Review J Hematol Oncol
. 2019 Sep 6;12(1):93. doi: 10.1186/s13045-019-0787-5.
Tumor Neoantigens: From Basic Research to Clinical Applications
Tao Jiang 1 2, Tao Shi 3, Henghui Zhang 4, Jie Hu 1, Yuanlin Song 1, Jia Wei 5, Shengxiang Ren 6, Caicun Zhou 7
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PMID: 31492199 PMCID: PMC6731555 DOI: 10.1186/s13045-019-0787-5
Free PMC article
Abstract
Tumor neoantigen is the truly foreign protein and entirely absent from normal human organs/tissues. It could be specifically recognized by neoantigen-specific T cell receptors (TCRs) in the context of major histocompatibility complexes (MHCs) molecules. Emerging evidence has suggested that neoantigens play a critical role in tumor-specific T cell-mediated antitumor immune response and successful cancer immunotherapies. From a theoretical perspective, neoantigen is an ideal immunotherapy target because they are distinguished from germline and could be recognized as non-self by the host immune system. Neoantigen-based therapeutic personalized vaccines and adoptive T cell transfer have shown promising preliminary results. Furthermore, recent studies suggested the significant role of neoantigen in immune escape, immunoediting, and sensitivity to immune checkpoint inhibitors. In this review, we systematically summarize the recent advances of understanding and identification of tumor-specific neoantigens and its role on current cancer immunotherapies. We also discuss the ongoing development of strategies based on neoantigens and its future clinical applications.

Keywords: Immune checkpoint; Immune escape; Immunotherapy; Neoantigen; Resistance.

Conflict of interest statement
Henghui Zhang is an employee of Beijing Genecast Biotechnology Co., Beijing, China. The other authors declare that they have no competing of interest.

Cited by 12 articles124 references2 figures
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2
Review J Hematol Oncol
. 2019 Sep 14;12(1):98. doi: 10.1186/s13045-019-0784-8.
Prospects for Combining Immune Checkpoint Blockade With PARP Inhibition
Anping Li 1, Ming Yi 2, Shuang Qin 2, Qian Chu 2, Suxia Luo 3, Kongming Wu 4 5
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PMID: 31521196 PMCID: PMC6744711 DOI: 10.1186/s13045-019-0784-8
Free PMC article
Abstract
The immunogenicity of a cancer cell is derived from accumulated somatic mutations. However, on the contrary to increased immunogenicity, anti-cancer immune response tends to be feeble. This impaired anti-cancer immunity could be attributed to multiple factors including loss of immunodominant epitopes, downregulation of major histocompatibility complex, and immunosuppressive microenvironment, as well as aberrant negative co-stimulatory signals. Immune checkpoint inhibitors block negative co-stimulatory signals such as programmed cell death-1 and cytotoxic T-lymphocyte-associated protein 4, ultimately reactivating anti-cancer immunity. Immune checkpoint inhibitors elicit potent anti-cancer effect and have been approved for multiple cancers. Nevertheless, there still are significant potential improvements for the applications of checkpoint inhibitor, especially considering frequent resistance. Recent studies demonstrated that additional PARP inhibition could alleviate resistance and enhance efficacy of immune checkpoint blockade therapy via promoting cross-presentation and modifying immune microenvironment. We proposed that PARP inhibitors could enhance the priming and tumor-killing activities of T cell, boost the whole cancer-immunity cycle, and thereby improve the response to immune checkpoint blockade. In this review, we focused the latest understanding of the effect of PARP inhibitors on anti-cancer immunity and PARP inhibitors combining immune checkpoint blockade therapy. Moreover, we summarized the preclinical and clinical evidence and discussed the feasibility of this combination therapy in future clinical practice.

Keywords: CTLA-4; Combination therapy; DNA damage response; Immunotherapy; PARP inhibitor; PD-1; PD-L1; Tumor immune microenvironment.

Conflict of interest statement
The authors declare that they have no competing interests.

Cited by 7 articles129 references2 figures
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3
Clinical Trial Ann Oncol
. 2019 Jul 1;30(7):1114-1120. doi: 10.1093/annonc/mdz122.
Prognostic Value of Circulating Tumour Cells in Limited-Stage Small-Cell Lung Cancer: Analysis of the Concurrent Once-Daily Versus Twice-Daily Radiotherapy (CONVERT) Randomised Controlled Trial
R Y Tay 1, F Fernández-Gutiérrez 2, V Foy 2, K Burns 3, J Pierce 2, K Morris 2, L Priest 2, J Tugwood 4, L Ashcroft 5, C R Lindsay 6, C Faivre-Finn 7, C Dive 4, F Blackhall 8
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PMID: 31020334 PMCID: PMC6637373 DOI: 10.1093/annonc/mdz122
Free PMC article
Abstract
Background: The clinical significance of circulating tumour cells (CTCs) in limited-stage small-cell lung cancer (LS-SCLC) is not well defined. We report a planned exploratory analysis of the prevalence and prognostic value of CTCs in LS-SCLC patients enrolled within the phase III randomised CONVERT (concurrent once-daily versus twice-daily chemoradiotherapy) trial.

Patients and methods: Baseline blood samples were enumerated for CTCs using CellSearch in 75 patients with LS-SCLC who were enrolled in the CONVERT trial and randomised between twice- and once-daily concurrent chemoradiation. Standard statistical methods were used for correlations of CTCs with clinical factors. Log-rank test and Cox regression analyses were applied to establish the associations of 2, 15 and 50 CTC thresholds with progression-free survival (PFS) and overall survival (OS). An optimal CTC count threshold for LS-SCLC was established.

Results: CTCs were detected in 60% (45/75) of patients (range 0-3750). CTC count thresholds of 2, 15 and 50 CTCs all significantly correlate with PFS and OS. An optimal CTC count threshold in LS-SCLC was established at 15 CTCs, defining 'favourable' and 'unfavourable' prognostic risk groups. The median OS in <15 versus ≥15 CTCs was 26.7 versus 5.9 m (P = 0.001). The presence of ≥15 CTCs at baseline independently predicted ≤1 year survival in 70% and ≤2 years survival in 100% of patients.

Conclusion: We report the prognostic value of baseline CTC count in an exclusive LS-SCLC population at thresholds of 2, 15 and 50 CTCs. Specific to LS-SCLC, ≥15 CTCs was associated with worse PFS and OS independent of all other factors and predicted ≤2 years survival. These results may improve disease stratification in future clinical trial designs and aid clinical decision making.

Trial registration: ClinicalTrials.gov identifier: NCT00433563.

Keywords: chemoradiotherapy; circulating tumour cells; limited disease; limited stage; prognosis; small-cell lung cancer.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Comment in
Circulating tumor cells are prognostic in SCLC, but still lack clinical application.
Tamminga M, Groen HJM.
Ann Oncol. 2019 Jul 1;30(7):1031-1033. doi: 10.1093/annonc/mdz162.
PMID: 31095269 No abstract available.
Cited by 3 articles27 references1 figure
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4
Mutagenesis
. 2019 Dec 19;34(5-6):403-411. doi: 10.1093/mutage/gez021.
KRAS Pathway Expression Changes in Pancreatic Cancer Models by Conventional and Experimental Taxanes
M Oliverius 1 2, D Flasarova 3, B Mohelnikova-Duchonova 3 4, M Ehrlichova 5, V Hlavac 5, M Kocik 2, O Strouhal 3, P Dvorak 5, I Ojima 6, P Soucek 4 5
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PMID: 31375828 PMCID: PMC6923165 (available on 2020-12-19) DOI: 10.1093/mutage/gez021
Free PMC article
Abstract
The KRAS signalling pathway is pivotal for pancreatic ductal adenocarcinoma (PDAC) development. After the failure of most conventional cytotoxic and targeted therapeutics tested so far, the combination of taxane nab-paclitaxel (Abraxane) with gemcitabine recently demonstrated promising improvements in the survival of PDAC patients. This study aimed to explore interactions of conventional paclitaxel and experimental taxane SB-T-1216 with the KRAS signalling pathway expression in in vivo and in vitro PDAC models in order to decipher potential predictive biomarkers or targets for future individualised therapy. Mouse PDAC PaCa-44 xenograft model was used for evaluation of changes in transcript and protein levels of the KRAS signalling pathway caused by administration of experimental taxane SB-T-1216 in vivo. Subsequently, KRAS wild-type (BxPc-3) and mutated (MiaPaCa-2 and PaCa-44) cell line models were treated with paclitaxel to verify dysregulation of the KRAS signalling pathway gene expression profile in vitro and investigate the role of KRAS mutation status. By comparing the gene expression profiles, this study observed for the first time that in vitro cell models differ in the basal transcriptional profile of the KRAS signalling pathway, but there were no differences between KRAS mutated and wild-type cells in sensitivity to taxanes. Generally, the taxane administration caused a downregulation of the KRAS signalling pathway both in vitro and in vivo, but this effect was not dependent on the KRAS mutation status. In conclusion, putative biomarkers for prediction of taxane activity or targets for stimulation of taxane anticancer effects were not discovered by the KRAS signalling pathway profiling in various PDAC models.

© The Author(s) 2019. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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5
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
Isabel Karkossa 1, Anne Bannuscher 2, Bryan Hellack 3 4, Aileen Bahl 2, Sophia Buhs 5, Peter Nollau 5, Andreas Luch 2, Kristin Schubert 1, Martin von Bergen 1 6, Andrea Haase 7
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PMID: 31653258 PMCID: PMC6814995 DOI: 10.1186/s12989-019-0321-5
Free PMC article
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.

Conflict of interest statement
The authors declare that they have no competing interests.

58 references5 figures
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6
J Glob Oncol
. 2019 Apr;5:1-8. doi: 10.1200/JGO.18.00223.
Advancing Cancer Research in Africa Through Early-Career Awards: The BIG Cat Initiative
Amanda L Vogel 1, Jordan A Freeman 2, Kalina Duncan 2, James Alaro 2, John J Welch 2, Belmira Rodrigues 3, Verna Vanderpuye 3, Joe B Harford 4, Makeda Williams 5
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PMID: 31009270 PMCID: PMC6528731 DOI: 10.1200/JGO.18.00223
Free PMC article
Abstract
Purpose: The burden of cancer in Africa is growing rapidly, and increased cancer research on the continent is a critical component of an effective response. In 2010, the US National Cancer Institute, in partnership with the African Organization for Research and Training in Cancer, launched the Beginning Investigator Grant for Catalytic Research (BIG Cat) initiative to support cancer research projects conducted by early-career African investigators.

Methods: To date, BIG Cat has provided 18 awards of up to $50,000 to support 2-year cancer research projects. In 2017, the National Cancer Institute evaluated BIG Cat's early outcomes for cancer research and impacts on career development and local cancer research capacity. Data collection consisted of a review of project documentation and a survey fielded to the 12 investigators who had completed their BIG Cat awards.

Results: BIG Cat-supported research projects have generated locally relevant findings that address a range of cancer sites and multiple areas of scientific interest. The 11 survey respondents produced 43 scholarly products (e.g., publications, presentations) about findings from their BIG Cat research. They reported increases in cancer research funding applications and awards after receipt of the BIG Cat award compared with before the award. They also reported increased resources for cancer research, participation in teaching and mentoring on cancer research, and supervision of cancer research staff. Investigators identified scientific mentoring as a key facilitator of the success of their BIG Cat projects and limited time and funding as key challenges.

Conclusion: Findings provide early evidence that BIG Cat advanced locally relevant cancer research and facilitated career advancement and development of local cancer research capacity. Findings have implications for the design of future related efforts.

Conflict of interest statement
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jgo/site/misc/authors.html.

Joe B. Harford
Employment: SynerGene Therapeutics

Leadership: SynerGene Therapeutics.

Stock and Other Ownership Interests: SynerGene Therapeutics

Patents, Royalties, Other Intellectual Property: Inventor on patents owned by Georgetown University that are licensed to SynerGene Therapeutics, no royalties have been received (I)

Travel, Accommodations, Expenses: SynerGene Therapeutics

No other potential conflicts of interest were reported.

14 references3 figures
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7
Review Nat Rev Clin Oncol
. 2020 Jun 22. doi: 10.1038/s41571-020-0387-x. Online ahead of print.
Towards New Horizons: Characterization, Classification and Implications of the Tumour Antigenic Repertoire
Sebastian P Haen 1 2 3, Markus W Löffler 4 5 6 7 8, Hans-Georg Rammensee 4 5 6, Peter Brossart 9
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PMID: 32572208 DOI: 10.1038/s41571-020-0387-x
Abstract
Immune-checkpoint inhibition provides an unmatched level of durable clinical efficacy in various malignancies. Such therapies promote the activation of antigen-specific T cells, although the precise targets of these T cells remain unknown. Exploiting these targets holds great potential to amplify responses to treatment, such as by combining immune-checkpoint inhibition with therapeutic vaccination or other antigen-directed treatments. In this scenario, the pivotal hurdle remains the definition of valid HLA-restricted tumour antigens, which requires several levels of evidence before targets can be established with sufficient confidence. Suitable antigens might include tumour-specific antigens with alternative or wild-type sequences, tumour-associated antigens and cryptic antigens that exceed exome boundaries. Comprehensive antigen classification is required to enable future clinical development and the definition of innovative treatment strategies. Furthermore, clinical development remains challenging with regard to drug manufacturing and regulation, as well as treatment feasibility. Despite these challenges, treatments based on diligently curated antigens combined with a suitable therapeutic platform have the potential to enable optimal antitumour efficacy in patients, either as monotherapies or in combination with other established immunotherapies. In this Review, we summarize the current state-of-the-art approaches for the identification of candidate tumour antigens and provide a structured terminology based on their underlying characteristics.

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8
Environ Mol Mutagen
. 2020 Jun 22. doi: 10.1002/em.22393. Online ahead of print.
Human Blood PIG-A Mutation and Micronucleated Reticulocyte Flow Cytometric Assays: Method Optimization and Evaluation of Intra- And Inter-Subject Variation
Dorothea K Torous 1, Svetlana L Avlasevich 1, Mona G Khattab 2, Ayesha Baig 3, Lawrence J Saubermann 3, Yuhchyau Chen 4, Jeffrey C Bemis 1, David P Lovell 5, Vernon E Walker 6, James T MacGregor 7, Stephen D Dertinger 1
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PMID: 32572998 DOI: 10.1002/em.22393
Abstract
We previously described flow cytometry-based methods for scoring the incidence of micronucleated reticulocytes (MN-RET) and PIG-A mutant phenotype reticulocytes (MUT RET) in rodent and human blood samples. The current report describes important methodological improvements for human blood analyses, including immunomagnetic enrichment of CD71-positive reticulocytes prior to MN-RET scoring, and procedures for storing frozen blood for later PIG-A analysis. Technical replicate variability in MN-RET and MUT RET frequencies based on blood specimens from 14 subjects, intra-subject variability based on serial blood draws from 6 subjects, and inter-subject variation based on up to 344 subjects age 0 to 73 years were quantified. Inter-subject variation explained most of the variability observed for both endpoints (≥ 77%), with much lower intra-subject and technical replicate variability. The relatively large degree of inter-subject variation is apparent from mean and standard deviation values for MN-RET (0.15 ± 0.10%) and MUT RET (4.7 ± 5.0 per million, after omission of two extreme outliers). The influences of age and sex on inter-subject variation were investigated, and neither factor affected MN-RET whereas both influenced MUT RET frequency. The lowest MUT RET values were observed for subjects < 11 years old, and males had moderately higher frequencies than females. These results indicate that MN-RET and MUT RET are automation-compatible biomarkers of genotoxicity that bridge species of toxicological interest to include human populations. These data will be useful for appropriately designing future human studies that include these biomarkers of genotoxicity, and highlight the need for additional work aimed at identifying the sources of inter-individual variability reported herein.

Keywords: biomonitoring; chromosomal damage; flow cytometry; genotoxicity; mutation.

This article is protected by copyright. All rights reserved.

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9
Int J Gynecol Cancer
. 2020 Jun 22;ijgc-2019-000526. doi: 10.1136/ijgc-2019-000526. Online ahead of print.
Prognostic Factors in Patients With Vulvar Cancer: The VULCAN Study
Ignacio Zapardiel 1, Sara Iacoponi 1, Pluvio J Coronado 2, Kamil Zalewski 3, Frank Chen 4, Christina Fotopoulou 4, Polat Dursun 5, Ioannis C Kotsopoulos 6, Robert Jach 7, Alessandro Buda 8, Maria J Martinez-Serrano 9, Christoph Grimm 10, Robert Fruscio 8, Enrique Garcia 11, Jacek Jan Sznurkowski 12, Cristina Ruiz 13, Maria C Noya 14, Dib Barazi 15, Javier Diez 16, Begoña Diaz De la Noval 17, Arnoldas Bartusevicius 18, Pierandrea De Iaco 19, Maria Otero 20, Maria Diaz 21, Dimitrios Haidopoulos 22, Silvia Franco 23, Pawel Blecharz 24, Miguel A Zuñiga 25, Patricia Rubio 26, Barbara Gardella 27, Dimitrios C Papatheodorou 28, Yusuf Yildirim 29, Francesc Fargas 30, Ronalds Macuks 31, VULCAN Study coinvestigators
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PMID: 32571891 DOI: 10.1136/ijgc-2019-000526
Abstract
Objective: This study aimed to analyze the prognostic factors for overall and progression-free survival in patients with vulvar cancer.

Methods: This international, multicenter, retrospective study included 2453 patients diagnosed with vulvar cancer at 100 different institutions. Inclusion criteria were institutional review board approval from each collaborating center, pathologic diagnosis of invasive carcinoma of the vulva, and primary treatment performed at the participating center. Patients with intraepithelial neoplasia or primary treatment at non-participating centers were excluded. Global survival analysis and squamous cell histology subanalysis was performed.

Results: After excluding patients due to incomplete data entry, 1727 patients treated for vulvar cancer between January 2001 and December 2005 were registered for analysis (1535 squamous, 42 melanomas, 38 Paget's disease and 112 other histologic types). Melanomas had the worse prognosis (p=0.02). In squamous vulvar tumors, independent factors for increase in local recurrence of vulvar cancer were: no prior radiotherapy (p<0.001) or chemotherapy (p=0.006), and for distant recurrence were the number of positive inguinal nodes (p=0.025), and not having undergone lymphadenectomy (p=0.03) or radiotherapy (p<0.001), with a HR of 1.1 (95% CI 1.2 to 1.21), 2.9 (95% CI 1.4 to 6.1), and 3.1 (95% CI 1.7 to 5.7), respectively. Number of positive nodes (p=0.008), FIGO stage (p<0.001), adjuvant chemotherapy (p=0.001), tumor resection margins (p=0.045), and stromal invasion >5 mm (p=0.001) were correlated with poor overall survival, and large case volume (≥9 vs <9 cases per year) correlated with more favorable overall survival (p=0.05).

Conclusions: Advanced patient age, number of positive inguinal lymph nodes, and lack of adjuvant treatment are significantly associated with a higher risk of relapse in patients with squamous cell vulvar cancer. Case volume per treating institution, FIGO stage, and stromal invasion appear to impact overall survival significantly. Future prospective trials are warranted to establish these prognostic factors for vulvar cancer.

Keywords: neoplasm recurrence, local; vulvar and vaginal cancer; vulvar neoplasms.

© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Conflict of interest statement
Competing interests: None declared.

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10
Review Clin Pharmacol Ther
. 2020 Jun 23. doi: 10.1002/cpt.1962. Online ahead of print.
Novel Treatment Paradigms in Acute Myeloid Leukemia
Nabin Khanal 1, Shristi Upadhyay Banskota 2, Vijaya Raj Bhatt 3 4
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PMID: 32572947 DOI: 10.1002/cpt.1962
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease marked by the presence of several driver mutations and molecular subgroups even in a single patient. The genetic and molecular heterogeneity is also reflected by a progressive shift from a morphologic classification to one informed by causative genomic changes. Cytogenetic results and somatic mutations are increasingly being utilized to guide use of intensive chemotherapy and low-intensity chemotherapy, particularly among older adults. Utilization of next generation sequencing in AML has led to increasing use of targeted treatments for actionable mutations. Quantitative real-time polymerase chain reaction based mutational analysis and multicolor flow cytometry offer sensitive assays that can detect minimal residual disease (MRD). Several studies have shown that MRD negativity, as defined by specified cutoff values, is highly prognostic with potential therapeutic implications. The last three years mark an unprecedented history in the drug development in AML with approval of eight new drugs and large portfolio of ongoing early and late phase trials of several promising drugs. Multiple combinatorial trials of approved agents and approval of newer agents in the future will continue to change the therapeutic landscape of AML.

Keywords: Acute myeloid leukemia; Minimal residual disease; genetic profiling; molecular mutation; therapy selection.

This article is protected by copyright. All rights reserved.

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11
Review Cancer Treat Rev
. 2020 Jun 10;88:102057. doi: 10.1016/j.ctrv.2020.102057. Online ahead of print.
Immune-checkpoint Inhibitors and Metastatic Prostate Cancer Therapy: Learning by Making Mistakes
Mélanie Claps 1, Alessia Mennitto 1, Valentina Guadalupi 1, Pierangela Sepe 1, Marco Stellato 1, Emma Zattarin 1, Sommer Silke Gillessen 2, Cora N Sternberg 3, Alfredo Berruti 4, Filippo Guglielmo Maria De Braud 5, Elena Verzoni 1, Giuseppe Procopio 6
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PMID: 32574991 DOI: 10.1016/j.ctrv.2020.102057
Abstract
Despite advances in metastatic prostate cancer therapy, expected survival for patients in the castration-resistant phase of disease is poor. Immune-checkpoints inhibitors significantly prolonged life expectancy in some solid tumors and have been evaluated also in advanced stage prostate cancer. The majority of data available derive from preliminary phase I and II trials evaluating CTLA-4 and PD-1 as monotherapy or in combination with each other, vaccines, radiotherapy or targeted/hormonal therapy, achieving only limited benefits in terms of biochemical and radiologic responses. There are many reasons that may explain why prostate cancer responds poorly to modern immunotherapies, such as its characteristic low tumor mutational burden or immune-suppressive tumor microenvironment. The present review summarizes the results obtained treating advanced prostate cancer patients with immune-checkpoints inhibitors and analyzes potential mechanisms of both resistance and sensitivity, in order to hypothesize possible avenues of special interest for future research.

Keywords: Combination therapy; Immune-checkpoints inhibitors; Immune-suppressive phenotype; Prostate cancer; Tumor mutational burden.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Conflict of interest statement
Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GP reports personal fees from: Bayer, BMS, Ipsen, Merck, MSD, Novartis, Pfizer (Advisory Boards, speaker honoraria). FGMDB reports personal fees from: Daiichi Sankyo, Ignyta, Novartis, Amgen, Pfizer, Octimet Oncology, Incyte, Teofarma, Pierre Fabre, Roche, EMD Serono, BMS, Hoffman La Roche (Advisory Boards). SSG reports personal fees from Astellas Pharma (Inst), Curevac (Inst), Novartis (Inst), Active Biotech (Inst), Bristol-Myers Squibb (Inst), Ferring (Inst), MaxiVax, Roche, Janssen (Inst), Innocrin Pharma (Inst), Sanofi, Bayer (Inst), Orion Pharma GmbH, Clovis Oncology (Inst), Menarini Silicon Biosystems (Inst), Nektar, ProteoMediX, outside the submitted work; in addition, SSG has a patent WO 3752009138392 A1. EV reports personal fees from BMS (speaker honoraria). MC, AM, VG, PS, MS, EZ, CNS, AB have nothing to disclose.

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12
J Clin Endocrinol Metab
. 2020 Jun 23;dgaa396. doi: 10.1210/clinem/dgaa396. Online ahead of print.
Functional Characterization of TMEM127 Variants Reveals Novel Insights Into Its Membrane Topology and Trafficking
Shahida K Flores 1, Yilun Deng 1, Ziming Cheng 1, Xingyu Zhang 1 2, Sifan Tao 1 2, Afaf Saliba 1, Irene Chu 1, Nelly Burnichon 3 4, Anne-Paule Gimenez-Roqueplo 3 4, Exing Wang 5, Ricardo C T Aguiar 1 6 7, Patricia L M Dahia 1 6
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PMID: 32575117 DOI: 10.1210/clinem/dgaa396
Abstract
Context: TMEM127 is a poorly known tumor suppressor gene associated with pheochromocytomas, paragangliomas and renal carcinomas. Our incomplete understanding of TMEM127 function has limited our ability to predict variant pathogenicity.

Purpose: To better understand the function of the transmembrane protein TMEM127 we undertook cellular and molecular evaluation of patient-derived germline variants.

Design: Subcellular localization and steady-state levels of tumor-associated, transiently expressed TMEM127 variants were compared to the wild-type protein using immunofluorescence and immunoblot analysis, respectively, in cells genetically modified to lack endogenous TMEM127. Membrane topology and endocytic mechanisms were also assessed.

Results: We identified three subgroups of mutations and determined that 71% of the variants studied are pathogenic or likely pathogenic through loss of membrane binding ability, stability and/or internalization capability. Investigation into an N-terminal cluster of missense variants uncovered a previously unrecognized transmembrane domain, indicating that TMEM127 is a four-, not a three-, transmembrane domain-containing protein. Additionally, a C-terminal variant with predominant plasma membrane localization revealed an atypical, extended acidic, dileucine-based motif required for TMEM127 internalization through clathrin-mediated endocytosis.

Conclusion: We characterized the functional deficits of several germline TMEM127 variants and identified novel structure-function features of TMEM127. These findings will assist in determining pathogenicity of TMEM127 variants and will help guide future studies investigating the cellular role of TMEM127.

Keywords: TMEM127; endocytic motif; germline variant; paraganglioma; pheochromocytoma; transmembrane protein; tumor suppressor gene; variant classification.

© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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13
Clin Radiol
. 2020 Jun 19;S0009-9260(20)30197-5. doi: 10.1016/j.crad.2020.05.011. Online ahead of print.
MRI of Benign Hyperplasia in the Nasopharynx: Is There an Association With Epstein-Barr Virus?
Q-Y Ai 1, A D King 2, T Y So 1, W K J Lam 3, F K F Mo 4, I O L Tse 3, J K S Woo 5, K C A Chan 3
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PMID: 32571521 DOI: 10.1016/j.crad.2020.05.011
Abstract
Aim: To evaluate whether there is an association between persistently positive plasma Epstein-Barr virus (EBV) DNA and the presence and the change in benign hyperplasia.

Materials and methods: One hundred and seventeen participants with positive-plasma EBV-DNA, but without NPC from previous nasopharyngeal carcinoma (NPC) screening, underwent follow-up magnetic resonance imaging (MRI) and plasma EBV-DNA after 2 years. Logistic regression was used to analyse associations between MRI (benign hyperplasia on the follow-up MRI and change from 2 years earlier), and plasma EBV-DNA, smoking, and age.

Results: At follow-up, EBV-DNA positivity and smoking were independent parameters for the presence of benign hyperplasia (p=0.027 and 0.023 respectively). Compared with participants in whom EBV-DNA became negative (n=44/117 37.6%), those in whom EBV-DNA remained positive (n=73/117 62.4%) had a greater risk of benign hyperplasia developing (previous MRI normal), being stable or processing (52/73 71.2% versus 18/44 40.9%; p=0.001).

Conclusion: These results suggest a potential link between benign hyperplasia on MRI and the EBV. As EBV contributes to NPC oncogenesis, future MRI research is warranted to determine if persistent benign hyperplasia is a risk marker for development of NPC.

Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Conflict of interest statement
Conflict of Interest The authors declare no conflict of interest.

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14
Review J Hematol Oncol
. 2020 Jun 22;13(1):81. doi: 10.1186/s13045-020-00916-z.
cGAS-STING, an Important Pathway in Cancer Immunotherapy
Minlin Jiang 1 2, Peixin Chen 1 2, Lei Wang 1, Wei Li 1, Bin Chen 1, Yu Liu 1 2, Hao Wang 1 2, Sha Zhao 1, Lingyun Ye 1, Yayi He 3, Caicun Zhou 4
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PMID: 32571374 DOI: 10.1186/s13045-020-00916-z
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Abstract
Cytosolic DNA sensing, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, is an important novel role in the immune system. Multiple STING agonists were developed for cancer therapy study with great results achieved in pre-clinical work. Recent progress in the mechanical understanding of STING pathway in IFN production and T cell priming, indicates its promising role for cancer immunotherapy. STING agonists co-administrated with other cancer immunotherapies, including cancer vaccines, immune checkpoint inhibitors such as anti-programmed death 1 and cytotoxic T lymphocyte-associated antigen 4 antibodies, and adoptive T cell transfer therapies, would hold a promise of treating medium and advanced cancers. Despite the applications of STING agonists in cancer immunotherapy, lots of obstacles remain for further study. In this review, we mainly examine the biological characters, current applications, challenges, and future directions of cGAS-STING in cancer immunotherapy.

Keywords: Cancer; Combined therapy; Immunotherapy; STING pathway; cGAS-STING.

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15
Emerg Microbes Infect
. 2020 Jun 23;1-30. doi: 10.1080/22221751.2020.1785951. Online ahead of print.
Perception of the 2020 SARS-CoV-2 Pandemic Among Medical Professionals in Germany: Results From a Nationwide Online Survey
Pia Paffenholz 1, Arne Peine 2, Martin Hellmich 3, Stella V Paffenholz 4 5, Lukas Martin 2, Mark Luedde 6, Miriam Haverkamp 7, Christoph Roderburg 8, Gernot Marx 2, Axel Heidenreich 1, Christian Trautwein 9, Tom Luedde 10 11, Sven H Loosen 9
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PMID: 32573350 DOI: 10.1080/22221751.2020.1785951
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Abstract
Background: The COVID-19 pandemic represents an unprecedented global challenge. While drastic measures within the German healthcare system and extensive restrictions of public life up to now have prevented a healthcare collapse, the current situation implicates a wide range of burden on medical professionals. We evaluated the perception and impact of the COVID-19 pandemic among medical professionals in Germany. Methods: A total of n=2827 medical professionals in Germany participated in an online survey between March 18th and April 11th. Results: While most participants stated that Germany was well prepared and rated the measures taken by their employer as positive, subgroup analyses revealed decisive differences. The preventive measures were rated significantly worse by nurses compared to doctors (p<0.001) and by participants from ambulatory healthcare centers compared to participants from maximum-care hospitals (p<0.001). Importantly, shortage of protective medical equipment was reported more commonly in the ambulatory sector (p<0.001) and in East German federal states (p=0.004). Moreover, the majority of health care professionals (72.4%) reported significant restrictions of daily work routine. Finally, most participants reported a negative influence on their mood (48.3%) and over 60% of medical professionals had concerns regarding their own health, which were more pronounced among female participants (p=0.024). Conclusion: This survey is the first to analyze the impact of the COVID-19 pandemic on medical professionals of both the hospital and ambulatory healthcare sector in Germany and may indicate starting points on how medical professionals could be supported in carrying out their important activities during the ongoing and future healthcare challenges.

Keywords: COVID-19; PPE; burden; healthcare workers; nurses; personal protective equipment.

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16
Arthritis Res Ther
. 2020 Jun 22;22(1):151. doi: 10.1186/s13075-020-02245-5.
Parenchymal Lung Disease in Adult Onset Still's Disease: An Emergent Marker of Disease Severity-Characterisation and Predictive Factors From Gruppo Italiano Di Ricerca in Reumatologia Clinica E Sperimentale (GIRRCS) Cohort of Patients
Piero Ruscitti 1, Onorina Berardicurti 2, Daniela Iacono 3, Ilenia Pantano 3, Vasiliki Liakouli 3, Francesco Caso 4, Giacomo Emmi 5, Rosa Daniela Grembiale 6, Francesco Paolo Cantatore 7, Fabiola Atzeni 8, Federico Perosa 9, Raffaele Scarpa 4, Giuliana Guggino 10, Francesco Ciccia 3, Antonio Barile 11, Paola Cipriani 2, Roberto Giacomelli 2
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PMID: 32571407 DOI: 10.1186/s13075-020-02245-5
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Abstract
Background: Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown aetiology usually affecting young adults. Interestingly, recent evidence from the juvenile counterpart of AOSD suggested the emergent high fatality rate of lung disease (LD) in these patients. In this work, we aimed to characterise LD in AOSD, to identify associated clinical features and predictive factors, and to describe long-term outcomes of the disease comparing patients with LD and those without.

Methods: A retrospective assessment of prospectively followed patients, from January 2001 to December 2019, was provided to describe the rate of LD in AOSD, associated clinical features and predictive factors, and long-term outcomes. Patients with AOSD, who were included in Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort, were assessed.

Results: Out of 147 patients included in GIRRCS cohort, 18 (12.25%) patients were reported to be affected by LD, at the time of diagnosis of AOSD, who were characterised by older age, a higher prevalence of myalgia, of lymph node involvement, of pleuritis, and abdominal pain. Furthermore, patients with LD showed higher values of systemic score and ferritin. Among those clinical variables, older age and systemic score were also independently predictors of LD. Chest CT scans were also obtained, and the most common finding was the peripheral consolidations in 8 (44.4%) patients. Finally, a higher mortality rate, of 38.9%, was registered in patients with LD than others, since it was associated with a significant decreased survival rate.

Conclusions: The presence of LD could suggest an emergent cause of mortality in AOSD, as observed in juvenile counterpart recognising a further marker of severity and poor prognosis to be careful evaluated. Patients with LD were also characterised by some clinical features, higher values of systemic score and ferritin than the others, identifying a subset of patients mostly burdened by systemic signs and symptoms. Although specific designed future studies are needed to fully elucidate the significance of LD in AOSD, a more accurate evaluation and management of this feature could improve the long-term outcomes of these patients.

Keywords: Adult onset Still’s disease; Lung disease; Mortality.

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17
Ann Surg Oncol
. 2020 Jun 22. doi: 10.1245/s10434-020-08743-9. Online ahead of print.
Systemic Pharmacokinetics of Oxaliplatin After Intraperitoneal Administration by Electrostatic Pressurized Intraperitoneal Aerosol Chemotherapy (ePIPAC) in Patients With Unresectable Colorectal Peritoneal Metastases in the CRC-PIPAC Trial
Robin J Lurvink 1, Rudaba Tajzai 1 2, Koen P Rovers 1, Emma C E Wassenaar 3, Dirk-Jan A R Moes 4, Giulia Pluimakers 2, Djamila Boerma 3, Jacobus W A Burger 1, Simon W Nienhuijs 1, Ignace H J T de Hingh 1 5, Maarten J Deenen 6 7
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PMID: 32572849 DOI: 10.1245/s10434-020-08743-9
Abstract
Background: Electrostatic pressurized intraperitoneal aerosol chemotherapy (ePIPAC) is a palliative treatment for unresectable peritoneal metastases from various primary cancers. However, little is known about the systemic pharmacokinetics of oxaliplatin after ePIPAC.

Methods: Twenty patients with unresectable colorectal peritoneal metastases were treated with repetitive ePIPAC monotherapy with oxaliplatin (92 mg/m2) and a simultaneous intravenous bolus of leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Samples were collected during each ePIPAC: whole blood at t = 0, t = 5, t = 10, t = 20, t = 30, t = 60, t = 120, t = 240, t = 360 and t = 1080 min for plasma and plasma ultrafiltrate concentrations; urine at t = 0, t = 1, t = 3, t = 5 and t = 7 days. Samples were analyzed using atomic absorption spectrometry. Pharmacokinetics were analyzed using nonlinear mixed-effects modeling.

Results: Four patients received one ePIPAC, three patients received two ePIPAC, and thirteen patients received ≥ 3 ePIPAC. The population pharmacokinetic models adequately described the pharmacokinetics of oxaliplatin after ePIPAC. The plasma ultrafiltrate Cmax of oxaliplatin reached 1.36-1.90 µg/mL after 30 min with an AUC0-24 h of 9.6-11.7 µg/mL * h. The plasma Cmax reached 2.67-3.28 µg/mL after 90 min with an AUC0-24 h of 49.0-59.5 µg/mL * h. The absorption rate constant (Ka) was 1.13/h. Urine concentrations of oxaliplatin rapidly decreased to less than 3.60 µg/mL in 90% of the samples at day 7.

Discussion: Systemic exposure to oxaliplatin after ePIPAC seemed comparable to that after systemic chemotherapy, as described in other literature. Since this is an indirect comparison, future research should focus on the direct comparison between the systemic exposure to oxaliplatin after ePIPAC and after systemic chemotherapy.

Trial registration: NCT03246321, Pre-results; ISRCTN89947480, Pre-results; NTR6603, Pre-results; EudraCT: 2017-000927-29, Pre-results.

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18
Phys Med Biol
. 2020 Jun 23. doi: 10.1088/1361-6560/ab9f5f. Online ahead of print.
Experimental Realization of Dynamic Fluence Field Optimization for Proton Computed Tomography
Jannis Dickmann 1, Christina Sarosiek 2, Victor Rykalin 3, Mark Pankuch 3, Simon Rit 4, Nicholas Detrich 3, George B Coutrakon 2, Robert P Johnson 5, Reinhard W Schulte 6, Katia Parodi 1, Guillaume Landry 7, Georgios Dedes 1
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PMID: 32575084 DOI: 10.1088/1361-6560/ab9f5f
Abstract
Proton computed tomography (pCT) has high accuracy and dose efficiency in producing spatial maps of the relative stopping power (RSP) required for treatment planning in proton therapy. With fluence-modulated pCT (FMpCT), prescribed noise distributions can be achieved, which allows to decrease imaging dose by employing object-specific dynamically modulated fluence during the acquisition. For FMpCT acquisitions we divide the image into region-of-interest (ROI) and non-ROI volumes. In proton therapy, the ROI volume would encompass all treatment beams. An optimization algorithm then calculates dynamically modulated fluence that achieves low prescribed noise inside the ROI and high prescribed noise elsewhere. It also produces a planned noise distribution, which is the expected noise map for that fluence, as calculated with a Monte Carlo simulation. The optimized fluence can be achieved by acquiring pCT images with grids of intensity modulated pencil beams. In this work, we interfaced the control system of a clinical proton beam line to deliver the optimized fluence. Using three phantoms we acquired images with uniform fluence, with a constant noise prescription, and with an FMpCT task. Image noise distributions as well as fluence maps were compared to the corresponding planned distributions as well as to the prescription. Furthermore, we propose a correction method that removes image artifacts stemming from the acquisition with pencil beams having a spatially varying energy distribution that is not seen in clinical operation. RSP accuracy of FMpCT scans was compared to uniform scans and was found to be comparable to standard pCT scans. While we identified technical improvements for future experimental acquisitions, in particular related to an unexpected pencil beam size reduction and a misalignment of the fluence pattern, agreement with the planned noise was satisfactory and we conclude that FMpCT optimized for specific image noise prescriptions is experimentally feasible.

Keywords: dose reduction; dynamic fluence modulation; proton CT; proton therapy; relative stopping power.

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19
Can Urol Assoc J
. 2020 Jun 16. doi: 10.5489/cuaj.6575. Online ahead of print.
Shared Decision-Making for the Management of Small Renal Masses - Development and Acceptability Testing of a Novel Patient Decision Aid
Kristen McAlpine 1, Rodney H Breau 1 2, Dawn Stacey 2 3, Christopher Knee 1 2, Michael A S Jewett 4, Philippe D Violette 5, Patrick O Richard 6, Ilias Cagiannos 1 2, Christopher Morash 1 2, Luke T Lavallée 1 2
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PMID: 32574143 DOI: 10.5489/cuaj.6575
Abstract
Introduction: Shared decision-making incorporates patient's values and preferences to achieve high-quality decisions. The objective of this study was to develop an acceptable patient decision aid to facilitate shared decision-making for the management of small renal masses (SRMs).

Methods: The International Patient Decision Aids Standards were used to guide an evidence-based development process. Management options included active surveillance, thermal ablation, partial nephrectomy, and radical nephrectomy. A literature review was performed to provide incidence rates for outcomes of each option. Once a prototype was complete, alpha-testing was performed using a 10-question survey to assess acceptability with patients, patient advocates, urologists, and methodological experts. The primary outcome was acceptability of the decision aid.

Results: A novel patient decision aid was created to facilitate shared decision-making for the management of SRMs. Acceptability testing was performed with 20 patients, 10 urologists, two patient advocates, and one methodological expert. Responders indicated the decision aid was appropriate in length (82%, 27 of 33), well-balanced (82%, 27 of 33), and had language that was easy to follow (94%, 31 of 33). All patient responders felt the decision aid would have been helpful during their consultation and would recommend the decision aid for future patients (100%, 20 of 20). Most urologists reported they intend to use the decision aid (90%, 9 of 10).

Conclusions: A novel patient decision aid was created to facilitate shared decision-making for management of SRMs. This clinical tool was acceptable with patients, patient advocates, and urologists and is freely available at: https://decisionaid.ohri.ca/decaids.html.

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20
Radiat Oncol
. 2020 Jun 22;15(1):157. doi: 10.1186/s13014-020-01592-6.
Radiobiological Model-Based Approach to Determine the Potential of Dose-Escalated Robust Intensity-Modulated Proton Radiotherapy in Reducing Gastrointestinal Toxicity in the Treatment of Locally Advanced Unresectable Pancreatic Cancer of the Head
Vijay P Raturi 1 2, Hidehiro Hojo 1, Kenji Hotta 1, Hiromi Baba 1, Ryo Takahashi 1, Toshiya Rachi 1, Naoki Nakamura 1, Sadamoto Zenda 1, Atsushi Motegi 1, Hidenobu Tachibana 1, Takaki Ariji 1, Kana Motegi 1, Masaki Nakamura 1, Masayuki Okumura 1, Yasuhiro Hirano 1, Tetsuo Akimoto 3 4
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PMID: 32571379 DOI: 10.1186/s13014-020-01592-6
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Abstract
Background: The purpose of this study was to determine the potential of escalated dose radiation (EDR) robust intensity-modulated proton radiotherapy (ro-IMPT) in reducing GI toxicity risk in locally advanced unresectable pancreatic cancer (LAUPC) of the head in term of normal tissue complication probability (NTCP) predictive model.

Methods: For 9 patients, intensity-modulated radiotherapy (IMRT) was compared with ro-IMPT. For all plans, the prescription dose was 59.4GyE (Gray equivalent) in 33 fractions with an equivalent organ at risk (OAR) constraints. Physical dose distribution was evaluated. GI toxicity risk for different endpoints was estimated using published NTCP Lyman Kutcher Burman (LKB) models for stomach, duodenum, small bowel, and combine stomach and duodenum (Stoduo). A Wilcoxon signed-rank test was used for dosimetry parameters and NTCP values comparison.

Result: The dosimetric results have shown that, with similar target coverage, ro-IMPT achieves a significant dose-volume reduction in the stomach, small bowel, and stoduo in low to high dose range in comparison to IMRT. NTCP evaluation for the endpoint gastric bleeding of stomach (10.55% vs. 13.97%, P = 0.007), duodenum (1.87% vs. 5.02%, P = 0.004), and stoduo (5.67% vs. 7.81%, P = 0.008) suggest reduced toxicity by ro-IMPT compared to IMRT. ∆NTCP IMRT - ro-IMPT (using parameter from Pan et al. for gastric bleed) of ≥5 to < 10% was seen in 3 patients (33%) for stomach and 2 patients (22%) for stoduo. An overall GI toxicity relative risk (NTCPro-IMPT/NTCPIMRT) reduction was noted (0.16-0.81) for all GI-OARs except for duodenum (> 1) with endpoint grade ≥ 3 GI toxicity (using parameters from Holyoake et al.).

Conclusion: With similar target coverage and better conformity, ro-IMPT has the potential to substantially reduce the risk of GI toxicity compared to IMRT in EDR of LAUPC of the head. This result needs to be further evaluated in future clinical studies.

Keywords: Intensity-modulated proton therapy; Intensity-modulated radiotherapy; Normal tissue complication probability; Pancreatic cancer.

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21
BMC Public Health
. 2020 Jun 22;20(1):973. doi: 10.1186/s12889-020-08854-8.
Building Towards Common Psychosocial Measures in U.S. Cohort Studies: Principal Investigators' Views Regarding the Role of Religiosity and Spirituality in Human Health
Alexandra E Shields 1 2, Tracy A Balboni 3 4
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PMID: 32571256 DOI: 10.1186/s12889-020-08854-8
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Abstract
Background: The goal of this study was to understand prospective cohort study Principal Investigators' (PIs') attitudes regarding the importance of religion and spirituality (R/S) on disease etiology in order to identify barriers and opportunities for greater inclusion of these domains in high-quality epidemiological research.

Methods: One-hour, semi-structured qualitative interviews were conducted with 20 PIs, who represent 24 different National Institutes of Health (NIH)-funded prospective cohort studies in the U.S. Collectively, these PIs collect detailed health data on approximately 1.25 of every 100 adult Americans. Sample size was calculated to achieve thematic saturation.

Results: The majority of PIs we interviewed viewed R/S as potentially important factors influencing disease etiology, particularly among minority communities that report higher levels of religiosity. Yet nearly all PIs interviewed felt there was not yet a compelling body of evidence elucidating R/S influences on health, and the potential mechanisms through which R/S may be operating to affect health outcomes. PIs identified 5 key areas that would need to be addressed before they would be persuaded to collect more R/S measures in their cohorts: (1) high-quality, prospective studies that include all appropriate covariates for the outcome under study; (2) studies that posit a plausible biological mechanism of effect; (3) well-validated R/S measures, collected in common across multiple cohorts; (4) the need to address bias against R/S research among investigators; and (5) NIH funding for R/S research.

Conclusions: Results of this study provide a roadmap for future R/S research investigating the impact of R/S influences on disease etiology within the context of U.S. prospective cohort studies. Identifying significant R/S influences on health could inform novel interventions to improve population health. Given the higher levels of religiosity/spirituality among minority communities, R/S research may also provide new leverage points for reducing health disparities.

Keywords: Chronic diseases; Health disparities; Interviews; Principle investigator; Prospective cohort study; Qualitative; Religion; Spirituality.

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