Future Oncol"
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1
J Med Chem
. 2019 Aug 22;62(16):7575-7582. doi: 10.1021/acs.jmedchem.9b00871. Epub 2019 Aug 2.
Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders
Shang Su 1, Zimo Yang 2, Hongying Gao 1 2, Haiyan Yang 1, Songbiao Zhu 3, Zixuan An 1, Juanjuan Wang 1, Qing Li 4, Sarat Chandarlapaty 4, Haiteng Deng 3, Wei Wu 1, Yu Rao 2
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PMID: 31330105 PMCID: PMC6790125 (available on 2020-08-22) DOI: 10.1021/acs.jmedchem.9b00871
Free PMC article
Abstract
A focused PROTAC library hijacking cancer therapeutic target CDK6 was developed. A design principle as "match/mismatch" was proposed for understanding the degradation profile differences in these PROTACs. Notably, potent PROTACs with specific and remarkable CDK6 degradation potential were generated by linking CDK6 inhibitor palbociclib and E3 ligase CRBN recruiter pomalidomide. The PROTAC strongly inhibited proliferation of hematopoietic cancer cells including multiple myeloma and robustly degraded copy-amplified/mutated forms of CDK6, indicating future potential clinical applications.

Cited by 4 articles
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2
Mol Cancer Res
. 2019 Dec;17(12):2457-2468. doi: 10.1158/1541-7786.MCR-19-0362. Epub 2019 Sep 24.
Therapeutic Implications of p53 Status on Cancer Cell Fate Following Exposure to Ionizing Radiation and the DNA-PK Inhibitor M3814
Qing Sun # 1, Yige Guo # 1, Xiaohong Liu 1, Frank Czauderna 1, Michael I Carr 1, Frank T Zenke 2, Andree Blaukat 2, Lyubomir T Vassilev 3
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PMID: 31551253 DOI: 10.1158/1541-7786.MCR-19-0362
Abstract
Inhibition of DNA double-strand break (DSB) repair in cancer cells has been proposed as a new therapeutic strategy for potentiating the anticancer effects of radiotherapy. M3814 is a novel, selective pharmacologic inhibitor of the serine/threonine kinase DNA-dependent protein kinase (DNA-PK), a key driver of nonhomologous end-joining, one of the main DSB-repair pathways, currently under clinical investigation. Here, we show that M3814 effectively blocks the repair of radiation-induced DSBs and potently enhances p53 phosphorylation and activation. In p53 wild-type cells, ataxia telangiectasia-mutated (ATM) and its targets, p53 and checkpoint kinase 2 (CHK2), were more strongly activated by combination treatment with M3814 and radiation than by radiation alone, leading to a complete p53-dependent cell-cycle block and premature cell senescence. Cancer cells with dysfunctional p53 were unable to fully arrest their cell cycle and entered S and M phases with unrepaired DNA, leading to mitotic catastrophe and apoptotic cell death. Isogenic p53-null/wild-type A549 and HT-1080 cell lines were generated and used to demonstrate that p53 plays a critical role in determining the response to ionizing radiation and M3814. Time-lapse imaging of cell death and measuring apoptosis in panels of p53 wild-type and p53-null/mutant cancer lines confirmed the clear differences in cell fate, dependent on p53 status. IMPLICATIONS: Our results identify p53 as a possible biomarker for response of cancer cells to combination treatment with radiation and a DNA-PK inhibitor and suggest that p53 mutation status should be considered in the design of future clinical trials. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/17/12/2457/F1.large.jpg.

©2019 American Association for Cancer Research.

Cited by 2 articles
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3
J Cachexia Sarcopenia Muscle
. 2019 Jun;10(3):662-686. doi: 10.1002/jcsm.12404. Epub 2019 Mar 27.
Compression of Morbidity in a Progeroid Mouse Model Through the Attenuation of myostatin/activin Signalling
Khalid Alyodawi 1 2, Wilbert P Vermeij 3 4, Saleh Omairi 1 2, Oliver Kretz 5 6 7, Mark Hopkinson 8, Francesca Solagna 6, Barbara Joch 7, Renata M C Brandt 3, Sander Barnhoorn 3, Nicole van Vliet 3, Yanto Ridwan 3 9, Jeroen Essers 3 10 11, Robert Mitchell 1, Taryn Morash 1, Arja Pasternack 12, Olli Ritvos 12 13, Antonios Matsakas 14, Henry Collins-Hooper 1, Tobias B Huber 5 6 15 16, Jan H J Hoeijmakers 3 4 17, Ketan Patel 1 16
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PMID: 30916493 PMCID: PMC6596402 DOI: 10.1002/jcsm.12404
Free PMC article
Abstract
Background: One of the principles underpinning our understanding of ageing is that DNA damage induces a stress response that shifts cellular resources from growth towards maintenance. A contrasting and seemingly irreconcilable view is that prompting growth of, for example, skeletal muscle confers systemic benefit.

Methods: To investigate the robustness of these axioms, we induced muscle growth in a murine progeroid model through the use of activin receptor IIB ligand trap that dampens myostatin/activin signalling. Progeric mice were then investigated for neurological and muscle function as well as cellular profiling of the muscle, kidney, liver, and bone.

Results: We show that muscle of Ercc1Δ/- progeroid mice undergoes severe wasting (decreases in hind limb muscle mass of 40-60% compared with normal mass), which is largely protected by attenuating myostatin/activin signalling using soluble activin receptor type IIB (sActRIIB) (increase of 30-62% compared with untreated progeric). sActRIIB-treated progeroid mice maintained muscle activity (distance travel per hour: 5.6 m in untreated mice vs. 13.7 m in treated) and increased specific force (19.3 mN/mg in untreated vs. 24.0 mN/mg in treated). sActRIIb treatment of progeroid mice also improved satellite cell function especially their ability to proliferate on their native substrate (2.5 cells per fibre in untreated progeroids vs. 5.4 in sActRIIB-treated progeroids after 72 h in culture). Besides direct protective effects on muscle, we show systemic improvements to other organs including the structure and function of the kidneys; there was a major decrease in the protein content in urine (albumin/creatinine of 4.9 sActRIIB treated vs. 15.7 in untreated), which is likely to be a result in the normalization of podocyte foot processes, which constitute the filtration apparatus (glomerular basement membrane thickness reduced from 224 to 177 nm following sActRIIB treatment). Treatment of the progeric mice with the activin ligand trap protected against the development of liver abnormalities including polyploidy (18.3% untreated vs. 8.1% treated) and osteoporosis (trabecular bone volume; 0.30 mm3 in treated progeroid mice vs. 0.14 mm3 in untreated mice, cortical bone volume; 0.30 mm3 in treated progeroid mice vs. 0.22 mm3 in untreated mice). The onset of neurological abnormalities was delayed (by ~5 weeks) and their severity reduced, overall sustaining health without affecting lifespan.

Conclusions: This study questions the notion that tissue growth and maintaining tissue function during ageing are incompatible mechanisms. It highlights the need for future investigations to assess the potential of therapies based on myostatin/activin blockade to compress morbidity and promote healthy ageing.

Keywords: Ageing; Bone; Compression; Kidney; Liver; Morbidity; Myostatin; Neurological; Progeroid; Skeletal muscle.

© 2019 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Conflict of interest statement
The authors declare no competing interests.

Cited by 1 article90 references8 figures
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4
Review Curr Oncol Rep
. 2019 Feb 4;21(2):17. doi: 10.1007/s11912-019-0759-5.
Bispecific Antibodies in Hematologic Malignancies: When, to Whom, and How Should Be Best Used?
Roberta Demichelis-Gómez 1, Daniela Pérez-Sámano 2, Christianne Bourlon 2
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PMID: 30715609 DOI: 10.1007/s11912-019-0759-5
Abstract
Purpose of review: The purpose of this review is to discuss the current recommendations for the use of bispecific antibodies (bsAb) in hematologic malignancies and explore the future in this field.

Recent findings: Bispecific antibodies are molecules able to target two different antigen-binding sites: one towards a tumor antigen and another to activate a cytotoxic cell. Phase II/III trials on blinatumomab for acute lymphoblastic leukemia (ALL) have demonstrated its efficacy for treating minimal residual disease (MRD+) and relapsed refractory (r/r) Philadelphia positive (Ph+) and negative (Ph-) ALL in adults and children. Currently, the only bispecific antibody (bsAb) approved for its use in hematologic malignancies is blinatumomab. However, multiple trials are under development not only to explore blinatumomab's clinical activity in other neoplasia, such as lymphoma or multiple myeloma, but also to develop new molecules against different antigens.

Keywords: Acute lymphoblastic leukemia; Antibodies; Antineoplastic agents; Bispecific antibodies; Immunotherapy; T-lymphocytes.

Cited by 1 article34 references
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5
Mol Cancer Res
. 2019 Dec;17(12):2522-2536. doi: 10.1158/1541-7786.MCR-19-0313. Epub 2019 Oct 8.
Functional Analysis of Aberrantly Spliced Caspase8 Variants in Adult T-Cell Leukemia Cells
Kazumi Nakano 1, Masako Iwanaga 2, Atae Utsunomiya 3, Kaoru Uchimaru 4, Toshiki Watanabe 5 6
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PMID: 31594868 DOI: 10.1158/1541-7786.MCR-19-0313
Abstract
The genetic and molecular alterations responsible for leukemogenesis and progression of HTLV-infected adult T-cell leukemia (ATL) have not been fully clarified. Previously, we reported that various genes are not only overexpressed but also abnormally spliced in ATL cells. Here, we identified various CASP8 transcript variants in PBMCs from a smoldering-type ATL patient, which encode aberrant truncated caspase 8 (Casp8) isoforms. Among those, we focus on the three transcript variants, CASP8L (including the first 136 bp of the intron 8 between exon 8 and exon 9), CASP8-ΔE4 (without the exon 4), and CASP8-ΔE7 (without the exon 7), because they encode isoforms, Casp8L, Casp8-ΔE4, and Casp8-ΔE7, respectively, without the C-terminal catalytic domains. In this study, we conducted in vitro characterization and functional analysis of those mutant Casp8 isoforms to clarify their changed functions compared with the wild-type (WT)-Casp8. We demonstrated that these abnormal Casp8 isoforms showed lower ability to induce apoptosis than WT-Casp8 due to their dominant-negative interactions with WT-Casp8, which impair WT-Casp8 homodimerization that is essential for induction of apoptosis. Moreover, Casp8L and Casp8-ΔE7, which have only two death-effector domains, significantly activated NFκB by forming filament-like structures, which probably function as scaffolds for the IKK complex formation. In view of increasing levels of these abnormal CASP8 transcripts in primary PBMCs from HTLV-1 carriers and patients with ATL, we propose a possibility that overexpression of those Casp8 mutants, with lower proapoptotic activities and higher NFκB-activating functions than WT-Casp8, may be one of the molecular abnormalities causing malignant transformation and growth of ATL cells. IMPLICATIONS: We describe naturally occurring CASP8 transcription variants in PBMCs from patients with ATL, which encode truncated Casp8-mutant isoforms with lower proapoptotic activities and higher NFκB-activating functions compared with WT-Casp8.

©2019 American Association for Cancer Research.

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6
JAMA Netw Open
. 2019 Sep 4;2(9):e1911528. doi: 10.1001/jamanetworkopen.2019.11528.
Physician Perceptions of the Use of Social Media for Recruitment of Patients in Cancer Clinical Trials
Mina S Sedrak 1, Virginia Sun 2, Jennifer Liu 1, Kevin George 1, Andrew R Wong 1, William Dale 3, Don S Dizon 4
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PMID: 31532517 PMCID: PMC6751756 DOI: 10.1001/jamanetworkopen.2019.11528
Free PMC article
Abstract
Importance: Social media campaigns have been successfully implemented in nontherapeutic trials. However, evidence to support their utility in cancer therapeutic trials is limited.

Objective: To examine physician attitudes toward and perceptions of social media use for therapeutic trial recruitment of patients with cancer.

Design, setting, and participants: This qualitative study engaged 44 physicians (24 academic based and 20 community based) at the main academic and 6 affiliated community sites of City of Hope in Duarte, California. Semistructured interviews were conducted in person or by telephone from March to June 2018. An interview guide was developed to explore perceptions of social media use for accrual of cancer therapeutic trials. Responses were recorded digitally and transcribed. Data were analyzed using qualitative content analysis.

Main outcomes and measures: Physicians' perceptions of the advantages and disadvantages of using social media for clinical trial recruitment, strategies to improve uptake of social media in clinical trials, and the barriers and facilitators to social media use for professional purposes in general.

Results: Of the 44 participants, 16 (36%) were women, 30 (68%) had more than 10 years of practice experience, 24 (55%) practiced in academia, and 20 (45%) practiced in the community. Physicians most commonly cited increased trial awareness and visibility as an advantage of using social media for trial recruitment. Cited disadvantages were increased administrative burden and risk of misinformation. Physicians also reported a need for institutional-level interventions (eg, restructuring of clinical trial offices to include personnel with social media expertise), increased evidence-based approaches to social media use, and more physician training on the use of social media. Perceived facilitators to professional social media use were networking and education; barriers included lack of time and lack of evidence of benefit.

Conclusions and relevance: In this qualitative study, physicians recognized the benefits of using social media for clinical trial recruitment but noted that barriers, including increased administrative burden, increased time, and the risk of misinformation, remain. Future interventions to address these concerns are a required first step in increasing digital engagement for clinical trial accrual purposes.

Conflict of interest statement
Conflict of Interest Disclosures: None reported.

Cited by 1 article37 references
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7
Review Future Med Chem
. 2019 Aug;11(16):2205-2231. doi: 10.4155/fmc-2018-0540.
When Polymers Meet Carbon Nanostructures: Expanding Horizons in Cancer Therapy
Giuseppe Cirillo 1, Claudia Peitzsch 2 3 4, Orazio Vittorio 5 6 7, Manuela Curcio 1, Annafranca Farfalla 1, Florida Voli 5, Anna Dubrovska 2 3 8 9, Francesca Iemma 1, Maria Kavallaris 5 6 7, Silke Hampel 10
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PMID: 31538523 DOI: 10.4155/fmc-2018-0540
Abstract
The development of hybrid materials, which combine inorganic with organic materials, is receiving increasing attention by researchers. As a consequence of carbon nanostructures high chemical versatility, they exhibit enormous potential for new highly engineered multifunctional nanotherapeutic agents for cancer therapy. Whereas many groups are working on drug delivery systems for chemotherapy, the use of carbon nanohybrids for radiotherapy is rarely applied. Thus, nanotechnology offers a wide range of solutions to overcome the current obstacles of conventional chemo- and/or radiotherapies. Within this review, the structure and properties of carbon nanostructures (carbon nanotubes, nanographene oxide) functionalized preferentially with different types of polymers (synthetic, natural) are discussed. In short, synthesis approaches, toxicity investigations and anticancer efficacy of different carbon nanohybrids are described.

Keywords: cancer therapy; carbon nanotubes; chemosensitization; functional polymers; graphene oxide; nanohybrids; radiosensitization.

Cited by 2 articles
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8
Clinical Trial Future Oncol
. 2020 Jan;16(1):4251-4264. doi: 10.2217/fon-2019-0633. Epub 2019 Nov 22.
Intrigue: Phase III Study of Ripretinib Versus Sunitinib in Advanced Gastrointestinal Stromal Tumor After Imatinib
John Nemunaitis 1 2, Sebastian Bauer 3, Jean-Yves Blay 4, Khalil Choucair 1, Hans Gelderblom 5, Suzanne George 6, Patrick Schöffski 7, Margaret von Mehren 8, John Zalcberg 9, Haroun Achour 10, Rodrigo Ruiz-Soto 10, Michael C Heinrich 11
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PMID: 31755321 DOI: 10.2217/fon-2019-0633
Abstract
Ripretinib (DCC-2618) is a novel, type II tyrosine switch control inhibitor designed to broadly inhibit activating and drug-resistant mutations in KIT and PDGFRA. Ripretinib has emerged as a promising investigational agent for the treatment of gastrointestinal stromal tumor owing to targeted inhibition of secondary resistance mutations that may develop following treatment with prior line(s) of tyrosine kinase inhibitors. Here we describe the rationale and design of intrigue (NCT03673501), a global, randomized (1:1), open-label, Phase III study comparing the safety and efficacy of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor following imatinib. The primary end point is progression-free survival and key secondary objectives include objective response rate and overall survival. Clinical Trial Registration: NCT03673501.

Keywords: DCC-2618; KIT; PDGFRA; Phase III trial; gastrointestinal stromal tumor; receptor tyrosine kinase; ripretinib; sarcoma; targeted therapy; tyrosine kinase inhibitor.

Cited by 2 articles
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9
Comparative Study Acta Neuropathol
. 2019 Jun;137(6):1003-1015. doi: 10.1007/s00401-019-01981-6. Epub 2019 Mar 2.
Desmoplastic/nodular Medulloblastomas (DNMB) and Medulloblastomas With Extensive Nodularity (MBEN) Disclose Similar Epigenetic Signatures but Different Transcriptional Profiles
Andrey Korshunov 1 2 3 4, Felix Sahm 5 6 7, Konstantin Okonechnikov 7 8, Marina Ryzhova 9, Damian Stichel 5 6, Daniel Schrimpf 5 6, Belen Casalini 5 6, Philipp Sievers 5 6, Jochen Meyer 5 6, Olga Zheludkova 10, Andrey Golanov 11, Peter Lichter 7 12, David T W Jones 7 13, Stefan M Pfister 7 8 14, Marcel Kool 7 8, Andreas von Deimling 5 6 7
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PMID: 30826918 DOI: 10.1007/s00401-019-01981-6
Abstract
Desmoplastic/nodular medulloblastomas (DNMB) and medulloblastomas with extensive nodularity (MBEN) were outlined in the current WHO classification of tumors of the nervous system as two distinct histological MB variants. However, they are often considered as cognate SHH MB entities, and it is a reason why some clinical MB trials do not separate the patients with DNMB or MBEN histology. In the current study, we performed an integrated DNA/RNA-based molecular analysis of 83 DNMB and 36 MBEN to assess the etiopathogenetic relationship between these SHH MB variants. Methylation profiling revealed "infant" and "children" SHH MB clusters but neither DNMB nor MBEN composed separate epigenetic cohorts, and their profiles were intermixed within the "infant" cluster. In contrast, RNA-based transcriptional profiling disclosed that expression signatures of all MBEN were clustered separately from most of DNMB and a set of differentially expressed genes was identified. MBEN transcriptomes were enriched with genes associated with synaptic transmission, neuronal differentiation and metabolism, whereas DNMB profiling signatures included sets of genes involved in phototransduction and NOTCH signaling pathways. Thus, DNMB and MBEN are distinct tumor entities within the SHH MB family whose biology is determined by different transcriptional programs. Therefore, we recommend a transcriptome analysis as an optimal molecular tool to discriminate between DNMB and MBEN, which may be of benefit for patients' risk stratification in clinical trials. Molecular events identified in DNMB by RNA sequencing could be considered in the future as potent molecular targets for novel therapeutic interventions in treatment-resistant cases.

Keywords: DNMB; Gene expression; MBEN; Medulloblastoma.

Cited by 1 article
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10
J Mol Diagn
. 2019 Mar;21(2):307-317. doi: 10.1016/j.jmoldx.2018.10.006. Epub 2018 Dec 18.
Next-Generation Sequencing-Based Assessment of JAK2, PD-L1, and PD-L2 Copy Number Alterations at 9p24.1 in Breast Cancer: Potential Implications for Clinical Management
Sounak Gupta 1, Chad M Vanderbilt 1, Paolo Cotzia 1, Javier A Arias-Stella 3rd 1, Jason C Chang 1, Ahmet Zehir 1, Ryma Benayed 1, Khedouja Nafa 1, Pedram Razavi 2, David M Hyman 2, José Baselga 2, Michael F Berger 1, Marc Ladanyi 1, Maria E Arcila 1, Dara S Ross 3
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PMID: 30576871 PMCID: PMC6432425 DOI: 10.1016/j.jmoldx.2018.10.006
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Abstract
Genomic amplification at 9p24.1, including the loci for JAK2, PD-L1, and PD-L2, has recently been described as a mechanism of resistance in postchemotherapy, triple-negative breast cancer. This genomic signature holds significant promise as a prognostic biomarker and has implications for targeted therapy with JAK2 inhibitors, as well as with immunotherapy. To guide future screening strategies, the frequency of these alterations was determined. A total of 5399 cases were included in the study. This encompassed 2890 institutional cases tested by the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets assay and 2509 cases from The Cancer Genome Atlas (TCGA). The combined incidence of 9p24.1 amplifications in both the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and TCGA cohorts was 1.0% (56/5399 cases) and showed a >10-fold higher incidence in triple-negative breast cancer (triple-negative: 5.1%; non-triple-negative: 0.5%). Tumor mutation burden and stromal tumor infiltrating lymphocytes, parameters used to assess response to immunotherapy, were not significantly higher for these cases. The significance of genomic losses at 9p24.1 is unclear, and further studies are needed. Herein, we studied the spectrum of copy number alterations in breast cancer cases within our institutional clinical sequencing cohort and those profiled by TCGA to determine the frequency of genomic alterations that may predict response or resistance to JAK2 inhibitors and/or immunotherapy.

Copyright © 2019 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Cited by 3 articles4 figures
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11
Meta-Analysis Ann Vasc Surg
. 2020 Feb;63:427-438.e1. doi: 10.1016/j.avsg.2019.09.007. Epub 2019 Oct 17.
Synchronous Versus Staged Carotid Endarterectomy and Coronary Artery Bypass Graft for Patients With Concomitant Severe Coronary and Carotid Artery Stenosis: A Systematic Review and Meta-analysis
Andreas Tzoumas 1, Stefanos Giannopoulos 2, Pavlos Texakalidis 3, Nektarios Charisis 4, Theofilos Machinis 5, George J Koullias 6
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PMID: 31629126 DOI: 10.1016/j.avsg.2019.09.007
Abstract
Background: Due to the systemic nature of atherosclerosis, arteries at different sites are commonly simultaneously affected. As a result, severe coronary artery disease (CAD) requiring coronary artery bypass grafting (CABG) frequently coexists with significant carotid stenosis that warrants revascularization. To compare simultaneous carotid endarterectomy (CEA) and CABG versus staged CEA and CABG for patients with concomitant CAD and carotid artery stenosis in terms of perioperative outcomes.

Methods: This study was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. A meta-analysis was conducted with the use of a random effects model. The I2 statistic was used to assess for heterogeneity.

Results: Eleven studies comprising 44,895 patients were included in this meta-analysis (21,710 in the synchronous group and 23,185 patients in the staged group). The synchronous CEA and CABG group had a statistically significant lower risk for myocardial infarction (MI) (odds ratio [OR] 0.15, 95% CI 0.04-0.61, I2 = 0%) and higher risk for stroke (OR 1.51, 95% CI 1.34-1.71, I2 = 0%) and death (OR 1.33, 95% CI 1.01-1.75, I2 = 47.8%). Transient ischemic attacks (TIAs) (OR 1.27, 95% CI 1.00-1.61, I2 = 0.0%), postoperative bleeding (OR 0.82, 95% CI 0.22-3.05, I2 = 0.0%), and pulmonary complications (OR 1.52, 95% CI 0.24-9.60, I2 = 67.5%) were similar between the 2 groups.

Conclusions: Patients in the simultaneous CEA and CABG group had a significantly higher risk of 30-day mortality and stroke and lower risk for MI as compared to staged CEA and CABG group. The rates of TIA, postoperative bleeding, and pulmonary complications were similar between the 2 groups. Future randomized trials or prospective cohorts are needed to validate our results.

Copyright © 2019 Elsevier Inc. All rights reserved.

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12
Review Med Image Anal
. 2019 May;54:149-167. doi: 10.1016/j.media.2019.01.002. Epub 2019 Jan 11.
Ultrasound Guidance in Minimally Invasive Robotic Procedures
Maria Antico 1, Fumio Sasazawa 2, Liao Wu 1, Anjali Jaiprakash 1, Jonathan Roberts 1, Ross Crawford 3, Ajay K Pandey 1, Davide Fontanarosa 4
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PMID: 30928829 DOI: 10.1016/j.media.2019.01.002
Abstract
In the past decade, medical robotics has gained significant traction within the surgical field. While the introduction of fully autonomous robotic systems for surgical procedures still remains a challenge, robotic assisted interventions have become increasingly more interesting for the scientific and clinical community. This happens especially when difficulties associated with complex surgical manoeuvres under reduced field of view are involved, as encountered in minimally invasive surgeries. Various imaging modalities can be used to support these procedures, by re-creating a virtual, enhanced view of the intervention site. Among them, ultrasound imaging showed several advantages, such as cost effectiveness, non-invasiveness and real-time volumetric imaging. In this review we comprehensively report about the interventional applications where ultrasound imaging has been used to provide guidance for the intervention tools, allowing the surgeon to visualize intra-operatively the soft tissue configuration in real-time and to compensate for possible anatomical changes. Future directions are also discussed, in particular how the recent developments in 3D/4D ultrasound imaging and the introduction of advanced imaging capabilities (such as elastography) in commercially available systems may fulfil the unmet needs towards fully autonomous robotic interventions.

Keywords: Minimally invasive; Robotic; Surgery; Ultrasound.

Copyright © 2019. Published by Elsevier B.V.

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13
J Clin Pathol
. 2020 Jun;73(6):341-346. doi: 10.1136/jclinpath-2019-206155. Epub 2019 Dec 19.
Current Opinion, Status and Future Development of Digital Pathology in Switzerland
Julia Unternaehrer 1, Rainer Grobholz 2, Andrew Janowczyk 3, Inti Zlobec 4, Swiss Digital Pathology Consortium (SDiPath)
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PMID: 31857377 DOI: 10.1136/jclinpath-2019-206155
Abstract
Aims: The transition from analogue to digital pathology (DP) is underway in Switzerland. To assess relevant experiences of pathologists with DP and gauge their outlook towards a digital future, a national survey was conducted by the Swiss Digital Pathology Consortium. Similar surveys were conducted in other countries, enabling a meta-analysis of DP experiences.

Methods: Pathologists and residents were asked to complete a survey containing 12 questions. Results were compared with similar studies conducted in the United Kingdom, Sweden, Canada, and India.

Results: The estimated response rate among practicing pathologists and trainees nationwide was 39.5%. Of these, 89% have experience with digital slides, mainly for education (61%) and primary diagnostics (20%). Further, 32% have worked with an image analysis programme and 26% use computer-based algorithms weekly. Interestingly, 66% would feel comfortable making a primary diagnosis digitally, while 10% would not. Most respondents believe more standards and regulations are necessary for the clinical employment of DP. Noted advantages include ease of access to slides and the resulting connectivity benefits, namely collaboration with experts across disciplines, off-site work, training purposes, and computational image analysis. Perceived disadvantages include implementation costs and issues associated with IT infrastructure and file formats.

Conclusion: The survey results suggest that experiences and perspectives of Swiss pathologists concerning DP is comparable to that of the other reporting countries undergoing transitions to digital workflows. Although more standards and regulations are needed to ensure the safe usage of these technologies, pathologists in Switzerland appear welcoming of this new digital era.

Keywords: diagnostics; digital pathology; image analysis.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Conflict of interest statement
Competing interests: None declared.

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14
Review Future Oncol
. 2020 Jan;16(1):4327-4336. doi: 10.2217/fon-2019-0254. Epub 2019 Dec 5.
Extended Endocrine Therapy in Early Breast Cancer: How Long and Who For?
John R Benson 1, Ismail Jatoi 2
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PMID: 31802715 DOI: 10.2217/fon-2019-0254
Abstract
Endocrine therapy for early stage breast cancer is currently in a state of flux with much uncertainty about choice of agents and duration of therapy. The standard treatment span of 5 years usually incorporates an aromatase inhibitor in the majority of postmenopausal patients. Hormonal therapy has a cytostatic action that provides a biological rationale for continuing treatment for more prolonged periods to reduce risk of late recurrence in estrogen receptor-positive disease. Several trials of extended endocrine therapy for periods varying from 7.5 to 10 years have shown mixed results for gains in disease-free survival. The challenge is to assimilate available data and apply clinical judgment to tailor therapies taking account of intrinsic risk of disease recurrence, patient preference, tolerability to date, and co-morbidities.

Keywords: aromatase inhibitor; breast cancer; endocrine; extended.

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15
Am J Pathol
. 2020 Jun;190(6):1175-1187. doi: 10.1016/j.ajpath.2020.01.020. Epub 2020 Mar 20.
Spontaneous Development of Hepatocellular Carcinoma and B-Cell Lymphoma in Mosaic and Heterozygous Brca2 and Cdkn1a Interacting Protein Knockout Mice
Huimei Lu 1, Caiyong Ye 1, Xing Feng 1, Jingmei Liu 1, Mantu Bhaumik 2, Bing Xia 1, Chen Liu 3, Zhiyuan Shen 4
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PMID: 32201259 PMCID: PMC7280756 (available on 2021-06-01) DOI: 10.1016/j.ajpath.2020.01.020
Free PMC article
Abstract
Hepatocellular carcinoma (HCC) is the most common form of liver tumors. Although HCC is associated with chronic viral infections, alcoholic cirrhosis, and nonalcoholic fatty liver disease, genetic factors that contribute to the HCC risk remain unknown. The BRCA2 DNA repair associated (BRCA2) and cyclin-dependent kinase inhibitor 1A (CDKN1A) interacting protein, known as BCCIP, are essential for cell viability and maintenance of genomic stability. In this study, we established a new genetically engineered mouse model with Bccip deficiency. Mosaic or heterozygous Bccip deletion conferred an increased risk of spontaneous liver tumorigenesis and B-cell lymphoma development at old age. These abnormalities are accompanied with chronic inflammation, histologic features of nonalcoholic steatohepatitis, keratin and ubiquitin aggregates within cytoplasmic Mallory-Denk bodies, and changes of the intracellular distribution of high-mobility group box 1 protein. Our study suggests BCCIP dysregulation as a risk factor for HCC and offers a novel mouse model for future investigations of nonviral or nonalcoholic causes of HCC development.

Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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16
Review Ann Oncol
. 2020 Jun 19;S0923-7534(20)39891-4. doi: 10.1016/j.annonc.2020.06.004. Online ahead of print.
The Forefront of Ovarian Cancer Therapy: Update on PARP Inhibitors
M R Mirza 1, R L Coleman 2, A González-Martín 3, K N Moore 4, N Colombo 5, I Ray-Coquard 6, S Pignata 7
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PMID: 32569725 DOI: 10.1016/j.annonc.2020.06.004
Abstract
Background: In recurrent ovarian cancer, poly(ADP-ribose) polymerase (PARP)-inhibiting agents have transformed the treatment of platinum-sensitive disease. New data support use of PARP inhibitors earlier in the treatment algorithm.

Design: We review results from recent phase III trials evaluating PARP inhibitors as treatment and/or maintenance therapy for patients with newly diagnosed ovarian cancer. We discuss the efficacy and safety of these agents in the all-comer and biomarker-selected populations studied in clinical trials, and compare the strengths and limitations of the various trial designs. We also consider priorities for future research, with a particular focus on patient selection and future regimens for populations with high unmet need.

Results: Four phase III trials (SOLO-1, PAOLA-1/ENGOT-OV25, PRIMA/ENGOT-OV26 and VELIA/GOG-3005) demonstrated remarkable improvements in progression-free survival with PARP inhibitor therapy (olaparib, niraparib or veliparib) for newly diagnosed ovarian cancer. Differences in trial design (treatment and/or maintenance setting; single-agent or combination; bevacizumab or no bevacizumab), patient selection (surgical outcome, biomarker eligibility, prognosis) and primary analysis population (intention-to-treat, BRCA mutated or homologous recombination deficiency positive) affect the conclusions that can be drawn from these trials. Overall survival data are pending and there is limited experience regarding long-term safety.

Conclusions: PARP inhibitors play a pivotal role in the management of newly diagnosed ovarian cancer, which will affect subsequent treatment choices. Refinement of testing for patient selection and identification of regimens to treat populations that appear to benefit less from PARP inhibitors are a priority.

Keywords: PARP inhibitor; niraparib; olaparib; ovarian cancer; phase III; veliparib.

Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

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17
Clinical Trial Future Oncol
. 2020 Jan;16(1):4289-4301. doi: 10.2217/fon-2019-0653. Epub 2019 Nov 28.
Dose-escalation Trial of the ALK, MET & ROS1 Inhibitor, Crizotinib, in Patients With Advanced Cancer
Jeffrey W Clark 1, D Ross Camidge 2, Eunice L Kwak 1, Robert G Maki 3, Geoffrey I Shapiro 4, Isan Chen 5, Weiwei Tan 5, Sophia Randolph 5, James G Christensen 5, Mark Ozeck 5, Yiyun Tang 5, Keith D Wilner 5, Ravi Salgia 6
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PMID: 31778074 DOI: 10.2217/fon-2019-0653
Abstract
Aim: This first-in-human, dose-finding study evaluated safety, pharmacokinetics and pharmacodynamics of crizotinib and established a recommended Phase II dose (RP2D) among patients with advanced solid malignancies. Patients & methods: Patients received oral crizotinib in a 3 + 3 dose escalation design. Results: Thirty-six patients received crizotinib (50 mg once daily-300 mg twice daily); maximum tolerated dose (and RP2D) was 250 mg twice daily. Most patients (89%) experienced ≥1 treatment-related adverse event. Three patients had grade 3 dose-limiting toxicities: alanine aminotransferase increased (n = 1) and fatigue (n = 2). Generally, an increase in soluble MET was found with increasing crizotinib concentrations. Conclusion: Crizotinib demonstrated a favorable safety profile. The observed pharmacodynamic effect on soluble MET provide evidence for targeted MET inhibition by crizotinib. Clinicaltrials. gov identifier: NCT00585195.

Keywords: ALK; MET pharmacodynamics; crizotinib; dose escalation; non-small cell lung cancer; pharmacokinetics.

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18
Tech Innov Patient Support Radiat Oncol
. 2020 Jun 12;14:32-35. doi: 10.1016/j.tipsro.2020.04.002. eCollection 2020 Jun.
Prevalence of Software Alerts in Radiotherapy
Petra Reijnders-Thijssen 1, Diana Geerts 1, Wouter van Elmpt 1, Todd Pawlicki 2, Andrew Wallis 3, Mary Coffey 4
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PMID: 32566767 PMCID: PMC7296428 DOI: 10.1016/j.tipsro.2020.04.002
Free PMC article
Abstract
Radiotherapy software messages (sometimes called alerts, pop-up windows, alarms, or error messages) to the user appear continuously on computer screens. These software messages sometimes require decisions to be made as to the next appropriate action. However, mainly these messages are for information only. Dealing with software messages is a well-recognized problem in healthcare and has contributed to catastrophic events both outside and within radiotherapy. The purpose of this work is to highlight the prevalence and raise awareness within the radiotherapy community of such software messages related to external beam radiation therapy procedures at the linear accelerator. Radiation Therapists (RTTs) were asked to record the type and frequency of software message over 50 fractions and for 50 different patients. The data was collected at 6 institutions in the Netherlands using linear accelerators from Elekta, Ltd. and Varian Medical Systems, Inc. Results show that linear accelerator software messages (including record and verify) occur at a rate of about 8.9 messages per patient fraction. This number of software messages is potentially impacting on patient safety as these messages range in level of importance. The impact and potential reduction of these software messages should be the focus of future research and improved implementation.

Keywords: Alerts; Fatigue; Incident reporting system; Patient safety.

© 2020 The Authors.

Conflict of interest statement
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

6 references2 figures
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19
F1000Res
. 2020 Apr 22;9:ELIXIR-278. doi: 10.12688/f1000research.20559.1. eCollection 2020.
A Community Proposal to Integrate Structural Bioinformatics Activities in ELIXIR (3D-Bioinfo Community)
Christine Orengo 1, Sameer Velankar 2, Shoshana Wodak 3, Vincent Zoete 4, Alexandre M J J Bonvin 5, Arne Elofsson 6, K Anton Feenstra 7, Dietland L Gerloff 8, Thomas Hamelryck 9, John M Hancock 10, Manuela Helmer-Citterich 11, Adam Hospital 12, Modesto Orozco 12, Anastassis Perrakis 13, Matthias Rarey 14, Claudio Soares 15, Joel L Sussman 16, Janet M Thornton 17, Pierre Tuffery 18, Gabor Tusnady 19, Rikkert Wierenga 20, Tiina Salminen 21, Bohdan Schneider 22
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PMID: 32566135 PMCID: PMC7284151 DOI: 10.12688/f1000research.20559.1
Free PMC article
Abstract
Structural bioinformatics provides the scientific methods and tools to analyse, archive, validate, and present the biomolecular structure data generated by the structural biology community. It also provides an important link with the genomics community, as structural bioinformaticians also use the extensive sequence data to predict protein structures and their functional sites. A very broad and active community of structural bioinformaticians exists across Europe, and 3D-Bioinfo will establish formal platforms to address their needs and better integrate their activities and initiatives. Our mission will be to strengthen the ties with the structural biology research communities in Europe covering life sciences, as well as chemistry and physics and to bridge the gap between these researchers in order to fully realize the potential of structural bioinformatics. Our Community will also undertake dedicated educational, training and outreach efforts to facilitate this, bringing new insights and thus facilitating the development of much needed innovative applications e.g. for human health, drug and protein design. Our combined efforts will be of critical importance to keep the European research efforts competitive in this respect. Here we highlight the major European contributions to the field of structural bioinformatics, the most pressing challenges remaining and how Europe-wide interactions, enabled by ELIXIR and its platforms, will help in addressing these challenges and in coordinating structural bioinformatics resources across Europe. In particular, we present recent activities and future plans to consolidate an ELIXIR 3D-Bioinfo Community in structural bioinformatics and propose means to develop better links across the community. These include building new consortia, organising workshops to establish data standards and seeking community agreement on benchmark data sets and strategies. We also highlight existing and planned collaborations with other ELIXIR Communities and other European infrastructures, such as the structural biology community supported by Instruct-ERIC, with whom we have synergies and overlapping common interests.

Keywords: ELIXIR; Instruct-ERIC; biomolecular structure; nucleic acids structure; protein structure; structural bioinformatics.

Copyright: © 2020 Orengo C et al.

Conflict of interest statement
No competing interests were disclosed.

70 references4 figures
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20
JCO Clin Cancer Inform
. 2020 Jun;4:555-566. doi: 10.1200/CCI.20.00025.
Development of a Data Model and Data Commons for Germ Cell Tumors
Bo Ci 1, Donghan M Yang 1, Mark Krailo 2 3, Caihong Xia 3, Bo Yao 1, Danni Luo 1, Qinbo Zhou 1, Guanghua Xiao 1 4, Lin Xu 1, Stephen X Skapek 5 6, Matthew M Murray 7, James F Amatruda 2 8, Lindsay Klosterkemper 9, Furqan Shaikh 10, Cecile Faure-Conter 11, Brice Fresneau 12, Samuel L Volchenboum 13, Sara Stoneham 14, Luiz Fernando Lopes 15, James Nicholson 16, A Lindsay Frazier 9, Yang Xie 1 4 6
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PMID: 32568554 DOI: 10.1200/CCI.20.00025
Free article
Abstract
Germ cell tumors (GCTs) are considered a rare disease but are the most common solid tumors in adolescents and young adults, accounting for 15% of all malignancies in this age group. The rarity of GCTs in some groups, particularly children, has impeded progress in treatment and biologic understanding. The most effective GCT research will result from the interrogation of data sets from historical and prospective trials across institutions. However, inconsistent use of terminology among groups, different sample-labeling rules, and lack of data standards have hampered researchers' efforts in data sharing and across-study validation. To overcome the low interoperability of data and facilitate future clinical trials, we worked with the Malignant Germ Cell International Consortium (MaGIC) and developed a GCT clinical data model as a uniform standard to curate and harmonize GCT data sets. This data model will also be the standard for prospective data collection in future trials. Using the GCT data model, we developed a GCT data commons with data sets from both MaGIC and public domains as an integrated research platform. The commons supports functions, such as data query, management, sharing, visualization, and analysis of the harmonized data, as well as patient cohort discovery. This GCT data commons will facilitate future collaborative research to advance the biologic understanding and treatment of GCTs. Moreover, the framework of the GCT data model and data commons will provide insights for other rare disease research communities into developing similar collaborative research platforms.

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21
Review Evid Based Complement Alternat Med
. 2020 May 25;2020:1618767. doi: 10.1155/2020/1618767. eCollection 2020.
The Effects of Auricular Therapy for Cancer Pain: A Systematic Review and Meta-Analysis
Yulan Yang 1, Jian Wen 2, Jianyun Hong 1
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PMID: 32565846 PMCID: PMC7267873 DOI: 10.1155/2020/1618767
Free PMC article
Abstract
Objective: This study aims to systematically assess the efficacy and safety of auricular therapy for cancer pain.

Methods: A systematic search was conducted using PubMed, EMBASE, Cochrane library databases, CNKI, VIP, WanFang Data, and CBM for randomized controlled trials (RCTs). Review Manager 5.3 was used for meta-analysis.

Results: Of the 275 screened studies, nine RCTs involving 783 patients with cancer pain were systematically reviewed. Compared with drug therapy, auricular therapy plus drug therapy has significant advantages both in the effective rate for pain relief (RR = 1.40; 95% CI 1.22, 1.60; P < 0.00001) and adverse effects rate (RR = 0.46; 95% CI 0.37, 0.58; P < 0.00001). And the result revealed that auricular acupuncture had superior pain-relieving effects as compared with sham auricular acupuncture (SMD = -1.45; 95% CI -2.80, -0.09; P=0.04). However, the analysis indicated no difference on the effective rate for pain relief between auricular therapy and drug therapy (RR = 1.24; 95% CI 0.71, 2.16; P=0.46).

Conclusion: Our meta-analysis indicated that auricular therapy is effective and safe for the treatment of cancer pain, and auricular therapy plus drug therapy is more effective than drug therapy alone, whether in terms of pain relief or adverse reactions. However, the included RCTs had some methodological limitations; future large, rigor, and high-quality RCTs are still needed to confirm the benefits of auricular therapy on cancer pain.

Copyright © 2020 Yulan Yang et al.

Conflict of interest statement
The authors declare that there are no conflicts of interest regarding the publication of this article.

34 references8 figures
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22
Pediatr Blood Cancer
. 2020 Jun 22;e28506. doi: 10.1002/pbc.28506. Online ahead of print.
Internet-delivered Insomnia Intervention Improves Sleep and Quality of Life for Adolescent and Young Adult Cancer Survivors
Eric S Zhou 1 2 3, Christopher J Recklitis 2
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PMID: 32568460 DOI: 10.1002/pbc.28506
Abstract
Background: Insomnia is common among adolescent and young adult (AYA) cancer survivors. Cognitive-behavioral therapy for insomnia (CBT-I) is considered the gold standard treatment. Standard CBT-I was designed for adults and not adapted to the unique medical, psychosocial, and developmental needs of AYA cancer survivors, which can exacerbate their insomnia. Further, the vast majority of cancer centers do not have a behavioral sleep medicine expert on staff. Our study objective was to examine the efficacy of an Internet-delivered CBT-I program that was tailored for AYA cancer survivors (NCT03279055).

Procedure: Twenty-two AYA cancer survivors (mean age 20.4; range 14-25) with insomnia enrolled in an automated CBT-I program modified for AYA cancer survivors following stakeholder feedback. Participants were blood cancer (54.5%) and solid tumor (45.5%) survivors, an average of 9.7 years postdiagnosis. Sleep health, fatigue, and quality of life were assessed at baseline and at two follow up timepoints (8 and 16 weeks postbaseline).

Results: Significant improvements in insomnia severity, daytime sleepiness, fatigue, and quality of life were reported at both follow up timepoints. However, most participants (72.7%) did not complete all of the six study sessions, with a mean completion rate of 3.2 sessions. Participants who completed at least two sessions reported better sleep (insomnia severity index total score) than those who did not.

Conclusions: An Internet-delivered insomnia intervention adapted for AYA cancer survivors was efficacious. This has important implications for access to evidence-based clinical care for this growing population. Future efforts should study stepped care models of care and ways to improve treatment adherence.

Keywords: adolescent and young adult cancer survivors; cognitive-behavioral therapy for insomnia; insomnia disorder; online intervention.

© 2020 Wiley Periodicals LLC.

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23
Cancer Med
. 2020 Jun 21. doi: 10.1002/cam4.3235. Online ahead of print.
Discordance Between Pediatric Self-Report and Parent Proxy-Report Symptom Scores and Creation of a Dyad Symptom Screening Tool (co-SSPedi)
Deborah Tomlinson 1, Erin Plenert 1, Grace Dadzie 1, Robyn Loves 1, Sadie Cook 1, Tal Schechter 2, Jennifer Furtado 2, L Lee Dupuis 1 3 4, Lillian Sung 1 2
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PMID: 32567173 DOI: 10.1002/cam4.3235
Free article
Abstract
Symptom Screening in Pediatrics Tool (SSPedi) (age 8-18 years) and mini-SSPedi (age 4-7 years) can be used to self-report and proxy-report bothersome symptoms in pediatric patients receiving cancer treatments. There are limitations of sole child self-report or proxy-report. An approach in which children and parents complete symptom reports together may be useful. The aim of our study was to describe discordance between child self-report and parent proxy-report symptom scores, and to determine how these scores compare to an approach in which reporting is performed together (co-SSPedi). Children and parents completed SSPedi or mini-SSPedi separately. Discordant symptoms were shared with respondents and discussed. Next, the dyad completed co-SSPedi together and were asked which approach they preferred. Discordance was evaluated for each symptom and was defined as a difference of at least 2 points on an ordinal scale ranging from 0 (not at all bothered) to 4 (extremely bothered). Of the 48 enrolled dyads (children, median age, 10.8 years; 54.2% male), 41 (85.4%) had discordance in at least one symptom. There was no clear pattern in discordance by age group. When a dyad approach was used, more co-SSPedi scores agreed with the original child self-report scores (59 dyads, 56.2%) compared to original parent proxy-report scores (15 dyads, 14.3%) for discordant symptoms. Forty-three (89.6%) dyads preferred to complete SSPedi together. Future work should evaluate the psychometric properties of co-SSPedi.

Keywords: SSPedi; cancer; child; discordance; hematopoietic stem cell transplantation; symptoms.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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24
Randomized Controlled Trial Future Oncol
. 2020 Jan;16(1):4315-4325. doi: 10.2217/fon-2019-0658. Epub 2019 Dec 4.
Tumor Burden and Liver Function in HCC Patient Selection for Selective Internal Radiation Therapy: SARAH Post-Hoc Study
Daniel H Palmer 1, Neil S Hawkins 2, Valérie Vilgrain 3 4, Helena Pereira 5 6, Gilles Chatellier 5 6, Paul J Ross 7 8
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PMID: 31797680 DOI: 10.2217/fon-2019-0658
Abstract
Aim: To determine whether a liver tumor burden ≤25% and well-preserved liver function (albumin-bilirubin grade 1) are appropriate criteria for identifying patients with unresectable hepatocellular carcinoma who may benefit from selective internal radiation therapy (SIRT) using 90yttrium resin microspheres versus sorafenib. Patients & methods: Post-hoc analysis of patients in the intention-to-treat population of the SARAH trial (SIRT vs sorafenib) with ≤25% tumor burden and albumin-bilirubin grade 1. Primary end point: overall survival. Results: Median overall survival was 21.9 months (95% CI: 15.2-32.5, n = 37) with SIRT and 17.0 months (11.6-20.8, n = 48) with sorafenib (hazard ratios: 0.73; 95% CI: 0.44-1.21; p = 0.22). Conclusion: A combination of good liver function and low tumor burden may be relevant for selection of hepatocellular carcinoma patients for SIRT.

Keywords: 90yttrium; SIR-spheres; albumin-bilirubin grade; hepatocellular carcinoma; resin microspheres; selective internal radiation therapy; sorafenib; tumor burden.

Cited by 2 articles
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25
Review Oxid Med Cell Longev
. 2020 May 22;2020:7265487. doi: 10.1155/2020/7265487. eCollection 2020.
Novel Molecular Mechanisms of Pulmonary Hypertension: A Search for Biomarkers and Novel Drug Targets-From Bench to Bed Site
Damian Gajecki 1, Jakub Gawrys 1, Ewa Szahidewicz-Krupska 1, Adrian Doroszko 1
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PMID: 32566097 PMCID: PMC7261339 DOI: 10.1155/2020/7265487
Free PMC article
Abstract
Pulmonary hypertension (PH) is defined as increased mean pulmonary artery pressure (mPAP) above 25 mmHg, measured at rest by right heart catheterization. The exact global prevalence of PH is difficult to estimate, mainly due to the complex aetiology, and its spread may be underestimated. To date, numerous studies on the aetiology and pathophysiology of PH at molecular level were conducted. Simultaneously, some clinical studies have shown potential usefulness of well-known and widely recognized cardiovascular biomarkers, but their potential clinical usefulness in diagnosis and management of PH is poor due to their low specificity accompanied with numerous other cardiovascular comorbidities of PH subjects. On the other hand, a large body of basic research-based studies provides us with novel molecular pathomechanisms, biomarkers, and drug targets, according to the evidence-based medicine principles. Unfortunately, the simple implementation of these results to clinical practice is impossible due to a large heterogeneity of the PH pathophysiology, where the clinical symptoms constitute only a common denominator and a final result of numerous crosstalking metabolic pathways. Therefore, future studies, based mostly on translational medicine, are needed in order to both organize better the pathophysiological classification of various forms of PH and define precisely the optimal diagnostic markers and therapeutic targets in particular forms of PH. This review paper summarizes the current state of the art regarding the molecular background of PH with respect to its current classification. Novel therapeutic strategies and potential biomarkers are discussed with respect to their limitations in use in common clinical practice.

Copyright © 2020 Damian Gajecki et al.

Conflict of interest statement
The author(s) declare(s) that they have no conflicts of interest.

134 references2 figures
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26
Int J Radiat Oncol Biol Phys
. 2020 Jun 19;S0360-3016(20)31313-4. doi: 10.1016/j.ijrobp.2020.06.026. Online ahead of print.
A Validated T Cell Radiomics Score Is Associated With Clinical Outcomes Following Multi-site SBRT and Pembrolizumab
Mark C Korpics 1, Mei-Yin Polley 2, Sandeep R Bhave 1, Gage Redler 1, Sean P Pitroda 1, Jason J Luke 3, Steven J Chmura 4
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PMID: 32569799 DOI: 10.1016/j.ijrobp.2020.06.026
Abstract
Purpose: Combining immune checkpoint blockade(ICB) with stereotactic body radiotherapy(SBRT) may improve the local response to radiation and the systemic response to immunotherapy. However, no prognostic markers exist to identify patients likely to benefit from combined therapy. The degree of T-cell-mediated immunity, which can be quantified with radiomics using computed tomography(CT) imaging, is predictive of immunotherapy response. Herein we investigated whether a validated T-cell radiomics score(RS) is correlated with clinical outcomes following multi-site SBRT and pembrolizumab(SBRT+P).

Methods and materials: The RS was quantified for 68 patients with metastatic treatment-refractory adult solid tumors that received SBRT(30-50Gy, 3-5 fractions) and pembrolizumab <7days following SBRT. RS was calculated using eight variables, including five radiomics features extracted from pre-treatment CT scans. At a pre-specified cutoff of 25th-percentile, we assessed the association between RS and clinical outcomes. The Kaplan-Meier method was used to estimate survival outcomes. The prognostic effect of RS was assessed via logistic regression or Cox proportional hazards models. In an exploratory analysis, RS was also analyzed as a continuous variable.

Results: 139 tumors were analyzed. At the 25th-percentile cutoff, high-RS patients were more likely to exhibit irradiated tumor responses to SBRT+P(odds ratio[OR]=10.2, 95% confidence interval[CI]: 1.76-59.17; p=0.012). High-RS was associated with improved TMC compared with low-RS tumors(hazard ratio[HR]=0.18; 95% CI: 0.04-0.74; p=0.018). Furthermore, high-RS patients had improved PFS(HR=0.47, 95% CI: 0.26-0.85; p=0.013) and OS(HR=0.39, 95% CI: 0.20-0.75; p=0.005). As a continuous variable, higher RS was associated with improved PFS(HR=0.12, 95% CI: 0.03-0.51; p=0.004) but did not reach statistical significance for TMC(HR=0.36, 95% CI: 0.02-7.02; p=0.502) or OS(HR=0.28, 95% CI: 0.05-1.55; p=0.144).

Conclusions: We demonstrated the clinical validity of RS(at the 25th-percentile cutoff) as a prognostic biomarker in patients treated with SBRT+P. Future validation of the prognostic value of RS in larger similarly treated patient cohorts is warranted.

Copyright © 2020 Elsevier Inc. All rights reserved.

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27
Future Oncol
. 2020 Jan;16(1):4303-4313. doi: 10.2217/fon-2019-0524. Epub 2019 Dec 5.
Real-world Incidence and Cost of Pneumonitis Post-Chemoradiotherapy for Stage III Non-Small-Cell Lung Cancer
Kellie J Ryan 1, Damion Nero 2, Bruce A Feinberg 2, Choo Hyung Lee 2, Rodrigo Pimentel 1, Ajeet Gajra 2, Jonathan K Kish 2, Brian Seal 1
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PMID: 31802700 DOI: 10.2217/fon-2019-0524
Abstract
Aim: To estimate the real-world incidence and timing of radiation pneumonitis following chemoradiotherapy for Stage III non-small-cell lung cancer and compare costs between patients with and without radiation pneumonitis. Methods: Retrospective analysis using the Symphony Health Integrated Dataverse. Results: Pneumonitis incidence was 12.4% with a 177-day mean time to onset. Patients with versus without pneumonitis were more frequently admitted to the hospital (33.8 vs 19.2%, p < 0.0001) and seen in the emergency room (51.9 vs 35.8%, p < 0.0001) and had higher mean total healthcare costs (US$4251 vs US$3969 per-patient per-month; p = 0.0163). Conclusion: Although pneumonitis significantly increased healthcare resource utilization and costs in chemoradiotherapy-treated Stage III non-small-cell lung cancer, the per-patient per-month differential was <10%. Such financial assessments are critical for cost-benefit analysis.

Keywords: burden of disease; chemoradiotherapy; cost; non-small-cell lung cancer; pneumonitis.

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28
J Surg Res
. 2020 Jun 19;255:247-254. doi: 10.1016/j.jss.2020.05.065. Online ahead of print.
Global Surgery Electives: A Strategy to Improve Care to Domestic Underserved Populations?
Rondi M Kauffmann 1, Kevin Neuzil 2, Rachel Koch 3, Kyla P Terhune 3
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PMID: 32570127 DOI: 10.1016/j.jss.2020.05.065
Abstract
Background: In the United States, a shortage of general surgeons exists, primarily in rural, poor, and minority communities. Identification of strategies that increase resident interest in underserved regions provides valuable information in understanding and addressing this shortage. In particular, surgical experience abroad exposes residents to practice in low-resource and rural settings. As residency programs increasingly offer global surgery electives, we explore whether the presence of an international surgical rotation affects graduates' future practice patterns in underserved communities domestically.

Methods: We surveyed general surgery residency graduates at a single academic institution. Those who finished general surgery residency from 2001 to 2018 were included. Participant demographics, current practice demographics, and perceptions related to global surgery and underserved populations were collected. Respondents were stratified based on whether they did ("after") or did not ("before") have the opportunity to participate in the Kijabe rotation (started in 2011), defined by graduation year.

Results: Out of 119 eligible program graduates, 64 (53.7%) completed the survey, and 33 (51.6%) of the respondents graduated following the implementation of the Kijabe rotation. Two participants defined their primary current practice location as international. Fifteen (45.5%) in the "After" group indicated an interest in working with underserved populations following residency, compared to 5 (17.8%) of the "Before" group (P = 0.074). Furthermore, 20 (60.6%) respondents in the "After" group expressed interest in working with underserved populations even if it meant making less money. In the "Before" group, only 13 (46.4%) responded similarly (P = 0.268). Eleven (9.2%) residents rotated at Kijabe. Those who participated in the Kijabe rotation reported an uninsured rate of 36.7% for their current patient population, compared to rate of 13.9% in those who did not rotate there (P = 0.22).

Conclusions: At a single institution, our results suggest that participation in an international surgical rotation in a resource-constrained setting may be associated with increased care for underserved populations in future clinical practice. These results could be due to self-selection of residents who prioritize global surgery as part of their residency experience, or due to increased exposure to underserved patients through global surgery.

Keywords: Global surgery; Surgical education.

Copyright © 2020 Elsevier Inc. All rights reserved.

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29
Health Technol Assess
. 2020 Jun;24(28):1-232. doi: 10.3310/hta24280.
Psychological Interventions to Improve Self-Management of Type 1 and Type 2 Diabetes: A Systematic Review
Kirsty Winkley 1, Rebecca Upsher 2, Daniel Stahl 3, Daniel Pollard 4, Architaa Kasera 2, Alan Brennan 4, Simon Heller 5, Khalida Ismail 2
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PMID: 32568666 DOI: 10.3310/hta24280
Free article
Abstract
Background: For people with diabetes mellitus to achieve optimal glycaemic control, motivation to perform self-management is important. The research team wanted to determine whether or not psychological interventions are clinically effective and cost-effective in increasing self-management and improving glycaemic control.

Objectives: The first objective was to determine the clinical effectiveness of psychological interventions for people with type 1 diabetes mellitus and people with type 2 diabetes mellitus so that they have improved (1) glycated haemoglobin levels, (2) diabetes self-management and (3) quality of life, and fewer depressive symptoms. The second objective was to determine the cost-effectiveness of psychological interventions.

Data sources: The following databases were accessed (searches took place between 2003 and 2016): MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library, PsycINFO, EMBASE, Cochrane Controlled Trials Register, Web of Science, and Dissertation Abstracts International. Diabetes conference abstracts, reference lists of included studies and Clinicaltrials.gov trial registry were also searched.

Review methods: Systematic review, aggregate meta-analysis, network meta-analysis, individual patient data meta-analysis and cost-effectiveness modelling were all used. Risk of bias of randomised and non-randomised controlled trials was assessed using the Cochrane Handbook (Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928).

Design: Systematic review, meta-analysis, cost-effectiveness analysis and patient and public consultation were all used.

Setting: Settings in primary or secondary care were included.

Participants: Adolescents and children with type 1 diabetes mellitus and adults with types 1 and 2 diabetes mellitus were included.

Interventions: The interventions used were psychological treatments, including and not restricted to cognitive-behavioural therapy, counselling, family therapy and psychotherapy.

Main outcome measures: Glycated haemoglobin levels, self-management behaviours, body mass index, blood pressure levels, depressive symptoms and quality of life were all used as outcome measures.

Results: A total of 96 studies were included in the systematic review (n = 18,659 participants). In random-effects meta-analysis, data on glycated haemoglobin levels were available for seven studies conducted in adults with type 1 diabetes mellitus (n = 851 participants) that demonstrated a pooled mean difference of -0.13 (95% confidence interval -0.33 to 0.07), a non-significant decrease in favour of psychological treatment; 18 studies conducted in adolescents/children with type 1 diabetes mellitus (n = 2583 participants) that demonstrated a pooled mean difference of 0.00 (95% confidence interval -0.18 to 0.18), indicating no change; and 49 studies conducted in adults with type 2 diabetes mellitus (n = 12,009 participants) that demonstrated a pooled mean difference of -0.21 (95% confidence interval -0.31 to -0.10), equivalent to reduction in glycated haemoglobin levels of -0.33% or ≈3.5 mmol/mol. For type 2 diabetes mellitus, there was evidence that psychological interventions improved dietary behaviour and quality of life but not blood pressure, body mass index or depressive symptoms. The results of the network meta-analysis, which considers direct and indirect effects of multiple treatment comparisons, suggest that, for adults with type 1 diabetes mellitus (7 studies; 968 participants), attention control and cognitive-behavioural therapy are clinically effective and cognitive-behavioural therapy is cost-effective. For adults with type 2 diabetes mellitus (49 studies; 12,409 participants), cognitive-behavioural therapy and counselling are effective and cognitive-behavioural therapy is potentially cost-effective. The results of the individual patient data meta-analysis for adolescents/children with type 1 diabetes mellitus (9 studies; 1392 participants) suggest that there were main effects for age and diabetes duration. For adults with type 2 diabetes mellitus (19 studies; 3639 participants), baseline glycated haemoglobin levels moderated treatment outcome.

Limitations: Aggregate meta-analysis was limited to glycaemic control for type 1 diabetes mellitus. It was not possible to model cost-effectiveness for adolescents/children with type 1 diabetes mellitus and modelling for type 2 diabetes mellitus involved substantial uncertainty. The individual patient data meta-analysis included only 40-50% of studies.

Conclusions: This review suggests that psychological treatments offer minimal clinical benefit in improving glycated haemoglobin levels for adults with type 2 diabetes mellitus. However, there was no evidence of benefit compared with control interventions in improving glycated haemoglobin levels for people with type 1 diabetes mellitus.

Future work: Future work should consider the competency of the interventionists delivering a therapy and psychological approaches that are matched to a person and their life course.

Study registration: This study is registered as PROSPERO CRD42016033619.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 28. See the NIHR Journals Library website for further project information.

Keywords: A1C; ADOLESCENTS; ADULTS; BLOOD PRESSURE; BMI; CBT; CHILDREN; COUNSELLING; DEPRESSION; DIABETES SELF-MANAGEMENT; DISTRESS; FAMILY THERAPY; GLYCAEMIC CONTROL; HBA1C; MOTIVATIONAL INTERVIEWING; PSYCHOLOGICAL INTERVENTIONS; PSYCHOTHERAPY; QUALITY OF LIFE; TYPE 1 DIABETES; TYPE 2 DIABETES.

Plain Language Summary
Living with diabetes mellitus (hereafter referred to as diabetes) involves taking on new roles and responsibilities and is key to success in achieving the best diabetes control. There are education programmes that help people with diabetes to access the information and skills needed but managing diabetes is hard and must be done 24/7, causing people to lose motivation. There are many emotional reasons for this. This research team aimed to discover if talking therapies that are designed to help people challenge their negative thoughts and feelings and be more motivated and confident could help improve their self-management and blood glucose levels. The team also wanted to find out if talking therapies could be good value for money and people with diabetes were asked for their views on the research. To conduct the research, electronic databases were searched for studies that have used talking therapies to support diabetes management. It was found that: For adults with type 2 diabetes, talking therapies improved diabetes control by only a small amount, although such therapies could represent value for money. People with type 2 diabetes who had talking therapy reported improved diet and quality of life. For adults with type 1 diabetes, some types of talking therapies could improve diabetes control, although this result was uncertain. Talking therapies were not effective for children or adolescents in improving diabetes control but there was not enough data to see if the therapies improved general health and well-being.When the results were presented to people with diabetes, they still wanted access to these treatments, even though results of this research did not suggest, overall, that talking therapies help improve diabetes control.Now that this research is complete, it is suggested that future studies look at whether or not more sessions of talking therapies should be delivered over a longer time period and whether or not the therapies should match the needs of the person with diabetes more closely.

Conflict of interest statement
No competing interests were declared.

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30
BMJ Open
. 2020 Jun 21;10(6):e036475. doi: 10.1136/bmjopen-2019-036475.
Pathways to a Cancer-Free Future: A Protocol for Modelled Evaluations to Minimise the Future Burden of Colorectal Cancer in Australia
Eleonora Feletto 1 2, Jie-Bin Lew 3 2, Joachim Worthington 3 2, Emily He 3 2, Michael Caruana 3 2, Katherine Butler 3, Harriet Hui 3, Natalie Taylor 3 4, Emily Banks 5, Karen Barclay 6, Kate Broun 7, Alison Butt 8, Rob Carter 9, Jeff Cuff 10 11, Anita Dessaix 12, Hooi Ee 13, Jon Emery 14, Ian M Frayling 15, Paul Grogan 3 2, Carol Holden 16, Christopher Horn 17, Mark A Jenkins 18, James G Kench 4 19, Maarit A Laaksonen 20, Barbara Leggett 21 22 23, Gillian Mitchell 24 25, Susan Morris 11 26, Bonny Parkinson 27, D James St John 28 29, Linda Taoube 2, Katherine Tucker 30 31, Melanie A Wakefield 7, Robyn L Ward 4, Aung Ko Win 18 32, Daniel L Worthley 16, Bruce K Armstrong 2, Finlay A Macrae 29 33, Karen Canfell 3 2 31
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PMID: 32565470 DOI: 10.1136/bmjopen-2019-036475
Free article
Abstract
Introduction: With almost 50% of cases preventable and the Australian National Bowel Cancer Screening Program in place, colorectal cancer (CRC) is a prime candidate for investment to reduce the cancer burden. The challenge is determining effective ways to reduce morbidity and mortality and their implementation through policy and practice. Pathways-Bowel is a multistage programme that aims to identify best-value investment in CRC control by integrating expert and end-user engagement; relevant evidence; modelled interventions to guide future investment; and policy-driven implementation of interventions using evidence-based methods. METHODS AND ANALYSIS: Pathways-Bowel is an iterative work programme incorporating a calibrated and validated CRC natural history model for Australia (Policy1-Bowel) and assessing the health and cost outcomes and resource use of targeted interventions. Experts help identify and prioritise modelled evaluations of changing trends and interventions and critically assess results to advise on their real-world applicability. Where appropriate the results are used to support public policy change and make the case for optimal investment in specific CRC control interventions. Fourteen high-priority evaluations have been modelled or planned, including evaluations of CRC outcomes from the changing prevalence of modifiable exposures, including smoking and body fatness; potential benefits of daily aspirin intake as chemoprevention; increasing CRC incidence in people aged <50 years; increasing screening participation in the general and Aboriginal and Torres Strait Islander populations; alternative screening technologies and modalities; and changes to follow-up surveillance protocols. Pathways-Bowel is a unique, comprehensive approach to evaluating CRC control; no prior body of work has assessed the relative benefits of a variety of interventions across CRC development and progression to produce a list of best-value investments.

Ethics and dissemination: Ethics approval was not required as human participants were not involved. Findings are reported in a series of papers in peer-reviewed journals and presented at fora to engage the community and policymakers.

Keywords: colorectal cancer; early detection; prevention; screening.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Conflict of interest statement
Competing interests: KC, EF, JW, JBL, EH, MC, NT, KBu and HH receive salary support from CCNSW. KC is co-PI of unrelated investigator-initiated trial of cervical screening in Australia (‘Compass’) conducted by the Victorian Cytology Service, which has received funding contribution from Roche Molecular Systems and Ventana, USA.

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31
Future Oncol
. 2020 Jun 21. doi: 10.2217/fon-2020-0193. Online ahead of print.
The Clinical Training Centers Fellowships: A European School of Oncology Career Development Program (2013-2019)
Nicholas Pavlidis 1 2, Fedro A Peccatori 2 3, Matti Aapro 4, Alex Eniu 2 5, Franco Cavalli 2 6, Alberto Costa 2
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PMID: 32567377 DOI: 10.2217/fon-2020-0193
Abstract
Aim: This article refers to the European School of Oncology Clinical Training Centers (CTCs) program, which is a granted Fellowships program dedicated to young oncologists in training. Materials & methods: A total of 74 fellowships were offered by several CTCs during the last 7 years. Candidates were enrolled for 3-6 months of training rotations as fellows or observers in more than 30 training programs in well known Cancer Centers around Europe. Fellowships were covering medical, surgical, radiation and pediatric oncology specialties, laboratory diagnostic training and experimental, translational and clinical research. Fellows originated from Europe, Latin America and Mediterranean Africa. Results: Analysis of the questionnaire assessment showed that 95.5% of the fellows evaluated CTC programs with an 'excellent' or 'very good' score, while 100% declare that they had reached their objectives. Conclusion: The European School of Oncology CTC program designed for an additional practical education abroad meets the needs of young oncologists.

Keywords: Clinical Training Centers; ESO; European School of Oncology; cancer education; fellowships; observership; oncology specialties; overall assessment; residency; young oncologists.

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32
Future Oncol
. 2020 Jan;16(1):4279-4288. doi: 10.2217/fon-2019-0268. Epub 2019 Dec 4.
PABPC1 Relevant Bioinformatic Profiling and Prognostic Value in Gliomas
Qiangwei Wang 1, Zhiliang Wang 1, Zhaoshi Bao 2, Chuanbao Zhang 2, Zheng Wang 2, Tao Jiang 1 2 3 4
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PMID: 31797689 DOI: 10.2217/fon-2019-0268
Abstract
Aim: We aimed at investigating molecular features and potential clinical value of PABPC1 in gliomas. Materials & methods: We assembled totally 1000 glioma samples with mRNA expression data from Chinese Glioma Genome Atlas and The Cancer Genome Atlas. We utilized R language as the main analysis tool. Gene Ontology was performed for functional analysis. Results: PABPC1 was downregulated in gliomas with higher malignance and PABPC1 may contribute as potential predictor of proneural subtype in gliomas. Higher expression of PABPC1 was significantly related to better prognosis and related to biological process of translation. Conclusion: Our finding improves the understanding of PABPC1 as a novel biomarker with potential therapeutic connotations.

Keywords: PABPC1; gliomas; mRNA; prognosis; translation.

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33
Phys Med Biol
. 2020 Jun 22. doi: 10.1088/1361-6560/ab9efe. Online ahead of print.
Reference Dosimetry in MRI-linacs: Evaluation of Available Protocols and Data to Establish a Code of Practice
Jacco A de Pooter 1, Ilias Billas 2, Leon Armand de Prez 1, Simon Duane 3, Ralf-Peter Kapsch 4, Christian Karger 5, Bram van Asselen 6, Jochem W H Wolthaus 7
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PMID: 32570225 DOI: 10.1088/1361-6560/ab9efe
Abstract
With the rapid increase in clinical treatments with MRI-linacs, a consistent, harmonized and sustainable ground for reference dosimetry in MRI-linacs is needed. Specific for reference dosimetry in MRI-linacs is the presence of a strong magnetic field. Therefore, existing Code of Practices (CoPs) are inadequate. In recent years, a vast amount of papers has been published in relation to this topic. The purpose of this review paper is twofold: to give an overview and evaluate the existing literature for reference dosimetry in MRI-linacs and to discuss whether this literature and datasets are adequate and complete to serve as basis for the development of a new or to extend existing CoPs. This review is prefaced with an overview of existing MRI-linac facilities. Then an introduction on the physics of radiation transport in magnetic fields is given. The main part of the review is devoted to the evaluation of the literature with respect to the following subjects: • beam characteristics of MRI-linac facilities; • formalisms for reference dosimetry in MRI-linacs; • characteristics of ionization chambers in the presence of magnetic fields; • ionization chamber beam quality correction factors; • ionization chamber magnetic field correction factors. The review is completed with a discussion whether the existing literature is adequate to serve as basis for a CoP. In addition, it highlights subjects for future research on this topic.

Keywords: Codes of Practice; Ionization chambers; MR-guided radiotherapy; MRI-linacs; Monte Carlo; Primary standards; reference dosimetry.

Creative Commons Attribution license.

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34
Future Oncol
. 2020 Jan;16(1):4265-4277. doi: 10.2217/fon-2019-0639. Epub 2019 Dec 5.
Economic Burden of Illness Associated With Localized Prostate Cancer in the United States
Gary Gustavsen 1, Laura Gullet 1, Doria Cole 1, Nicolas Lewine 1, Jay T Bishoff 2
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PMID: 31802704 DOI: 10.2217/fon-2019-0639
Abstract
Aim: Prior studies have established the economic burden of prostate cancer on society. However, changes to screening, novel therapies and increased use of active surveillance (AS) create a need for an updated analysis. Methods: A deterministic, decision-analytic model was developed to estimate medical costs associated with localized prostate cancer over 10 years. Results: 10-year costs averaged $45,957, $99,445 and $188,928 for low-, intermediate- and high-risk patients, respectively. For low-risk patients, AS 10-year costs averaged $33,912/patient, whereas definitive treatment averaged $49,667/patient. Despite higher failure rates in intermediate-risk patients, AS remained less costly than definitive treatment, with 10-year costs averaging $90,614/patient and $99,394/patient, respectively. Conclusion: Broader incorporation of AS, guided by additional prognostic tools, may mitigate this growing economic burden.

Keywords: health economics; hormonal therapy; radiation therapy/radiotherapy; surgery; surveillance; urologic/prostate.

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35
Cancer
. 2020 Jun 22. doi: 10.1002/cncr.32966. Online ahead of print.
Vitamin D Intake Is Associated With Decreased Risk of Immune Checkpoint Inhibitor-Induced Colitis
Shilpa Grover 1 2, Michael Dougan 1 3, Kevin Tyan 1 4, Anita Giobbie-Hurder 5, Steven M Blum 1 4 6 7, Jeffrey Ishizuka 8, Taha Qazi 2 9, Rawad Elias 10, Kruti B Vora 1, Alex B Ruan 1, William Martin-Doyle 1 11, Michael Manos 4, Lauren Eastman 4, Meredith Davis 4, Maria Gargano 4, Rizwan Haq 1 4, Elizabeth I Buchbinder 1 4 11, Ryan J Sullivan 7, Patrick A Ott 1 4 6 11, F Stephen Hodi 1 4, Osama E Rahma 1 4
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PMID: 32567084 DOI: 10.1002/cncr.32966
Abstract
Background: There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis.

Methods: We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination ICIs between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariable logistic regression analyses. External confirmation was performed on an independent cohort from Massachusetts General Hospital.

Results: The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1-0.9). These results were also demonstrated in the confirmatory cohort (OR 0.46, 95% CI 0.2-0.9) of 169 patients of whom 49 developed ICI colitis (29%). Pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1-0.9) only in the discovery cohort.

Conclusions: This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies.

Keywords: colitis; immunotherapy; irAE; melanoma; toxicity; vitamin D.

© 2020 American Cancer Society.

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36
Case Reports Cureus
. 2020 Jun 16;12(6):e8651. doi: 10.7759/cureus.8651.
Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type: A Case Report
Ammar Al-Obaidi 1, Nathaniel A Parker 1, Khalil Choucair 1, Daniel Lalich 2, Phu Truong 3
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PMID: 32566435 PMCID: PMC7301429 DOI: 10.7759/cureus.8651
Free PMC article
Abstract
Primary cutaneous diffuse large B-cell lymphoma, leg type, is an exceedingly rare and aggressive variant of primary cutaneous lymphoma. An 84-year-old male presented to an oncologist for new skin lesions on his abdomen and right thigh. Excisional biopsy followed by histopathology and immunohistochemistry confirmed the diagnosis of primary cutaneous diffuse large B-cell lymphoma, leg type. His clinical course was complicated by multiple relapses and refractory disease. Ultimately, he achieved complete response with fourth-line ibrutinib therapy. Due to the contentious nature of this disease, poor prognosis, and higher rates of recurrence, prompt identification and aggressive treatment are recommended. Given the different cellular pathways and genomic alterations identified in its carcinogenesis, various chemotherapy regimens and targeted immunotherapies have emerged as potential therapeutic options to halt disease progression and prevent future relapses.

Keywords: bruton’s tyrosine kinase; diffuse large b-cell lymphoma; ibrutinib; leg type; lenalidomide; myd88; primary cutaneous b-cell lymphoma.

Copyright © 2020, Al-Obaidi et al.

Conflict of interest statement
The authors have declared that no competing interests exist.

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37
Future Oncol
. 2020 Jun 21. doi: 10.2217/fon-2020-0224. Online ahead of print.
B-cell Epitope Peptide Cancer Vaccines: A New Paradigm for Combination Immunotherapies With Novel Checkpoint Peptide Vaccine
Pravin Tp Kaumaya 1
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PMID: 32564612 DOI: 10.2217/fon-2020-0224
Abstract
In light of the numerous US FDA-approved humanized monoclonal antibodies (mAbs) for cancer immunotherapy, it is surprising that the advancement of B-cell epitope vaccines designed to elicit a natural humoral polyclonal antibody response has not gained traction in the immune-oncology landscape. Passive immunotherapy with humanized mAbs (Trastuzumab [Herceptin®]; Pertuzumab [Perjeta®]) has provided clinical benefit to breast cancer patients, albeit with significant shortcomings including toxicity problems and resistance, high costs, sophisticated therapeutic regimen and long half-life. The role of B-cell humoral immunity in cancer is under appreciated and underdeveloped. We have advanced the idea of active immunotherapy with chimeric B-cell epitope peptides incorporating a 'promiscuous' T-cell epitope that elicits a polyclonal antibody response, which provides safe, cost-effective therapeutic advantage over mAbs. We have created a portfolio of validated B-cell peptide epitopes against multiple receptor tyrosine kinases (HER-1, HER-3, IGF-1R and VEGF). We have successfully translated two HER-2 combination B-cell peptide vaccines in Phase I and II clinical trials. We have recently developed an effective novel programmed cell death-1 vaccine. In this article, I will review our approaches and strategies that focus on B-cell epitope cancer vaccines.

Keywords: B-cell epitopes; CT-26/HER-2; PD-1; combination immunotherapy; immuno-oncology; peptide cancer vaccines; syngeneic model.

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38
Editorial Future Oncol
. 2020 Jun 21. doi: 10.2217/fon-2020-0440. Online ahead of print.
What Is the Alternative? Responding Strategically to Cancer Misinformation
John S Peterson 1, Briony Swire-Thompson 2 3, Skyler B Johnson 1
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PMID: 32564627 DOI: 10.2217/fon-2020-0440
Abstract
No abstract available
Keywords: alternative therapy; communication; internet; misinformation; oncology; patient trust; social media.

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Editorial Future Oncol
. 2020 Jun 21. doi: 10.2217/fon-2020-0501. Online ahead of print.
A Clinical Dilemma Amid COVID-19 Pandemic: Missed or Encountered Diagnosis of Cancer?
Emre Yekedüz 1 2, Ayşe Müge Karcıoğlu 3, Güngör Utkan 1 2, Yüksel Ürün 1 2
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PMID: 32564611 DOI: 10.2217/fon-2020-0501
Abstract
No abstract available
Keywords: COVID-19; incidental cancer diagnosis; missed cancer diagnosis.

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40
Am J Clin Pathol
. 2020 Jun 22;aqaa077. doi: 10.1093/ajcp/aqaa077. Online ahead of print.
Interobserver Variability in Ductal Carcinoma In Situ of the Breast
Mieke R Van Bockstal 1 2 3, Martine Berlière 3 4, Francois P Duhoux 3 4 5, Christine Galant 1 3
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PMID: 32566938 DOI: 10.1093/ajcp/aqaa077
Abstract
Objectives: Since most patients with ductal carcinoma in situ (DCIS) of the breast are treated upon diagnosis, evidence on its natural progression to invasive carcinoma is limited. It is estimated that around half of the screen-detected DCIS lesions would have remained indolent if they had never been detected. Many patients with DCIS are therefore probably overtreated. Four ongoing randomized noninferiority trials explore active surveillance as a treatment option. Eligibility for these trials is mainly based on histopathologic features. Hence, the call for reproducible histopathologic assessment has never sounded louder.

Methods: Here, the available classification systems for DCIS are discussed in depth.

Results: This comprehensive review illustrates that histopathologic evaluation of DCIS is characterized by significant interobserver variability. Future digitalization of pathology, combined with development of deep learning algorithms or so-called artificial intelligence, may be an innovative solution to tackle this problem. However, implementation of digital pathology is not within reach for each laboratory worldwide. An alternative classification system could reduce the disagreement among histopathologists who use "conventional" light microscopy: the introduction of dichotomous histopathologic assessment is likely to increase interobserver concordance.

Conclusions: Reproducible histopathologic assessment is a prerequisite for robust risk stratification and adequate clinical decision-making. Two-tier histopathologic assessment might enhance the quality of care.

Keywords: Artificial intelligence; Breast; Ductal carcinoma in situ; Interobserver variability; Interrater agreement; Nuclear atypia; Reproducibility.

© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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41
Int J Biol Markers
. 2020 Jun 20;1724600820931861. doi: 10.1177/1724600820931861. Online ahead of print.
Analysis of Risk Factors for High Postoperative D-dimer Levels: A Single-Center Nurse-Observational Study
Ling Qin 1, Yan Fu 2, Cong Li 3, Shuang Chen 2, Ying Lv 4, Meijuan Hao 2, Hao Zhang 2, Yanqiu Wang 5
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PMID: 32567475 DOI: 10.1177/1724600820931861
Abstract
Background: As an elevated D-dimer level is directly proportional to the degrees of trauma and coagulation, it is often used to assess the severity of the trauma as well as the risk of thrombosis. This study aimed to investigate the risk factors for a high postoperative D-dimer level.

Methods: A total of 623 patients undergoing radical mastectomy were included. The association between various clinicopathological factors and D-dimer variation was examined.

Results: Age, neoadjuvant chemotherapy, diabetes, and elevated neutrophil count were significant risk factors for D-dimer variation, after adjusting for other factors.

Conclusions: This study has identified the characteristics of patients who are likely to experience considerable postoperative increases in the D-dimer level. The development of effective nursing interventions for these patients is the focus of future studies.

Keywords: D-dimer; breast cancer; nursing; surgery.

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