1
Review Lancet Infect Dis
. 2019 Dec;19(12):e405-e421. doi: 10.1016/S1473-3099(19)30312-3. Epub 2019 Nov 5.
Global Guideline for the Diagnosis and Management of Mucormycosis: An Initiative of the European Confederation of Medical Mycology in Cooperation With the Mycoses Study Group Education and Research Consortium
Oliver A Cornely 1, Ana Alastruey-Izquierdo 2, Dorothee Arenz 3, Sharon C A Chen 4, Eric Dannaoui 5, Bruno Hochhegger 6, Martin Hoenigl 7, Henrik E Jensen 8, Katrien Lagrou 9, Russell E Lewis 10, Sibylle C Mellinghoff 3, Mervyn Mer 11, Zoi D Pana 12, Danila Seidel 3, Donald C Sheppard 13, Roger Wahba 14, Murat Akova 15, Alexandre Alanio 16, Abdullah M S Al-Hatmi 17, Sevtap Arikan-Akdagli 18, Hamid Badali 19, Ronen Ben-Ami 20, Alexandro Bonifaz 21, Stéphane Bretagne 16, Elio Castagnola 22, Methee Chayakulkeeree 23, Arnaldo L Colombo 24, Dora E Corzo-León 25, Lubos Drgona 26, Andreas H Groll 27, Jesus Guinea 28, Claus-Peter Heussel 29, Ashraf S Ibrahim 30, Souha S Kanj 31, Nikolay Klimko 32, Michaela Lackner 33, Frederic Lamoth 34, Fanny Lanternier 35, Cornelia Lass-Floerl 33, Dong-Gun Lee 36, Thomas Lehrnbecher 37, Badre E Lmimouni 38, Mihai Mares 39, Georg Maschmeyer 40, Jacques F Meis 41, Joseph Meletiadis 42, C Orla Morrissey 43, Marcio Nucci 44, Rita Oladele 45, Livio Pagano 46, Alessandro Pasqualotto 47, Atul Patel 48, Zdenek Racil 49, Malcolm Richardson 50, Emmanuel Roilides 12, Markus Ruhnke 51, Seyedmojtaba Seyedmousavi 52, Neeraj Sidharthan 53, Nina Singh 54, János Sinko 55, Anna Skiada 56, Monica Slavin 57, Rajeev Soman 58, Brad Spellberg 59, William Steinbach 60, Ban Hock Tan 61, Andrew J Ullmann 62, Jörg J Vehreschild 63, Maria J G T Vehreschild 64, Thomas J Walsh 65, P Lewis White 66, Nathan P Wiederhold 67, Theoklis Zaoutis 68, Arunaloke Chakrabarti 69, Mucormycosis ECMM MSG Global Guideline Writing Group
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PMID: 31699664 DOI: 10.1016/S1473-3099(19)30312-3
Abstract
Mucormycosis is a difficult to diagnose rare disease with high morbidity and mortality. Diagnosis is often delayed, and disease tends to progress rapidly. Urgent surgical and medical intervention is lifesaving. Guidance on the complex multidisciplinary management has potential to improve prognosis, but approaches differ between health-care settings. From January, 2018, authors from 33 countries in all United Nations regions analysed the published evidence on mucormycosis management and provided consensus recommendations addressing differences between the regions of the world as part of the "One World One Guideline" initiative of the European Confederation of Medical Mycology (ECMM). Diagnostic management does not differ greatly between world regions. Upon suspicion of mucormycosis appropriate imaging is strongly recommended to document extent of disease and is followed by strongly recommended surgical intervention. First-line treatment with high-dose liposomal amphotericin B is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. Amphotericin B deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings. Management of mucormycosis depends on recognising disease patterns and on early diagnosis. Limited availability of contemporary treatments burdens patients in low and middle income settings. Areas of uncertainty were identified and future research directions specified.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Cited by 14 articles
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2
Cancer Res
. 2019 Sep 1;79(17):4326-4330. doi: 10.1158/0008-5472.CAN-19-0803.
Recent Developments and Therapeutic Strategies Against Hepatocellular Carcinoma
Mark Yarchoan # 1, Parul Agarwal # 2, Augusto Villanueva 3, Shuyun Rao 4, Laura A Dawson 5, Josep M Llovet 6 7 8, Richard S Finn 9, John D Groopman 10, Hashem B El-Serag 11, Satdarshan P Monga 12, Xin Wei Wang 13, Michael Karin 14, Robert E Schwartz 15, Kenneth K Tanabe 16, Lewis R Roberts 17, Preethi H Gunaratne 18, Allan Tsung 19, Kimberly A Brown 20, Theodore S Lawrence 21, Riad Salem 22, Amit G Singal 23, Amy K Kim 24, Atoosa Rabiee 25, Linda Resar 24, Yujin Hoshida 23, Aiwu Ruth He 26, Kalpana Ghoshal 27, Patrick B Ryan 28, Elizabeth M Jaffee 1, Chandan Guha 29, Lopa Mishra 4 25, C Norman Coleman 30, Mansoor M Ahmed 31
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PMID: 31481419 DOI: 10.1158/0008-5472.CAN-19-0803
Free article
Erratum in
Correction: Recent Developments and Therapeutic Strategies against Hepatocellular Carcinoma.
Yarchoan M, Agarwal P, Villanueva A, Rao S, Dawson L, Karasic T, Llovet J, Finn R, Groopman J, El-Serag H, Monga S, Wang XW, Karin M, Schwartz R, Tanabe K, Roberts L, Gunaratne P, Tsung A, Brown K, Lawrence T, Salem R, Singal A, Kim A, Rabiee A, Resar L, Meyer J, Hoshida Y, He AR, Ghoshal K, Ryan P, Jaffee E, Guha C, Mishra L, Coleman N, Ahmed M.
Cancer Res. 2019 Nov 15;79(22):5897. doi: 10.1158/0008-5472.CAN-19-2958.
PMID: 31772073 No abstract available.
Abstract
Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer deaths globally. The landscape of systemic therapy has recently changed, with six additional systemic agents either approved or awaiting approval for advanced stage HCC. While these agents have the potential to improve outcomes, a survival increase of 2-5 months remains poor and falls short of what has been achieved in many other solid tumor types. The roles of genomics, underlying cirrhosis, and optimal use of treatment strategies that include radiation, liver transplantation, and surgery remain unanswered. Here, we discuss new treatment opportunities, controversies, and future directions in managing HCC.

©2019 American Association for Cancer Research.

Cited by 4 articles
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3
Review J Hematol Oncol
. 2019 May 14;12(1):48. doi: 10.1186/s13045-019-0735-4.
Technologies for Circulating Tumor Cell Separation From Whole Blood
Petra Bankó 1, Sun Young Lee 2 3, Viola Nagygyörgy 4, Miklós Zrínyi 5, Chang Hoon Chae 5, Dong Hyu Cho 6 7, András Telekes 8
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PMID: 31088479 PMCID: PMC6518774 DOI: 10.1186/s13045-019-0735-4
Free PMC article
Abstract
The importance of early cancer diagnosis and improved cancer therapy has been clear for years and has initiated worldwide research towards new possibilities in the care strategy of patients with cancer using technological innovations. One of the key research fields involves the separation and detection of circulating tumor cells (CTC) because of their suggested important role in early cancer diagnosis and prognosis, namely, providing easy access by a liquid biopsy from blood to identify metastatic cells before clinically detectable metastasis occurs and to study the molecular and genetic profile of these metastatic cells. Provided the opportunity to further progress the development of technology for treating cancer, several CTC technologies have been proposed in recent years by various research groups and companies. Despite their potential role in cancer healthcare, CTC methods are currently mainly used for research purposes, and only a few methods have been accepted for clinical application because of the difficulties caused by CTC heterogeneity, CTC separation from the blood, and a lack of thorough clinical validation. Therefore, the standardization and clinical application of various developed CTC technologies remain important subsequent necessary steps. Because of their suggested future clinical benefits, we focus on describing technologies using whole blood samples without any pretreatment and discuss their advantages, use, and significance. Technologies using whole blood samples utilize size-based, immunoaffinity-based, and density-based methods or combinations of these methods as well as positive and negative enrichment during separation. Although current CTC technologies have not been truly implemented yet, they possess high potential as future clinical diagnostic techniques for the individualized therapy of patients with cancer. Thus, a detailed discussion of the clinical suitability of these new advanced technologies could help prepare clinicians for the future and can be a foundation for technologies that would be used to eliminate CTCs in vivo.

Keywords: CTC; Cancer; Circulating; Separation; Tumor cell; Whole blood.

Conflict of interest statement
Ethics approval and consent to participate
Not applicable

Consent for publication
Not applicable

Competing interests
The authors declare that they have no competing interests.

Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Cited by 5 articles121 references4 figures
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4
J Hematol Oncol
. 2019 Jul 12;12(1):75. doi: 10.1186/s13045-019-0762-1.
Genomic Landscape and Its Correlations With Tumor Mutational Burden, PD-L1 Expression, and Immune Cells Infiltration in Chinese Lung Squamous Cell Carcinoma
Tao Jiang 1, Jinpeng Shi 1, Zhengwei Dong 2, Likun Hou 2, Chao Zhao 3, Xuefei Li 3, Beibei Mao 4, Wei Zhu 4, Xianchao Guo 4, Henghui Zhang 4, Ji He 4, Xiaoxia Chen 1, Chunxia Su 1, Shengxiang Ren 1, Chunyan Wu 5, Caicun Zhou 6
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PMID: 31299995 PMCID: PMC6625041 DOI: 10.1186/s13045-019-0762-1
Free PMC article
Abstract
Introduction: To depict the genomic landscape of Chinese early-stage lung squamous cell carcinoma (LUSC) and investigate its correlation with tumor mutation burden (TMB), PD-L1 expression, and immune infiltrates.

Methods: Whole-exome sequencing was performed on 189 surgically resected LUSC. TMB was defined as the sum of nonsynonymous single nucleotide and indel variants. CD8+ tumor-infiltrating lymphocyte (TIL) density and PD-L1 expression were evaluated by immunohistochemistry. Six immune infiltrates were estimated using an online database.

Results: The median TMB was 9.43 mutations per megabase. Positive PD-L1 expression and CD8+ TILs density were identified in 24.3% and 78.8%. PIK3CA amplification was associated with significantly higher TMB (P = 0.036). Frequent genetic alterations had no impact on PD-L1 expression but PIK3CA amplification and KEAP1 mutation were independently associated with significantly lower CD8+ TIL density (P < 0.001, P = 0.005, respectively). Low TMB and high CD8+ TIL density were independently associated with longer disease-free survival (DFS) while none of them could individually predict the overall survival (OS). Combination of TMB and PD-L1 expression or TMB and CD8+ TIL density could stratify total populations into two groups with distinct prognosis. Classifying tumor-immune microenvironment based on PD-L1 expression and CD8+ TIL density showed discrepant genomic alterations but similar TMB, clinical features, and OS. Notably, patients with different smoking status had distinct prognostic factors.

Conclusion: The combination of TMB, PD-L1 expression, immune infiltrates, and smoking status showed the feasibility to subgroup stratification in Chinese patients with early-stage LUSC, which might be helpful for future design of personalized immunotherapy trials in LUSC.

Keywords: Genome; Immune cells; Lung squamous cell carcinoma; PD-L1; TMB.

Conflict of interest statement
Beibei Mao, Wei Zhu, Xianchao Guo, Henghui Zhang, and Ji He are employees of Beijing Genecast Biotechnology Co., Beijing, China. The other authors declare that they have no conflicts of interest.

Cited by 5 articles44 references4 figures
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5
Clin Epigenetics
. 2019 Aug 13;11(1):117. doi: 10.1186/s13148-019-0708-z.
DNA Methylation Signature Is Prognostic of Choroid Plexus Tumor Aggressiveness
Malgorzata Pienkowska 1, Sanaa Choufani 1, Andrei L Turinsky 1 2, Tanya Guha 1, Diana M Merino 3, Ana Novokmet 1, Michael Brudno 1 2 4, Rosanna Weksberg 1 5 6, Adam Shlien 1 7, Cynthia Hawkins 1 7, Eric Bouffet 8 6, Uri Tabori 1 8 6, Richard J Gilbertson 9, Jonathan L Finlay 10, Nada Jabado 11, Christian Thomas 12, Martin Sill 13 14, David Capper 15 16, Martin Hasselblatt 12, David Malkin 17 18 19 20
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PMID: 31409384 PMCID: PMC6692938 DOI: 10.1186/s13148-019-0708-z
Free PMC article
Erratum in
Correction to: DNA methylation signature is prognostic of choroid plexus tumor aggressiveness.
Pienkowska M, Choufani S, Turinsky AL, Guha T, Merino DM, Novokmet A, Brudno M, Weksberg R, Shlien A, Hawkins C, Bouffet E, Tabori U, Gilbertson RJ, Finlay JL, Jabado N, Thomas C, Sill M, Capper D, Hasselblatt M, Malkin D.
Clin Epigenetics. 2019 Oct 21;11(1):144. doi: 10.1186/s13148-019-0737-7.
PMID: 31639040 Free PMC article.
Abstract
Background: Histological grading of choroid plexus tumors (CPTs) remains the best prognostic tool to distinguish between aggressive choroid plexus carcinoma (CPC) and the more benign choroid plexus papilloma (CPP) or atypical choroid plexus papilloma (aCPP); however, these distinctions can be challenging. Standard treatment of CPC is very aggressive and often leads to severe damage to the young child's brain. Therefore, it is crucial to distinguish between CPC and less aggressive entities (CPP or aCPP) to avoid unnecessary exposure of the young patient to neurotoxic therapy. To better stratify CPTs, we utilized DNA methylation (DNAm) to identify prognostic epigenetic biomarkers for CPCs.

Methods: We obtained DNA methylation profiles of 34 CPTs using the HumanMethylation450 BeadChip from Illumina, and the data was analyzed using the Illumina Genome Studio analysis software. Validation of differentially methylated CpG sites chosen as biomarkers was performed using pyrosequencing analysis on additional 22 CPTs. Sensitivity testing of the CPC DNAm signature was performed on a replication cohort of 61 CPT tumors obtained from Neuropathology, University Hospital Münster, Germany.

Results: Generated genome-wide DNAm profiles of CPTs showed significant differences in DNAm between CPCs and the CPPs or aCPPs. The prediction of clinical outcome could be improved by combining the DNAm profile with the mutational status of TP53. CPCs with homozygous TP53 mutations clustered as a group separate from those carrying a heterozygous TP53 mutation or CPCs with wild type TP53 (TP53-wt) and showed the worst survival outcome. Specific DNAm signatures for CPCs revealed AK1, PER2, and PLSCR4 as potential biomarkers for CPC that can be used to improve molecular stratification for diagnosis and treatment.

Conclusions: We demonstrate that combining specific DNAm signature for CPCs with histological approaches better differentiate aggressive tumors from those that are not life threatening. These findings have important implications for future prognostic risk prediction in clinical disease management.

Keywords: Choroid plexus tumors; DNA methylation; HumanMethylation450 arrays; Quantitative sodium bisulfite pyrosequencing.

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

Cited by 3 articles40 references8 figures
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6
Review J Hematol Oncol
. 2019 Jul 12;12(1):76. doi: 10.1186/s13045-019-0760-3.
Tumor-associated Macrophages in Tumor Metastasis: Biological Roles and Clinical Therapeutic Applications
Yuxin Lin 1, Jianxin Xu 2, Huiyin Lan 3 4
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PMID: 31300030 PMCID: PMC6626377 DOI: 10.1186/s13045-019-0760-3
Free PMC article
Abstract
Tumor metastasis is a major contributor to the death of cancer patients. It is driven not only by the intrinsic alterations in tumor cells, but also by the implicated cross-talk between cancer cells and their altered microenvironment components. Tumor-associated macrophages (TAMs) are the key cells that create an immunosuppressive tumor microenvironment (TME) by producing cytokines, chemokines, growth factors, and triggering the inhibitory immune checkpoint proteins release in T cells. In doing so, TAMs exhibit important functions in facilitating a metastatic cascade of cancer cells and, meanwhile, provide multiple targets of certain checkpoint blockade immunotherapies for opposing tumor progression. In this article, we summarize the regulating networks of TAM polarization and the mechanisms underlying TAM-facilitated metastasis. Based on the overview of current experimental evidence dissecting the critical roles of TAMs in tumor metastasis, we discuss and prospect the potential applications of TAM-focused therapeutic strategies in clinical cancer treatment at present and in the future.

Keywords: Macrophages; Metastasis; Polarization; TAMs; TME.

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

Cited by 19 articles172 references3 figures
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7
Lancet Oncol
. 2019 Jun;20(6):e313-e326. doi: 10.1016/S1470-2045(19)30177-9.
Novel Prognostic Clinical Factors and Biomarkers for Outcome Prediction in Head and Neck Cancer: A Systematic Review
Volker Budach 1, Ingeborg Tinhofer 2
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PMID: 31162105 DOI: 10.1016/S1470-2045(19)30177-9
Abstract
Current algorithms for the clinical management of patients with squamous cell carcinoma of the head and neck (HNSCC) are based on a stage-dependent strategy where all patients at the same TNM stage receive the same treatment. Patient outcomes might be substantially improved by biomarker-guided treatment selection based on individual differences in the genetic and biological characteristics of tumours. Rapid technical advances enabling fast and affordable comprehensive molecular characterisation of tumours have led to increased knowledge of the molecular pathways involved in neoplastic transformation and disease progression in HNSCC. Despite notable successes in other tumour entities, the exploitation of molecular data for the improvement of tumour staging, prognosis, and individual treatment selection for patients with HNSCC has not yet become clinical routine. In this Review, we discuss and merge existing and new information on prognostic biomarkers for HNSCC, with the potential to improve clinical management of patients in the near future.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Cited by 6 articles
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8
Meta-Analysis J Clin Oncol
. 2019 Nov 1;37(31):2899-2915. doi: 10.1200/JCO.19.00572. Epub 2019 Sep 18.
Effect of Psychological Intervention on Fear of Cancer Recurrence: A Systematic Review and Meta-Analysis
Nina M Tauber 1 2, Mia S O'Toole 1, Andreas Dinkel 2 3, Jacqueline Galica 2 4, Gerry Humphris 2 5, Sophie Lebel 2 6, Christine Maheu 2 7, Gozde Ozakinci 2 5, Judith Prins 2 8, Louise Sharpe 2 9, Allan Ben Smith 2 10, Belinda Thewes 2 9, Sébastien Simard 2 11, Robert Zachariae 1 2 12
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PMID: 31532725 PMCID: PMC6823887 (available on 2020-11-01) DOI: 10.1200/JCO.19.00572
Free PMC article
Abstract
Purpose: Fear of cancer recurrence (FCR) is a significantly distressing problem that affects a substantial number of patients with and survivors of cancer; however, the overall efficacy of available psychological interventions on FCR remains unknown. We therefore evaluated this in the present systematic review and meta-analysis.

Methods: We searched key electronic databases to identify trials that evaluated the effect of psychological interventions on FCR among patients with and survivors of cancer. Controlled trials were subjected to meta-analysis, and the moderating influence of study characteristics on the effect were examined. Overall quality of evidence was evaluated using the GRADE system. Open trials were narratively reviewed to explore ongoing developments in the field (PROSPERO registration no.: CRD42017076514).

Results: A total of 23 controlled trials (21 randomized controlled trials) and nine open trials were included. Small effects (Hedges's g) were found both at postintervention (g = 0.33; 95% CI, 0.20 to 0.46; P < .001) and at follow-up (g = 0.28; 95% CI, 0.17 to 0.40; P < .001). Effects at postintervention of contemporary cognitive behavioral therapies (CBTs; g = 0.42) were larger than those of traditional CBTs (g = 0.24; β = .22; 95% CI, .04 to .41; P = .018). At follow-up, larger effects were associated with shorter time to follow-up (β = -.01; 95% CI, -.01 to -.00; P = .027) and group-based formats (β = .18; 95% CI, .01 to .36; P = .041). A GRADE evaluation indicated evidence of moderate strength for effects of psychological intervention for FCR.

Conclusion: Psychological interventions for FCR revealed a small but robust effect at postintervention, which was largely maintained at follow-up. Larger postintervention effects were found for contemporary CBTs that were focused on processes of cognition-for example, worry, rumination, and attentional bias-rather than the content, and aimed to change the way in which the individual relates to his or her inner experiences. Future trials could investigate how to further optimize and tailor interventions to individual patients' FCR presentation.

Cited by 2 articles85 references
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9
Review Curr Pharm Des
. 2019;25(31):3323-3338. doi: 10.2174/1381612825666190902155957.
Combination Therapies of Artemisinin and Its Derivatives as a Viable Approach for Future Cancer Treatment
Maushmi S Kumar 1, Tanuja T Yadav 1, Rohan R Khair 1, Godefridus J Peters 2, Mayur C Yergeri 1
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PMID: 31475891 DOI: 10.2174/1381612825666190902155957
Abstract
Background: Many anticancer drugs have been developed for clinical usage till now, but the major problem is the development of drug-resistance over a period of time in the treatment of cancer. Anticancer drugs produce huge adverse effects, ultimately leading to death of the patient. Researchers have been focusing on the development of novel molecules with higher efficacy and lower toxicity; the anti-malarial drug artemisinin and its derivatives have exhibited cytotoxic effects.

Methods: We have done extensive literature search for artemisinin for its new role as anti-cancer agent for future treatment. Last two decades papers were referred for deep understanding to strengthen its role.

Result: Literature shows changes at 9, 10 position in the artemisinin structure produces anticancer activity. Artemisinin shows anticancer activity in leukemia, hepatocellular carcinoma, colorectal and breast cancer cell lines. Artemisinin and its derivatives have been studied as combination therapy with several synthetic compounds, RNA interfaces, recombinant proteins and antibodies etc., for synergizing the effect of these drugs. They produce an anticancer effect by causing cell cycle arrest, regulating signaling in apoptosis, angiogenesis and cytotoxicity activity on the steroid receptors. Many novel formulations of artemisinin are being developed in the form of carbon nanotubes, polymer-coated drug particles, etc., for delivering artemisinin, since it has poor water/ oil solubility and is chemically unstable.

Conclusion: We have summarize the combination therapies of artemisinin and its derivatives with other anticancer drugs and also focussed on recent developments of different drug delivery systems in the last 10 years. Various reports and clinical trials of artemisinin type drugs indicated selective cytotoxicity along with minimal toxicity thus projecting them as promising anti-cancer agents in future cancer therapies.

Keywords: Artemisinin; anticancer properties; combination therapy; formulations; reactive oxygen species; repurposing..

Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

Cited by 1 article
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10
Review J Reprod Immunol
. 2019 Jun;133:37-42. doi: 10.1016/j.jri.2019.06.001. Epub 2019 Jun 18.
Treatment With Intravenous Immunoglobulin in Patients With Recurrent Pregnancy Loss: An Update
Ole B Christiansen 1, Astrid M Kolte 2, Maria C Krog 2, Henriette S Nielsen 2, Pia Egerup 3
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PMID: 31238263 DOI: 10.1016/j.jri.2019.06.001
Abstract
Intravenous immunoglobulin (IVIg) has a documented clinical effect in many autoimmune diseases and has so far been tested in >10 randomised controlled trials (RCTs) in women with recurrent pregnancy loss (RPL). The results of the RCTs have, however, been very divergent. In meta-analyses of all trials, no significant impact on live birth rate has been reported. In contrast, in sensitivity analyses, IVIg significantly increased live birth rates when initiated prior to conception and it had a borderline significant therapeutic effect in women with secondary RPL. Higher dosages of IVIg and serological signs of autoimmunity in the treated patients tended to increase the success rate after treatment. A follow-up study of patients from our recent RCT also supports a significant therapeutic effect in patients who had received IVIg before conception. The lessons learned from the published trials and meta-analyses should be incorporated in the design of future RCTs of IVIg in the treatment of RPL.

Keywords: Immunomodulation; Intravenous immunoglobulin; Recurrent Miscarriage; Recurrent pregnancy loss.

Copyright © 2019 Elsevier B.V. All rights reserved.

Cited by 2 articles
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11
Meta-Analysis Lancet Oncol
. 2019 Mar;20(3):361-370. doi: 10.1016/S1470-2045(18)30750-2. Epub 2019 Jan 29.
Disease-free Survival as a Surrogate for Overall Survival in Patients With HER2-positive, Early Breast Cancer in Trials of Adjuvant Trastuzumab for Up to 1 Year: A Systematic Review and Meta-Analysis
Everardo D Saad 1, Pierre Squifflet 2, Tomasz Burzykowski 3, Emmanuel Quinaux 2, Suzette Delaloge 4, Dimitris Mavroudis 5, Edith Perez 6, Martine Piccart-Gebhart 7, Bryan P Schneider 8, Dennis Slamon 9, Norman Wolmark 10, Marc Buyse 11
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PMID: 30709633 PMCID: PMC7050571 DOI: 10.1016/S1470-2045(18)30750-2
Free PMC article
Erratum in
Correction to Lancet Oncol 2019; 20: 361-70.
Lancet Oncol. 2019 Mar;20(3):e132. doi: 10.1016/S1470-2045(19)30110-X.
PMID: 30842056 No abstract available.
Abstract
Background: Although frequently used as a primary endpoint, disease-free survival has not been validated as a surrogate for overall survival in early breast cancer. We investigated this surrogacy in the adjuvant setting of treatment with anti-HER2 antibodies.

Methods: In a systematic review and meta-analysis, we identified published and non-published randomised controlled trials with completed accrual and available disease-free survival and overall survival results for the intention-to-treat population as of September 2016. Bibliographic databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials), clinical trial registries (Clinicaltrials.gov, EU Clinical Trials Register, WHO International Clinical Trials Registry Platform, and PharmNet.Bund), and trial registries from relevant pharmaceutical companies were searched. Eligibility for treatment of HER2-positive early breast cancer required at least one group to have an anti-HER antibody treatment (ie, trastuzumab, pertuzumab, or trastuzumab emtansine) planned for 12 months, and at least one control arm with chemotherapy without the antibody, a lower total dose or duration of the antibody, or observation alone. Units of analysis were contrasts: two-group trials gave rise to one contrast, whereas trials with more than two groups gave rise to more than one contrast. We excluded trials enrolling patients with recurrent, metastatic, or non-invasive disease, and those testing neoadjuvant therapy exclusively. Our primary objective was to estimate patient-level and trial-level correlations between disease-free survival and overall survival. We measured the association between disease-free survival and overall survival using Spearman's correlation coefficient (rs), and the association between hazard ratios (HRs) for disease-free survival and overall survival using R2. We computed the surrogate threshold effect, the maximum HR for disease-free survival that statistically predicts an HR for overall survival less than 1·00 in a future trial.

Findings: Eight trials (n=21 480 patients) gave rise to a full set (12 contrasts). Patient-level associations between disease-free and overall survival were strong (rs=0·90 [95% CI 0·89-0·90]). Trial-level associations gave rise to values of R2 of 0·75 (95% CI 0·50-1·00) for the full set. Subgroups defined by nodal status and hormone receptor status yielded qualitatively similar results. Depending on the expected number of deaths in a future trial, the surrogate threshold effects ranged from 0·56 to 0·81, based on the full set.

Interpretation: These findings suggest that it is appropriate to continue to use disease-free survival as a surrogate for overall survival in trials in HER-2-positive, early breast cancer. The key limitation of this study is the dependence of its results on the trials included and on the existence of an outlying trial.

Funding: Roche Pharma AG.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Conflict of interest statement
Declaration of interests

EDS and PS report grants from Roche Pharma AG to the International Drug Development Institute (their employer) during the conduct of the study. SD reports grants, personal fees, and non-financial support from Roche-Genentech, and grants and personal fees from Puma, outside of the submitted work. MP-G reports personal fees from Roche-Genentech, outside of the submitted work. DS reports consultancy for Novartis, Eli Lilly, and Seattle Genetics, and is a board member at BioMarin. NW reports grants from the National Cancer Institute, during the conduct of the study. MB is an employee and holds stock at the International Drug Development Institute. All other authors declare no competing interests.

Comment in
Endpoint selection in HER2-positive early breast cancer.
Amir E.
Lancet Oncol. 2019 Mar;20(3):315-316. doi: 10.1016/S1470-2045(18)30779-4. Epub 2019 Jan 29.
PMID: 30709632 No abstract available.
Cited by 3 articles3 figures
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12
J Immunother Cancer
. 2019 Mar 14;7(1):75. doi: 10.1186/s40425-019-0525-0.
Therapeutic Efficacy, Pharmacokinetic Profiles, and Toxicological Activities of Humanized Antibody-Drug Conjugate Zt/g4-MMAE Targeting RON Receptor Tyrosine Kinase for Cancer Therapy
Hang-Ping Yao 1, Liang Feng 2 3, Sreedhar Reddy Suthe 3, Ling-Hui Chen 4 5, Tian-Hao Weng 1, Chen-Yu Hu 1, Eun Sung Jun 6, Zhi-Gang Wu 4, Wei-Lin Wang 7 8, Song Cheol Kim 9, Xiang-Min Tong 10, Ming-Hai Wang 11 12 13
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PMID: 30871619 PMCID: PMC6419354 DOI: 10.1186/s40425-019-0525-0
Free PMC article
Erratum in
Correction to: Therapeutic efficacy, pharmacokinetic profiles, and toxicological activities of humanized antibody-drug conjugate Zt/g4-MMAE targeting RON receptor tyrosine kinase for cancer therapy.
Yao HP, Feng L, Suthe SR, Chen LH, Weng TH, Hu CY, Jun ES, Wu ZG, Wang WL, Kim SC, Tong XM, Wang MH.
J Immunother Cancer. 2019 Apr 2;7(1):94. doi: 10.1186/s40425-019-0571-7.
PMID: 30940188 Free PMC article.
Abstract
Background: Aberrant expression of the RON receptor tyrosine kinase is a pathogenic feature and a validated drug target in various types of cancers. Currently, therapeutic antibodies targeting RON for cancer therapy are under intensive evaluation. Here we report the development and validation of a novel humanized anti-RON antibody-drug conjugate for cancer therapy.

Methods: Antibody humanization was achieved by grafting sequences of complementarity-determining regions from mouse monoclonal antibody Zt/g4 into human IgG1/κ acceptor frameworks. The selected humanized Zt/g4 subclone H1L3 was conjugated with monomethyl auristatin E using a dipeptide linker to form H-Zt/g4-MMAE. Pharmacokinetic analysis of H-Zt/g4-MMAE was determined using hydrophobic interaction chromatography and a MMAE ADC ELISA kit. Biochemical and biological assays were used for measuring RON expression, internalization, cell viability and death. Therapeutic efficacies of H-Zt/g4-MMAE were validated in vivo using three pancreatic cancer xenograft models. Toxicological activities of H-Zt/g4-MMAE were determined in mouse and cynomolgus monkey.

Results: H-Zt/g4-MMAE had a drug to antibody ratio of 3.77:1 and was highly stable in human plasma with a dissociation rate less than 5% within a 20 day period. H-Zt/g4-MMAE displayed a favorable pharmacokinetic profile in both mouse and cynomolgus monkey. In vitro, H-Zt/g4-MMAE induced RON internalization, which results in killing of pancreatic cancer cells with IC50 values at 10-20 nM. In vivo, H-Zt/g4-MMAE inhibited pancreatic cancer xenograft growth with tumoristatic concentrations at 1~3 mg/kg bodyweight. Significantly, H-Zt/g4-MMAE eradicated tumors across multiple xenograft models regardless their chemoresistant and metastatic statuses. Moreover, H-Zt/g4-MMAE inhibited and eradicated xenografts mediated by pancreatic cancer stem-like cells and by primary cells from patient-derived tumors. Toxicologically, H-Zt/g4-MMAE is well tolerated in mice up to 60 mg/kg. In cynomolgus monkey, H-Zt/g4-MMAE up to 30 mg/kg had a manageable and reversible toxicity profile.

Conclusions: H-Zt/g4-MMAE is superior in eradication of pancreatic cancer xenografts with favorable pharmacokinetic profiles and manageable toxicological activities. These findings warrant the transition of H-Zt/g4-MMAE into clinical trials in the future.

Keywords: Antibody-rug conjugates; Pancreatic cancer; Pharmacokinetics; RON receptor tyrosine kinase; Therapeutic efficacy; Toxicological profiles; Xenograft tumor model.

Conflict of interest statement
Ethics approval and consent to participate
The use of athymic nude mice for in vivo studies was approved by TTUHSC Institutional Animal Use Committee. The use of cynomolgus monkey was approved by the Zhejiang University School of Medicine Institutional Review Committee according to the guidelines from the China Food and Drug Administration.

Consent for publication
Not applicable.

Competing interests
The authors declare that they have no competing interests.

Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Cited by 6 articles50 references6 figures
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13
Biochem Biophys Res Commun
. 2019 Oct 1;517(4):677-683. doi: 10.1016/j.bbrc.2019.07.109. Epub 2019 Aug 8.
Targeted Gene Therapy in Human-Induced Pluripotent Stem Cells From a Patient With Primary Hyperoxaluria Type 1 Using CRISPR/Cas9 Technology
Julie Estève 1, Jean-Marc Blouin 1, Magalie Lalanne 1, Lamia Azzi-Martin 2, Pierre Dubus 2, Audrey Bidet 3, Jérôme Harambat 4, Brigitte Llanas 4, Isabelle Moranvillier 1, Aurélie Bedel 1, François Moreau-Gaudry 1, Emmanuel Richard 5
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PMID: 31402115 DOI: 10.1016/j.bbrc.2019.07.109
Abstract
Primary hyperoxaluria type 1 (PH1) is an inherited metabolic disorder caused by a deficiency of the peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which leads to overproduction of oxalate by the liver and results in urolithiasis, nephrocalcinosis and renal failure. The only curative treatment for PH1 is combined liver and kidney transplantation, which is limited by the lack of suitable organs, significant complications, and the life-long requirement for immunosuppressive agents to maintain organ tolerance. Hepatocyte-like cells (HLCs) generated from CRISPR/Cas9 genome-edited human-induced pluripotent stem cells would offer an attractive unlimited source of autologous gene-corrected liver cells as an alternative to orthotopic liver transplantation (OLT). Here we report the CRISPR/Cas9 nuclease-mediated gene targeting of a single-copy AGXT therapeutic minigene into the safe harbour AAVS1 locus in PH1-induced pluripotent stem cells (PH1-iPSCs) without off-target inserts. We obtained a robust expression of a codon-optimized AGT in HLCs derived from AAVS1 locus-edited PH1-iPSCs. Our study provides the proof of concept that CRISPR/Cas9-mediated integration of an AGXT minigene into the AAVS1 safe harbour locus in patient-specific iPSCs is an efficient strategy to generate functionally corrected hepatocytes, which in the future may serve as a source for an autologous cell-based gene therapy for the treatment of PH1.

Keywords: AAVS1 locus; CRISPR/Cas9; Genome editing; Hepatic differentiation; Hyperoxaluria; Induced pluripotent stem cells.

Copyright © 2019 Elsevier Inc. All rights reserved.

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14
Review Br J Cancer
. 2019 Oct;121(8):631-639. doi: 10.1038/s41416-019-0516-4. Epub 2019 Aug 13.
In Order for the Light to Shine So Brightly, the Darkness Must Be Present-Why Do Cancers Fluoresce With 5-aminolaevulinic Acid?
Kym McNicholas 1 2, Melanie N MacGregor 3, Jonathan M Gleadle 4 5
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PMID: 31406300 PMCID: PMC6889380 (available on 2020-08-13) DOI: 10.1038/s41416-019-0516-4
Free PMC article
Abstract
Photodynamic diagnosis and therapy have emerged as a promising tool in oncology. Using the visible fluorescence from photosensitisers excited by light, clinicians can both identify and treat tumour cells in situ. Protoporphyrin IX, produced in the penultimate step of the haem synthesis pathway, is a naturally occurring photosensitiser that visibly fluoresces when exposed to light. This fluorescence is enhanced considerably by the exogenous administration of the substrate 5-aminolaevulinic acid (5-ALA). Significantly, 5-ALA-induced protoporphyrin IX accumulates preferentially in cancer cells, and this enhanced fluorescence has been harnessed for the detection and photodynamic treatment of brain, skin and bladder tumours. However, surprisingly little is known about the mechanistic basis for this phenomenon. This review focuses on alterations in the haem pathway in cancer and considers the unique features of the cancer environment, such as altered glucose metabolism, oncogenic mutations and hypoxia, and their potential effects on the protoporphyrin IX phenomenon. A better understanding of why cancer cells fluoresce with 5-ALA would improve its use in cancer diagnostics and therapies.

Conflict of interest statement
The authors declare no competing interests.

Cited by 2 articles92 references
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15
Addict Behav
. 2019 Apr;91:51-60. doi: 10.1016/j.addbeh.2018.11.027. Epub 2018 Nov 17.
Associations of Risk Factors of E-Cigarette and Cigarette Use and Susceptibility to Use Among Baseline PATH Study Youth Participants (2013-2014)
Michael D Sawdey 1, Hannah R Day 2, Blair Coleman 2, Lisa D Gardner 2, Sarah E Johnson 2, Jean Limpert 2, Hoda T Hammad 2, Maciej L Goniewicz 3, David B Abrams 4, Cassandra A Stanton 5, Jennifer L Pearson 6, Annette R Kaufman 7, Heather L Kimmel 8, Cristine D Delnevo 9, Wilson M Compton 8, Maansi Bansal-Travers 3, Raymond S Niaura 4, Andrew Hyland 3, Bridget K Ambrose 2
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PMID: 30473246 DOI: 10.1016/j.addbeh.2018.11.027
Abstract
Introduction: Improved understanding of the distribution of traditional risk factors of cigarette smoking among youth who have ever used or are susceptible to e-cigarettes and cigarettes will inform future longitudinal studies examining transitions in use.

Methods: Multiple logistic regression analysis was conducted using data from youth (ages 12-17 years) who had ever heard of e-cigarettes at baseline of the PATH Study (n = 12,460) to compare the distribution of risk factors for cigarette smoking among seven mutually exclusive groups based on ever cigarette/e-cigarette use and susceptibility status.

Results: Compared to committed never users, youth susceptible to e-cigarettes, cigarettes, or both had increasing odds of risk factors for cigarette smoking, with those susceptible to both products at highest risk, followed by cigarettes and e-cigarettes. Compared to e-cigarette only users, dual users had higher odds of nearly all risk factors (aOR range = 1.6-6.8) and cigarette only smokers had higher odds of other (non-e-cigarette) tobacco use (aOR range = 1.5-2.3), marijuana use (aOR = 1.9, 95%CI = 1.4-2.5), a high GAIN substance use score (aOR = 1.9, 95%CI = 1.1-3.4), low academic achievement (aOR range = 1.6-3.4), and exposure to smoking (aOR range = 1.8-2.1). No differences were observed for externalizing factors (depression, anxiety, etc.), sensation seeking, or household use of non-cigarette tobacco.

Conclusions: Among ever cigarette and e-cigarette users, dual users had higher odds of reporting traditional risk factors for smoking, followed by single product cigarette smokers and e-cigarette users. Understanding how e-cigarette and cigarette users differ may inform youth tobacco use prevention efforts and advise future studies assessing probability of progression of cigarette and e-cigarette use.

Keywords: Cigarettes; E-cigarettes; Risk factors of tobacco use; Susceptibility.

Published by Elsevier Ltd.

Cited by 7 articles
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16
J Adolesc Young Adult Oncol
. 2018 Dec;7(6):652-659. doi: 10.1089/jayao.2018.0044. Epub 2018 Jul 10.
Understanding and Utilizing the Unmet Needs of Teenagers and Young Adults With Cancer to Determine Priorities for Service Development: The Macmillan On Target Programme
Michael C G Stevens 1 2, Paul Beynon 1, Alison Cameron 1, Jamie Cargill 1, Jennifer Cheshire 1, Sue Dolby 1 3
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PMID: 29989481 DOI: 10.1089/jayao.2018.0044
Abstract
Purpose: A systematic attempt to identify and address unmet needs among patients in a large regional teenagers and young adults (TYA) cancer service in the United Kingdom, including perspectives obtained from patients themselves, their families/supporters, and professionals. Methods: Questionnaires, focus groups, and interviews were undertaken with the following: patients (diagnosed ≥16 years, and aged 16-24 years at the time of study)-participation was 42 for questionnaire, 7 for focus group, and 6 for interview; family members/others in patients' lives ("networkers") (participation: 28, 0, and 4); and professionals (participation: 54, 0, and 97). Requirement management methodology was used to specify components for potential service interventions, which were then scored and prioritized. Co-creation was utilized to incorporate a deeper understanding of patient experience. Results: 42/108(39%) patients, 28/177(24%) networkers, and 122/322(38%) professionals participated. For patients, seven themes that "mattered most" (identified by >60% responders) were defined. For many, support was provided both to a lesser extent than needed and was sometimes unsatisfactory. For networkers, results identified the significant support offered by those around the patient and the impact on their own lives. For professionals, consensus was reached on interventions that could be utilized in clinical encounters with TYA to enhance care. A list of prioritized "requirements" was created to drive future service improvement. Conclusions: Areas identified for development included three specific initiatives applicable to other TYA services: a support website (www.tyahelp.co.uk); an electronic, age/developmentally specific, holistic needs assessment tool (the Integrated Assessment Map www.tyaiam.co.uk); and a portal linking use of the IAM to resources within the Help website (video illustration available at: https://vimeo.com/191019826).

Keywords: co-creation; need assessment; requirement management; service development.

Cited by 1 article
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17
J Palliat Med
. 2019 Mar;22(3):267-273. doi: 10.1089/jpm.2018.0360. Epub 2018 Nov 12.
Empower Seriously Ill Older Adults to Formulate Their Goals for Medical Care in the Emergency Department
Kei Ouchi 1 2 3 4, Naomi George 1 2, Anna C Revette 5, Mohammad Adrian Hasdianda 1 2, Lauren Fellion 1 2, Audrey Reust 1 2, Lynda H Powell 6, Rebecca Sudore 7, Jeremiah D Schuur 1 2, Mara A Schonberg 8, Edward Bernstein 9 10, James A Tulsky 4 11, Susan D Block 3 4 10 11 12
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PMID: 30418094 PMCID: PMC6391608 DOI: 10.1089/jpm.2018.0360
Free PMC article
Abstract
Background: Most seriously ill older adults visit the emergency department (ED) near the end of life, yet no feasible method exists to empower them to formulate their care goals in this setting.

Objective: To develop an intervention to empower seriously ill older adults to formulate their future care goals in the ED.

Design: Prospective intervention development study.

Setting: In a single, urban, academic ED, we refined the prototype intervention with ED clinicians and patient advisors. We tested the intervention for its acceptability in English-speaking patients ≥65 years old with serious illness or patients whose treating ED clinician answered "No" to the "surprise question" ("would not be surprised if died in the next 12 months"). We excluded patients with advance directives or whose treating ED clinician determined the patient to be inappropriate.

Measurements: Our primary outcome was perceived acceptability of our intervention. Secondary outcomes included perceived main intent and stated attitude toward future care planning.

Results: We refined the intervention with 16 mock clinical encounters of ED clinicians and patient advisors. Then, we administered the refined intervention to 23 patients and conducted semistructured interviews afterward. Mean age of patients was 76 years, 65% were women, and 43% of patients had metastatic cancer. Most participants (n = 17) positively assessed our intervention, identified questions for their doctors, and reflected on how they feel about their future care.

Conclusion: An intervention to empower seriously ill older adults to understand the importance of future care planning in the ED was developed, and they found it acceptable.

Keywords: advance care planning; behavioral intervention; emergency department.

Conflict of interest statement
All authors report no conflict of interest.

Cited by 3 articles1 figure
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18
BMC Cancer
. 2020 Jan 6;20(1):12. doi: 10.1186/s12885-019-6425-3.
Loss of the SWI/SNF-ATPase Subunit Members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in Oesophageal Adenocarcinoma
Simon Schallenberg 1, Julian Bork 2, Ahlem Essakly 2, Hakan Alakus 3, Reinhard Buettner 2, Axel M Hillmer 2, Christiane Bruns 3, Wolfgang Schroeder 3, Thomas Zander 4, Heike Loeser 2, Florian Gebauer 3, Alexander Quaas 2
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PMID: 31906887 PMCID: PMC6945480 DOI: 10.1186/s12885-019-6425-3
Free PMC article
Abstract
Background: The SWI/SNF complex is an important chromatin remodeler, commonly dysregulated in cancer, with an estimated mutation frequency of 20%. ARID1A is the most frequently mutated subunit gene. Almost nothing is known about the other familiar members of the SWI/SNF complexes, SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1), in oesophageal adenocarcinoma (EAC).

Methods: We analysed a large cohort of 685 patients with EAC. We used four different antibodies to detect a loss-of-protein of ARID1A BRM, BRG1 and INI1 by immunohistochemistry and correlated these findings with molecular and clinical data.

Results: Loss of ARID1A, BRG1, BRM and INI1 was observed in 10.4, 3.4, 9.9 and 2% of EAC. We found a co-existing protein loss of ARID1A and BRM in 9.9% and of ARID1A and BRG1 in 2.2%. Patients with loss of ARID1A and TP53 wildtype EACs showed a shortened overall survival compared with AIRDA1A-positive tumours [median overall survival was 60.1 months (95%CI 1.2-139.9 months)] in patients with ARIDA-1A expression and 26.2 months (95%CI 3.7-19.1 months) in cases of ARIDA-1A loss (p = 0.044). Tumours with loss or expression of ARID1A and TP53 loss were not associated with a difference in survival. Only one tumour revealed high microsatellite instability (MSI-H) with concomitant ARID1A loss. All other ARID1A loss-EACs were microsatellite-stable (MSS). No predictive relevance was seen for SWI/SNF-complex alterations and simultaneous amplification of different genes (PIK3CA, KRAS, c-MYC, MET, GATA6, ERBB2).

Conclusion: Our work describes, for the first time, loss of one of the SWI/SNF ATPase subunit proteins in a large number of adenocarcinomas of the oesophagus. Several papers discuss possible therapeutic interventions for tumours showing a loss of function of the SWI/SNF complex, such as PARP inhibitors or PI3K and AKT inhibitors. Future studies will be needed to show whether SWI/SNF complex-deficient EACs may benefit from personalized therapy.

Keywords: Heterogeneity; Loss-of-function; Oesophageal adenocarcinoma; SWI/SNF-complex; TP53 loss.

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

49 references6 figures
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19
Review Cell Prolif
. 2020 May;53(5):e12801. doi: 10.1111/cpr.12801. Epub 2020 Apr 6.
Systematic Characterization of Non-Coding RNAs in Triple-Negative Breast Cancer
Jie Mei 1, Leiyu Hao 2, Huiyu Wang 1, Rui Xu 2, Yan Liu 2, Yichao Zhu 2 3, Chaoying Liu 1
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PMID: 32249490 PMCID: PMC7260065 DOI: 10.1111/cpr.12801
Free PMC article
Abstract
Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer with negativity for oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2). Non-coding RNAs (ncRNAs) make up most of the transcriptome and are widely present in eukaryotic cells. In recent years, emerging evidence suggests that ncRNAs, mainly microRNAs (miRNAs), long ncRNAs (lncRNAs) and circular RNAs (circRNAs), play prominent roles in the tumorigenesis and development of TNBC, but the functions of most ncRNAs have not been fully described. In this review, we systematically elucidate the general characteristics and biogenesis of miRNAs, lncRNAs and circRNAs, discuss the emerging functions of these ncRNAs in TNBC and present future perspectives in clinical practice.

© 2020 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.

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

161 references5 figures
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20
Review Exp Biol Med (Maywood)
. 2019 May;244(8):621-629. doi: 10.1177/1535370219833624. Epub 2019 Mar 5.
Pharmacological Inhibition of Bax-induced Cell Death: Bax-inhibiting Peptides and Small Compounds Inhibiting Bax
Kelsey Jensen 1, David Jasen WuWong 1, Sean Wong 1, Mieko Matsuyama 1, Shigemi Matsuyama 1
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PMID: 30836793 PMCID: PMC6552396 DOI: 10.1177/1535370219833624
Free PMC article
Abstract
Bax induces mitochondria-dependent programed cell death. While cytotoxic drugs activating Bax have been developed for cancer treatment, clinically effective therapeutics suppressing Bax-induced cell death rescuing essential cells have not been developed. This mini-review will summarize previously reported Bax inhibitors including peptides, small compounds, and antibodies. We will discuss potential applications and the future direction of these Bax inhibitors.

Keywords: Apoptosis; Bax; Bax inhibitor; Ku70; cell death; cell-penetrating peptide; drug delivery.

Cited by 1 article3 figures
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21
DNA Cell Biol
. 2020 Jun;39(6):1051-1063. doi: 10.1089/dna.2020.5460. Epub 2020 Apr 30.
Prognostic Alternative mRNA Splicing Signature and a Novel Biomarker in Triple-Negative Breast Cancer
Qiang Liu 1, Xiangyu Wang 1, Xiangyi Kong 1, Xue Yang 1, Ran Cheng 1, Wenxiang Zhang 1, Peng Gao 1, Li Chen 1, Zhongzhao Wang 1, Yi Fang 1, Jing Wang 1
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PMID: 32379494 DOI: 10.1089/dna.2020.5460
Abstract
Triple-negative breast cancer (TNBC) is a high-risk subtype of breast cancer defined by negative expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Accumulating evidence indicates that alternative splicing (AS) events are correlated with the prognosis of cancer. RNA sequencing data and AS event data were manually curated from The Cancer Genome Atlas (TCGA) dataset and TCGA Splice Seq, respectively. Univariate and multivariate Cox regression analyses were applied to screen AS events associated with TNBC survival and to establish a prognostic model. A receiver operating characteristic (ROC) curve was used to evaluate the performance of the prognostic model. Differentially expressed gene analysis and functional enrichment analysis were harnessed to reveal the functional role of gene sets and to screen novel biomarkers. By integrated bioinformatics analysis of AS events and gene expression in TNBC, our study is the first to generate specific AS event profiles, prognostic AS event interaction networks, and splice factor-AS interaction networks for TNBC. Surprisingly, we found that the performance of the AS-based prognostic model was encouraging with a mean area under the ROC curve of 0.957 at 2-10 years. We also found that chemokine (C-C motif) ligand 16 (CCL16) expression was correlated with TNBC grade and could be a potential novel biomarker. In conclusion, this study provided a systematic analysis of prognostic AS event profiles and gene expression in TNBC. A novel prognostic model based on AS events may establish a foundation for future research investigating the diagnosis and treatment of TNBC.

Keywords: TNBC; alternative splicing; biomarker; prognostic signature.

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22
Curr Opin Oncol
. 2020 Jul;32(4):364-369. doi: 10.1097/CCO.0000000000000643.
Adjuvant Chemotherapy in Biliary Tract Cancer: State of the Art and Future Perspectives
Dilara Akhoundova Sanoyan 1, Mairéad G McNamara 2 3, Angela Lamarca 3, Juan W Valle 2 3
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PMID: 32541326 DOI: 10.1097/CCO.0000000000000643
Abstract
Purpose of review: Biliary tract cancers (BTCs) have a poor prognosis; most patients present with advanced disease and, even after surgical resection for early-stage disease local and distant relapses are frequent. Involved resection margins and lymph node involvement are the most relevant known adverse prognostic factors. Historically clinicians have made clinical decisions based on data from institutional series and uncontrolled studies, with their inherent limitations. In this review, data from recently-reported prospective randomized trials are reviewed and clinical implications discussed.

Recent findings: Results from prospective randomized phase III trials (namely BILCAP, PRODIGE-12, and BCAT) are reviewed: none of the studies met their primary endpoint by intention-to-treat analysis. However, following a per-protocol sensitivity analysis of the BILCAP study, adjuvant capecitabine (for 6 months) showed a clinically-relevant improvement in overall survival and provides reference data for future clinical trials.

Summary: Adjuvant chemotherapy with capecitabine should be considered following curative resection of BTC. Identification of benefit in anatomical subgroups is ongoing and future trials should also consider the implication of molecular subtypes of BTC (for prognostic impact and on-target therapeutic options).

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23
Review Curr Oncol Rep
. 2020 Jun 15;22(7):71. doi: 10.1007/s11912-020-00932-9.
Prehabilitative Exercise for the Enhancement of Physical, Psychosocial, and Biological Outcomes Among Patients Diagnosed With Cancer
Kyuwan Lee 1, Judy Zhou 2, Mary K Norris 3, Christina Chow 2, Christina M Dieli-Conwright 4
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PMID: 32537699 DOI: 10.1007/s11912-020-00932-9
Abstract
Purpose of review: This review summarizes the effects of prehabilitative exercise interventions on the physical, psychosocial, and biological outcomes among patients with cancer. Current gaps and future directions in prehabilitative exercise research will be addressed.

Recent findings: Prehabilitative exercise mitigates the detrimental impact of cancer surgery on physical fitness, noted by increases in maximal oxygen consumption and 6-min walk distance. Beneficial effects on psychosocial and biological outcomes remain inconclusive. Aerobic exercise interventions were often prescribed and included low-, moderate-, or high-intensity exercise. Resistance exercise interventions were often performed in conjunction with aerobic exercise. Prehabilitative exercise elicits robust improvements in physical fitness; however, effect on psychosocial and biological outcomes remains inconclusive. Exercise prescription parameters varied greatly by frequency, intensity, time, and type across multiple cancer diagnoses. Future investigations are needed to systematically dose exercise for a wider variety of outcome measures, with an overall goal to set forth pre-operative exercise guidelines.

Keywords: Cancer patients; Cancer-related biomarkers; Physical fitness; Prehabilitative exercise; Psychosocial health.

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24
Review Crit Rev Oncol Hematol
. 2020 May 21;152:102991. doi: 10.1016/j.critrevonc.2020.102991. Online ahead of print.
COVID 19 Therapies and Anti-Cancer Drugs: A Systematic Review of Recent Literature
Giuseppe Di Lorenzo 1, Rossella Di Trolio 2, Zisis Kozlakidis 3, Giuseppina Busto 4, Concetta Ingenito 4, Luciana Buonerba 4, Claudia Ferrara 4, Annamaria Libroia 4, Gianluca Ragone 4, Concetta Dello Ioio 4, Beatrice Savastano 4, Mario Polverino 4, Ferdinando De Falco 4, Simona Iaccarino 4, Emilio Leo 4
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PMID: 32544802 DOI: 10.1016/j.critrevonc.2020.102991
Abstract
Background: It is reasonable to think that cancer patients undergoing chemotherapy, targeted therapy or immunotherapy could have a more aggressive course if positive for Coronavirus disease CoV-2 (COVID- 19).

Methods: We conducted a literature review on https://www.ncbi.nlm.nih.gov/pubmed/, https://scholar.google.com, www.arxiv.org, www.biorxiv.org, of all articles published using the keywords COVID-19 therapy or treatment and cancer until May 2, 2020. A total of 205 articles were identified and 53 were included in this review.

Results: We describe the ongoing COVID-19 therapies that should be known by oncologists and highlight the potential interactions with antineoplastic drugs, commonly used in clinical practice. The main drug interactions were found with tocilizumab, ruxolitinib and colchicine.

Conclusions: The literature provides an inconclusive picture on potential preferred treatments for COVID-19 and their interactions with antineoplastic agents. Future clinical trials are needed to better understand the interactions between different drugs in the context of COVID-19 pandemic.

Keywords: Antiviral therapy; Cancer; Coronavirus disease SARS-CoV-2 (COVID-19); Drug-interactions; Management.

Copyright © 2020 Elsevier B.V. All rights reserved.

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25
Radiother Oncol
. 2020 Jun 13;S0167-8140(20)30336-4. doi: 10.1016/j.radonc.2020.06.013. Online ahead of print.
The Utility of Multiparametric MRI to Characterize Hypoxic Tumor Subvolumes in Comparison to FMISO PET/CT. Consequences for Diagnosis and Chemoradiation Treatment Planning in Head and Neck Cancer
Nicole Wiedenmann 1, Anca-Ligia Grosu 1, Martin Büchert 2, Hans C Rischke 3, Juri Ruf 4, Lars Bielak 2, Liette Majerus 1, Alexander Rühle 1, Fabian Bamberg 5, Dimos Baltas 1, Jürgen Hennig 5, Michael Mix 4, Michael Bock 5, Nils H Nicolay 6
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PMID: 32544609 DOI: 10.1016/j.radonc.2020.06.013
Abstract
Background and purpose: Hypoxia is an essential metabolic marker that determines chemo- and radiation resistance in head-and-neck squamous cell carcinoma (HNSCC) patients. Our exploratory analysis aimed to identify multiparametric MRI (mpMRI) parameters linked to hypoxia that might be used as surrogate for [18F]FMISO-PET in diagnosis and chemoradiation treatment (CRT) of HNSCC.

Materials and methods: 21 patients undergoing definitive CRT for HNSCC were prospectively imaged with serial [18F]FMISO-PET and 3 Tesla mpMRI for T1- and T2-weighted and dynamic contrast-enhanced perfusion and diffusion-weighted measurements (ktrans, ve, kep, ADC) in weeks 0, 2 and 5 and FDG-PET in week 0. [18F]FMISO-PET-derived hypoxic subvolumes (HSV) and complementary non-hypoxic subvolumes (nonHSV) were created for tumor and lymph nodes and projected on the mpMRI images after PET/MRI image co-registration. mpMRI and [18F]FMISO-PET parameters within HSVs and nonHSVs were statistically compared.

Results: FMISO-PET-based HSVs of the primary tumors on MRI were characterized by lower ADC at all time points (p=0.012 at baseline; p=0.015 in week 2) and reduced interstitial space volume fraction ve and perfusion ktrans at baseline (p=0.006, p=0.047) compared to nonHSVs. Hypoxic lymph nodes were characterized by significantly lower ADC values at baseline (p=0.039), but not at later time points and a reduction in ktrans-based perfusion at week 2 (p=0.018).

Conclusion: MpMRI parameters differ significantly between hypoxic and non-hypoxic tumor regions, defined on FMISO-PET/CT as gold standard and might represent surrogate markers for hypoxia. These findings suggest that mpMRI may be useful in the future as a surrogate modality for hypoxia imaging in order to personalize CRT.

Keywords: Chemoradiation; FMISO; Head-and-neck cancer; Hypoxia; Multiparametric MRI.

Copyright © 2020. Published by Elsevier B.V.

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26
Review Curr Hematol Malig Rep
. 2020 Jun 15. doi: 10.1007/s11899-020-00580-7. Online ahead of print.
Frontline Therapy of Chronic Lymphocytic Leukemia: Changing Treatment Paradigm
Manju Sengar 1, Hasmukh Jain 2, Akhil Rajendra 3, Karthik Rengaraj 3, Jayashree Thorat 2
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PMID: 32542586 DOI: 10.1007/s11899-020-00580-7
Abstract
Purpose of review: The treatment landscape of treatment-naive chronic lymphocytic leukemia (TN-CLL) is rapidly evolving. As more and more new drugs and combinations are becoming part of therapeutic armamentarium, it becomes highly pertinent to understand the evidence for each of the treatment options to select the right drug for the right patient. We summarize the recent data of the available frontline treatment options.

Recent findings: The novel agents can overcome adverse biological attributes and provide long-term disease control. MRD may become a reliable surrogate for survival in the evaluation of future therapies. FCR still remains one of the best options in a young fit CLL with mutated IGVH. Long-term follow-up data of ibrutinib confirm its efficacy and safety in both high-risk and elderly TN-CLL patients. A combination of venetoclax with obinutuzumab has provided the hope of fixed-duration therapy and the potential for functional cure in TN-CLL. Several other trials testing the efficacy of other targeted agents and the optimal sequencing approaches are underway. Chemoimmunotherapy holds its ground as an effective treatment in the IGVH-mutated CLL. The targeted agents either singly or in combination have become standard of care in many subsets of TN-CLL.

Keywords: CLL; Chemoimmunotherapy; Ibrutinib; Targeted therapy; Venetoclax.

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27
Plast Reconstr Surg Glob Open
. 2020 Mar 25;8(3):e2700. doi: 10.1097/GOX.0000000000002700. eCollection 2020 Mar.
Pectoral Fascia Preservation in Oncological Mastectomy to Reduce Complications and Improve Reconstructions: A Systematic Review
Jaco Suijker 1, Yara L Blok 1, Ralph de Vries 2, Monique P van den Tol 3, Nicole M A Krekel 4
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PMID: 32537356 PMCID: PMC7253268 DOI: 10.1097/GOX.0000000000002700
Free PMC article
Abstract
Excision of the pectoral fascia (PF) is routinely performed in oncological mastectomies. Preservation of the PF may, however, decrease postoperative complication rates for bleeding, infections, and seroma. It may also improve reconstructive outcomes by better prosthesis coverage, thereby reducing implant extrusion rates and improving cosmetic outcomes.

Methods: A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis principles was performed. Studies describing PF preservation were searched in 3 databases. All studies including more than 10 patients were included. The main outcomes were oncological safety (local recurrence, regional and distant metastases, and mortality rates), complication rates (bleeding, infections, seroma), loss of the prosthesis after reconstructive surgery, and cosmetic outcomes following reconstruction.

Results: Five studies were included. Three reported on 2 different randomized controlled trials (n = 73, and n = 244), and 2 studies were retrospective case series (n = 203 and n = 256). PF preservation did not affect oncological outcomes in terms of local recurrences, regional and distant metastases, or mortality rates. One study described a significantly lower incidence of seroma in the PF preservation group. No differences were found for bleeding complications and infections. No objective data were provided for reconstructive complications or cosmetic outcomes.

Conclusions: The literature on PF preservation is scarce. Based on the current evidence, PF preservation seems oncologically safe while potentially reducing postoperative complication rates. It is expected that reconstructive outcomes will benefit from PF preservation, but these studies lack evidence on this topic. Future studies should provide insight into all aspects of PF preservation.

Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.

Conflict of interest statement
Disclaimer: The authors have no financial interest to declare in relation to the content of this article.

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28
Eur Urol Oncol
. 2020 Jun 11;S2588-9311(20)30058-4. doi: 10.1016/j.euo.2020.05.004. Online ahead of print.
Metastasis-directed Therapy Prolongs Efficacy of Systemic Therapy and Improves Clinical Outcomes in Oligoprogressive Castration-resistant Prostate Cancer
Matthew P Deek 1, Kekoa Taparra 2, Ryan Phillips 1, Pedro Isaacsson Velho 3, Robert W Gao 2, Curtiland Deville 1, Daniel Y Song 1, Stephen Greco 1, Michael Carducci 3, Mario Eisenberger 3, Theodore L DeWeese 1, Samuel Denmeade 3, Kenneth Pienta 3, Channing J Paller 3, Emmanuel S Antonarakis 3, Kenneth R Olivier 2, Sean S Park 2, Phuoc T Tran 4, Bradley J Stish 5
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PMID: 32536574 DOI: 10.1016/j.euo.2020.05.004
Abstract
Background: Available therapies for castrate-resistant prostate cancer (CRPC) confer minimal survival advantage; thus, there is interest in metastasis-directed therapy (MDT) for oligometastatic or oligoprogressive disease to improve outcomes. Here, we describe outcomes of oligoprogressive CRPC treated with stereotactic ablative radiotherapy (SABR).

Objective: To report outcomes of oligoprogressive CRPC treated with MDT using SABR.

Design, setting, and participants: Patients with oligoprogressive CRPC were retrospectively evaluated, and outcomes following MDT were reported. Outcomes were additionally compared with oligoprogressive CRPC treated with change in systemic therapy alone.

Intervention: SABR to oligoprogressive lesions.

Outcome measurements and statistical analysis: Outcomes of interest were time to prostate-specific antigen (PSA) failure, time to next intervention (TTNI), distant metastasis-free survival (DMFS), and overall survival. Survival analysis was performed using the Kaplan-Meier method, and univariable analysis and multivariable analysis (MVA) were performed.

Results and limitations: A total of 68 patients were included. After MDT, median time to PSA recurrence, TTNI, and DMFS were 9.7, 15.6, and 10.8 months, respectively. A total of 112 lesions were treated, and the cumulative incidences of local failure at 12 and 24 months were 2.1% and 13.8%, respectively. Factors associated with the risk of local recurrence on univariable analysis were age (hazard ratio [HR] 1.07, p = 0.03) and Gleason grade group (HR 2.20, p = 0.07). Compared with change in systemic therapy alone (n = 52), MDT (n = 31) was associated with improved median time to PSA failure (9.7 vs 4.2 months, p = 0.066)), TTNI (14.9 vs 8.8 months, p = 0.025), and DMFS (12.7 vs 8.9 months, p = 0.045), and remained associated with improved outcomes on MVA.

Conclusions: In a retrospective cohort of oligoprogressive CRPC patients, MDT was associated with favorable outcomes and improved cancer control as compared with change in systemic treatment alone. Future prospective trials are needed to confirm these findings.

Patient summary: In this report, we retrospectively analyzed outcomes of patients with oligoprogressive castrate-resistant prostate cancer treated with radiation therapy to progressing lesions. Our results suggest that treatment of these lesions with radiation therapy can result in sustained periods of disease-free survival and might add benefit in addition to systemic therapy at the time of progression. These results need to be verified in a prospective trial to identify the optimal integration of radiation therapy into metastatic castrate-resistant prostate cancer.

Keywords: Castrate-resistant prostate cancer; Metastasis-directed therapy; Oligoprogressive.

Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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29
Review Semin Cancer Biol
. 2020 Jun 13;S1044-579X(20)30140-1. doi: 10.1016/j.semcancer.2020.06.005. Online ahead of print.
Pathology of Triple Negative Breast Cancer
Filippo Borri 1, Annarita Granaglia 2
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PMID: 32544511 DOI: 10.1016/j.semcancer.2020.06.005
Abstract
Triple negative breast cancer (TNBC) is a subtype of breast tumor lacking hormone receptors expression and HER2 gene amplification and represents 24% of newly diagnosed breast neoplasms. In this review, pathological aspects of triple-negative breast cancer are illustrated, with particular attention to the seminal studies that defined this subtype of breast cancer by a molecular point of view. This paper also focuses on practical issues raised in clinical routine by the introduction of genetic expression breast cancer profiling and the innovative prognostic and predictive impact on triple-negative breast cancer pathology. Moreover, histopathological aspects of triple-negative neoplasms are also mentioned, underlying the importance of histologic diagnosis of particular cancer subtypes with decisive impact on clinical outcome. Importantly, focus on new therapeutic frontier represented by immunotherapy is illustrated, with particular mention of immune checkpoint inhibitors introduction in TNBC therapy and their impact on future treatments.

Keywords: basal-like; breast cancer; intrinsic; molecular; pathology; triple negative.

Copyright © 2020. Published by Elsevier Ltd.

Conflict of interest statement
Declaration of Competing Interest The authors declare they have no conflicts of interest.

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30
Pediatr Res
. 2020 Jun 16. doi: 10.1038/s41390-020-1008-1. Online ahead of print.
Intrathecal Chemotherapy-Associated Cerebral Vasospasm in Children With Hematologic Malignancies
Lisa R Sun 1 2, Wendy Ziai 3, Patrick Brown 4, Adriana Gonzalez Torriente 5, Stacy Cooper 4, Rebecca F Gottesman 6, Ryan J Felling 7 6
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PMID: 32544924 DOI: 10.1038/s41390-020-1008-1
Abstract
Background: Mechanisms of chemotherapy-associated neurotoxicity are poorly understood, and therefore, prevention strategies have not been developed. We hypothesized that a subgroup of children receiving intrathecal cytarabine develop subclinical vasospasm, which may contribute to long-term neurocognitive sequelae of cancer.

Methods: We used transcranial Doppler ultrasound to serially evaluate cerebral blood flow velocities in participants ≤25 years old receiving intrathecal cytarabine for hematologic malignancies.

Results: Four of 18 participants (22%) met the criteria for subclinical vasospasm within 4 days of intrathecal cytarabine administration. The distribution of oncologic diagnoses differed between the vasospasm and non-vasospasm groups (p = 0.02). Acute myeloid leukemia was identified as a potential risk factor for vasospasm. Children with vasospasm were more likely to have received intravenous cytarabine (75% versus 0%, p = 0.01) and less likely to have received steroids (25% versus 100%, p = 0.01).

Conclusions: A subpopulation of children with hematologic malignancies develop subclinical vasospasm after intrathecal cytarabine treatment. Future research is needed to determine the long-term clinical consequences of cerebral vasospasm in this population.

Impact: A subset of children with hematologic malignancies who receive intrathecal cytarabine experience subclinical cerebral vasospasm, as measured by transcranial Doppler ultrasound.Of children receiving intrathecal cytarabine, those who develop cerebral vasospasm are more likely to have diagnosis of acute myeloid leukemia, more likely to receive concurrent intravenous cytarabine, and less likely to receive steroids as part of their chemotherapy regimen, as compared with children without vasospasm.Future research is needed to determine if vasospasm during chemotherapy is associated with higher rates of neurocognitive dysfunction, and if so, to focus on prevention of these long-term sequelae of childhood cancer.

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31
Meta-Analysis BMC Palliat Care
. 2020 Jan 9;19(1):6. doi: 10.1186/s12904-019-0506-6.
Are the MORECare Guidelines on Reporting of Attrition in Palliative Care Research Populations Appropriate? A Systematic Review and Meta-Analysis of Randomised Controlled Trials
Anna Oriani 1, Lesley Dunleavy 2, Paul Sharples 3, Guillermo Perez Algorta 4, Nancy J Preston 2
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PMID: 31918702 PMCID: PMC6953282 DOI: 10.1186/s12904-019-0506-6
Free PMC article
Abstract
Background: Palliative care trials have higher rates of attrition. The MORECare guidance recommends applying classifications of attrition to report attrition to help interpret trial results. The guidance separates attrition into three categories: attrition due to death, illness or at random. The aim of our study is to apply the MORECare classifications on reported attrition rates in trials.

Methods: A systematic review was conducted and attrition classifications retrospectively applied. Four databases, EMBASE; Medline, CINHAL and PsychINFO, were searched for randomised controlled trials of palliative care populations from 01.01.2010 to 08.10.2016. This systematic review is part of a larger review looking at recruitment to randomised controlled trials in palliative care, from January 1990 to early October 2016. We ran random-effect models with and without moderators and descriptive statistics to calculate rates of missing data.

Results: One hundred nineteen trials showed a total attrition of 29% (95% CI 28 to 30%). We applied the MORECare classifications of attrition to the 91 papers that contained sufficient information. The main reason for attrition was attrition due to death with a weighted mean of 31.6% (SD 27.4) of attrition cases. Attrition due to illness was cited as the reason for 17.6% (SD 24.5) of participants. In 50.8% (SD 26.5) of cases, the attrition was at random. We did not observe significant differences in missing data between total attrition in non-cancer patients (26%; 95% CI 18-34%) and cancer patients (24%; 95% CI 20-29%). There was significantly more missing data in outpatients (29%; 95% CI 22-36%) than inpatients (16%; 95% CI 10-23%). We noted increased attrition in trials with longer durations.

Conclusion: Reporting the cause of attrition is useful in helping to understand trial results. Prospective reporting using the MORECare classifications should improve our understanding of future trials.

Keywords: MORECare guidelines; Randomised controlled trials; attrition; missing data; palliative care; systematic review.

Conflict of interest statement
Nancy Preston is a member of the editorial board (Associate Editor) of BMC Palliative Care. She had no role in the editorial process of this article.

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32
Scand J Urol
. 2020 Jun 13;1-7. doi: 10.1080/21681805.2020.1777195. Online ahead of print.
Delayed Blood Transfusion Is Associated With Mortality Following Radical Cystectomy
Wei Shen Tan 1 2 3, Ye Wang 1, Quoc-Dien Trinh 1 4, Mark A Preston 1 4, John D Kelly 2, David Hrouda 5, Adam S Kibel 1 4, Ross E Krasnow 6, Jen-Jane Liu 7, Benjamin I Chung 8, Steven L Chang 1 4, Matthew Mossanen 1 4
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PMID: 32538224 DOI: 10.1080/21681805.2020.1777195
Abstract
Objectives: To examine the temporal association between blood transfusion and 90-day mortality in patients with bladder cancer treated with radical cystectomy.Methods: This represents a retrospective cohort study of patients treated with radical cystectomy within the Premier Hospital network between 2003 and 2015. Patients outcomes were stratified those who received early blood transfusion (day of surgery) vs delayed blood transfusion (postoperative day ≥1) during the index admission. Primary end point was 90-day mortality following surgery.Results: The median age of 12,056 patients identified was 70 years. A total of 7,201 (59.7%) patients received blood transfusion. Within 90 days following surgery, 57 (2.2%), 162 (5.9%) and 123 (6.7%) patients in the early, delayed and both early and delayed transfused patients died respectively. Following multivariate logistic regression to account for patient (age and Charlson Comorbidity Index [CCI]) and hospital (surgeon volume, surgical approach and academic status) factors, delayed blood transfusion was independently associated with 90-day mortality (Odds ratio [OR], 2.64; 95% Confidence Interval [CI], 1.98-3.53; p < 0.001). A sensitivity analysis defining early blood transfusion as <2 days postoperatively, increased 90-day mortality persisted in patients receiving delayed transfusion (OR, 2.20; 95% CI, 1.63-3.00; p < 0.001). Older patients (≥77 years) with the highest CCI (≥2) had a 7% absolute increase in the predicted probability of 90-day mortality if they were transfused late compared to patients transfused early.Conclusion: Patient undergoing cystectomy may benefit from expedited transfusion to prevent subsequent clinical deterioration which may lead to patient mortality. Future work is needed to elucidate the optimal timing of blood transfusion.

Keywords: Blood transfusion; bladder cancer; mortality; radical cystectomy; timing.

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33
Curr Opin Oncol
. 2020 Jul;32(4):295-300. doi: 10.1097/CCO.0000000000000652.
Novel Therapeutic Options for Alveolar Soft Part Sarcoma: Antiangiogenic Therapy, Immunotherapy and Beyond
Mehdi Brahmi 1 2, Hélène Vanacker 1, Armelle Dufresne 1
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PMID: 32541316 DOI: 10.1097/CCO.0000000000000652
Abstract
Purpose of review: Alveolar soft part sarcoma (ASPS) represent 0.5% of sarcomas, defining a rarest among rare malignancies. It affects young adults, displaying slow-growing mass of the thigh, head and neck, and trunk. Although quite indolent, a majority of cases displays an advanced disease with lung bone or central nervous system metastasis. Complete surgery is the cornerstone of localized ASPS, and advanced diseases poorly respond to chemotherapy. Here discuss recent progress in molecular characterization of ASPS and future prospects of therapeutic approaches.

Recent findings: ASPS is characterized by a specific oncogenic translocation ASPSCR1-TFE3 that induce hepatocyte growth factor receptor (MET) overexpression, angiogenesis, and immunosuppression in the tumor microenvironment. These specific biological features have encouraged the successful exploration of MET inhibitors, antiangiogenic drugs, and immunotherapy. We reviewed the main tracks of ASPS biology and recent insights from targeted therapies is ASPS mainly driven tyrosine kinase inhibitors (especially antiangiogenics), immune-checkpoint inhibitors, and their combinations.

Summary: Overall, antiangiogenics and anti Programmed cell death 1/Programmed cell death ligand 1 therapies showed a significant activity in ASPS that warrants additional investigation through randomized trials to validate those results and through ancillary biological studies to better understand resistance mechanisms and biomarkers of response.

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34
Expert Opin Pharmacother
. 2020 Jun 16;1-10. doi: 10.1080/14656566.2020.1770726. Online ahead of print.
An Evaluation of Apalutamide for the Treatment of Prostate Cancer
Myrto Boukovala 1, Nicholas Spetsieris 1, Eleni Efstathiou 1
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PMID: 32543237 DOI: 10.1080/14656566.2020.1770726
Abstract
Introduction: Novel androgen signaling inhibitors are currently standard of care in the treatment of patients with prostate cancer. Second-generation androgen receptor antagonists have demonstrated efficacy in earlier disease settings, fulfilling an unmet need in the treatment of patients with advanced prostate cancer.

Areas covered: The present article focuses on the development and establishment of apalutamide among the available treatment options for prostate cancer. A literature search was performed in Pubmed/Medline for past studies and reviews of the drug. Ongoing clinical trials were also examined in the Clinicaltrials.gov online database.

Expert opinion: Apalutamide has demonstrated benefit for patients with non-metastatic castration resistant and metastatic hormone naive prostate cancer. It is an efficacious, tolerable, and convenient oral agent, thus a valuable addition in the armamentarium of prostate cancer therapeutics for both non-metastatic castrate resistant and metastatic hormone naïve prostate cancer. Ongoing trials are investigating the drug as monotherapy and in combinations in other disease settings. Results are expected to further expand the drug's indications and shape the future landscape of prostate cancer therapy.

Keywords: Androgen receptor antagonist; androgen signaling inhibitor; apalutamide; prostate cancer treatment; second generation antiandrogen.

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35
Int J Adolesc Med Health
. 2020 Jun 10;/j/ijamh.ahead-of-print/ijamh-2019-0253/ijamh-2019-0253.xml. doi: 10.1515/ijamh-2019-0253. Online ahead of print.
Experiences of Involvement Processes During Participation in Cancer Service User Initiatives From an Adolescent and Young Adult Perspective
Signe Hanghøj 1, Helle Pappot 2, Lisa Lyngsie Hjalgrim 3, Maiken Hjerming 4, Camilla Louise Visler 5, Kirsten A Boisen 6
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PMID: 32543451 DOI: 10.1515/ijamh-2019-0253
Abstract
Background Service user participation contributes to the improvement of health care services for the betterment of conditions experienced by patients. However, there is a lack of knowledge about how adolescents and young adults (AYAs) experience involvement processes in practice and what it would take to achieve a high degree of involvement according to AYAs. Objectives To explore: (1) how AYAs with cancer experienced involvement processes during participation in three different service user involvement initiatives (development of an app, development of a book and youth panel meetings), and (2) AYAs' perceptions of determination and collaborative areas between AYAs and professionals. Methods Individual semi-structured interviews were conducted with 12 AYAs with cancer aged 16-29 who had participated in at least one of the service user initiatives in Kræftværket, a youth cancer support centre and social organisation located at Copenhagen University Hospital, Denmark. We analysed data with thematic analysis. Results We identified three main themes with matching sub-themes: Working procedures (Agenda setting, Workflow, Dialogue), Knowledge sharing (AYAs' needs and ideas, Areas of expertise), Influence (Decisions, Ownership). Generally, the participants experienced an equal dialogue with professionals and felt they had the final say on decisions. Conclusions This study produced specific suggestions on how to involve AYAs to a high extent. Based on AYAs' own perceptions of involvement, AYAs', professionals' and shared determination areas were illuminated. Additionally, the AYAs highlighted how the professionals gave feedback during co-creation processes, which may inspire future service user involvement projects.

Keywords: AYA; cancer; co-creation; participation; service user involvement.

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36
JCO Oncol Pract
. 2020 Jun 15;JOP1900605. doi: 10.1200/JOP.19.00605. Online ahead of print.
Time-Driven Activity-Based Costing Comparison of CT-Guided Versus MR-Guided SBRT
Neil R Parikh 1, Percy P Lee 1, Steven S Raman 2, Minsong Cao 1, James Lamb 1, Marguerite Tyran 1 3, Walter Chin 1, Travis Gilchrist 1, Nzhde Agazaryan 1, Kathryn Mittauer 4, Michael L Steinberg 1, Ann C Raldow 1
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PMID: 32539652 DOI: 10.1200/JOP.19.00605
Abstract
Purpose: Magnetic resonance-guided radiation therapy (MRgRT) has recently become commercially available, offering the opportunity to accurately image and target moving tumors as compared with computed tomography-guided radiation therapy (CTgRT) systems. However, the costs of delivering care with these 2 modalities remain poorly described. With localized unresectable hepatocellular carcinoma as an example, we were able to use time-driven activity-based costing to determine the cost of treatment on linear accelerators with CTgRT compared with MRgRT.

Materials and methods: Process maps, informed via interviews with departmental personnel, were created for each phase of the care cycle. Stereotactic body radiation therapy was delivered at 50 Gy in 5 fractions, either with CTgRT using fiducial placement, deep inspiration breath-hold (DIBH) with real-time position management, and volumetric-modulated arc therapy, or with MRgRT using real-time tumor gating, DIBH, and static-gantry intensity-modulated radiation therapy.

Results: Direct clinical costs were $7,306 for CTgRT and $8,622 for MRgRT comprising personnel costs ($3,752 v $3,603), space and equipment costs ($2,912 v $4,769), and materials costs ($642 v $250). Increased MRgRT costs may be mitigated by forgoing CT simulation ($322 saved) or shortening treatment to 3 fractions ($1,815 saved). Conversely, adaptive treatment with MRgRT would result in an increase in cost of $529 per adaptive treatment.

Conclusion: MRgRT offers real-time image guidance, avoidance of fiducial placement, and ability to use adaptive treatments; however, it is 18% more expensive than CTgRT under baseline assumptions. Future studies that elucidate the magnitude of potential clinical benefits of MRgRT are warranted to clarify the value of using this technology.

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37
Case Reports Acta Haematol
. 2020 Jun 15;1-11. doi: 10.1159/000505715. Online ahead of print.
Comprehensive Genomic Analysis of Noonan Syndrome and Acute Myeloid Leukemia in Adults: A Review and Future Directions
Muhned S Alhumaid 1 2, Majed J Dasouki 3 4, Syed O Ahmed 1, Halah AbalKhail 5, Samya Hagos 3, Salma Wakil 3, Shahrukh K Hashmi 6 7
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PMID: 32541138 DOI: 10.1159/000505715
Abstract
Acute myeloid leukemia (AML) in the setting of Noonan syndrome (NS) has been reported before without clear guidelines for treatment or prognosis in these subgroups of patients, most likely due to its rarity and incomplete understanding of the pathogenesis of both diseases. In the current era of next-generation sequencing-based genomic analysis, we can better identify patients with NS with more accurate AML-related prognostic markers. Germline mutations in PTPN11 are the most common cause of NS. Somatic mutations in NPM1 occur frequently in AML. Here, we describe a young adult patient with a novel combined germline PTPN11 and somatic NPM1, IDH1,and BCL6 mutations who presented with fatal AML. In addition, a 50.5-Mb interstitial deletion of 7q21.11-q33 in tumor DNA was detected by chromosomal microarray analysis. While mutations in the transcriptional repressor BCL6 are known to contribute to the pathogenesis of diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), its novel identification in this patient suggests an expanded role in aggressive AML. The identification of key molecular aberrations including the overexpression of SHP2, which drives leukemogenesis and tumorigenesis, has led to the development of novel investigational targeted SHP2 inhibitors.

Keywords: Acute myeloid leukemia; B cell lymphoma/leukemia 6; Leukemogenesis; Noonan syndrome; SNP microarray; Whole-exome sequencing.

© 2020 S. Karger AG, Basel.

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38
Vox Sang
. 2020 Jun 15. doi: 10.1111/vox.12973. Online ahead of print.
Clinical Use of Convalescent Plasma in the COVID-19 Pandemic; A Transfusion-Focussed Gap Analysis With Recommendations for Future Research Priorities
Arwa Z Al-Riyami 1, Richard Schäfer 2, Karin van der Berg 3 4, Evan M Bloch 5, Lise J Escourt 6, Ruchika Goel 7 8, Salwa Hindawi 9, Cassandra D Josephson 10 11, Kevin Land 12 13, Zoe K McQuilten 14 15, Steven L Spitalnik 16, Erica M Wood 14 15, Dana V Devine 17 18, Cynthia So-Osman 19 20, ISBT Convalescent Plasma Working Group
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PMID: 32542847 DOI: 10.1111/vox.12973
Abstract
Background and objectives: Use of convalescent plasma for Coronavirus disease 2019 (COVID-19) treatment has gained interest worldwide. However, there is lack of evidence on its dosing, safety and effectiveness. Until data from clinical studies are available to provide solid evidence for worldwide applicable guidelines, there is a need to provide guidance to the transfusion community and researchers on this emergent therapeutic option. This paper aims to identify existing key gaps in current knowledge in the clinical application of COVID-19 convalescent plasma (CCP).

Materials and methods: The International Society of Blood Transfusion (ISBT) initiated a multidisciplinary working group with worldwide representation from all six continents with the aim of reviewing existing practices on CCP use from donor, product and patient perspectives. A subgroup of clinical transfusion professionals was formed to draft a document for CCP clinical application to identify the gaps in knowledge in existing literature.

Results: Gaps in knowledge were identified in the following main domains: study design, patient eligibility, CCP dose, frequency and timing of CCP administration, parameters to assess response to CCP treatment and long-term outcome, adverse events, and CCP application in less resourced countries as well as in paediatrics and neonates.

Conclusion: This paper outlines a framework of gaps in the knowledge of clinical deployment of CPP that were identified as being most relevant. Studies to address the identified gaps are required to provide better evidence on the effectiveness and safety of CCP use.

Keywords: COVID-19; Convalescent plasma; SARS-CoV-2; gap analysis; patient outcome.

This article is protected by copyright. All rights reserved.

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39
Editorial Expert Rev Anticancer Ther
. 2020 Jun 16. doi: 10.1080/14737140.2020.1781621. Online ahead of print.
COVID-19: How Will This Impact Children With Cancer, Now and in the Future?
Gertjan J L Kaspers 1
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PMID: 32543935 DOI: 10.1080/14737140.2020.1781621
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40
Future Oncol
. 2020 Jun 15. doi: 10.2217/fon-2020-0215. Online ahead of print.
Targeting DNA Damage Response and Repair Genes to Enhance Anticancer Immunotherapy: Rationale and Clinical Implication
Giuseppe Lamberti 1, Elisa Andrini 1, Monia Sisi 1, Alessandro Di Federico 1, Biagio Ricciuti 2
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PMID: 32539551 DOI: 10.2217/fon-2020-0215
Abstract
DNA damage response and repair (DDR) genes play a central role in the life of actively replicating cells, cooperating to maintenance of genomic integrity. However, exogenous or endogenous factors, including deficiency in DDR genes, can cause different degrees of DNA damage that profoundly impacts the tumor immunogenicity and enhance antitumor immune response through neoantigen-dependent and neoantigen-independent mechanisms. Inhibition of DDRs is already an effective therapeutic strategy in different cancer types. In addition, because DDR inhibition can also induce and amplify DNA damage in cancer cells, with a deep impact on antitumor immune responses, combining DDR inhibitors with immune checkpoint inhibitors represent an attractive therapeutic strategy to potentially improve the clinical outcomes of patients with metastatic cancer. In this review, we provide an overview of the rational and potential of combining DDR and immune checkpoint inhibition to exploit the enhanced antitumor immune response induced by DNA damage.

Keywords: DNA damage and repair; PARP inhibitor; PD-L1; STING; immune checkpoint inhibitors; mutational burden.

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41
Pancreas
. 2020 Jun 12. doi: 10.1097/MPA.0000000000001563. Online ahead of print.
Nomogram for Estimating Overall Survival in Patients With Metastatic Pancreatic Cancer
David Goldstein 1 2, Daniel D Von Hoff 3 4, E Gabriela Chiorean 5, Michele Reni 6, Josep Tabernero 7 8, Ramesh K Ramanathan 9, Marc Botteman 10, Abdalla Aly 10, Sandra Margunato-Debay 11 12 13, Brian Lu 11 12 13, Chrystal U Louis 11 12 13, Desmond McGovern 11 12 13, Chee Khoon Lee 14
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PMID: 32541630 DOI: 10.1097/MPA.0000000000001563
Abstract
Objectives: This analysis investigated nomogram use to evaluate metastatic pancreatic cancer prognosis.

Methods: Thirty-four baseline factors were examined in the Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) (nab-paclitaxel plus gemcitabine vs gemcitabine) data set. Factors significantly (P < 0.1) associated with overall survival (OS) in a univariable model or with known clinical relevance were tested further. In a multivariable model, factors associated with OS (P < 0.1) were selected to generate the primary nomogram, which was internally validated using bootstrapping, a concordance index, and calibration plots.

Results: Using data from 861 patients, 6 factors were retained (multivariable analysis): neutrophil-lymphocyte ratio, albumin level, Karnofsky performance status, sum of longest diameter of target lesions, presence of liver metastases, and previous Whipple procedure. The nomogram distinguished low-, medium-, and high-risk groups (concordance index, 0.67; 95% confidence interval, 0.65-0.69; median OS, 11.7, 8.0, and 3.3 months, respectively).

Conclusions: This nomogram may guide estimates of the range of OS outcomes and contribute to patient stratification in future prospective metastatic pancreatic cancer trials; however, external validation is required to improve estimate reliability and applicability to a general patient population. Caution should be exercised in interpreting these results for treatment decisions: patient characteristics could differ from those included in the nomogram development.

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42
Future Oncol
. 2020 Jun 16. doi: 10.2217/fon-2020-0452. Online ahead of print.
Unscheduled Hydrations: Redefining Complete Response in Chemotherapy-Induced Nausea and Vomiting Studies
Rudolph M Navari 1, Eric J Roeland 2
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PMID: 32543309 DOI: 10.2217/fon-2020-0452
Abstract
Breakthrough chemotherapy-induced nausea and vomiting (CINV) is nausea and/or vomiting occurring within 5 days of chemotherapy administration despite using guideline-directed prophylactic antiemetic agents. It is highly prevalent (30-40%), usually requiring immediate treatment or "rescue" medication. If breakthrough CINV occurs, antiemetic guidelines recommend using an antiemetic agent from a different class not used in prophylaxis, along with intravenous hydration and/or dexamethasone. Data supporting these guideline recommendations are limited. Importantly, costs associated with breakthrough CINV can be substantial (i.e., unscheduled hydrations). Two retrospective analyses evaluating guideline-adherent CINV prophylaxis suggest that the initial antiemetic selection may decrease breakthrough CINV. Here we review optimal CINV prophylactic strategies and introduce unscheduled hydration as a potential important surrogate for breakthrough CINV aligning with cost-effective cancer care.

Keywords: CINV; HEC; breakthrough; granisetron injection extended-release; hydration.

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43
JMIR Pediatr Parent
. 2020 Jun 14. doi: 10.2196/20049. Online ahead of print.
Digital Approaches for Remote Pediatric Healthcare Delivery During the Coronavirus (Covid-19) Pandemic: Existing Evidence and A Call for Further Research
Sherif M Badawy 1 2, Ana Radovic 3
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PMID: 32540841 DOI: 10.2196/20049
Free article
Abstract
The global spread of the COVID-19 outbreak has posed a public health threat and has affected all of us in various unprecedented ways, personally and professionally. There is no question that the current global COVID-19 crisis, now more than ever, has underscored the importance of leveraging digital approaches to optimize pediatric healthcare delivery in the era of this pandemic. In this perspective piece, we highlight some of the available digital approaches that have been and can continue to be utilized to streamline remote pediatric patient care in the era of the COVID-19 pandemic including and beyond telemedicine alone. JMIR Pediatrics and Parenting (JPP) currently has a COVID-19 special theme issue for investigators to share their interim and final research data related to the digital approaches for remote pediatric healthcare delivery in different settings. The COVID-19 pandemic has rapidly transformed healthcare systems worldwide with significant variations and innovations in adaptation. There has been rapid expansion leveraging and optimizing digital approaches for health care delivery, particularly integrated telemedicine or virtual health. Digital approaches have and will play a major role as an invaluable and reliable resource to overcome restrictions and challenges implied during the COVID-19 pandemic and to increase access to effective, accessible, and consumer-friendly care to more patients and families. Nevertheless, a number of challenges remain, and further research is needed. Optimizing and integrating digital approaches for healthcare delivery into the public health response is an ongoing process, during the current COVID-19 outbreak and for other possible future pandemics. Regulatory changes are likely essential to support the safe and wide adoption of these approaches. Involving all relevant stakeholders in addressing current and future challenges as well as logistical, technological, and financial barriers will be key for success. Future studies should consider evaluating the following research areas related to telemedicine and other digital approaches: (1) cost-effectiveness return on investment (ROI); (2) impact on quality of care; (3) balance in utilization and number of visits needed for the management of both acute illness and chronic health conditions; (4) system readiness for further adoption in other settings, such as inpatient services, subspecialist consultations and in rural areas; (5) ongoing user-centered evaluations with feedback from patients, families and healthcare providers; (6) strategies to optimize health equity and address disparities in access to care related to race and ethnicity, socioeconomic status, immigration status, and for rural communities; (7) privacy and security concerns for protected health information with HIPAA-secured programs; (8) confidentiality issues for some specific populations, especially adolescents and those in need of mental health services; (9) early detection of violence exposure and child neglect; and finally (10) integration with training for undergraduate and graduate medical education and subspecialty fellowship. Addressing these research areas is essential to understanding the benefits, sustainability, safety and optimization strategies of telemedicine and other digital approaches as key parts of modern healthcare delivery. These efforts will inform long-term adoption of these approaches with expanded dissemination and implementation efforts.

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44
Curr Opin Oncol
. 2020 Jul;32(4):347-355. doi: 10.1097/CCO.0000000000000630.
Multimodality Treatment for Localized Gastric Cancer: State of the Art and New Insights
Angelica Petrillo 1 2, Elizabeth C Smyth 3
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PMID: 32541324 DOI: 10.1097/CCO.0000000000000630
Abstract
Purpose of review: Surgery represents the only curative approach for resectable gastric cancer. However, rates of recurrence remain high. This review summarizes the state of the art and future perspectives regarding perioperative, neoadjuvant and adjuvant chemotherapy for localized gastric cancer with insights regarding precision medicine.

Recent findings: Perioperative chemotherapy with FLOT has significantly improved outcomes for non-Asian patients with resectable gastric cancer, removing the role for anthracyclines. Preliminary results demonstrate that the perioperative approach is an option for Asian patients; however, long-term outcomes are awaited. For adjuvant treatment in Asian gastric cancer patients, S-1 as well as docetaxel may be a new treatment option. In this context, the right selection of patients is crucial. Among several biomarkers, microsatellite instability/mismatch repair deficiency has been linked with a lack of benefit from chemotherapy as well as better prognosis.

Summary: Multimodality treatment represents the standard of care for resectable gastric cancer. Perioperative chemotherapy with FLOT is the standard treatment in western countries; in patients who are not suitable for triplet, a platinum-fluoropyrimidine doublet can be considered. In Asian countries, adjuvant chemotherapy based on fluoropyrimidine monotherapy or in association with oxaliplatin/docetaxel are options. Validation of prognostic and predictive biomarkers is needed in order to improve patient selection.

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45
Review Therap Adv Gastroenterol
. 2020 Jun 1;13:1756284820917527. doi: 10.1177/1756284820917527. eCollection 2020.
Advances in Immunotherapy for Colorectal Cancer: A Review
Gol Golshani 1, Yue Zhang 2
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PMID: 32536977 PMCID: PMC7268115 DOI: 10.1177/1756284820917527
Free PMC article
Abstract
Immunotherapy is a new and exciting modality of cancer treatments. Its role in gastrointestinal malignancies has been promising, especially in advanced disease. Although various therapies are available for treatment of advanced colorectal cancer, survival rates for these patients remain very poor. The application of immunotherapy in colorectal cancer has shown remarkable results for a subset of patients with mismatch-repair-deficient mutations or microsatellite instability in their tumors. This literature review evaluates the current role of immunotherapy in advanced colorectal cancer, potential challenges clinicians face with immunotherapy-based regimens, and the possible future approach of combined modality immunotherapy.

Keywords: MSIH; PDL1; advanced colorectal cancer; dMMR; immunotherapy; mCRC; nivolumab; pembrolizumab.

© The Author(s), 2020.

Conflict of interest statement
Conflict of interest statement: The authors declare that there is no conflict of interest.

56 references
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46
Cancer Sci
. 2020 Jun 15. doi: 10.1111/cas.14528. Online ahead of print.
Risk Factors of Local Recurrence After Surgery in Extra-Abdominal Desmoid-Type Fibromatosis: A Multicenter Study in Japan
Yoshihiro Nishida 1 2, Shunsuke Hamada 3, Akira Kawai 4, Toshiyuki Kunisada 5, Akira Ogose 6, Yoshihiro Matsumoto 7, Keisuke Ae 8, Junya Toguchida 9, Toshifumi Ozaki 5, Akihiro Hirakawa 10, Toru Motoi 11, Tomohisa Sakai 2, Eisuke Kobayashi 4, Tabu Gokita 12, Takeshi Okamoto 9 13, Tomoya Matsunobu 14, Koki Shimizu 2 15, Hiroshi Koike 2
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PMID: 32539220 DOI: 10.1111/cas.14528
Free article
Abstract
This study was undertaken to clarify the risk factors, including the mutation status of CTNNB1, for the local recurrence after surgery of the rare disease, desmoid-type fibromatosis. It was designed as a multi-institutional joint research project with seven major centers in Japan participating. The committee members of seven major medical centers specializing in bone and soft tissue tumors formed this study group to develop clinical care guidelines. Of 196 cases with specimens and medical records collected from the 7 institutions, 88 surgically treated ones were analyzed regarding clinicopathological prognostic factors including CTNNB1 mutation status. Excluding R2 cases (n=3), 5-year local recurrence free survival (LRFS) was 52.9%. No case had received pre- or post-operative radiotherapy. Univariate analysis revealed that extremity location (P<0.001) and larger size (≧8cm, P=0.036) were significant adverse risk factors for LRFS. Multivariate analysis demonstrated that extremity location (P<0.001) was a significantly adverse factor in addition to recurrent tumor (P=0.041), S45F mutation (P=0.028), and R1 surgical margin (P=0.039). Pre-operative drug treatment including NSAIDs did not reduce the incidence of local recurrence (P=0.199). This is the first study to analyze the factors correlating with outcomes of surgical treatment including CTNNB1 mutation status in a relatively large number of cases from an Asian country. Tumor location was found to be the most influential prognostic factor for local recurrence, similar to the results from Western countries. The development of more sensitive method(s) for determination of CTNNB1 mutation is a priority for future study.

Keywords: CTNNB1; desmoid; local recurrence; prognostic factor; surgery.

This article is protected by copyright. All rights reserved.

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47
Editorial Future Oncol
. 2020 Jun 15. doi: 10.2217/fon-2020-0220. Online ahead of print.
Multimodal Approach: Combining Radiation Therapy With Immunotherapy in Solid Tumors
Angela Botticella 1, Antonin Levy 1 2 3, Cécile Le Pechoux 1
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PMID: 32539458 DOI: 10.2217/fon-2020-0220
Abstract
No abstract available
Keywords: SBRT; immunotherapy; radiotherapy.

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48
Editorial Future Oncol
. 2020 Jun 15. doi: 10.2217/fon-2020-0399. Online ahead of print.
Adipocyte-tumor Cell Native Encounter in Oral Squamous Cell Carcinoma
Sachin C Sarode 1, Gargi S Sarode 1, Namrata Sengupta 1, Nilesh Kumar Sharma 2, Shankargouda Patil 3
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PMID: 32539566 DOI: 10.2217/fon-2020-0399
Abstract
No abstract available
Keywords: carcinogenesis; lipid metabolism; oral cancer; stromal tumor interaction; tumor microenvironment.

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49
Editorial Future Oncol
. 2020 Jun 15. doi: 10.2217/fon-2020-0421. Online ahead of print.
Upcoming First-Line Chemotherapy for HER2-negative Gastric Cancer in Japan: Which Patients Benefit From Immunotherapy?
Daisuke Takahari 1, Keisho Chin 1, Kensei Yamaguchi 1
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PMID: 32539457 DOI: 10.2217/fon-2020-0421
Abstract
No abstract available
Keywords: SOL; TAS-118 plus oxaliplatin; first-line chemotherapy; gastric cancer; pembrolizumab monotherapy.

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