10:664. doi: 10.3389/fonc.2020.00664. eCollection 2020.
Anlotinib for Patients With Metastatic Renal Cell Carcinoma Previously Treated With One Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor: A Phase 2 Trial
Jianhui Ma 1, Yan Song 2, Jianzhong Shou 1, Yuxian Bai 3, Hanzhong Li 4, Xiaodong Xie 5, Hong Luo 6, Xiubao Ren 7, Jiyan Liu 8, Dingwei Ye 9, Xianzhong Bai 10, Cheng Fu 11, Shukui Qin 12, Jinwan Wang 2, Ai-Ping Zhou 2
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PMID: 32457838 PMCID: PMC7221023 DOI: 10.3389/fonc.2020.00664
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Abstract
Introduction: Sequential therapy with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) is effective in some patients with metastatic renal cell carcinoma (mRCC) progressed from or were intolerant to a prior TKIs. Anlotinib is a multi-kinase inhibitor targeting VEGFR1/2/3, PDGFR and FGFR, which has demonstrated efficacy and safety in first-line treatment of mRCC. This study assessed the potential of anloitnib as second-line treatment for patients with mRCC after prior one VEGFR-TKI. Methods: This is a single-arm, open-label, phase 2 study. Patients progressed after or were intolerant to sorafenib or sunitinib were enrolled. Anlotinib was administrated orally 12 mg once daily for 14 days every 3 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), safety and quality of life (QoL). Results: Forty three patients were enrolled and 42 received anlotinib, of whom 32 progressed after and 10 were intolerant to sorafenib or sunitinib. Median PFS were 14.0 months (95% CI 8.3-20.3) and 8.5 months (95% CI 5.6-16.6) for overall population and patients progressed after a previous VEGFR-TKI, respectively. Median OS was 21.4 months (95% CI 16.0-34.5), confirmed ORR and DCR were 16.7 and 83.3% in overall population. The most common adverse events included diarrhea (47.6%), hypertension (45.2%), hand and foot syndrome (42.9%), and fatigue (40.5%). Grade 3 hematological adverse events occurred in four cases, while no grade 4 hematological adverse events was observed. Conclusions: Anlotinib showed promising efficacy as well as favorable safety as second-line treatment for patients with mRCC. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02072044.

Keywords: FGFR; anlotinib; metastatic renal cell carcinoma; second-line; tyrosine kinase inhibitor.

Copyright © 2020 Ma, Song, Shou, Bai, Li, Xie, Luo, Ren, Liu, Ye, Bai, Fu, Qin, Wang and Zhou.

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20
Front Oncol
. 2020 May 12;10:589. doi: 10.3389/fonc.2020.00589. eCollection 2020.
Downregulation of HMGA1 Mediates Autophagy and Inhibits Migration and Invasion in Bladder Cancer via miRNA-221/TP53INP1/p-ERK Axis
Xiaoqiang Liu 1 2, Zhengtao Zhou 1, Yibing Wang 3, Ke Zhu 1 2, Wen Deng 1, Yulei Li 1, Xiaochen Zhou 1, Luyao Chen 1, Yu Li 1, An Xie 2, Tao Zeng 4, Gongxian Wang 1 2, Bin Fu 1 2
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PMID: 32477928 PMCID: PMC7235162 DOI: 10.3389/fonc.2020.00589
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Abstract
MicroRNAs (miRNAs) have been implicated in regulating the development and metastasis of human cancers. MiR-221 is reported to be an oncogene in multiple cancers, including bladder cancer (BC). Deregulation of autophagy is associated with multiple human malignant cancers. Whether and how miR-221 regulates autophagy and how miR-221 has been regulated in BC are poorly understood. This study explored the potential functions and mechanisms of miR-221 in the autophagy and tumorigenesis of BC. We showed that the downregulation of miR-221 induces autophagy via increasing TP53INP1 (tumor protein p53 inducible nuclear protein 1) and inhibits migration and invasion of BC cells through suppressing activation of extracellular signal-regulated kinase (ERK). Furthermore, the expression of miR-221 is regulated by high-mobility group AT-hook 1 (HMGA1) which is overexpressed in BC. And both miR-221 and HMGA1 are correlated with poor patient survival in BC. Finally, the downregulation of HMGA1 suppressed the proliferative, migrative, and invasive property of BC by inducing toxic autophagy via miR-221/TP53INP1/p-ERK axis. Collectively, our findings demonstrate that the downregulation of miR-221 and HMGA1 mediates autophagy in BC, and both of them are valuable therapeutic targets for BC.

Keywords: TP53INP1; autophagy; bladder cancer; high-mobility group AT-hook 1 (HMGA1); miR-221.

Copyright © 2020 Liu, Zhou, Wang, Zhu, Deng, Li, Zhou, Chen, Li, Xie, Zeng, Wang and Fu.

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Front Oncol
. 2020 May 8;10:691. doi: 10.3389/fonc.2020.00691. eCollection 2020.
Immunoscore Predicts Survival in Early-Stage Lung Adenocarcinoma Patients
Zihuan Zhao 1 2 3, Dan Zhao 4, Ji Xia 2, Yi Wang 3 5, Buhai Wang 1 2
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PMID: 32457841 PMCID: PMC7225293 DOI: 10.3389/fonc.2020.00691
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Abstract
Background: The lung cancer staging system is insufficient for a comprehensive evaluation of patient prognosis. We constructed a novel immunoscore model to predict patients with high risk and poor survival. Method: Immunoscore was developed based on z-score transformed enrichment score of 11 immune-related gene sets of 109 immune risk genes. The immunoscore model was trained in lung adenocarcinoma cohort from The Cancer Genome Atlas (TCGA-LUAD) (n = 400), and validated in other two independent cohorts from Gene Expression Omnibus (GEO), GSE31210 (n = 219) and GSE68465 (n = 356). Meta-set (n = 975) was formed by combining all training and testing sets. Result: High immunoscore conferred worse prognosis in all sets. It was an independent prognostic factors in multivariate Cox analysis in training, testing and meta-set [hazard ratio (HR) = 2.96 (2.24-3.9), P < 0.001 in training set; HR = 1.99 (1.21-3.26), P = 0.006 in testing set 1; HR = 1.48 (1.69-2.39), P = 0.005 in testing set 2; HR = 2.01 (1.69-2.39), P < 0.001 in meta-set]. Immunoscore-clinical prognostic signature (ICPS) was developed by integrating immunoscore and clinical characteristic, and had higher C-index than immunoscore or stage alone in all sets [0.72 (ICPS) vs. 0.7 (immunoscore) or 0.59 (stage) in training set; 0.75 vs. 0.72 or 0.7 in testing set 1; 0.65 vs. 0.61 or 0.62 in testing set 2; 0.7 vs. 0.66 or 0.64 in meta-set]. Genome analysis revealed that immunoscore was positively correlated with tumor mutation burden (R = 0.22, P < 0.001). Besides, high immunoscore was correlated with high proportion of carcinoma-associated fibroblasts (R = 0.32, P < 0.001) in tumor microenvironment but fewer CD8+ cells infiltration (R = -0.28, P < 0.001). Conclusion: The immunoscore and ICPS are potential biomarkers for evaluating patient survival. Further investigations are required to validate and improve their prediction accuracy.

Keywords: immune gene set; immunoscore; lung adenocarcinoma; prognosis; ridge regression.

Copyright © 2020 Zhao, Zhao, Xia, Wang and Wang.

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Front Oncol
. 2020 May 8;10:640. doi: 10.3389/fonc.2020.00640. eCollection 2020.
Identification of a Splenic Marginal Zone Lymphoma Signature: Preliminary Findings With Diagnostic Potential
Jacob E Robinson 1, Timothy C Greiner 2, Alyssa C Bouska 2, Javeed Iqbal 2, Christine E Cutucache 1
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PMID: 32457837 PMCID: PMC7225304 DOI: 10.3389/fonc.2020.00640
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Abstract
Splenic marginal zone lymphoma (SMZL) is a rare, indolent non-Hodgkin's lymphoma that affects 0. 13 per 100,000 persons annually. Overall survival of SMZL is estimated to reach 8-11 years in most cases, but up to 30% of SMZL cases develop aggressive presentations resulting in greatly diminished time of survival. SMZL presents with a very heterogeneous molecular profile, making diagnosis problematic, and accurate prognosis even less likely. The study herein has identified a potential diagnostic gene expression signature with highly specific predictive utility, coined the SMZL-specific Gene Expression Signature (SSGES). Additionally, five of the most impactful markers identified within the SSGES were selected for a five-protein panel, for further evaluation among control and SMZL patient samples. These markers included EME2, ERCC5, SETBP1, USP24, and ZBTB32. When compared with control spleen and other B-cell lymphoma subtypes, significantly higher expression was noticed in SMZL samples when stained for EME2 and USP24. Additionally, ERCC5, SETBP1, USP24, and ZBTB32 staining displayed indications of prognostic value for SMZL patients. Delineation of the SSGES offers a unique SMZL signature that could provide diagnostic utility for a malignancy that has historically been difficult to identify, and the five-marker protein panel provides additional support for such findings. These results should be further investigated and validated in subsequent molecular investigations of SMZL so it may be potentially incorporated into standard oncology practice for improving the understanding and outlook for SMZL patients.

Keywords: SMZL; diagnostic; lymphoma; marginal zone lymphoma; signature.

Copyright © 2020 Robinson, Greiner, Bouska, Iqbal and Cutucache.

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Front Oncol
. 2020 May 13;10:637. doi: 10.3389/fonc.2020.00637. eCollection 2020.
Novel Predictive Nomogram for Identifying Difficult Guidewire Insertion in Patients With Malignant Colorectal Obstruction and Sphincterotome-Assisted Guidewire Insertion for Improving the Success Rate of Self-Expandable Metal Stent Insertion
Zhenhua Zhu 1, Biming Li 1, Wangdi Liao 1, Nonghua Lv 1, Youxiang Chen 1, Xu Shu 1
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PMID: 32477935 PMCID: PMC7237730 DOI: 10.3389/fonc.2020.00637
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Abstract
Aims: This study aimed to identify risk factors related to guidewire insertion (GWI) failure and construct a novel predictive nomogram. In addition, sphincterotome-assisted guidewire insertion (SAGWI) in difficult cases was evaluated for efficacy and safety. Methods: We reviewed the data of 509 patients with malignant colorectal obstruction who underwent endoscopic self-expandable metal stent (SEMS) insertion from 2007 to 2018 in our center, retrospectively. We identify risk factors associated with GWI failure by multivariate logistic regression analysis and construct a novel predictive nomogram. Improvements in the GWI and technical and clinical success rates were assessed for the SAGWI technique. Results: A total of 509 patients with malignant colorectal obstruction were included. Increases of 6.9% and 7.0% were found in the GWI success rate by intention-to-treat (ITT; p < 0.001) and per-protocol (PP; p < 0.001) analyses after SAGWI, respectively. Increases of 6.5% and 6.6% in the technical success rate were found by ITT (p < 0.001) and PP (p < 0.001) analyses after SAGWI, respectively. Increases of 5.8% and 6.0% in the clinical success rate were found by ITT (p < 0.001) and PP (p < 0.001) analyses after SAGWI, respectively. Regarding the GWI failure-related factors, a sharply angulated stricture was an independent risk factor, and an experienced colonoscopist was an independent protective factor. A novel effective predictive nomogram was constructed. Conclusion: The novel predictive nomogram can be conveniently used to identify difficult cases. A sharply angulated stricture and an experienced colonoscopist are independent factors related to GWI failure. The SAGWI technique is an effective and safe method for addressing technically difficult cases.

Keywords: colorectal cancer; malignant colorectal obstruction; nomogram; self-expandable metal stent; sphincterotome-assisted guidewire insertion.

Copyright © 2020 Zhu, Li, Liao, Lv, Chen and Shu.

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Case Reports Front Oncol
. 2020 May 5;10:578. doi: 10.3389/fonc.2020.00578. eCollection 2020.
Managing Metastatic Thymoma With Metabolic and Medical Therapy: A Case Report
Matthew C L Phillips 1, Deborah K J Murtagh 2, Sanjay K Sinha 3, Ben G Moon 4
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PMID: 32457832 PMCID: PMC7227442 DOI: 10.3389/fonc.2020.00578
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Abstract
Thymomas consist of neoplastic thymic cells intermixed with variable numbers of non-neoplastic lymphocytes. Metastatic thymomas are typically managed with non-curative chemotherapy to control tumor-related symptoms; no prolonged survival is expected. Metabolic-based approaches, such as fasting and ketogenic diets, target cancer cell metabolism by creating an increased reliance on ketones while decreasing glucose, glutamine, and growth factor availability, theoretically depriving cancer cells of their metabolic fuels while creating an unfavorable environment for cancer growth, which may be beneficial in metastatic thymoma. We report the case of a 37-year-old woman with myasthenia gravis, diagnosed with an inoperable type AB, stage IVA thymoma, who pursued a metabolic intervention consisting of periodic fasting (7-day, fluid-only fasts every 1-2 months), combined with a modified ketogenic diet on feeding days, for 2 years. Fasting-related adverse effects included cold intolerance, fatigue, and generalized muscle aches, all of which resolved during the second year. She experienced two myasthenia relapses, each associated with profoundly reduced oral intake, marked weight loss, and tumor regression-the first relapse was followed by a 32% decrease in tumor volume over 4 months, the second relapse by a dramatic 96% decrease in tumor volume over 4 months. The second relapse also required prednisone to control the myasthenia symptoms. We hypothesize that 2 years of fasting and ketogenic diet therapy metabolically weakened the neoplastic thymic cell component of the thymoma, "setting the stage" for immune activation and extreme energy restriction to destroy the majority of cancer cells during both relapses, while prednisone-induced apoptosis eradicated the remaining lymphocytic component of the thymoma during the second relapse. This case is unique in that a metabolic-based fasting and ketogenic diet intervention was used as the primary management strategy for a metastatic cancer in the absence of surgery, chemotherapy, or radiotherapy, culminating in a near-complete regression. Nearly 3 years after being diagnosed with inoperable metastatic cancer, our patient shows no signs of disease and leads a full and active life.

Keywords: cancer; fasting; ketogenic diet; metastatic thymoma; prednisone.

Copyright © 2020 Phillips, Murtagh, Sinha and Moon.

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Front Oncol
. 2020 May 13;10:609. doi: 10.3389/fonc.2020.00609. eCollection 2020.
Development of Volumetric Independent Dose Calculation System for Verification of the Treatment Plan in Image-Guided Adaptive Brachytherapy
Sang-Won Kang 1 2, Jin-Beom Chung 3, Kyeong-Hyeon Kim 1 2, Ji-Yeon Park 4, Hae-Jin Park 5, Woong Cho 6, Sven Olberg 7 8, Tae Suk Suh 1 2, Justin C Park 7 8
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PMID: 32477931 PMCID: PMC7237701 DOI: 10.3389/fonc.2020.00609
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Purpose: This study aimed to develop a volumetric independent dose calculation (vIDC) system for verification of the treatment plan in image-guided adaptive brachytherapy (IGABT) and to evaluate the feasibility of the vIDC in clinical practice with simulated cases. Methods: The vIDC is based on the formalism of TG-43. Four simulated cases of cervical cancer were selected to retrospectively evaluate the dose distributions in IGABT. Some reference point doses, such as points A and B and rectal points, were calculated by vIDC using absolute coordinate. The 3D dose volume was also calculated to acquire dose-volume histograms (DVHs) with grid resolutions of 1.0 × 1.0 (G1.0), 2.5 × 2.5 (G2.5), and 0.5 × 0.5 mm2 (G0.5). Dosimetric parameters such as D90% and D2cc doses covering 90% of the high-risk critical target volume (HR-CTV) and 2 cc of the organs at risk (OARs) were obtained from DVHs. D90% also converted to equivalent dose in 2-Gy fractions (EQD2) to produce the same radiobiological effect as external beam radiotherapy. In addition, D90% was obtained in two types with or without the applicator volume to confirm the effect of the applicator itself. Validation of the vIDC was also performed using gamma evaluation by comparison with Monte Carlo simulation. Results: The average percentage difference of point doses was <2.28%. The DVHs for the HR-CTV and OARs showed no significant differences between the vIDC and the treatment planning system (TPS). Without considering the applicator volume, the D90% of the HR-CTV calculated by the vIDC decreases with a decreasing calculated dose-grid size (32.4, 5.65, and -2.20 cGy in G2.5, G1.0, and G0.5, respectively). The overall D90% is higher when considering the applicator volume. The converted D90% by EQD2 ranged from -1.29 to 1.00%. The D2cc of the OARs showed that the averaged dose deviation is <10 cGy regardless of the dose-grid size. Based on gamma analysis, the passing rate was 98.81% for 3%/3-mm criteria. Conclusion: The vIDC was developed as an independent dose verification system for verification of the treatment plan in IGABT. We confirmed that the vIDC is suitable for second-check dose validation of the TPS under various conditions.

Keywords: American Association of Physicists in Medicine Task Group 43; dose grid; equivalent dose in 2-Gy fractions; image-guided adaptive brachytherapy; independent dose calculation system.

Copyright © 2020 Kang, Chung, Kim, Park, Park, Cho, Olberg, Suh and Park.

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Review Front Oncol
. 2020 May 7;10:723. doi: 10.3389/fonc.2020.00723. eCollection 2020.
Cysteine Depletion, a Key Action to Challenge Cancer Cells to Ferroptotic Cell Death
Boutaina Daher 1, Milica Vučetić 1, Jacques Pouysségur 1 2
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PMID: 32457843 PMCID: PMC7221143 DOI: 10.3389/fonc.2020.00723
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Abstract
Cancer cells are characterized as highly proliferative at the expense of enhancement of metabolic rate. Consequently, cancer cells rely on antioxidant defenses to overcome the associated increased production of reactive oxygen species (ROS). The reliance of tumor metabolism on amino acids, especially amino acid transport systems, has been extensively studied over the past decade. Although cysteine is the least abundant amino acid in the cell, evidences described it as one of the most important amino acid for cell survival and growth. Regarding its multi-functionality as a nutrient, protein folding, and major component for redox balance due to its involvement in glutathione synthesis, disruption of cysteine homeostasis appears to be promising strategy for induction of cancer cell death. Ten years ago, ferroptosis, a new form of non-apoptotic cell death, has been described as a result of cysteine insufficiency leading to a collapse of intracellular glutathione level. In the present review, we summarized the metabolic networks involving the amino acid cysteine in cancer and ferroptosis and we focused on describing the recently discovered glutathione-independent pathway, a potential player in cancer ferroptosis resistance. Then, we discuss the implication of cysteine as key player in ferroptosis as a precursor for glutathione first, but also as metabolic precursor in glutathione-independent ferroptosis axis.

Keywords: cysteine; ferroptosis; glutathione; lipid peroxides; tumor-resistance; xCT transporter.

Copyright © 2020 Daher, Vučetić and Pouysségur.

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Front Oncol
. 2020 May 12;10:731. doi: 10.3389/fonc.2020.00731. eCollection 2020.
Radiomics of Multiparametric MRI to Predict Biochemical Recurrence of Localized Prostate Cancer After Radiation Therapy
Qiu-Zi Zhong 1, Liu-Hua Long 2, An Liu 3, Chun-Mei Li 4, Xia Xiu 1, Xiu-Yu Hou 1, Qin-Hong Wu 1, Hong Gao 1, Yong-Gang Xu 1, Ting Zhao 1, Dan Wang 1, Hai-Lei Lin 1, Xiang-Yan Sha 1, Wei-Hu Wang 2, Min Chen 4, Gao-Feng Li 1
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PMID: 32477949 PMCID: PMC7235325 DOI: 10.3389/fonc.2020.00731
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Background: To identify multiparametric magnetic resonance imaging (mp-MRI)-based radiomics features as prognostic factors in patients with localized prostate cancer after radiotherapy. Methods:From 2011 to 2016, a total of 91 consecutive patients with T1-4N0M0 prostate cancer were identified and divided into two cohorts for an adaptive boosting (Adaboost) model (training cohort: n = 73; test cohort: n = 18). All patients were treated with neoadjuvant endocrine therapy followed by radiotherapy. The optimal feature set, identified through an Inception-Resnet v2 network, consisted of a combination of T1, T2, and diffusion-weighted imaging (DWI) MR series. Through a Wilcoxon sign rank test, a total of 45 distinct signatures were extracted from 1,536 radiomics features and used in our Adaboost model. Results:Among 91 patients, 29 (32%) were classified as biochemical recurrence (BCR) and 62 (68%) as non-BCR. Once trained, the model demonstrated a predictive classification accuracy of 50.0 and 86.1% respectively for BCR and non-BCR groups on our test samples. The overall classification accuracy of the test cohort was 74.1%. The highest classification accuracy was 77.8% between three-fold cross-validation. The areas under the curve (AUC) of receiver operating characteristic curve (ROC) indices for the training and test cohorts were 0.99 and 0.73, respectively. Conclusion:The potential of multiparametric MRI-based radiomics to predict the BCR of localized prostate cancer patients was demonstrated in this manuscript. This analysis provided additional prognostic factors based on routine MR images and holds the potential to contribute to precision medicine and inform treatment management.

Keywords: imaging; prognosis; prostate neoplasm; radiomics; radiotherapy.

Copyright © 2020 Zhong, Long, Liu, Li, Xiu, Hou, Wu, Gao, Xu, Zhao, Wang, Lin, Sha, Wang, Chen and Li.

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Front Oncol
. 2020 May 8;10:726. doi: 10.3389/fonc.2020.00726. eCollection 2020.
The Genomic Characteristics of ALK Fusion Positive Tumors in Chinese NSCLC Patients
Shaokun Liu 1 2 3, Tanxiao Huang 4, Ming Liu 4, Wenlong He 1 2 3, YingShen Zhao 4, Lizhen Yang 1 2 3, Yingjiao Long 1 2 3, Dandan Zong 1 2 3, Huihui Zeng 1 2 3, Yuanyuan Liu 4, Wenting Liao 4, Jingxian Duan 4, Subo Gong 5, Shifu Chen 4
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PMID: 32457845 PMCID: PMC7225306 DOI: 10.3389/fonc.2020.00726
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Anaplastic lymphoma kinase (ALK) fusion events account for ~3-7% genetic alterations in patients with non-small cell lung cancer (NSCLC). In this study, we identified the ALK fusion patterns and a novel ALK fusion partner in 44 ALK positive NSCLC patients using a customized HapOncoCDx panel, and identified ALK fusion partners. The most common partner is EML4, forming the variant 1 (v1, E13:A20, 18/44), variant 2 (v2, E20:A20, 5/44), and variant 3 (v3, E6:A20, 13/44). Moreover, we detected a new ALK fusion partner HMBOX1. At the mutation level, TP53 is the most frequently mutated gene (24%), followed by ALK (12%) and STED2 (12%). The median tumor mutation burden (TMB) of these samples is 2.29 mutations/Mb, ranging from 0.76 mut/Mb to 16.79 muts/Mb. We further elaborately portrayed the TP53 mutation sites on the peptide sequence of the encoded protein by lollipop. The mutational signature and copy number alterations (CNAs) of the samples were also analyzed. The CNA events were found in 13 (13/44) patients, and the most commonly amplified genes were MDM2 (n = 4/13) and TERT (n = 4/13). Together, these results may guide personalized clinical management of patients with ALK fusion in the era of precision medicine.

Keywords: ALK; NGS—next generation sequencing; NSCLC; copy number aberrations; genomic landscape.

Copyright © 2020 Liu, Huang, Liu, He, Zhao, Yang, Long, Zong, Zeng, Liu, Liao, Duan, Gong and Chen.

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Front Oncol
. 2020 May 13;10:706. doi: 10.3389/fonc.2020.00706. eCollection 2020.
The Impact of Perioperative Arterial Infarct on Recurrence, Functional Outcomes, and Survival in Glioblastoma Patients
Jakob T Lupa 1, Jeffrey J Raizer 2, Irene B Helenowski 3, Benjamin P Liu 4 5, Kartik Kesavabhotla 6, Matthew C Tate 2 6
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PMID: 32477945 PMCID: PMC7237731 DOI: 10.3389/fonc.2020.00706
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Abstract
Background: Perioperative infarcts are a known complication that can occur during the resection of glioblastoma (GBM). Recent studies suggest that gross total and even "supra-total" resections may be associated with an increased survival but the rate of complications, including perioperative ischemia, may increase with these more aggressive resection strategies. However, little is known about the impact that perioperative infarcts have on survival, functional outcomes, and tumor recurrence patterns. Our study attempted to quantify and characterize the functional consequences of a perioperative infarct, as well as risk factors associated with occurrence. Methods: Seventy-three patients with a diagnosis of GBM and perioperative ischemia by MRI were identified from the electronic medical record system. We obtained demographic, prognostic, and stroke risk factor data. Infarct volumes were calculated from diffusion-weighted MRI scans, and subjects were segregated into an infarct cohort or a control cohort based on whether the identified lesion appeared to be an infarct in an arterial distribution or instead appeared to be expected postoperative changes. A multivariate statistical analysis was performed on the dataset. Results: Median age was 58.6 years, median post-op KPS (Karnofsky Performance Status) was 90, and median extent of resection (based on MRI) was 97.8%. Overall, perioperative arterial infarcts were uncommon (2.0%), did not have a statistically significant impact on survival (17.9 vs. 18.9 months), did not worsen neurologic function, and did not alter the pattern of recurrence. Conclusion: Perioperative arterial infarcts were uncommon in our patients despite aggressive resection and when present had no impact on survival or neurologic function. Given the clear benefit of maximal tumor resection, the risk of perioperative infarct should not deter maximal safe resection.

Keywords: glioblastoma; infarct; recurrence; resection; survival.

Copyright © 2020 Lupa, Raizer, Helenowski, Liu, Kesavabhotla and Tate.

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Front Oncol
. 2020 May 8;10:693. doi: 10.3389/fonc.2020.00693. eCollection 2020.
Stereotactic Cavity Irradiation or Whole-Brain Radiotherapy Following Brain Metastases Resection-Outcome, Prognostic Factors, and Recurrence Patterns
Rami A El Shafie 1 2 3, Thorsten Dresel 1 2, Dorothea Weber 4, Daniela Schmitt 1 2, Kristin Lang 1 2 3, Laila König 1 2 3, Simon Höne 1 2 3, Tobias Forster 1 2 3, Bastian von Nettelbladt 1 2 3, Tanja Eichkorn 1 2 3, Sebastian Adeberg 1 2 3, Jürgen Debus 1 2 3 5 6 7, Stefan Rieken 1 2 3 8, Denise Bernhardt 1 2 3
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PMID: 32477942 PMCID: PMC7232539 DOI: 10.3389/fonc.2020.00693
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Abstract
Introduction: Following the resection of brain metastases (BM), whole-brain radiotherapy (WBRT) is a long-established standard of care. Its position was recently challenged by the less toxic single-session radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) of the resection cavity, reducing dose exposure of the healthy brain. Patients and Methods: We analyzed 101 patients treated with either SRS/FSRT (n = 50) or WBRT (n = 51) following BM resection over a 5-year period. Propensity score adjustment was done for age, total number of BM, timepoint of BM diagnosis, controlled primary and extracranial metastases. A Cox Proportional Hazards model with univariate and multivariate analysis was fitted for overall survival (OS), local control (LC) and distant brain control (DBC). Results: Median patient age was 61 (interquartile range, IQR: 56-67) years and the most common histology was non-small cell lung cancer, followed by breast cancer. 38% of the patients had additional unresected BM. Twenty-four patients received SRS, 26 patients received FSRT and 51 patients received WBRT. Median OS in the SRS/FSRT subgroup was not reached (IQR NA-16.7 months) vs. 12.6 months (IQR 21.3-4.4) in the WBRT subgroup (hazard ratio, HR 3.3, 95%-CI: [1.5; 7.2] p < 0.002). Twelve-months LC-probability was 94.9% (95%-CI: [88.3; 100.0]) in the SRS subgroup vs. 81.7% (95%-CI: [66.6; 100.0]) in the WBRT subgroup (HR 0.2, 95%-CI: [0.01; 0.9] p = 0.037). Twelve-months DBC-probabilities were 65.0% (95%-CI: [50.8; 83.0]) and 58.8% (95%-CI: [42.9; 80.7]), respectively (HR 1.4, 95%-CI: [0.7; 2.7] p = 0.401). In propensity score-adjusted multivariate analysis, incomplete resection negatively impacted OS (HR 3.9, 95%-CI: [2.0;7.4], p < 0.001) and LC (HR 5.4, 95%-CI: [1.3; 21.9], p = 0.018). Excellent clinical performance (HR 0.4, 95%-CI: [0.2; 0.9], p = 0.030) and better graded prognostic assessment (GPA) score (HR 0.4, 95%-CI: [0.2; 1.0], p = 0.040) were prognostic of superior OS. A higher number of BM was associated with a greater risk of developing new distant BM (HR 5.6, 95%-CI: [1.0; 30.4], p = 0.048). In subgroup analysis, larger cavity volume (HR 1.1, 95%-CI: [1.0; 1.3], p = 0.033) and incomplete resection (HR 12.0, 95%-CI: [1.2; 118.3], p = 0.033) were associated with inferior LC following SRS/FSRT. Conclusion: This is the first propensity score-adjusted direct comparison of SRS/FSRT and WBRT following the resection of BM. Patients receiving SRS/FSRT showed longer OS and LC compared to WBRT. Future analyses will address the optimal choice of safety margin, dose and fractionation for postoperative stereotactic RT of the resection cavity.

Keywords: linear accelerator; palliative; radiosurgery; radiotherapy; resection cavity; robotic radiosurgery; stereotactic; whole-brain radiotherapy.

Copyright © 2020 El Shafie, Dresel, Weber, Schmitt, Lang, König, Höne, Forster, von Nettelbladt, Eichkorn, Adeberg, Debus, Rieken and Bernhardt.

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Front Oncol
. 2020 May 11;10:604. doi: 10.3389/fonc.2020.00604. eCollection 2020.
Radiomics-Based Preoperative Prediction of Lymph Node Status Following Neoadjuvant Therapy in Locally Advanced Rectal Cancer
Xuezhi Zhou 1 2, Yongju Yi 3 4, Zhenyu Liu 2 5, Zhiyang Zhou 6, Bingjia Lai 7, Kai Sun 1, Longfei Li 8, Liyu Huang 1, Yanqiu Feng 3, Wuteng Cao 6, Jie Tian 1 2 5 9
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PMID: 32477930 PMCID: PMC7233118 DOI: 10.3389/fonc.2020.00604
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Background and Purpose: Lymph node status is a key factor for the recommendation of organ preservation for patients with locally advanced rectal cancer (LARC) following neoadjuvant therapy but generally confirmed post-operation. This study aimed to preoperatively predict the lymph node status following neoadjuvant therapy using multiparametric magnetic resonance imaging (MRI)-based radiomic signature. Materials and Methods: A total of 391 patients with LARC who underwent neoadjuvant therapy and TME were included, of which 261 and 130 patients were allocated to the primary cohort and the validation cohort, respectively. The tumor area, as determined by preoperative MRI, underwent radiomics analysis to build a radiomic signature related to lymph node status. Two radiologists reassessed the lymph node status on MRI. The radiomic signature and restaging results were included in a multivariate analysis to build a combined model for predicting the lymph node status. Stratified analyses were performed to test the predictive ability of the combined model in patients with post-therapeutic MRI T1-2 or T3-4 tumors, respectively. Results: The combined model was built in the primary cohort, and predicted lymph node metastasis (LNM+) with an area under the curve of 0.818 and a negative predictive value (NPV) of 93.7% were considered in the validation cohort. Stratified analyses indicated that the combined model could predict LNM+ with a NPV of 100 and 87.8% in the post-therapeutic MRI T1-2 and T3-4 subgroups, respectively. Conclusion: This study reveals the potential of radiomics as a predictor of lymph node status for patients with LARC following neoadjuvant therapy, especially for those with post-therapeutic MRI T1-2 tumors.

Keywords: locally advanced rectal cancer; lymph node metastasis; neoadjuvant therapy; prediction; radiomics.

Copyright © 2020 Zhou, Yi, Liu, Zhou, Lai, Sun, Li, Huang, Feng, Cao and Tian.

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Front Oncol
. 2020 May 13;10:719. doi: 10.3389/fonc.2020.00719. eCollection 2020.
Interdisciplinary Surgical Approaches in Vaginal and Perineal Reconstruction of Advanced Rectal and Anal Female Cancer Patients
Raymund E Horch 1, Ingo Ludolph 1, Aijia Cai 1, Klaus Weber 2, Robert Grützmann 2, Andreas Arkudas 1
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PMID: 32477947 PMCID: PMC7237715 DOI: 10.3389/fonc.2020.00719
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Abstract
Relapsing or far advanced rectal and anal cancers remain difficult to treat and require interdisciplinary approaches. Due to modern standard protocols all patients receive irradiation and neoadjuvant chemotherapy-and in case of a relapse a second irradiation-rendering the surgical site prone to surgical site infections and oftentimes long lasting sinus and septic complications after exenteration in the pelvis. Despite an improved overall survival rate in these patients the downside of radical tumor surgery in the pelvis is a major loss of quality of life, especially in women when parts of the vagina need to be resected. Derived from our experince with over 300 patients receiving pelvic and perineal reconstruciton with a transpelvic vertical rectus abdominis myocutaneous (tpVRAM) flap we studied the impact of this surgical technique on the outcomes of female patients with or without vaginal reconstruction following pelvic exenteration. We found out that the tpVRAM flap is reliably perfused and helps to reduce long term wound healing desasters in the irradiated perineal/vaginal/gluteal region.

Keywords: VRAM; anal cancer; rectal cancer; transpelvic vertical rectus abdominis myocutaneous flap; vaginal reconstruction.

Copyright © 2020 Horch, Ludolph, Cai, Weber, Grützmann and Arkudas.

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Front Oncol
. 2020 May 8;10:533. doi: 10.3389/fonc.2020.00533. eCollection 2020.
The Quest for Improving Treatment of Cancer of Unknown Primary (CUP) Through Molecularly-Driven Treatments: A Systematic Review
Roberta Lombardo 1 2, Federica Tosi 1 2, Annunziata Nocerino 1, Katia Bencardino 1, Valentina Gambi 1, Riccardo Ricotta 1, Francesco Spina 1, Salvatore Siena 1 2, Andrea Sartore-Bianchi 1 2
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PMID: 32457826 PMCID: PMC7225282 DOI: 10.3389/fonc.2020.00533
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Background: Carcinomas of unknown primary (CUP) account for 3-5% of all malignancy and, despite a reduction in incidence, the overall survival has not improved over the last decade. Chemotherapy regimens have not provided encouraging results. New diagnostic technologies, such as next generation sequencing (NGS), could represent a chance to identify potentially targetable genomic alterations in order to personalize treatment of CUP and provide insights into tumor biology. Methods: A systematic review of studies of patients with CUP, whose tumor specimen was evaluated through a NGS panel, has been performed on June 10th, 2019 according to PRISMA criteria from PubMed, ASCO meeting library and Clinicaltrial.gov. We have identified potentially targetable alterations for which approved/off-label/in clinical trials drugs are available. Moreover, we have included case reports about CUP patients treated with targeted therapies driven by NGS results in order to explore the clinical role of NGS in this setting. Results: We have evaluated 15 publications of which eleven studies (9 full-text articles and 2 abstracts) have analyzed the genomic profiling of CUPs through NGS technology, with different platforms and with different patients cohorts, ranging from 16 to 1,806 patients. Among all these studies, 85% of patients demonstrated at least one molecular alteration, the most frequent involving TP53 (41.88%), KRAS (18.81%), CDKN2A (8.8%), and PIK3CA (9.3%). A mean of 47.3% of patients harbored a potentially targetable alteration for which approved/off-label/in clinical trials drugs were available. Furthermore, we have identified 4 case reports in order to evaluate the clinical relevance of a specific targeted therapy identified through NGS. Conclusions: NGS may represent a tool to improve diagnosis and treatment of CUP by identifying therapeutically actionable alterations and providing insights into tumor biology.

Keywords: cancer of unknown primary (CUP); comprehensive genomic profiling; genomic alterations; next generation sequencing (NGS); targeted therapy.

Copyright © 2020 Lombardo, Tosi, Nocerino, Bencardino, Gambi, Ricotta, Spina, Siena and Sartore-Bianchi.

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Review Front Oncol
. 2020 May 12;10:737. doi: 10.3389/fonc.2020.00737. eCollection 2020.
Diacylglycerol Kinase Alpha in Radiation-Induced Fibrosis: Potential as a Predictive Marker or Therapeutic Target
Chun-Shan Liu 1, Peter Schmezer 1, Odilia Popanda 1
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PMID: 32477950 PMCID: PMC7235333 DOI: 10.3389/fonc.2020.00737
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Radiotherapy is an efficient tool in cancer treatment, but it brings along the risk of side effects such as fibrosis in the irradiated healthy tissue thus limiting tumor control and impairing quality of life of cancer survivors. Knowledge on radiation-related fibrosis risk and therapeutic options is still limited and requires further research. Recent studies demonstrated that epigenetic regulation of diacylglycerol kinase alpha (DGKA) is associated with radiation-induced fibrosis. However, the specific mechanisms are still unknown. In this review, we scrutinized the role of DGKA in the radiation response and in further cellular functions to show the potential of DGKA as a predictive marker or a novel target in fibrosis treatment. DGKA was reported to participate in immune response, lipid signaling, exosome production, and migration as well as cell proliferation, all processes which are suggested to be critical steps in fibrogenesis. Most of these functions are based on the conversion of diacylglycerol (DAG) to phosphatidic acid (PA) at plasma membranes, but DGKA might have also other, yet not well-known functions in the nucleus. Current evidence summarized here underlines that DGKA activation may play a central role in fibrosis formation post-irradiation and shows a potential of direct DGKA inhibitors or epigenetic modulators to attenuate pro-fibrotic reactions, thus providing novel therapeutic choices.

Keywords: diacylglycerol; fibrosis; late adverse effects; lipid signaling; phosphatidic acid; radiotherapy.

Copyright © 2020 Liu, Schmezer and Popanda.

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Review Front Oncol
. 2020 May 12;10:620. doi: 10.3389/fonc.2020.00620. eCollection 2020.
Biochemical Predictors of Response to Neoadjuvant Therapy in Pancreatic Ductal Adenocarcinoma
Seifeldin Awad 1, Ahmad M Alkashash 1, Magi Amin 2, Samantha J Baker 1, J Bart Rose 1
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PMID: 32477933 PMCID: PMC7235358 DOI: 10.3389/fonc.2020.00620
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Pancreatic ductal adenocarcinoma (PDAC) is becoming increasingly more common. Treatment for PDAC is dependent not only on stage at diagnosis, but complex anatomical relationships. Recently, the therapeutic approach to this disease has shifted from upfront surgery for technically resectable lesions to a neoadjuvant therapy first approach. Selecting an appropriate regimen and determining treatment response is crucial for optimal oncologic outcome, especially since radiographic imaging has proven unreliable in this setting. Tumor biomarkers have the potential to play a key role in treatment planning, treatment monitoring, and surveillance as an adjunct laboratory test. In this review, we will discuss common chemotherapeutic options, mechanisms of resistance, and potential biomarkers for PDAC. The aim of this paper is to present currently available biomarkers for PDAC and to discuss how these markers may be affected by neoadjuvant chemotherapy treatment. Understanding current chemotherapy regiments and mechanism of resistance can help us understand which markers may be most affected and why; therefore, determining to what ability we can use them as a marker for treatment progression, prognosis, or potential relapse.

Keywords: CA 19-9–carbohydrate antigen 19-9; biomarker (development); neoadjuvant chemotheraphy; pancreatic duct adenocarcinoma (PDAC); tumor biomarker.

Copyright © 2020 Awad, Alkashash, Amin, Baker and Rose.

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Front Oncol
. 2020 May 14;10:559. doi: 10.3389/fonc.2020.00559. eCollection 2020.
Expression and Significance of MyD88 in Patients With Gastric Cardia Cancer in a High-Incidence Area of China
Jingyao Chen 1, Di Xia 1, Muming Xu 2, Ruibing Su 1, Wenting Lin 1, Dan Guo 1, Guangcan Chen 3, Shuhui Liu 1
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PMID: 32477927 PMCID: PMC7239990 DOI: 10.3389/fonc.2020.00559
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Background: Gastric cardia cancer (GCC) arises in the area of the stomach adjoining the esophageal-gastric junction and has unique risk factors. It was suggested that the involvement of Helicobacter pylori is associated with GCC from high-risk population. Myeloid differentiation factor 88 (MyD88) is a crucial adaptor molecule in Toll-like signaling pathway recognizing H. pylori. Its role in GCC has not been elucidated yet. In this study, our purpose is to investigate the expression and significance of MyD88 in GCC tissue. Methods: Expression of MyD88 and nuclear factor κB (NF-κB) p105/p50 and infection of H. pylori were detected by immunohistochemistry in gastric cardia tissue. The correlation of MyD88 expression to NF-κB p105/p50 expression, H. pylori infection, and clinicopathologic characteristics in gastric cardia tissue was analyzed. The involvement of MyD88 in patient prognosis was also analyzed. Results: Our data showed that the expression of MyD88 elevated from normal mucosa to inflammation (p = 0.071). The expression of MyD88 was enhanced in GCC tissues by contrast to non-malignant cardia mucosa (p = 0.025). What's more, overexpression of MyD88 was detected in intestinal-type adenocarcinoma with inflammation. Patients with high MyD88 staining revealed a better differentiation (p = 0.02). MyD88 also positively correlated with NF-κB p105/p50 expression (p = 0.012) in cancer tissue. Expression of MyD88 was increased but not significantly in biopsies with H. pylori infection compared with non-infected biopsies. Multivariate analyses revealed lymph node metastasis but not MyD88 expression was an independent predictor for patient survival. Conclusion: These findings provide pathological evidence that upregulating MyD88 and inducing inflammation might be involved in gastric cardia carcinogenesis in high-risk population. MyD88 plays a role in gastric cardia carcinogenesis with NF-κB pathway activation. Higher MyD88 expression is not a major prognostic determinant in GCC, but it may relate to the tumor cell differentiation.

Keywords: Helicobacter pylori; MyD88; cancer and inflammation; gastric cardia cancer; prognosis.

Copyright © 2020 Chen, Xia, Xu, Su, Lin, Guo, Chen and Liu.

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Front Oncol
. 2020 May 8;10:704. doi: 10.3389/fonc.2020.00704. eCollection 2020.
Noise-Corrected, Exponentially Weighted, Diffusion-Weighted MRI (niceDWI) Improves Image Signal Uniformity in Whole-Body Imaging of Metastatic Prostate Cancer
Matthew D Blackledge 1, Nina Tunariu 1 2, Fabio Zungi 1 2, Richard Holbrey 1, Matthew R Orton 1, Ana Ribeiro 1, Julie C Hughes 1, Erica D Scurr 1, David J Collins 1, Martin O Leach 1, Dow-Mu Koh 1 2
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PMID: 32457842 PMCID: PMC7225292 DOI: 10.3389/fonc.2020.00704
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Abstract
Purpose: To characterize the voxel-wise uncertainties of Apparent Diffusion Coefficient (ADC) estimation from whole-body diffusion-weighted imaging (WBDWI). This enables the calculation of a new parametric map based on estimates of ADC and ADC uncertainty to improve WBDWI imaging standardization and interpretation: NoIse-Corrected Exponentially-weighted diffusion-weighted MRI (niceDWI). Methods: Three approaches to the joint modeling of voxel-wise ADC and ADC uncertainty (σADC) are evaluated: (i) direct weighted least squares (DWLS), (ii) iterative linear-weighted least-squares (IWLS), and (iii) smoothed IWLS (SIWLS). The statistical properties of these approaches in terms of ADC/σADC accuracy and precision is compared using Monte Carlo simulations. Our proposed post-processing methodology (niceDWI) is evaluated using an ice-water phantom, by comparing the contrast-to-noise ratio (CNR) with conventional exponentially-weighted DWI. We present the clinical feasibility of niceDWI in a pilot cohort of 16 patients with metastatic prostate cancer. Results: The statistical properties of ADC and σADC conformed closely to the theoretical predictions for DWLS, IWLS, and SIWLS fitting routines (a minor bias in parameter estimation is observed with DWLS). Ice-water phantom experiments demonstrated that a range of CNR could be generated using the niceDWI approach, and could improve CNR compared to conventional methods. We successfully implemented the niceDWI technique in our patient cohort, which visually improved the in-plane bias field compared with conventional WBDWI. Conclusions: Measurement of the statistical uncertainty in ADC estimation provides a practical way to standardize WBDWI across different scanners, by providing quantitative image signals that improve its reliability. Our proposed method can overcome inter-scanner and intra-scanner WBDWI signal variations that can confound image interpretation.

Keywords: apparent diffusion coefficient; imaging biomarker reproducibility; imaging biomarker uncertainty; metastatic prostate cancer; whole-body diffusion-weighted MRI.

Copyright © 2020 Blackledge, Tunariu, Zungi, Holbrey, Orton, Ribeiro, Hughes, Scurr, Collins, Leach and Koh.

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Front Oncol
. 2020 May 8;10:568. doi: 10.3389/fonc.2020.00568. eCollection 2020.
Single-Isocenter Volumetric Modulated Arc Therapy vs. CyberKnife M6 for the Stereotactic Radiosurgery of Multiple Brain Metastases
Rami A El Shafie 1 2, Eric Tonndorf-Martini 1 2, Daniela Schmitt 1 2, Aylin Celik 1 2, Dorothea Weber 3, Kristin Lang 1 2, Laila König 1 2, Simon Höne 1 2, Tobias Forster 1 2, Bastian von Nettelbladt 1 2, Sebastian Adeberg 1 2, Jürgen Debus 1 2 4 5, Stefan Rieken 1 2 6, Denise Bernhardt 1 2
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PMID: 32457829 PMCID: PMC7225280 DOI: 10.3389/fonc.2020.00568
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Abstract
Introduction: Stereotactic radiosurgery (SRS) is becoming more frequently used for patients with multiple brain metastases (BMs). Single-isocenter volumetric modulated arc therapy (SI-VMAT) is an emerging alternative to dedicated systems such as CyberKnife (CK). We present a dosimetric comparison between CyberKnife M6 and SI-VMAT, planned at RayStation V8B, for the simultaneous SRS of five or more BM. Patients and Methods: Twenty treatment plans of CK-based single-session SRS to ≥5 brain metastases were replanned using SI-VMAT for delivery at an Elekta VersaHD linear accelerator. Prescription dose was 20 or 18 Gy, conformally enclosing at least 98% of the total planning target volume (PTV), with PTV margin-width adapted to the respective SRS technique. Comparatively analyzed quality metrics included dose distribution to the healthy brain (HB), including different isodose volumes, conformity, and gradient indices. Estimated treatment time was also compared. Results: Median HB isodose volumes for 3, 5, 8, 10, and 12 Gy were consistently smaller for CK-SRS compared to SI-VMAT (p < 0.001). Dose falloff outside the target volume, as expressed by the gradient indices GI_high and GI_low, was consistently steeper for CK-SRS compared to SI-VMAT (p < 0.001). CK-SRS achieved a median GI_high of 3.1 [interquartile range (IQR), 2.9-1.3] vs. 5.0 (IQR 4.3-5.5) for SI-VMAT (p < 0.001). For GI_low, the results were 3.0 (IQR, 2.9-3.1) for CK-SRS vs. 5.6 (IQR, 4.3-5.5) for SI-VMAT (p < 0.001). The median conformity index (CI) was 1.2 (IQR, 1.1-1.2) for CK-SRS vs. 1.5 (IQR, 1.4-1.7) for SI-VMAT (p < 0.001). Estimated treatment time was shorter for SI-VMAT, yielding a median of 13.7 min (IQR, 13.5-14.0) compared to 130 min (IQR, 114.5-154.5) for CK-SRS (p < 0.001). Conclusion: SI-VMAT offers enhanced treatment efficiency in cases with multiple BM, as compared to CyberKnife, but requires compromise regarding conformity and integral dose to the healthy brain. Additionally, delivery at a conventional linear accelerator (linac) may require a larger PTV margin to account for delivery and setup errors. Further evaluations are warranted to determine whether the detected dosimetric differences are clinically relevant. SI-VMAT could be a reasonable alternative to a dedicated radiosurgery system for selected patients with multiple BM.

Keywords: linear accelerator; multiple brain metastases; palliative; radiosurgery; radiotherapy; robotic radiosurgery; stereotactic; whole-brain radiotherapy.

Copyright © 2020 El Shafie, Tonndorf-Martini, Schmitt, Celik, Weber, Lang, König, Höne, Forster, von Nettelbladt, Adeberg, Debus, Rieken and Bernhardt.

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Front Oncol
. 2020 May 13;10:766. doi: 10.3389/fonc.2020.00766. eCollection 2020.
A Novel Prognostic Marker Systemic Inflammation Response Index (SIRI) for Operable Cervical Cancer Patients
Bei Chao 1, Xiaoli Ju 2, Lirong Zhang 1, Xin Xu 1, Yan Zhao 1
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PMID: 32477958 PMCID: PMC7237698 DOI: 10.3389/fonc.2020.00766
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It has been confirmed that the systemic inflammation response index (SIRI) based on peripheral blood neutrophil, monocyte and lymphocyte counts can be used for the prognostication of patients with various malignant tumors. However, the prognostic value of SIRI in cervical cancer patients has not yet been reported. This study found that a higher SIRI was related to lymphovascular invasion and was also significantly associated with FIGO stage, radiotherapy, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and monocyte/lymphocyte ratio (MLR) but not related to other clinical and pathological parameters. According to the Kaplan-Meier survival analysis, a high SIRI was associated with the poor prognosis of cervical cancer patients in the primary and validation groups. SIRI, NLR, PLR, and MLR can all be used to determine the prognosis of patients with operable cervical cancer. Moreover, it was confirmed that only SIRI was an independent prognostic factor for patients with operable cervical cancer. The same result was obtained in the propensity score matching (PSM) analysis. In the ROC curve analysis, SIRI was more accurate in predicting the prognosis of cervical cancer patients. Then, a nomogram was established based on SIRI, FIGO stage and lymphovascular invasion, which could determine the prognosis of cervical cancer patients more accurately than FIGO stage. The validation cohort showed the same results. In addition, the changes in SIRI relative to the baseline value at 4-8 weeks after surgery were closely related to the survival of cervical cancer patients. Compared with those with unchanged SIRI (absolute value of variation <25%), cervical cancer patients with an increase in SIRI > 75% had worse OS (P < 0.001), while patients with a decrease in SIRI > 75% had a better prognosis (P < 0.001). SIRI can serve as a new independent prognostic index and a potential marker for therapeutic response monitoring in patients with curable cervical cancer. Compared with the traditional FIGO staging system, the nomogram integrating SIRI can predict the survival of cervical cancer patients more objectively and reliably after radical surgery.

Keywords: PSM; cervical cancer; nomogram; prognosis; systemic inflammation response index.

Copyright © 2020 Chao, Ju, Zhang, Xu and Zhao.

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Front Oncol
. 2020 May 13;10:742. doi: 10.3389/fonc.2020.00742. eCollection 2020.
CT Derived Hounsfield Unit: An Easy Way to Determine Osteoporosis and Radiation Related Fracture Risk in Irradiated Patients
Gokhan Yaprak 1, Cengiz Gemici 1, Ozgur O Seseogullari 2, Irem S Karabag 3, Nilsu Cini 1
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PMID: 32477951 PMCID: PMC7237579 DOI: 10.3389/fonc.2020.00742
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Background: We aimed to evaluate osteoporosis, bone mineral density, and fracture risk in irradiated patients by computerized tomography derived Hounsfield Units (HUs) calculated from radiation treatment planning system. Methods: Fifty-seven patients operated for gastric adenocarcinoma who received adjuvant abdominal radiotherapy were included in the study group. Thirty-four patients who were not irradiated after surgery comprised the control group. HUs of T12, L1, L2 vertebral bodies were measured from the computerized tomographies imported to the treatment planning system for all the patients. While the measurements were obtained just after surgery and 1 year later after surgery in the control group, the same measurements were obtained just before irradiation and 1 year after radiotherapy in the study group. Percent change in HU values (Δ%HU) was determined for each group. Vertebral compression fractures, which are the consequence of radiation induced osteoporosis and bone toxicity were assessed during follow-up. Results: There was no statistical significant difference in HU values measured for all the vertebrae between the study and the control group at the onset of the study. While HU values decreased significantly in the study group, there was no significant reduction in HU values in the control group after 1 year. significant correlation was found between Δ%HU and the radiation dose received by each vertebra. Insufficiency fractures (IFs) were observed only in the irradiated patients (4 out of 57 patients) with the cumulative incidence of 7%. Conclusions: HU values are very valuable in determining bone mineral density and fracture risk. Radiation treatment planning system can be utilized to determine HU values. IFs are common after abdominal radiotherapy in patients with low vertebral HU values detected during radiation treatment planning. Radiation dose to the vertebral bones with low HU values should be limited below 20 Gy to prevent late radiation related bone toxicity.

Keywords: bone; bone mineral density; hounsfield unit; osteoporosis; radiation toxicity.

Copyright © 2020 Yaprak, Gemici, Seseogullari, Karabag and Cini.

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Front Oncol
. 2020 May 12;10:645. doi: 10.3389/fonc.2020.00645. eCollection 2020.
Protective Role of Decorin in Primary Hepatocellular Carcinoma
Andrea Reszegi 1, Zsolt Horváth 1, Hajnalka Fehér 1, Barnabás Wichmann 2, Péter Tátrai 3, Ilona Kovalszky 1, Kornélia Baghy 1
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PMID: 32477937 PMCID: PMC7235294 DOI: 10.3389/fonc.2020.00645
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Hepatocellular carcinoma (HCC) represents one of the most frequent type of primary liver cancers. Decorin, a small leucine-rich proteoglycan of the extracellular matrix, represents a powerful tumor cell growth and migration inhibitor by hindering receptor tyrosine kinases and inducing p21WAF1/CIP1. In this study, first we tested decorin expression in HCCs utilizing in silico data, as well as formalin fixed paraffin embedded tissue samples of HCC in a tissue microarray (TMA). In silico data revealed that DCN/SMA mRNA ratio is decreased in HCC compared to normal tissues and follows the staging of the disease. Among TMA samples, 52% of HCCs were decorin negative, 33% exhibited low, and 15% high decorin levels corroborating in silico results. In addition, applying conditioned media of hepatoma cells inhibited decorin expression in LX2 stellate cells in vitro. These results raise the possibility that decorin acts as a tumor suppressor in liver cancer and that is why its expression decreased in HCCs. To further test the protective role of decorin, the proteoglycan was overexpressed in a mouse model of hepatocarcinogenesis evoked by thioacetamide (TA). After transfection, the excessive proteoglycan amount was mainly detected in hepatocytes around the central veins. Upon TA-induced hepatocarcinogenesis, the highest tumor count was observed in mice with no decorin production. Decorin gene delivery reduced tumor formation, in parallel with decreased pEGFR, increased pIGF1R levels, and with concomitant induction of pAkt (T308) and phopho-p53, suggesting a novel mechanism of action. Our results suggest the idea that decorin can be utilized as an anti-cancer agent.

Keywords: decorin (DCN); extracellular matrix (ECM); hepatocarcinogenesis; hepatocellular carcinoma; proteoglycan (PG).

Copyright © 2020 Reszegi, Horváth, Fehér, Wichmann, Tátrai, Kovalszky and Baghy.

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Case Reports Front Oncol
. 2020 May 8;10:611. doi: 10.3389/fonc.2020.00611. eCollection 2020.
Talimogene Laherparepvec in Advanced Mucosal Melanoma of the Urethra Upon Primary Resistance on Immune Checkpoint Inhibition: A Case Report
Anne Fröhlich 1, Friederike Hoffmann 1, Dennis Niebel 1, Eva Egger 2, Guido M Kukuk 3, Marieta Toma 4, Judith Sirokay 1, Thomas Bieber 1, Jennifer Landsberg 1
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PMID: 32457834 PMCID: PMC7225290 DOI: 10.3389/fonc.2020.00611
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Background: Mucosal melanomas including melanomas of the urogenital tract represent a rare type of melanoma characterized by low mutational burden and poor prognosis. Immune checkpoint inhibition has so far only been assessed in a limited number of mucosal melanoma patients and, in contrast to response in cutaneous melanoma, was associated with disappointing response rates. The oncolytic viral immunotherapy Talimogene laherparepvec (T-VEC) has recently been approved for treatment of locally advanced or unresectable melanoma. T-VEC combines direct oncolytic effects with local and systemic immune-mediated anti-tumor response. Our rationale to use T-VEC in this case was an expected augmentation of immunogenicity by tumor lysis to overcome primary resistance of a mucosal melanoma to immune checkpoint blockade. Objective: To report the first case of an advanced mucosal melanoma of the urethra treated with intralesional application of Talimogene laherparepvec. Case Report: A 78-years old female patient was diagnosed with an advanced mucosal melanoma of the urethra with inguinal lymph node metastases and intravaginal mucosal metastases. Shortly after surgical resection of the tumor mass, intravaginal mucosal metastases, and new nodal metastases in proximity of the left iliac vessels were diagnosed. The patient was treated with the anti-PD1 antibody pembrolizumab and obtained a stable disease lasting for 30 weeks. However, upon checkpoint inhibition the patient developed a loco-regional progressive disease featuring bleeding intravaginal metastases, while nodal metastases remained stable. We stopped treatment with pembrolizumab and administered T-VEC directly into the intravaginal mucosal metastases. After five injections T-VEC yielded a partial response with clinical regression of the injected mucosal metastases. Disease remained stable for 16 weeks under biweekly T-VEC treatment. Thereafter the patient showed disease progression in nodal metastases. T-VEC was discontinued. Immunotherapy with pembrolizumab was restarted but failed to achieve a response. Finally, targeted therapy with imatinib was induced in presence of a druggable c-KIT mutation, leading to a considerable response of all tumor sites that is still ongoing. Conclusion: T-VEC represents an effective and well-tolerated treatment option for patients with loco-regionally advanced mucosal melanoma. In combination with immunotherapy, T-VEC bears the potential of synergistic effects to overcome the specific primary resistance of mucosal melanoma to immune checkpoint blockade.

Keywords: immune checkpoint blockade; intralesional treatment; mucosal melanoma; primary resistance; talimogene laherparepvec.

Copyright © 2020 Fröhlich, Hoffmann, Niebel, Egger, Kukuk, Toma, Sirokay, Bieber and Landsberg.

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43
Front Oncol
. 2020 May 12;10:729. doi: 10.3389/fonc.2020.00729. eCollection 2020.
Co-Occurring Alterations of ERBB2 Exon 20 Insertion in Non-Small Cell Lung Cancer (NSCLC) and the Potential Indicator of Response to Afatinib
Bo Yuan 1, Jun Zhao 2, Chengzhi Zhou 3, Xiumei Wang 4, Bo Zhu 5, Minglei Zhuo 2, Xilin Dong 1, Jiemei Feng 6, Cuihua Yi 7, Yunpeng Yang 8, Hua Zhang 9, Wangyan Zhou 10, Zhengtang Chen 5, Sheng Yang 11, Xinghao Ai 12, Kehe Chen 13, Xuefan Cui 14, Difa Liu 15, Chunmei Shi 11, Wei Wu 16, Yanjun Zhang 17, Lianpeng Chang 18, Jin Li 18, Rongrong Chen 18, Shuanying Yang 1
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PMID: 32477948 PMCID: PMC7236802 DOI: 10.3389/fonc.2020.00729
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Background: Human epidermal growth factor receptor 2 (ERBB2, HER-2) exon 20 insertion (ERBB2ex20ins) remains a refractory oncogenic driver in lung cancer. So far there is limited data showing the co-occurring mutation background of ERBB2ex20ins in Chinese lung cancer and its relationship with response to afatinib. Patients and Methods: A total of 112 Chinese patients with ERBB2ex20ins identified by next-generation sequencing from 17 hospitals were enrolled. The clinical outcomes of 18 patients receiving afatinib treatment were collected. Results: Among the 112 patients, insertion-site subtypes comprised of A775ins (71%; 79/112), G776indel (17%; 19/112), and P780ins (12%; 14/112). There were 66.1% (74/112) of patients carrying TP53 co-mutation and FOXA1 was the most prevalent co-amplified gene (5.5%, 3/55). The co-occurring genomic feature was similar among three insertional-site subtypes and had an overall strong concordance with the western population from the MSKCC cohort (R 2 = 0.74, P < 0.01). For the prognosis, patients with co-occurring mutation in cell-cycle pathway especially TP53 showed shorter OS than patients without [median OS: 14.5 m (95% CI:12.7-16.3 m) vs. 30.3 m (95% CI: not reached), p = 0.04], while the OS was comparable among three subtypes. For the response to afatinib, ERBB2ex20ins as a subclonal variant was an independent factor relating to shorter PFS [median PFS: 1.2 m (95% CI: 0.8-1.6 m) vs. 4.3 m (95% CI: 3.3-5.3 m), p < 0.05]. Conclusion: Our data revealed co-occurring TP53 represent an unfavorable prognosis of patients with ERBB2ex20ins, emphasizing the more valuable role of the co-mutation patterns than insertion-site subtypes in predicting prognosis of this group of patients. Moreover, the clonality status of ERBB2ex20ins was identified as a potential indicator for response to afatinib.

Keywords: ERBB2 exon 20 insertion; afatinib; clonality status; co-occurring alterations; non-small cell lung cancer.

Copyright © 2020 Yuan, Zhao, Zhou, Wang, Zhu, Zhuo, Dong, Feng, Yi, Yang, Zhang, Zhou, Chen, Yang, Ai, Chen, Cui, Liu, Shi, Wu, Zhang, Chang, Li, Chen and Yang.

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Front Oncol
. 2020 May 12;10:656. doi: 10.3389/fonc.2020.00656. eCollection 2020.
LncRNA UCA1 Induces Acquired Resistance to Gefitinib by Epigenetically Silencing CDKN1A Expression in Non-small-Cell Lung Cancer
Tianwei Xu 1, Shuai Yan 1 2, Mengwei Wang 1, Lihua Jiang 1, Pei Ma 3, Binbin Lu 1, Qinnan Chen 1, Chenchen Wei 1, Zhaoxia Wang 1
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PMID: 32477939 PMCID: PMC7235350 DOI: 10.3389/fonc.2020.00656
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Lung cancer is the most common cancer globally and is associated with high morbidity and mortality. Gefitinib has been widely used for treating advanced non-small-cell lung cancer (NSCLC). However, acquired resistance usually develops, although we still know little about the mechanism underlying this. In the present study, we found that the lncRNA UCA1 was upregulated in NSCLC tissues and cells with acquired gefitinib resistance, indicating the special role of UCA1 in gefitinib resistance. Knockdown of UCA1 promoted the sensitivity to gefitinib both in vitro and in vivo by suppressing cell proliferation and inducing apoptosis. Moreover, UCA1 could interact with EZH2 (enhancer of zeste homolog 2) to epigenetically reduce the expression of CDKN1A. Taking the obtained findings together, our study suggests that UCA1 is important for NSCLC to develop gefitinib resistance, and is a potential biomarker for gefitinib resistance and a therapeutic target for advanced NSCLC.

Keywords: CDKN1A; NSCLC; UCA1; gefitinib; lncRNA; resistance.

Copyright © 2020 Xu, Yan, Wang, Jiang, Ma, Lu, Chen, Wei and Wang.

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Front Oncol
. 2020 May 7;10:560. doi: 10.3389/fonc.2020.00560. eCollection 2020.
Clinical Multigene Panel Sequencing Identifies Distinct Mutational Association Patterns in Metastatic Colorectal Cancer
Francesca Belardinilli 1, Carlo Capalbo 1, Umberto Malapelle 2, Pasquale Pisapia 2, Domenico Raimondo 1, Edoardo Milanetti 3, Mahdavian Yasaman 1, Carlotta Liccardi 1, Paola Paci 4, Pasquale Sibilio 4, Francesco Pepe 2, Caterina Bonfiglio 5, Silvia Mezi 6, Valentina Magri 7, Anna Coppa 8, Arianna Nicolussi 8, Angela Gradilone 1, Marialaura Petroni 9, Stefano Di Giulio 1, Francesca Fabretti 1, Paola Infante 9, Sonia Coni 1, Gianluca Canettieri 1 10, Giancarlo Troncone 2, Giuseppe Giannini 1 10
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PMID: 32457828 PMCID: PMC7221020 DOI: 10.3389/fonc.2020.00560
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Extensive molecular characterization of human colorectal cancer (CRC) via Next Generation Sequencing (NGS) indicated that genetic or epigenetic dysregulation of a relevant, but limited, number of molecular pathways typically occurs in this tumor. The molecular picture of the disease is significantly complicated by the frequent occurrence of individually rare genetic aberrations, which expand tumor heterogeneity. Inter- and intratumor molecular heterogeneity is very likely responsible for the remarkable individual variability in the response to conventional and target-driven first-line therapies, in metastatic CRC (mCRC) patients, whose median overall survival remains unsatisfactory. Implementation of an extensive molecular characterization of mCRC in the clinical routine does not yet appear feasible on a large scale, while multigene panel sequencing of most commonly mutated oncogene/oncosuppressor hotspots is more easily achievable. Here, we report that clinical multigene panel sequencing performed for anti-EGFR therapy predictive purposes in 639 formalin-fixed paraffin-embedded (FFPE) mCRC specimens revealed previously unknown pairwise mutation associations and a high proportion of cases carrying actionable gene mutations. Most importantly, a simple principal component analysis directed the delineation of a new molecular stratification of mCRC patients in eight groups characterized by non-random, specific mutational association patterns (MAPs), aggregating samples with similar biology. These data were validated on a The Cancer Genome Atlas (TCGA) CRC dataset. The proposed stratification may provide great opportunities to direct more informed therapeutic decisions in the majority of mCRC cases.

Keywords: NGS; genes; mCRC; molecular stratification; mutation.

Copyright © 2020 Belardinilli, Capalbo, Malapelle, Pisapia, Raimondo, Milanetti, Yasaman, Liccardi, Paci, Sibilio, Pepe, Bonfiglio, Mezi, Magri, Coppa, Nicolussi, Gradilone, Petroni, Di Giulio, Fabretti, Infante, Coni, Canettieri, Troncone and Giannini.

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Front Oncol
. 2020 May 12;10:618. doi: 10.3389/fonc.2020.00618. eCollection 2020.
Predicting Progression-Free Survival Using MRI-Based Radiomics for Patients With Nonmetastatic Nasopharyngeal Carcinoma
Hesong Shen 1 2, Yu Wang 1 2, Daihong Liu 1 2, Rongfei Lv 3, Yuanying Huang 4, Chao Peng 3, Shixi Jiang 1, Ying Wang 5, Yongpeng He 6, Xiaosong Lan 1, Hong Huang 3, Jianqing Sun 7, Jiuquan Zhang 1 2
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PMID: 32477932 PMCID: PMC7235342 DOI: 10.3389/fonc.2020.00618
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Objectives: This study aimed to explore the predictive value of MRI-based radiomic model for progression-free survival (PFS) in nonmetastatic nasopharyngeal carcinoma (NPC). Methods: A total of 327 nonmetastatic NPC patients [training cohort (n = 230) and validation cohort (n = 97)] were enrolled. The clinical and MRI data were collected. The least absolute shrinkage selection operator (LASSO) and recursive feature elimination (RFE) were used to select radiomic features. Five models [Model 1: clinical data, Model 2: overall stage, Model 3: radiomics, Model 4: radiomics + overall stage, Model 5: radiomics + overall stage + Epstein-Barr virus (EBV) DNA] were constructed. The prognostic performances of these models were evaluated by Harrell's concordance index (C-index). The Kaplan-Meier method was applied for the survival analysis. Results: Model 5 incorporating radiomics, overall stage, and EBV DNA yielded the highest C-indices for predicting PFS in comparison with Model 1, Model 2, Model 3, and Model 4 (training cohorts: 0.805 vs. 0.766 vs. 0.749 vs. 0.641 vs. 0.563, validation cohorts: 0.874 vs. 0.839 vs. 836 vs. 0.689 vs. 0.456). The survival curve showed that the high-risk group yielded a lower PFS than the low-risk group. Conclusions: The model incorporating radiomics, overall stage, and EBV DNA showed better performance for predicting PFS in nonmetastatic NPC patients.

Keywords: magnetic resonance imaging; nasopharyngeal carcinoma; prediction; progression-free survival; radiomics.

Copyright © 2020 Shen, Wang, Liu, Lv, Huang, Peng, Jiang, Wang, He, Lan, Huang, Sun and Zhang.

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Front Oncol
. 2020 May 12;10:596. doi: 10.3389/fonc.2020.00596. eCollection 2020.
Topographical Mapping of 436 Newly Diagnosed IDH Wildtype Glioblastoma With vs. Without MGMT Promoter Methylation
Fatih Incekara 1 2, Sebastian R van der Voort 2, Hendrikus J Dubbink 3, Peggy N Atmodimedjo 3, Rishi Nandoe Tewarie 4, Geert Lycklama 5, Arnaud J P E Vincent 1, Johan M Kros 3, Stefan Klein 2, Martin van den Bent 6, Marion Smits 2
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PMID: 32477929 PMCID: PMC7235346 DOI: 10.3389/fonc.2020.00596
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Introduction: O6 -methylguanine-methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase (IDH) mutation status are important prognostic factors for patients with glioblastoma. There are conflicting reports about a differential topographical distribution of glioblastoma with vs. without MGMT promoter methylation, possibly caused by molecular heterogeneity in glioblastoma populations. We initiated this study to re-evaluate the topographical distribution of glioblastoma with vs. without MGMT promoter methylation in light of the updated WHO 2016 classification. Methods: Preoperative T2-weighted/FLAIR and postcontrast T1-weighted MRI scans of patients aged 18 year or older with IDH wildtype glioblastoma were collected. Tumors were semi-automatically segmented, and the topographical distribution between glioblastoma with vs. without MGMT promoter methylation was visualized using frequency heatmaps. Then, voxel-wise differences were analyzed using permutation testing with Threshold Free Cluster Enhancement. Results: Four hundred thirty-six IDH wildtype glioblastoma patients were included; 211 with and 225 without MGMT promoter methylation. Visual examination suggested that when compared with MGMT unmethylated glioblastoma, MGMT methylated glioblastoma were more frequently located near bifrontal and left occipital periventricular area and less frequently near the right occipital periventricular area. Statistical analyses, however, showed no significant difference in topographical distribution between MGMT methylated vs. MGMT unmethylated glioblastoma. Conclusions: This study re-evaluated the topographical distribution of MGMT promoter methylation in 436 newly diagnosed IDH wildtype glioblastoma, which is the largest homogenous IDH wildtype glioblastoma population to date. There was no statistically significant difference in anatomical localization between MGMT methylated vs. unmethylated IDH wildtype glioblastoma.

Keywords: MGMT; atlas; glioblastoma; heatmap; localization.

Copyright © 2020 Incekara, van der Voort, Dubbink, Atmodimedjo, Nandoe Tewarie, Lycklama, Vincent, Kros, Klein, van den Bent and Smits.

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Front Oncol
. 2020 May 8;10:612. doi: 10.3389/fonc.2020.00612. eCollection 2020.
Small Molecule Inhibitor C188-9 Synergistically Enhances the Demethylated Activity of Low-Dose 5-Aza-2'-Deoxycytidine Against Pancreatic Cancer
Rui Kong 1 2, Guangming Sun 1 2, Xina Li 1, Linfeng Wu 1 2, Le Li 1 2, Yilong Li 1 2, Fei Wang 1, Ping Xuan 3, Shifeng Yang 1, Bei Sun 1 2, Jisheng Hu 1 2
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PMID: 32457835 PMCID: PMC7225308 DOI: 10.3389/fonc.2020.00612
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Aberrant DNA methylation, especially hypermethylation of tumor suppressor genes, has been associated with many cancers' progression. 5-Aza-2'-deoxycytidine (DAC) can reverse hypermethylation-induced gene silencing via regulating DNA methyltransferases (DNMTs) activity, In addition, low-dose of DAC was proved to exert durable antitumor effects against solid tumor cells. Nevertheless, no clinical effect of DAC has been made when fighting against pancreatic cancer. Hence, it is necessary to raise a novel therapeutic strategy that further enhance the efficacy of DAC but not increase side effect, which impede the utilization of DAC. In the present study, we have discovered that C188-9, a novel signal transduction activator of transcription (STAT) inhibitor, could improve the antitumor effects of low-dose DAC in vivo and in vitro. Further study demonstrated that such improvement was attributed to re-expression of Ras association domain family member 1A (RASSF1A), a well-known tumor suppressor gene. Bisulfite sequencing PCR (BSP) assay showed that C188-9 combined with DAC treatment could significantly reverse the hypermethylation status of RASSF1A promoter, which indicated that C188-9 could enhance the demethylation efficacy of DAC. Our data demonstrated that DNA methyltransferase 1 (DNMT1) was the underlying mechanism that C188-9 regulates the demethylation efficacy of DAC. Overall, these findings provide a novel therapeutic strategy combining low-dose DAC and C188-9 to improve therapeutic efficacy by inhibiting DNMT1-inducing promoter methylation.

Keywords: 5-aza-2′-deoxycytidine; C188-9; DNA methylation; RASSF1A; STAT3; epithelial-to-mesenchymal transition.

Copyright © 2020 Kong, Sun, Li, Wu, Li, Li, Wang, Xuan, Yang, Sun and Hu.

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Front Oncol
. 2020 May 13;10:743. doi: 10.3389/fonc.2020.00743. eCollection 2020.
Preoperative Prediction of Lymph Node Metastasis in Patients With Early-T-Stage Non-small Cell Lung Cancer by Machine Learning Algorithms
Yijun Wu 1 2, Jianghao Liu 1 2, Chang Han 1 2, Xinyu Liu 2 3, Yuming Chong 1 2, Zhile Wang 1 2, Liang Gong 1 2, Jiaqi Zhang 1, Xuehan Gao 1, Chao Guo 1, Naixin Liang 1, Shanqing Li 1
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PMID: 32477952 PMCID: PMC7237747 DOI: 10.3389/fonc.2020.00743
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Background: Lymph node metastasis (LNM) is difficult to precisely predict before surgery in patients with early-T-stage non-small cell lung cancer (NSCLC). This study aimed to develop machine learning (ML)-based predictive models for LNM. Methods: Clinical characteristics and imaging features were retrospectively collected from 1,102 NSCLC ≤ 2 cm patients. A total of 23 variables were included to develop predictive models for LNM by multiple ML algorithms. The models were evaluated by the receiver operating characteristic (ROC) curve for predictive performance and decision curve analysis (DCA) for clinical values. A feature selection approach was used to identify optimal predictive factors. Results: The areas under the ROC curve (AUCs) of the 8 models ranged from 0.784 to 0.899. Some ML-based models performed better than models using conventional statistical methods in both ROC curves and decision curves. The random forest classifier (RFC) model with 9 variables introduced was identified as the best predictive model. The feature selection indicated the top five predictors were tumor size, imaging density, carcinoembryonic antigen (CEA), maximal standardized uptake value (SUVmax), and age. Conclusions: By incorporating clinical characteristics and radiographical features, it is feasible to develop ML-based models for the preoperative prediction of LNM in early-T-stage NSCLC, and the RFC model performed best.

Keywords: cross-validation; lymph node metastasis; machine learning; non-small cell lung cancer; predictive model.

Copyright © 2020 Wu, Liu, Han, Liu, Chong, Wang, Gong, Zhang, Gao, Guo, Liang and Li.

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Front Oncol
. 2020 May 13;10:629. doi: 10.3389/fonc.2020.00629. eCollection 2020.
Extracellular Vesicles From Gastric Cancer Cells Induce PD-L1 Expression on Neutrophils to Suppress T-Cell Immunity
Yinghong Shi 1 2, Jiahui Zhang 1 2, Zheying Mao 1 2, Han Jiang 1 2, Wei Liu 1 2, Hui Shi 1 2, Runbi Ji 2 3, Wenrong Xu 1 2, Hui Qian 1 2, Xu Zhang 1 2
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PMID: 32477934 PMCID: PMC7237746 DOI: 10.3389/fonc.2020.00629
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Abstract
Neutrophils are prominent components of solid tumors and exhibit distinct phenotypes in different tumor milieu. We have previously shown that tumor extracellular vesicles (EVs) could induce pro-tumor activation of neutrophils; however, the role of tumor EV-elicited neutrophils in tumor immunity remains unclear. Herein, we reported that gastric cancer cell-derived EVs (GC-EVs) induced the expression of programmed death-ligand 1 (PD-L1) on neutrophils. GC-EVs transported high-mobility group box-1 (HMGB1) to activate signal transducer and activator of transcription 3 (STAT3) and upregulate PD-L1 gene expression in neutrophils. Blocking STAT3 pathway and silencing HMGB1 reversed GC-EV-induced PD-L1 expression on neutrophils. GC-EV-elicited neutrophils suppressed T cell proliferation, activation, and function in vitro, which could be antagonized by a specific PD-L1 antibody. Furthermore, GC tissue-derived EVs also showed similar effects. Taken together, our results indicate that EVs from the GC microenvironment induce PD-L1 expression on neutrophils to suppress T-cell immunity, which provides a new insight into the pro-tumor roles of neutrophils in GC and sheds light on the multifaceted roles of EVs in orchestrating an immunosuppressive microenvironment.

Keywords: extracellular vesicles; gastric cancer; immune suppression; neutrophils; programmed death-ligand 1 (PD-L1).

Copyright © 2020 Shi, Zhang, Mao, Jiang, Liu, Shi, Ji, Xu, Qian and Zhang.

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51
Case Reports Front Oncol
. 2020 May 8;10:730. doi: 10.3389/fonc.2020.00730. eCollection 2020.
Diagnostic Capability of Next-Generation Sequencing Fusion Analysis in Identifying a Rare CASE of TRAF1-ALK- Associated Anaplastic Large Cell Lymphoma
Indu Agarwal 1, Linda Sabatini 1, Mir B Alikhan 1
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PMID: 32457846 PMCID: PMC7225296 DOI: 10.3389/fonc.2020.00730
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Abstract
Background: Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is a rare T-cell neoplasm, accounting for approximately 3% of adult non-Hodgkin lymphomas. Although NPM1 is the most common fusion partner with ALK, many others have been described, necessitating break-apart FISH studies for confirmation of the diagnosis. TNF receptor-associated factor 1 (TRAF1) is a rare ALK partner that is thought to confer a worse prognosis in patients. We describe the utility of next-generation sequencing (NGS) RNA analysis in detection of this uncommon ALK partner. Case Description: A 42-year-old male with cervical lymphadenopathy presented for excisional biopsy. Following a tissue diagnosis of ALCL, ALK+, RNA from the biopsy was extracted from Formalin-fixed paraffin-embedded (FFPE) tissue and prepared for Anchored Multiplex PCR using the Archer® FusionPlex® v2 assay, which employs unidirectional gene-specific primers using NGS to detect novel or unknown gene partners. Results: Histologic evaluation of the excised lymph node showed atypical cells, including "horseshoe/kidney"-shaped nuclei. Neoplastic cells were immunoreactive against CD30, ALK (diffuse, cytoplasmic), CD2, CD4, granzyme B, and TIA-1. A diagnosis of ALCL, ALK+ was made. The pattern of ALK immunostaining suggested a non-NPM1-associated ALK translocation pattern, prompting further investigation. NGS fusion analysis showed a translocation involving exon 7 of TRAF1 and exon 20 of ALK. Conclusion: ALK positivity suggests an overall favorable prognosis of ALCL as compared to ALK-negative cases. However, in the rare published cases of TRAF1-ALK, an aggressive clinical course has been observed, which may reflect the aggressive propensity of this particular fusion, as these cases appear to be refractory to standard chemotherapy and also to the first generation ALK inhibitors. This study highlights the advantage of using NGS in RNA-based fusion assays to detect rare translocations, which can be of some clinical importance in detecting rare but aggressive fusion partners of ALK. As these technologies become more available, there is potential to identify such changes and effectively stratify the prognosis of ALCL patients.

Keywords: ALK (anaplastic lymphoma kinase); RNA based sequencing; anaplastic T-cell lymphoma; lymphoma - diagnosis; next- generation sequencing.

Copyright © 2020 Agarwal, Sabatini and Alikhan.

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52
Front Oncol
. 2020 May 14;10:675. doi: 10.3389/fonc.2020.00675. eCollection 2020.
Generalization vs. Specificity: In Which Cases Should a Clinic Train Its Own Segmentation Models?
Jan Schreier 1, Francesca Attanasi 1, Hannu Laaksonen 1
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PMID: 32477941 PMCID: PMC7241256 DOI: 10.3389/fonc.2020.00675
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Abstract
As artificial intelligence for image segmentation becomes increasingly available, the question whether these solutions generalize between different hospitals and geographies arises. The present study addresses this question by comparing multi-institutional models to site-specific models. Using CT data sets from four clinics for organs-at-risk of the female breast, female pelvis and male pelvis, we differentiate between the effect from population differences and differences in clinical practice. Our study, thus, provides guidelines to hospitals, in which case the training of a custom, hospital-specific deep neural network is to be advised and when a network provided by a third-party can be used. The results show that for the organs of the female pelvis and the heart the segmentation quality is influenced solely on bases of the training set size, while the patient population variability affects the female breast segmentation quality above the effect of the training set size. In the comparison of site-specific contours on the male pelvis, we see that for a sufficiently large data set size, a custom, hospital-specific model outperforms a multi-institutional one on some of the organs. However, for small hospital-specific data sets a multi-institutional model provides the better segmentation quality.

Keywords: deep learning; generalizability; neural network; radiotherapy planning; segmentation.

Copyright © 2020 Schreier, Attanasi and Laaksonen.

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53
Front Oncol
. 2020 May 14;10:702. doi: 10.3389/fonc.2020.00702. eCollection 2020.
Effective Treatment of Glioblastoma Multiforme With Oncolytic Virotherapy: A Case-Series
Benjamin Gesundheit 1, Eliel Ben-David 2, Yehudit Posen 1, Ronald Ellis 1, Guido Wollmann 3 4, E Marion Schneider 5, Karl Aigner 6, Lars Brauns 7, Thomas Nesselhut 8, Ingrid Ackva 9, Christine Weisslein 9, Arno Thaller 9
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PMID: 32477944 PMCID: PMC7241257 DOI: 10.3389/fonc.2020.00702
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Abstract
Glioblastoma multiforme (GBM) remains an incurable condition, associated with a median survival time of 15 months with best standard of care and 5-year survival rate of <10%. We report on four GBM patients on combination treatment regimens that included oncolytic virus (OV) immunotherapy, who achieved clinical and radiological responses with long-term survival, thus far, of up to 14 years, and good quality of life. We discuss the radiological findings that provide new insights into this treatment, the scientific rationale of this innovative and promising therapy, and considerations for future research.

Keywords: Newcastle disease virus (NDV); biological therapy; glioblastoma; immunotherapy; oncolytic virotherapy.

Copyright © 2020 Gesundheit, Ben-David, Posen, Ellis, Wollmann, Schneider, Aigner, Brauns, Nesselhut, Ackva, Weisslein and Thaller.

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54
Editorial Front Oncol
. 2020 May 12;10:754. doi: 10.3389/fonc.2020.00754. eCollection 2020.
Editorial: Advances in Biological Understanding of Tumor Radiation Resistance
Ira Ida Skvortsova 1 2, Paul N Span 3
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PMID: 32477955 PMCID: PMC7235188 DOI: 10.3389/fonc.2020.00754
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Abstract
No abstract available
Keywords: DNA damage repair; cancer stem cells; hypoxia; radiotherapy; treatment resistance.

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55
Front Oncol
. 2020 May 12;10:674. doi: 10.3389/fonc.2020.00674. eCollection 2020.
M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells
Zhuo-Xun Wu 1, Zheng Peng 2, Yuqi Yang 1, Jing-Quan Wang 1, Qiu-Xu Teng 1, Zi-Ning Lei 1, Yi-Ge Fu 1, Ketankumar Patel 1, Lili Liu 3, Lizhu Lin 4, Chang Zou 2, Zhe-Sheng Chen 1
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PMID: 32477940 PMCID: PMC7235170 DOI: 10.3389/fonc.2020.00674
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Abstract
M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to increased ABCG2 substrate drugs accumulation. Furthermore, M3814 can stimulate the ABCG2 ATPase activity in a concentration-dependent manner without affecting the ABCG2 protein expression or cell surface localization of ABCG2. Moreover, the molecular docking analysis indicated a high affinity between M3814 and ABCG2 transporter at the drug-binding cavity. Taken together, our work reveals M3814 as an ABCG2 modulator and provides a potential combination of co-administering M3814 with ABCG2 substrate-drugs to overcome MDR.

Keywords: ABCG2; ATP-binding cassette (ABC) transporter; M3814; multidrug resistance (MDR); nedisertib.

Copyright © 2020 Wu, Peng, Yang, Wang, Teng, Lei, Fu, Patel, Liu, Lin, Zou and Chen.

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56
Front Oncol
. 2020 May 12;10:700. doi: 10.3389/fonc.2020.00700. eCollection 2020.
Sitravatinib, a Tyrosine Kinase Inhibitor, Inhibits the Transport Function of ABCG2 and Restores Sensitivity to Chemotherapy-Resistant Cancer Cells in vitro
Yuqi Yang 1, Ning Ji 1 2, Qiu-Xu Teng 1, Chao-Yun Cai 1, Jing-Quan Wang 1, Zhuo-Xun Wu 1, Zi-Ning Lei 1, Sabrina Lusvarghi 3, Suresh V Ambudkar 3, Zhe-Sheng Chen 1
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PMID: 32477943 PMCID: PMC7236772 DOI: 10.3389/fonc.2020.00700
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Abstract
Sitravatinib, also called MGCD516 or MG-516, is a broad-spectrum tyrosine kinase inhibitor (TKI) under phase III clinical evaluation. Herein, we explored the activity of sitravatinib toward multidrug resistance (MDR) by emphasizing its inhibitory effect on ATP-binding cassette super-family G member 2 (ABCG2). ABCG2 is a member of ATP-binding cassette (ABC) transporter family and plays a critical role in mediating MDR. Sitravatinb received an outstanding docking score for binding to the human ABCG2 model (PDB code: 6ETI) among thirty screened TKIs. Also, an MTT assay indicated that sitravatinib at 3 μM had the ability to restore the antineoplastic effect of various ABCG2 substrates in both drug-selected and gene-transfected ABCG2-overexpressing cell lines. In further tritium-labeled mitoxantrone transportation study, sitravatinib at 3 μM blocked the efflux function mediated by ABCG2 and as a result, increased the intracellular concentration of anticancer drugs. Interestingly, sitravatinib at 3 μM altered neither protein expression nor subcellular localization of ABCG2. An ATPase assay demonstrated that ATPase activity of ABCG2 was inhibited in a concentration-dependent manner with sitravatinib; thus, the energy source to pump out compounds was interfered. Collectively, the results of this study open new avenues for sitravatinib working as an ABCG2 inhibitor which restores the antineoplastic activity of anticancer drugs known to be ABCG2 substrates.

Keywords: ATP-binding cassette (ABC) transporters; ATP-binding cassette super-family G member 2 (ABCG2); multidrug resistance; sitravatinib; tyrosine kinase inhibitor.

Copyright © 2020 Yang, Ji, Teng, Cai, Wang, Wu, Lei, Lusvarghi, Ambudkar and Chen.

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57
Front Oncol
. 2020 May 14;10:758. doi: 10.3389/fonc.2020.00758. eCollection 2020.
Pharmacological STING Activation Is a Potential Alternative to Overcome Drug-Resistance in Melanoma
Sandhya Chipurupalli 1 2, Raja Ganesan 1, S P Dhanabal 3, M Suresh Kumar 3, Nirmal Robinson 1
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PMID: 32477956 PMCID: PMC7241280 DOI: 10.3389/fonc.2020.00758
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Melanoma is the most aggressive type of skin cancer and resistance to the conventional chemotherapy is the major cause for its poor prognosis. Metabolic perturbations leading to increased production of reactive oxygen species activate NRF2-dependent anti-oxidative responses to survive oxidative stress. This protective function of NRF2 is the primary cause for therapy resistance in cancer as anti-cancer agents such as BRAF inhibitors also induce NRF2-dependent antioxidative response. We had reported that type I interferons produced upon activation of STING, abrogates NRF2 function. Therefore, we investigated if STING agonists such as the newly developed dimeric aminobenzimidazole (diABZI) could sensitize melanoma cells to the clinically used BRAF inhibitors. Our results reveal that pharmacological activation of STING by diABZI, down regulates NRF2-dependent anti-oxidative responses and potentiates cell-death in melanoma cells when used in combination with BRAF inhibitors.

Keywords: BRAF; NRF2; STING; dabrafenib; diABZI; melanoma; vemurafenib.

Copyright © 2020 Chipurupalli, Ganesan, Dhanabal, Kumar and Robinson.

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58
Front Oncol
. 2020 May 14;10:642. doi: 10.3389/fonc.2020.00642. eCollection 2020.
ETS1 Suppresses Tumorigenesis of Human Breast Cancer via Trans-Activation of Canonical Tumor Suppressor Genes
Gi-Cheon Kim 1 2, Choong-Gu Lee 3, Ravi Verma 4, Dipayan Rudra 4, Taemook Kim 5, Keunsoo Kang 6, Jong Hee Nam 7, Young Kim 8, Sin-Hyeog Im 4 9, Ho-Keun Kwon 1 2 10
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PMID: 32477936 PMCID: PMC7239993 DOI: 10.3389/fonc.2020.00642
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Abstract
ETS1 has shown dichotomous roles as an oncogene and a tumor suppressor gene in diverse cancers, but its functionality in breast cancer tumorigenesis still remains unclear. We utilized the Cancer Genome Atlas (TCGA) database to analyze comprehensive functions of ETS1 in human breast cancer (BRCA) patients by investigating its expression patterns and methylation status in relation to clinical prognosis. ETS1 expression was significantly diminished by hyper-methylation of the ETS1 promoter region in specimens from BRCA patients compared to a healthy control group. Moreover, ETS1 high BRCA patients showed better prognosis and longer survival compared to ETS1 low BRCA patients. Consistent with clinical evidence, comparative transcriptome analysis combined with CRISPR/Cas9 or shRNA based perturbation of ETS1 expression revealed direct as well as indirect mechanisms of ETS1 that hinder tumorigenesis of BRCA cells. Taken together, our study enlightens a novel function of ETS1 as a tumor suppressor in breast cancer cells.

Keywords: DNA methylation; ETS1; breast cancer; regulatory elements; tumor suppressor.

Copyright © 2020 Kim, Lee, Verma, Rudra, Kim, Kang, Nam, Kim, Im and Kwon.

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