Future Drug Discov. 2019 Oct 11;1(2):FDD18. doi: 10.4155/fdd-2019-0021.
Practical considerations for the implementation of adaptive designs for oncology Phase I dose-finding trials.
Wei L1, Pan X1, Fernandez S1.
Author information
1
Center for Biostatistics, Department of Biomedical Informatics, College of Medicine, The Ohio State University, 1800 Cannon Dr. Columbus, OH 43210, USA.
Abstract
The traditional 3 + 3 design continues to be commonly used for Phase I dose-finding oncology trials, despite increasing criticisms and development of innovative methods. Unfortunately, it is a challenge to convince principal investigators to use novel designs. The goal of this paper is to persuade researchers to break away from 3 + 3 design and provide potential solutions to better designs and implementation strategy. We reviewed the statistical methods for adaptive Phase I designs. The barriers among all the major components of the implementation team have been emphasized and potential solutions have been discussed. Institutional support to the principal investigators and statistician, as well as to other team members is essential to design and implement adaptive trials in academic medical institutions.

© 2019 Lai Wei.

KEYWORDS:
3 + 3; adaptive designs; algorithm-based; model-assisted; model-based; oncology Phase I dose-finding design

PMID: 31656956 PMCID: PMC6811732 DOI: 10.4155/fdd-2019-0021
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Conflict of interest statement
Publication type
Select item 31656027
2.
J Cancer Educ. 2019 Oct 26. doi: 10.1007/s13187-019-01631-1. [Epub ahead of print]
Advance Care Planning Conversations in the Oncology Setting: Tips from the Experts.
Nortjé N1, Stepan K2.
Author information
1
The University of Texas MD Anderson Cancer Center, Houston, TX, USA. nortjenico@gmail.com.
2
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract
Advance care planning (ACP) has been identified as a fundamental part of every patient's total health care plan and is actively supported by a number of health care organizations. Despite these endorsements, however, having advance care planning conversations has not come easily for physicians. Training future physicians should include practical ways to address this issue. Fifty physicians at an oncology hospital, who were identified as having the most ACP conversations, were approached. Twenty-six percent participated in a survey which was sent out electronically via Qualitrics. All answers were recorded online and responses were collected and analyzed according to thematic analysis methodology. Major themes were noted and summarized for each of the survey's 10 questions, resulting in how the physicians can successfully plan for and initiate advance care planning conversations with their patients and families. Themes touched upon self-awareness, one's outlook on the value of life, and the importance of death as part of the care continuum. A physician's own perception of the value of ACP conversations greatly influences them having those conversations. Furthermore, it is key that the physician understands and be aware of the patient's perspective regarding their cancer and how it impacts them. This dynamic will then allow the physician to better align their plan of care with the treatment goals and expectations of the patient. Future training programs should incorporate these suggestions.

KEYWORDS:
Advanced care planning; Cancer; Death; Oncology; Physicians

PMID: 31656027 DOI: 10.1007/s13187-019-01631-1
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Select item 31655811
3.
Cells Tissues Organs. 2019 Oct 25:1-17. doi: 10.1159/000503280. [Epub ahead of print]
Investigating the Osteoinductive Potential of a Decellularized Xenograft Bone Substitute.
Bracey DN1, Jinnah AH1, Willey JS2, Seyler TM3, Hutchinson ID4, Whitlock PW5, Smith TL1, Danelson KA1, Emory CL1, Kerr BA6,7,8.
Author information
1
Orthopaedic Surgery, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA.
2
Radiation Oncology, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA.
3
Orthopaedic Surgery, Duke University, Durham, North Carolina, USA.
4
Orthopaedic Surgery, Albany Medical Center, Albany, New York, USA.
5
Orthopaedic Surgery, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
6
Orthopaedic Surgery, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA, bkerr@wakehealth.edu.
7
Virginia Tech-Wake Forest University School for Bioengineering and Sciences, Winston-Salem, North Carolina, USA, bkerr@wakehealth.edu.
8
Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA, bkerr@wakehealth.edu.
Abstract
Bone grafting is the second most common tissue transplantation procedure worldwide. One of the alternative methods for bone repair under investigation is a tissue-engineered bone substitute. An ideal property of tissue-engineered bone substitutes is osteoinductivity, defined as the ability to stimulate primitive cells to differentiate into a bone-forming lineage. In the current study, we use a decellularization and oxidation protocol to produce a porcine bone scaffold and examine whether it possesses osteoinductive potential and can be used to create a tissue-engineered bone microenvironment. The decellularization protocol was patented by our lab and consists of chemical decellularization and oxidation steps using combinations of deionized water, trypsin, antimicrobials, peracetic acid, and triton-X100. To test if the bone scaffold was a viable host, preosteoblasts were seeded and analyzed for markers of osteogenic differentiation. The osteoinductive potential was observed in vitro with similar osteogenic markers being expressed in preosteoblasts seeded on the scaffolds and demineralized bone matrix. To assess these properties in vivo, scaffolds with and without preosteoblasts preseeded were subcutaneously implanted in mice for 4 weeks. MicroCT scanning revealed 1.6-fold increased bone volume to total volume ratio and 1.4-fold increase in trabecular thickness in scaffolds after implantation. The histological analysis demonstrates new bone formation and blood vessel formation with pentachrome staining demonstrating osteogenesis and angiogenesis, respectively, within the scaffold. Furthermore, CD31+ staining confirmed the endothelial lining of the blood vessels. These results demonstrate that porcine bone maintains its osteoinductive properties after the application of a patented decellularization and oxidation protocol developed in our laboratory. Future work must be performed to definitively prove osteogenesis of human mesenchymal stem cells, biocompatibility in large animal models, and osteoinduction/osseointegration in a relevant clinical model in vivo. The ability to create a functional bone microenvironment using decellularized xenografts will impact regenerative medicine, orthopedic reconstruction, and could be used in the research of multiple diseases.

© 2019 S. Karger AG, Basel.

KEYWORDS:
Angiogenesis; Bone microenvironment; Bone scaffold; Osteoinductivity; Tissue engineering

PMID: 31655811 DOI: 10.1159/000503280
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Select item 31654937
4.
Oral Oncol. 2019 Oct 22;99:104438. doi: 10.1016/j.oraloncology.2019.09.030. [Epub ahead of print]
Prognostic value of radiologic extranodal extension and its potential role in future N classification for nasopharyngeal carcinoma.
Lu T1, Hu Y1, Xiao Y2, Guo Q3, Huang SH4, O'Sullivan B4, Fang Y2, Zong J5, Chen Y2, Lin S5, Chen Y6, Pan J7.
Author information
1
Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fuzhou, China.
2
Department of Radiology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, China.
3
Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, China; Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
4
Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Canada.
5
Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, China.
6
Department of Radiology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, China. Electronic address: yunbinchen@126.com.
7
Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, China; Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fujian Medical University Cancer Hospital, Fuzhou, China. Electronic address: panjianji1956@fjmu.edu.cn.
Abstract
PURPOSE:
We evaluated the prognostic value of various grades of radiologic extranodal extension (rENE) and their potential roles in N-classification refinement for nasopharyngeal carcinoma (NPC).

METHODS AND MATERIALS:
All NPC patients treated with IMRT in our institution between 2005 and 2011 were included. Pre-treatment MR of cN+ cases were reviewed and rENE was recorded asG0: lymph nodes (LNs) without rENE; G1: tumor infiltrating beyond individual nodal capsule(s) into the surrounding fat plane; G2: coalescent nodal mass with unequivocal evidence of rENE; G3: tumor infiltrating beyond nodal capsule into adjacent structures. Multivariable analysis (MVA) assessed prognostic value of rENE for distant metastasis (DM) and death adjusted for age, gender, LDH, T-classification, N-classification, and chemotherapy cycles.

RESULTS:
A total of 1390 of 1616 (86%) NPC were cN+, and rENE was detected in 826/1390 (59%) patients: 256 (18.4%) G1-rENE, 487 (35%) G2-rENE, and 83 (6%) G3-rENE. MVA confirmed that G2-/G3-rENE had increased risk of DM (HR: 2.05/3.18, both p < 0.001) and death (HR: 1.62/2.39, p = 0.002/p < 0.001), while G1-rENE was non-prognostic (DM: p = 0.172; death: p = 0.320). We propose a refined N: New-N1: N1/N2 without G2-/G3-rENE; New-N2: N1_G2-rENE; New-N3: N2_G2-rENE, N1/N2_G3-rENE, or N3. The New-N classification had a lower AIC and higher c-index for DM (AIC: 3809.6 vs 3830.9; c-index: 0.700 vs. 0.677) and death (AIC: 3693.8 vs. 3705.9; c-index: 0.735 vs. 0.725) versus TNM-8 N.

CONCLUSIONS:
G2- and G3-rENE are independently prognostic for DM and death in NPC. Compared to the TNM8 N-classification, a refined N-classification incorporating G2- and G3-rENE improves prognostication of DM and mortality risk.

Copyright © 2019 Elsevier Ltd. All rights reserved.

KEYWORDS:
Extranodal extension; Head and neck cancers; N classification; Nasopharyngeal carcinoma; Prognostication

PMID: 31654937 DOI: 10.1016/j.oraloncology.2019.09.030
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Select item 31654782
5.
Int J Radiat Oncol Biol Phys. 2019 Oct 22. pii: S0360-3016(19)33904-5. doi: 10.1016/j.ijrobp.2019.10.022. [Epub ahead of print]
Post-Mastectomy Radiation Therapy in HER-2 Positive Breast Cancer Patients: Analysis of the HERA Trial.
Jaoude JA1, de Azambuja E2, Makki M3, Tamim H4, Tfayli A5, Geara F6, Piccart M2, Poortmans P7, Zeidan YH8.
Author information
1
Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
2
Institut Jules Bordet and l'Université Libre de Bruxelles (U.L.B), Brussels, Belgium.
3
Clinical Research Institute, American University of Beirut Medical Center, Beirut, Lebanon.
4
Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
5
Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut Medical Center, Beirut, Lebanon.
6
Department of Radiation Oncology, American University of Beirut Medical Center, Beirut, Lebanon.
7
Department of Radiation Oncology, Institut Curie & Paris Sciences & Lettres - PSL University; Paris, France.
8
Department of Radiation Oncology, American University of Beirut Medical Center, Beirut, Lebanon. Electronic address: yz09@aub.edu.lb.
Abstract
PURPOSE:
Post-mastectomy radiation therapy (PMRT) improves recurrence rates and overall survival in breast cancer patients. However, it remains unclear whether these findings can be applied to HER-2 positive patients treated with trastuzumab.

METHODS AND MATERIALS:
The HERA trial is a phase III randomized clinical trial that established the efficacy of trastuzumab in HER-2 positive early stage breast cancer. The current study is a retrospective analysis of prospective data of 1633 trial patients treated with mastectomy and adjuvant trastuzumab. The primary objective of the study was to determine the effect of PMRT on loco-regional recurrence rates (LRR). Hazard ratios were estimated from Cox models and LRR curves were generated by the Kaplan-Meier method.

RESULTS:
Our analysis included 940 patients (57·6%) who received PMRT and 693 patients (42·4%) who did not. Patients in the PMRT group had worse prognostic disease characteristics. At a median follow up of 11 years, no significant difference in LRR was noted after PMRT in node negative (N0) patients (p-value = 0·96). Patients with 1-3 positive lymph nodes had a LRR-free survival of 97% in the PMRT group as compared to 90% in the no PMRT group (HR = 0·28, p-value = 0·004) and a non-significant improved overall survival (OS) after PMRT (HR = 0·63, p-value = 0·06).

CONCLUSIONS:
PMRT delivery in HER-2 positive breast cancer patients with 1-3 positive lymph nodes decreases the risk of LRR. Although the magnitude of PMRT benefit is lower than historical studies, the current findings are in favor of PMRT for HER-2 positive breast cancer patients with 1-3 involved nodes. Future studies are needed to determine which HER-2 positive breast cancer patients benefit the most from PMRT.

Copyright © 2019 Elsevier Inc. All rights reserved.

KEYWORDS:
Breast Cancer; HER-2; Post-mastectomy radiation therapy; Trastuzumab

PMID: 31654782 DOI: 10.1016/j.ijrobp.2019.10.022
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Select item 31654628
6.
Exp Mol Pathol. 2019 Oct 22:104314. doi: 10.1016/j.yexmp.2019.104314. [Epub ahead of print]
Cervical cancer patients that respond to chemoradiation therapy display an intense tumor infiltrating immune profile before treatment.
Martins PR1, Machado CMT1, Coxir SA1, de Oliveira AJ1, Moreira TB1, Campos LS1, Alcântara R1, de Paula SOC1, de Oliveira Salles PG1, Gollob KJ2, Magalhães WCS3.
Author information
1
Mário Penna Institute, Center for Teaching and Research, Belo Horizonte, MG, Brazil.
2
Mário Penna Institute, Center for Teaching and Research, Belo Horizonte, MG, Brazil; AC Camargo Cancer Center, Center for International Research, Translational Immuno-oncology Group, São Paulo, SP, Brazil. Electronic address: kenneth.gollob@accamargo.org.br.
3
Mário Penna Institute, Center for Teaching and Research, Belo Horizonte, MG, Brazil. Electronic address: wagner.magalhaes@mariopenna.org.br.
Abstract
Cervical cancer (CC) is a major cause of death and suffering to women globally with 570,000 new cases in 2017. It disproportionately affects those living in resource-constrained countries such as Brazil, with 90% of the deaths from CC happening in low and middle-income countries. Early detection is still the best strategy for improving response to therapy and survival and cases detected in advanced stages show variable response rates to the standard chemoradiation therapy protocols. Both the genetic landscape and the immune status of patients can dramatically affect cancer progression and response to therapy, as well as disease recurrence. Here we performed a comprehensive sequencing analysis using the cancer gene panel - Ion AmpliSeq™ Cancer hotspot Panel V2 CHPv2, as well as determined the immune infiltrate composition of a group of locally advanced CC patients with the goal of identifying genetic and immune characteristics associated with a clinical response to therapy. The expression levels of CD68+ tumor-associated macrophages (TAMs) and CD8+ tumor-infiltrating lymphocytes (TILs), as well as the immune checkpoint molecules PD-1, PD-L1 and PD-L2 in stroma and in tumor regions were analyzed by immunohistochemistry (IHC). The HPV infection status with high-risk strains was also determined. Twenty-one samples from patients with squamous cell carcinoma segregated into responder (11) and non-responder (10) groups according to standard chemoradiation therapy response were studied. Our findings indicate that responder patients showed an increase in an inflammatory tumor environment as indicated by higher numbers of CD8+ and PD-L2+ TILs, as well as higher expression of PD-L1 immunoreactive area, as compared to the non-responder group. Additionally, our results demonstrate a correlation between the number of gene mutations and PD-L2+ TILs in the responder group. The genes PIK3CA and KDR/VEGFR were the most mutated genes, corroborating past findings. Together, these findings indicate an inflammatory tumor microenvironment present in patients that will respond to future chemoradiation treatment as compared to those that will not. This points to possible future predictors of response to therapy in CC patients.

Copyright © 2019. Published by Elsevier Inc.

PMID: 31654628 DOI: 10.1016/j.yexmp.2019.104314
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Select item 31654503
7.
Birth Defects Res. 2019 Oct 25. doi: 10.1002/bdr2.1606. [Epub ahead of print]
Genome-wide association studies of structural birth defects: A review and commentary.
Lupo PJ1, Mitchell LE2, Jenkins MM3.
Author information
1
Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas.
2
Department of Epidemiology, Human Genetics and Environmental Sciences, UTHealth School of Public Health, Houston, Texas.
3
National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia.
Abstract
BACKGROUND:
While there is strong evidence that genetic risk factors play an important role in the etiologies of structural birth defects, compared to other diseases, there have been relatively few genome-wide association studies (GWAS) of these conditions. We reviewed the current landscape of GWAS conducted for birth defects, noting novel insights, and future directions.

METHODS:
This article reviews the literature with regard to GWAS of structural birth defects. Key defects included in this review include oral clefts, congenital heart defects (CHDs), biliary atresia, pyloric stenosis, hypospadias, craniosynostosis, and clubfoot. Additionally, other issues related to GWAS are considered, including the assessment of polygenic risk scores and issues related to genetic ancestry, as well as utilizing genome-wide single nucleotide polymorphism array data to evaluate gene-environment interactions and Mendelian randomization.

RESULTS:
For some birth defects, including oral clefts and CHDs, several novel susceptibility loci have been identified and replicated through GWAS, including 8q24 for oral clefts, DGKK for hypospadias, and 4p16 for CHDs. Relatively common birth defects for which there are currently no published GWAS include neural tube defects, anotia/microtia, anophthalmia/microphthalmia, gastroschisis, and omphalocele.

CONCLUSIONS:
Overall, GWAS have been successful in identifying several novel susceptibility genes and genomic regions for structural birth defects. These findings have provided new insights into the etiologies of these phenotypes. However, GWAS have been underutilized for understanding the genetic etiologies of several birth defects.

© 2019 Wiley Periodicals, Inc.

KEYWORDS:
GWAS; birth defects; epidemiology; genetics

PMID: 31654503 DOI: 10.1002/bdr2.1606
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Publication type, Grant support
Select item 31653348
8.
Biochem Biophys Res Commun. 2019 Oct 22. pii: S0006-291X(19)32016-9. doi: 10.1016/j.bbrc.2019.10.114. [Epub ahead of print]
High-throughput screening identified mitoxantrone to induce death of hepatocellular carcinoma cells with autophagy involvement.
Xie B1, He X2, Guo G2, Zhang X3, Li J4, Liu J5, Lin Y6.
Author information
1
Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China; Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden.
2
Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
3
Department of Neuroscience, University of Uppsala, Uppsala, Sweden.
4
Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden.
5
School of Clinical Medicine, Dali University, Yunnan, China. Electronic address: liujianping88@hotmail.com.
6
Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden. Electronic address: yingbo.lin@ki.se.
Abstract
The use of highly efficient high-throughput screening (HTS) platform has recently gained more attention as a plausible approach to identify de novo therapeutic application potential of conventional anti-tumor drugs for cancer treatments. In this study, we used hepatocellular carcinoma (HCC) cells as models to identify cytotoxic compounds by HTS. To identify cytotoxic compounds for potential HCC treatments, 3271 compounds from three well established small molecule libraries were screened against HCC cell lines. Thirty-two small molecules were identified from the primary screen to induce cell death. Particularly, mitoxantrone (MTX), which is an established antineoplastic drug, significantly and specifically inhibited the growth and proliferation of HCC cells in vitro. Mechanistic studies of LC3-II, p62 and phosphorylation of p70S6K in HepG2 cells revealed that MTX treatment induced mTOR-dependent autophagy activation, which was further confirmed by the autophagic flux assay using lysosomal inhibitor chloroquine (CQ). In the combined treatment of MTX and CQ, where autophagy was inhibited by CQ, the elevations of cleaved Caspase-3 and PARP were observed, indicating the enhanced apoptosis in HepG2 cells. Taken together, we hypothesize that MTX-induced autophagy plays an pro-survival role in HCC treatment. Combined treatment with autophagy inhibitor may combat the chemo-resistance of HCC to MTX treatment and therefore deserves future clinical investment.

Copyright © 2019 Elsevier Inc. All rights reserved.

KEYWORDS:
Autophagy; Cell death; Hepatocellular carcinoma; Mitoxantrone (MTX); Small molecule screen

PMID: 31653348 DOI: 10.1016/j.bbrc.2019.10.114
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Select item 31653258
9.
Part Fibre Toxicol. 2019 Oct 25;16(1):38. doi: 10.1186/s12989-019-0321-5.
An in-depth multi-omics analysis in RLE-6TN rat alveolar epithelial cells allows for nanomaterial categorization.
Karkossa I1, Bannuscher A2, Hellack B3,4, Bahl A2, Buhs S5, Nollau P5, Luch A2, Schubert K1, von Bergen M1,6, Haase A7.
Author information
1
Department of Molecular Systems Biology, Helmholtz-Centre for Environmental Research (UFZ), Permoserstraße 15, 04318, Leipzig, Germany.
2
Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Straße 8-10, 10589, Berlin, Germany.
3
Institute of Energy and Environmental Technology (IUTA) e.V, Bliersheimerstraße 58-60, 47229, Duisburg, Germany.
4
German Environment Agency, 06844, Dessau-Roßlau, Germany.
5
Research Institute Children's Cancer Center and Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.
6
Institute of Biochemistry, Leipzig University, Brüderstraße 34, 04103, Leipzig, Germany.
7
Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Straße 8-10, 10589, Berlin, Germany. Andrea.Haase@bfr.bund.de.
Abstract
BACKGROUND:
Nanomaterials (NMs) can be fine-tuned in their properties resulting in a high number of variants, each requiring a thorough safety assessment. Grouping and categorization approaches that would reduce the amount of testing are in principle existing for NMs but are still mostly conceptual. One drawback is the limited mechanistic understanding of NM toxicity. Thus, we conducted a multi-omics in vitro study in RLE-6TN rat alveolar epithelial cells involving 12 NMs covering different materials and including a systematic variation of particle size, surface charge and hydrophobicity for SiO2 NMs. Cellular responses were analyzed by global proteomics, targeted metabolomics and SH2 profiling. Results were integrated using Weighted Gene Correlation Network Analysis (WGCNA).

RESULTS:
Cluster analyses involving all data sets separated Graphene Oxide, TiO2_NM105, SiO2_40 and Phthalocyanine Blue from the other NMs as their cellular responses showed a high degree of similarities, although apical in vivo results may differ. SiO2_7 behaved differently but still induced significant changes. In contrast, the remaining NMs were more similar to untreated controls. WGCNA revealed correlations of specific physico-chemical properties such as agglomerate size and redox potential to cellular responses. A key driver analysis could identify biomolecules being highly correlated to the observed effects, which might be representative biomarker candidates. Key drivers in our study were mainly related to oxidative stress responses and apoptosis.

CONCLUSIONS:
Our multi-omics approach involving proteomics, metabolomics and SH2 profiling proved useful to obtain insights into NMs Mode of Actions. Integrating results allowed for a more robust NM categorization. Moreover, key physico-chemical properties strongly correlating with NM toxicity were identified. Finally, we suggest several key drivers of toxicity that bear the potential to improve future testing and assessment approaches.

KEYWORDS:
Grouping; Metabolomics; Multi-omics; Nanomaterials; Proteomics; SH2 profiling; WGCNA

PMID: 31653258 DOI: 10.1186/s12989-019-0321-5
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Grant support
Select item 31653079
10.
J Clin Med. 2019 Oct 24;8(11). pii: E1777. doi: 10.3390/jcm8111777.
Neurological Immune Related Adverse Events Associated with Nivolumab, Ipilimumab, and Pembrolizumab Therapy-Review of the Literature and Future Outlook.
Möhn N1,2, Beutel G3,4, Gutzmer R5,6, Ivanyi P7,8, Satzger I9,10, Skripu T11,12.
Author information
1
Department of Neurology, Hannover Medical School, Hannover 30625, Germany. moehn.nora@mh-hannover.de.
2
Center for Immuno-Oncology (IOZ) Hannover Medical School, Hannover 30625, Germany. moehn.nora@mh-hannover.de.
3
Center for Immuno-Oncology (IOZ) Hannover Medical School, Hannover 30625, Germany. beutel.gernot@mh-hannover.de.
4
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover 30625, Germany. beutel.gernot@mh-hannover.de.
5
Center for Immuno-Oncology (IOZ) Hannover Medical School, Hannover 30625, Germany. gutzmer.ralf@mh-hannover.de.
6
Skin Cancer Center Hannover, Department of Dermatology and Allergy, Hannover Medical School, Hannover 30625, German. gutzmer.ralf@mh-hannover.de.
7
Center for Immuno-Oncology (IOZ) Hannover Medical School, Hannover 30625, Germany. ivanyi.philipp@mh-hannover.de.
8
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover 30625, Germany. ivanyi.philipp@mh-hannover.de.
9
Center for Immuno-Oncology (IOZ) Hannover Medical School, Hannover 30625, Germany.
10
Skin Cancer Center Hannover, Department of Dermatology and Allergy, Hannover Medical School, Hannover 30625, German.
11
Department of Neurology, Hannover Medical School, Hannover 30625, Germany. Skripuletz.Thomas@MH-Hannover.de.
12
Center for Immuno-Oncology (IOZ) Hannover Medical School, Hannover 30625, Germany. Skripuletz.Thomas@MH-Hannover.de.
Abstract
Immune checkpoint inhibitor (ICI) therapy has revolutionized the management of various cancers with previously poor prognosis. Despite its great efficacy, the therapy is associated with a wide spectrum of immune-related adverse events (irAE) including neurological symptoms which can affect all parts of the central and peripheral nervous system. Even though these events are rare, they are of high relevance as the rate of residual symptoms or even fatal outcomes is remarkable. To provide a detailed overview of neurological adverse events associated with immune checkpoint-inhibitor therapy we conducted a literature search. While focusing on ipilimumab, nivolumab, and pembrolizumab therapy, all available case reports as well as larger case series and clinical trials have been considered. Eighty-two case reports about checkpoint-inhibitor therapy induced symptoms of the peripheral nervous system have been published, while only 43 case reports addressed central nervous system abnormalities. The frequency of immune checkpoint-inhibitor therapy inducing neurological adverse events is about 1% in larger studies. Especially neuromuscular adverse events exhibit distinct clinical and diagnostic characteristics. Additionally, several affected patients presented with overlap-syndromes, which means that symptoms and diagnostic findings indicating myositis, myasthenia gravis, and neuropathy were present in one individual patient at the same time. Thus, neurological and particularly neuromuscular adverse events of immune checkpoint-inhibitor therapy may constitute a new disease entity.

KEYWORDS:
Guillain-Barré syndrome; encephalitis; immune checkpoint inhibitor therapy; immune-related adverse events; ipilimumab; myasthenia gravis; myositis; nivolumab; pembrolizumab

PMID: 31653079 DOI: 10.3390/jcm8111777
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Conflict of interest statement
Publication type
Select item 31652449
11.
Biosci Rep. 2019 Oct 30;39(10). pii: BSR20192091. doi: 10.1042/BSR20192091.
Effects of the MAML2 genetic variants in glioma susceptibility and prognosis.
Zhang M1, Zhao Y2, Zhao J3, Huang T1, Guo X3, Ma X3, Wu Y4.
Author information
1
Department of Neurosurgery, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
2
Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
3
Department of Neurosurgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
4
Department of Critical Care Medicine, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
Abstract
BACKGROUND:
Abnormal expression of the mastermind-like transcriptional co-activator 2 (MAML2) gene is oncogenic in several human cancers, including glioma. However, the relevance of MAML2 variants with glioma remains unknown. We aimed to investigate the role of MAML2 polymorphisms in glioma risk and prognosis among the Chinese Han population.

METHODS:
Seven MAML2 single-nucleotide polymorphisms (SNPs) were genotyped using Agena MassARRAY system among 575 patients with glioma and 500 age- and gender-matched healthy controls. Logistic regression was used to estimate the association between MAML2 polymorphisms and glioma risk by calculating odds ratios (ORs) and 95% confidence intervals (CI). Kaplan-Meier survival analysis and univariate, multivariate Cox proportional hazard regression analyses for hazard ratios (HRs) and 95% CIs were performed to evaluate the contribution of MAML2 polymorphisms to glioma prognosis.

RESULTS:
MAML2 rs7938889 and rs485842 polymorphisms were associated with the reduced risk of glioma (OR = 0.69, P=0.023; and OR = 0.81, P=0.032, respectively). Rs7115578 polymorphism had a lower susceptibility to glioma in males (OR = 0.68, P=0.034), while rs4598633 variant with a higher risk in females (OR = 1.66, P=0.016). Additionally, rs7115578 AG genotype represented a poorer prognosis of glioma (HR = 1.24, P=0.033) and astrocytoma (log-rank P=0.037, HR = 1.31, P=0.036). Furthermore, rs11021499 polymorphism had lower overall survival (OS) and progression-free survival (PFS) in patients with low-grade glioma.

CONCLUSION:
We provided some novel data suggesting MAML2 polymorphisms might contribute to glioma risk and prognosis. Future studies are warranted to validate these findings and characterize mechanisms underlying these associations.

© 2019 The Author(s).

KEYWORDS:
Glioma; MAML2; prognosis; susceptibility

PMID: 31652449 DOI: 10.1042/BSR20192091
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Select item 31652396
12.
Mol Oncol. 2019 Oct 25. doi: 10.1002/1878-0261.12591. [Epub ahead of print]
Multiplex screening of 275 plasma protein biomarkers to identify a signature for early detection of colorectal cancer.
Bhardwaj M1,2, Weigl K2,3,4, Tikk K3,4, Benner A5, Schrotz-King P1, Brenner H1,3,4.
Author information
1
Division of Preventive Oncology, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Heidelberg, Germany.
2
Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany.
3
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Abstract
Blood-based protein biomarkers may be an attractive option for early detection of colorectal cancer (CRC). Here, we used a two-stage design to measure 275 protein markers by proximity extension assay (PEA), first in plasma samples of a discovery set consisting of 98 newly diagnosed CRC cases and 100 age and gender matched controls free of neoplasm at screening colonoscopy. An algorithm predicting the presence of early or late stage CRC was derived by Lasso regression with .632+ bootstrap method and the algorithms were then validated using PEA again in an independent validation set consisting of participants of screening colonoscopy with and without CRC (n= 56 and 102, respectively). Three different signatures for all, early, and late stages CRC consisting of 9, 12, and 11 protein markers were obtained in the discovery set with areas under the curves (AUCs) after .632+ bootstrap adjustment of 0.92, 0.91 and 0.96, respectively. External validation among participants of screening colonoscopy yielded AUCs of 0.76 (95%CI, 0.67-0.84), 0.75 (95%CI, 0.62-0.87) and 0.80 (95%CI, 0.68-0.89) for all, early, and late stage CRC, respectively. Although the identified protein markers are not competitive with the best available stool tests, these proteins may contribute to the development of powerful blood-based tests for CRC early detection in the future.

© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

KEYWORDS:
Colorectal Cancer; Diagnostic Biomarkers; Early Detection; Proximity Extension Assay; Screening; Sensitivity and Specificity

PMID: 31652396 DOI: 10.1002/1878-0261.12591
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Select item 31652083
13.
Expert Rev Mol Diagn. 2019 Oct 25. doi: 10.1080/14737159.2019.1685383. [Epub ahead of print]
Liquid biopsy in germ cell tumors: biology and clinical management.
Chovanec M1,2, Kalavska K3, Mego M1,3, Cheng L4,5.
Author information
1
2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute , Klenova 1, 83310 , Bratislava , Slovakia.
2
Division of Hematology Oncology, Indiana University Simon Cancer Center , Indianapolis , 535 Barnhill drive, IN , 46202 , USA.
3
Translational Research Unit at 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute , Klenova 1, 83310 , Bratislava , Slovakia.
4
Department of Pathology and Laboratory Medicine0, Indiana University School of Medicine , Indianapolis , IN , 46202 , USA.
5
Department of Urology, Indiana University School of Medicine , Indianapolis , IN , 46202 , USA.
Abstract
INTRODUCTION: Liquid biopsy is an increasingly studied approach for optimal and minimally invasive diagnostics of malignant tumors. The aim of this review is to provide evidence and discuss the utility of liquid biopsy in the management of germ cell tumors (GCTs). AREAS COVERED: Herein, we summarize the evidence on liquid biopsy in GCTs including serum tumor markers, circulating tumor cells, microRNA and cell-free DNA. The search of literature was conducted from Pubmed/Medline, ASCO-meeting library searching for terms "liquid biopsy", "germ cell tumors", "circulating tumor cells", "microRNA", "cell-free DNA". Obtained original studies were included. Reference lists of review articles and key original articles were searched for additional original studies. We included articles published between1990-2019. EXPERT OPINION: Liquid biopsy is a minimally invasive tool using body fluids for diagnostic purposes in cancer. The established value of serum tumor markers may be already considered a liquid biopsy technique in diagnosis of GCTs. Possible near-future refinements in diagnosis of GCTs are emerging. Further information on diagnosis, prognosis and resistance is added with recently described microRNAs, circulating tumor cells and cell-free DNA. While great promise is shown, further large-scale validation is needed to incorporate these novel liquid biopsies into clinical practice.

KEYWORDS:
Liquid biopsy; biomarker; cell-free DNA; circulating tumor cells; germ cell tumors; microRNA; testicular cancer

PMID: 31652083 DOI: 10.1080/14737159.2019.1685383
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Select item 31651528
14.
Curr Opin Support Palliat Care. 2019 Oct 16. doi: 10.1097/SPC.0000000000000467. [Epub ahead of print]
Mechanisms and treatment of bone pain in multiple myeloma.
Davies MP1, Fingas S2, Chantry A1.
Author information
1
Department of Oncology and Metabolism, Faculty of Medicine, Dentistry and Health, University of Sheffield.
2
Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK.
Abstract
PURPOSE OF REVIEW:
Multiple myeloma is a haematological malignancy of differentiated B lymphocytes, known as plasma cells. The disease is common in the UK (incidence of 9 cases per 100 000 people) and the most frequent presentation is bone pain caused by skeletal damage. Patients with myeloma also experience neuropathic pain induced by chemotherapy. The management of pain in multiple myeloma is frequently demanding and often sub-optimally addressed. This review seeks to summarize a rational approach to the management of pain experienced by multiple myeloma patients.

RECENT FINDINGS:
Bone pain has a dramatic detrimental impact on a patient's physical capacity, and therefore, quality of life. Various mechanisms of bone pain have been elucidated; however, neuropathic bone pain in multiple myeloma is not completely understood. Potential mechanisms for this phenomenon; namely increased intraosseous pressure and the acidity of the bone marrow in the disease state will be interrogated. The current analgesic pathways used to treat multiple myeloma bone pain and new advances in therapies that may confer future benefit to patients will briefly be reviewed.

SUMMARY:
Holistic care and the provision of an array of pain relief methods is required to achieve effective pain control in multiple myeloma bone pain and requires a concerted effort from the healthcare team to be realized.

PMID: 31651528 DOI: 10.1097/SPC.0000000000000467
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Select item 31651465
15.
Cancer Nurs. 2019 Oct 21. doi: 10.1097/NCC.0000000000000757. [Epub ahead of print]
A Dimension in Recovery: Return to Working Life After Breast Cancer.
Şengün İnan F1, Günüşen N, Özkul B, Aktürk N.
Author information
1
Author Affiliations: Psychiatric Nursing Department, Faculty of Nursing Dokuz Eylül University, İzmir, Turkey (Drs Şengün İnan, Günüşen, Ms Özkul); Institute of Health Sciences Dokuz Eylül, University, İzmir, Turkey (Ms Özkul); and Department of Radiation Oncology, Dokuz Eylül University Hospital, İzmir, Turkey (Dr Aktürk).
Abstract
BACKGROUND:
Returning to work (RTW) after breast cancer is an important step in psychosocial recovery.

OBJECTIVE:
To explore experiences of Turkish breast cancer survivors about returning or continuing to work.

METHODS:
This study utilized a qualitative descriptive approach. Data were collected through semistructured interviews conducted with 12 breast cancer survivors with full employment. The data were analyzed using inductive content analysis method.

RESULTS:
Four themes emerged as a result of analysis of obtained data: decision-making process, difficulties in work life, sources of motivation for maintenance of work life, and benefits of RTW.

CONCLUSIONS:
The results of the study showed that RTW involves many uncertainties, and women experience difficulties resulting from themselves, work life, and colleagues. Support from family, colleagues, and employers is an important source of motivation in women's coping with these difficulties. In addition, RTW positively influences psychosocial well-being.

IMPLICATIONS FOR PRACTICE:
Health professionals should provide support as part of follow-up care regarding difficulties in the return to and continuation of work experienced by breast cancer survivors. Future studies could focus on experiences of all stakeholders including physicians, nurses, colleagues, and employers.

PMID: 31651465 DOI: 10.1097/NCC.0000000000000757
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Select item 31651454
16.
Am J Clin Oncol. 2019 Oct 22. doi: 10.1097/COC.0000000000000621. [Epub ahead of print]
An Update to Changing Patterns of Anal Carcinoma in the United States.
Mahal AR1,2, Johung KL1,2,3,4, Mahal BA5, Nguyen PL5,6, Yu JB1,2,3,4.
Author information
1
Yale School of Medicine.
2
Cancer Outcomes, Public Policy, and Effectiveness Research Center at Yale.
3
Yale Cancer Center.
4
Department of Therapeutic Radiology, Yale-New Haven Hospital, New Haven, CT.
5
Harvard Radiation Oncology Program.
6
Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA.
Abstract
OBJECTIVES:
Approximately 8,300 new cases of anal carcinoma will be diagnosed in the United States in 2019. Anal squamous cell carcinoma (SCC) accounts for about 70% of all anal cancers. As cancer prevention and treatments have evolved over time, medical management of human immunodeficiency virus has improved, and sexual behaviors have changed, anal carcinoma incidence rates (IRs) may have also changed.

METHODS:
The 9 oldest Surveillance, Epidemiology, and End Results registries were used to identify and determine IR of carcinoma in situ (CIS) and invasive SCC for 9757 patients below 65 years diagnosed with anal SCC/CIS from 1973 to 2014. Joinpoint regression models identified time points at which incidence trends changed.

RESULTS:
The incidence of CIS decreased since 2010 (age-adjusted IR annual percent change [APC]: -5.65, 95% CI: -10.0 to -1.1), especially for men (APC: -8.30, 95% CI: -12.6 to -3.8). In contrast, the incidence of SCC increased since 2007 (APC: 2.59, 95% CI: 0.1-5.2). During 2010-2014, men were more likely to present with CIS (incidence rate ratio [IRR]: 3.234, 95% CI: 3.000-3.489) but less likely to present with localized (IRR: 0.827, 95% CI: 0.754-0.906), regional (IRR: 0.603, 95% CI: 0.537-0.676), and distant SCC (IRR: 0.751, 95% CI: 0.615-0.915) compared with women.

CONCLUSIONS:
The previously observed rise in anal SCC/CIS incidence slowed in 2010, largely due to a decline in CIS rates. Patients were more likely to present with CIS than SCC at any stage. Future studies are necessary to determine if this decline in CIS precedes a decline in invasive SCC.

PMID: 31651454 DOI: 10.1097/COC.0000000000000621
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Select item 31651361
17.
Mil Med Res. 2019 Oct 25;6(1):32. doi: 10.1186/s40779-019-0224-7.
Boron neutron capture therapy: moving towards targeted therapy for locally recurrent head and neck squamous cell carcinoma.
Sun Y1.
Author information
1
Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, China. sunying@sysucc.org.cn.
Abstract
Locally recurrent head and neck squamous cell carcinoma (HNSCC) is often unresectable, and a repeat course of radiotherapy is associated with incremental toxicities. Boron neutron capture therapy (BNCT) is a novel targeted radiotherapy modality that can achieve a high dose gradient between cancerous and adjacent normal tissues. However, the relationships among the dose resulting from BNCT, tumor response to BNCT, and survival are not completely understood. Recently, a study published in Radiotherapy and Oncology investigated the efficacy of BNCT in the treatment of patients with locally recurrent HNSCC and the factors associated with favorable treatment response and survival. In this article, the findings, strengths and limitations of this study are discussed in depth, and the significance of the study and motivations for future research are highlighted.

KEYWORDS:
Boron neutron capture therapy; Locally recurrent head and neck squamous cell carcinoma; Treatment efficacy

PMID: 31651361 DOI: 10.1186/s40779-019-0224-7
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Publication type
Select item 31651337
18.
BMC Med Genomics. 2019 Oct 24;12(1):144. doi: 10.1186/s12920-019-0602-8.
Whole-genome bisulfite sequencing in systemic sclerosis provides novel targets to understand disease pathogenesis.
Lu T1,2, Klein KO1, Colmegna I3, Lora M3, Greenwood CMT1,4,5,6, Hudson M7,8.
Author information
1
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte Sainte-Catherine Road, Montreal, H3T 1E2, Canada.
2
Quantitative Life Sciences Program, McGill University, Montreal, Canada.
3
Division of Rheumatology, Department of Medicine, McGill University, Montreal, Canada.
4
Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, Canada.
5
Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada.
6
Department of Human Genetics, McGill University, Montreal, Canada.
7
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte Sainte-Catherine Road, Montreal, H3T 1E2, Canada. marie.hudson@mcgill.ca.
8
Division of Rheumatology, Department of Medicine, McGill University, Montreal, Canada. marie.hudson@mcgill.ca.
Abstract
BACKGROUND:
Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease whose pathogenesis remains incompletely understood. Increasing evidence suggests that both genetic susceptibilities and changes in DNA methylation influence pivotal biological pathways and thereby contribute to the disease. The role of DNA methylation in SSc has not been fully elucidated, because existing investigations of DNA methylation predominantly focused on nucleotide CpGs within restricted genic regions, and were performed on samples containing mixed cell types.

METHODS:
We performed whole-genome bisulfite sequencing on purified CD4+ T lymphocytes from nine SSc patients and nine controls in a pilot study, and then profiled genome-wide cytosine methylation as well as genetic variations. We adopted robust statistical methods to identify differentially methylated genomic regions (DMRs). We then examined pathway enrichment associated with genes located in these DMRs. We also tested whether changes in CpG methylation were associated with adjacent genetic variation.

RESULTS:
We profiled DNA methylation at more than three million CpG dinucleotides genome-wide. We identified 599 DMRs associated with 340 genes, among which 54 genes exhibited further associations with adjacent genetic variation. We also found these genes were associated with pathways and functions that are known to be abnormal in SSc, including Wnt/β-catenin signaling pathway, skin lesion formation and progression, and angiogenesis.

CONCLUSION:
The CD4+ T cell DNA cytosine methylation landscape in SSc involves crucial genes in disease pathogenesis. Some of the methylation patterns are also associated with genetic variation. These findings provide essential foundations for future studies of epigenetic regulation and genome-epigenome interaction in SSc.

KEYWORDS:
Differential methylation; Pathway analysis; SNP-CpG association; Systemic sclerosis; Whole-genome bisulfite sequencing

PMID: 31651337 DOI: 10.1186/s12920-019-0602-8
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Grant support
Select item 31651220
19.
OMICS. 2019 Oct 25. doi: 10.1089/omi.2019.0143. [Epub ahead of print]
Mapping Keratoconus Molecular Substrates by Multiplexed High-Resolution Proteomics of Unpooled Corneas.
Shinde V1, Hu N1, Renuse S2, Mahale A3, Pandey A2, Eberhart C4, Stone D5, Al-Swailem SA6, Maktabi A7, Chakravarti S1,8.
Author information
1
Department of Ophthalmology, NYU Langone Health, New York, New York.
2
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
3
Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
4
Pathology, Ophthalmology and Oncology Department, Johns Hopkins Hospital, Baltimore, Maryland.
5
Department of Ophthalmology, Johns Hopkins University, Baltimore, Maryland.
6
Anterior Segment Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
7
Department of Pathology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
8
Department of Pathology, NYU Langone Health, New York, New York.
Abstract
Keratoconus (KCN) is a leading cause for cornea grafting worldwide. Keratoconus is a multifactorial disease that causes progressive thinning of the cornea and whose etiology is poorly understood. Several studies have used proteomics on patient tear fluids to identify potential biomarkers. However, proteome of the cornea itself has not been investigated fully. We report here new findings from a case-control study using multiplexed mass spectrometry (MS) on individual (unpooled) corneas to gain deeper insights into proteins and biomarkers relevant to keratoconus. We employed a high-pressure approach to extract total protein from individual corneas from five cases and five controls, followed by trypsin digestion and tandem mass tag (TMT) labeling. The MS-derived data were searched using the Human NCBI RefSeq protein database v92, with peptides and proteins filtered at 1% false discovery rate. A total of 3132 proteins were detected, of which 627 were altered significantly (p ≤ 0.05) in keratoconus corneas. The increases were overwhelmingly in the mTOR/PI3/AKT signal-mediated regulations of cell survival and proliferation, nonsense-mediated decay of transcripts, and proteasomal pathways. The decreases were in several extracellular matrix proteins and in many members of the complement system. Importantly, this multiplexed proteomic study of keratoconus corneas identified, to our knowledge, the largest number of corneal proteins. The novel findings include changes in pathways that regulate transcript stability, proteasomal degradation, and the complement system in corneas with keratoconus. These observations offer new prospects toward future discovery of novel molecular targets for diagnostic and therapeutic innovations for patients with keratoconus.

KEYWORDS:
ER stress; complement; cornea; keratoconus; proteasomal degradation; proteomics

PMID: 31651220 DOI: 10.1089/omi.2019.0143
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Select item 31651200
20.
Future Oncol. 2019 Oct 25. doi: 10.2217/fon-2019-0522. [Epub ahead of print]
Clinical utility versus futility: a tipping point for liquid biopsies in bladder cancer.
Kouba E1, Cheng L2,3.
Author information
1
Associated Pathologists at Medical Center of Central Georgia, Macon, GA 46202, USA.
2
Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
3
Department of Urology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
KEYWORDS:
biomarker; cell-free DNA; liquid biopsy; precision medicine; urinary bladder

PMID: 31651200 DOI: 10.2217/fon-2019-0522