Future Oncology

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1
Guideline
Blood Adv




. 2019 Dec 10;3(23):3829-3866. doi: 10.1182/bloodadvances.2019000966.
American Society of Hematology 2019 guidelines for immune thrombocytopenia
Cindy Neunert 1, Deirdra R Terrell 2, Donald M Arnold 3 4, George Buchanan 5, Douglas B Cines 6, Nichola Cooper 7, Adam Cuker 8, Jenny M Despotovic 9, James N George 2, Rachael F Grace 10, Thomas Kühne 11, David J Kuter 12, Wendy Lim 13, Keith R McCrae 14, Barbara Pruitt 15, Hayley Shimanek 16, Sara K Vesely 2
Affiliations expand
PMID: 31794604
PMCID: PMC6963252
DOI: 10.1182/bloodadvances.2019000966Free PMC article

Erratum in
Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829-3866.
[No authors listed]Blood Adv. 2020 Jan 28;4(2):252. doi: 10.1182/bloodadvances.2019001380.PMID: 31945156 Free PMC article. No abstract available.

Abstract


Background: Despite an increase in the number of therapies available to treat patients with immune thrombocytopenia (ITP), there are minimal data from randomized trials to assist physicians with the management of patients.

Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about the management of ITP.

Methods: In 2015, ASH formed a multidisciplinary guideline panel that included 8 adult clinical experts, 5 pediatric clinical experts, 2 methodologists with expertise in ITP, and 2 patient representatives. The panel was balanced to minimize potential bias from conflicts of interest. The panel reviewed the ASH 2011 guideline recommendations and prioritized questions. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including evidence-to-decision frameworks, to appraise evidence (up to May 2017) and formulate recommendations.

Results: The panel agreed on 21 recommendations covering management of ITP in adults and children with newly diagnosed, persistent, and chronic disease refractory to first-line therapy who have non-life-threatening bleeding. Management approaches included: observation, corticosteroids, IV immunoglobulin, anti-D immunoglobulin, rituximab, splenectomy, and thrombopoietin receptor agonists.

Conclusions: There was a lack of evidence to support strong recommendations for various management approaches. In general, strategies that avoided medication side effects were favored. A large focus was placed on shared decision-making, especially with regard to second-line therapy. Future research should apply standard corticosteroid-dosing regimens, report patient-reported outcomes, and include cost-analysis evaluations.

© 2019 by The American Society of Hematology.

Conflict of interest statement


Conflict-of-interest disclosure: All authors were members of the guideline panel or members of the systematic review team or both. As such, they completed disclosure-of-interest forms, which were reviewed by ASH and are available as supplemental Files 2 and 3.

Cited by 20 articles
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2
Cell Rep




. 2019 Nov 19;29(8):2321-2337.e7. doi: 10.1016/j.celrep.2019.10.083.
Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas
Makoto Yamagishi 1, Makoto Hori 2, Dai Fujikawa 3, Takeo Ohsugi 4, Daisuke Honma 5, Nobuaki Adachi 6, Harutaka Katano 7, Tsunekazu Hishima 8, Seiichiro Kobayashi 9, Kazumi Nakano 2, Makoto Nakashima 2, Masako Iwanaga 10, Atae Utsunomiya 11, Yuetsu Tanaka 12, Seiji Okada 13, Kunihiro Tsukasaki 14, Kensei Tobinai 15, Kazushi Araki 16, Toshiki Watanabe 17, Kaoru Uchimaru 18
Affiliations expand
PMID: 31747604
DOI: 10.1016/j.celrep.2019.10.083Free article

Abstract


Although global H3K27me3 reprogramming is a hallmark of cancer, no effective therapeutic strategy for H3K27me3-high malignancies harboring EZH2WT/WT has yet been established. We explore epigenome and transcriptome in EZH2WT/WT and EZH2WT/Mu aggressive lymphomas and show that mutual interference and compensatory function of co-expressed EZH1 and EZH2 rearrange their own genome-wide distribution, thereby establishing restricted chromatin and gene expression signatures. Direct comparison of leading compounds introduces potency and a mechanism of action of the EZH1/2 dual inhibitor (valemetostat). The synthetic lethality is observed in all lymphoma models and primary adult T cell leukemia-lymphoma (ATL) cells. Opposing actions of EZH1/2-polycomb and SWI/SNF complexes are required for facultative heterochromatin formation. Inactivation of chromatin-associated genes (ARID1A, SMARCA4/BRG1, SMARCB1/SNF5, KDM6A/UTX, BAP1, KMT2D/MLL2) and oncovirus infection (HTLV-1, EBV) trigger EZH1/2 perturbation and H3K27me3 deposition. Our study provides the mechanism-based rationale for chemical dual targeting of EZH1/2 in cancer epigenome.

Keywords: EZH1; EZH2; H3K27me3; HTLV-1; adult T cell leukemia-lymphoma (ATL); epigenetic drug; malignant lymphoma; polycomb.

Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

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3
Guideline
Blood Adv




. 2019 Dec 10;3(23):3867-3897. doi: 10.1182/bloodadvances.2019000916.
American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease
Robert I Liem 1 2, Sophie Lanzkron 3, Thomas D Coates 4, Laura DeCastro 5, Ankit A Desai 6, Kenneth I Ataga 7, Robyn T Cohen 8, Johnson Haynes 9, Ifeyinwa Osunkwo 10, Jeffrey D Lebensburger 11, James P Lash 12, Theodore Wun 13, Madeleine Verhovsek 14, Elodie Ontala 15, Rae Blaylark 16, Fares Alahdab 17, Abdulrahman Katabi 17, Reem A Mustafa 18
Affiliations expand
PMID: 31794601
PMCID: PMC6963257
DOI: 10.1182/bloodadvances.2019000916Free PMC article

Abstract


Background: Prevention and management of end-organ disease represent major challenges facing providers of children and adults with sickle cell disease (SCD). Uncertainty and variability in the screening, diagnosis, and management of cardiopulmonary and renal complications in SCD lead to varying outcomes for affected individuals.

Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD.

Methods: ASH formed a multidisciplinary guideline panel that included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews up to September 2017. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment.

Results: The panel agreed on 10 recommendations for screening, diagnosis, and management of cardiopulmonary and renal complications of SCD. Recommendations related to anticoagulation duration for adults with SCD and venous thromboembolism were also developed.

Conclusions: Most recommendations were conditional due to a paucity of direct, high-quality evidence for outcomes of interest. Future research was identified, including the need for prospective studies to better understand the natural history of cardiopulmonary and renal disease, their relationship to patient-important outcomes, and optimal management.

© 2019 by The American Society of Hematology.

Conflict of interest statement


Conflict-of-interest disclosure: All authors were members of the guideline panel or members of the systematic review team or both. As such, they completed disclosure-of-interest forms, which were reviewed by ASH and are available as supplemental Files 2 and 3.

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4
Review
J Adolesc Health




. 2019 May;64(5):563-573. doi: 10.1016/j.jadohealth.2018.10.297. Epub 2019 Jan 14.
Development of a Pediatric Fertility Preservation Program: A Report From the Pediatric Initiative Network of the Oncofertility Consortium
Molly B Moravek 1, Leslie C Appiah 2, Antoinette Anazodo 3, Karen C Burns 4, Veronica Gomez-Lobo 5, Holly R Hoefgen 6, Olivia Jaworek Frias 7, Monica M Laronda 8, Jennifer Levine 9, Lillian R Meacham 10, Mary Ellen Pavone 11, Gwendolyn P Quinn 12, Erin E Rowell 13, Andrew C Strine 14, Teresa K Woodruff 15, Leena Nahata 16
Affiliations expand
PMID: 30655118
PMCID: PMC6478520
DOI: 10.1016/j.jadohealth.2018.10.297Free PMC article

Abstract


Infertility is known to decrease quality of life among adults. In some cases, infertility is caused by medical conditions and/or treatments prescribed in childhood, and using methods to protect or preserve fertility may expand future reproductive possibilities. Structured programs to offer counseling about infertility risk and fertility preservation options are essential in the care of pediatric patients facing fertility-threatening conditions or treatments, yet multiple barriers to program development exist. This report was developed from the institutional experiences of members of the Pediatric Initiative Network of the Oncofertility Consortium, with the intent of providing guidance for health care providers aiming to establish programs at institutions lacking pediatric fertility preservation services. The mechanics of building a fertility preservation program are discussed, including essential team members, target populations, fertility preservation options (both established and experimental), survivorship issues, research opportunities, and ethical considerations. Common barriers to program development and utilization, including low referral rates and financial concerns, are also discussed, and recommendations made for overcoming such barriers.

Keywords: Adolescent; Child; Fertility preservation; Program development; Tissue preservation.

Copyright © 2018 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Conflict of interest statement


Disclosures:

Dr. Pavone serves on the Ferring advisory board. All other authors have no conflicts of interest.

Comment in
Pediatric Fertility Counseling.
Tishelman AC.J Adolesc Health. 2019 May;64(5):547-548. doi: 10.1016/j.jadohealth.2019.02.004.PMID: 31010548 No abstract available.

Cited by 7 articles
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5
Viruses




. 2019 Oct 3;11(10):914. doi: 10.3390/v11100914.
Immunological Effects and Viral Gene Expression Determine the Efficacy of Oncolytic Measles Vaccines Encoding IL-12 or IL-15 Agonists
Paul S Backhaus 1 2 3, Rūta Veinalde 4 5, Laura Hartmann 6 7 8, Jessica E Dunder 9 10 11, Lara M Jeworowski 12, Jessica Albert 13 14 15, Birgit Hoyler 16 17 18, Tanja Poth 19, Dirk Jäger 20 21 22, Guy Ungerechts 23 24 25 26, Christine E Engeland 27 28 29
Affiliations expand
PMID: 31623390
PMCID: PMC6832518
DOI: 10.3390/v11100914Free PMC article

Abstract


Tumor-targeted immunomodulation using oncolytic viral vectors is currently being investigated as a promising strategy in cancer therapy. In a previous study, we showed that a measles virus Schwarz vaccine strain (MeVac) vector encoding an interleukin-12 fusion protein (FmIL-12) is an effective immunotherapy in the MC38cea murine colon adenocarcinoma model. We hypothesized that MeVac encoding interleukin-15 may mediate enhanced T and NK cell responses and thus increase the therapeutic efficacy, especially in NK cell-controlled tumors. Therefore, we generated MeVac vectors encoding an interleukin-15 superagonist, FmIL-15. Replication and oncolytic capacity, transgene expression, and functionality of MeVac FmIL-15 vectors were validated in vitro. Effects on the tumor immune landscape and therapeutic efficacy of both FmIL-12 and FmIL-15 vectors were studied in the MC38cea and B16hCD46 tumor models. Treatment with MeVac FmIL-15 increased T and NK cell infiltration in both models. However, MeVac FmIL-12 showed more robust viral gene expression and immune activation, resulting in superior anti-tumor efficacy. Based on these results, MeVac encoding a human IL-12 fusion protein was developed for future clinical translation.

Keywords: cancer immunotherapy; interleukin-12; interleukin-15; measles virus; oncolytic virus.

Conflict of interest statement


R.V., C.E.E. and G.U. are listed as inventors on patents regarding RNA viruses for cancer immunotherapy owned by Heidelberg University. G.U. serves as CMO and CSO for CanVirex, which is developing immune-modulating oncolytic viruses. All other authors declare no conflict of interest.

Cited by 5 articles
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6
Clin Cancer Res




. 2019 Jul 15;25(14):4271-4279. doi: 10.1158/1078-0432.CCR-18-3065. Epub 2019 Apr 11.
Prognostic Value of Deep Learning PET/CT-Based Radiomics: Potential Role for Future Individual Induction Chemotherapy in Advanced Nasopharyngeal Carcinoma
Hao Peng # 1, Di Dong # 2 3, Meng-Jie Fang # 2 3, Lu Li # 4 5, Ling-Long Tang 1, Lei Chen 1, Wen-Fei Li 1, Yan-Ping Mao 1, Wei Fan 5, Li-Zhi Liu 6, Li Tian 6, Ai-Hua Lin 7, Ying Sun 1, Jie Tian 8 9 10, Jun Ma 11
Affiliations expand
PMID: 30975664
DOI: 10.1158/1078-0432.CCR-18-3065Free article

Abstract


Purpose: We aimed to evaluate the value of deep learning on positron emission tomography with computed tomography (PET/CT)-based radiomics for individual induction chemotherapy (IC) in advanced nasopharyngeal carcinoma (NPC).

Experimental design: We constructed radiomics signatures and nomogram for predicting disease-free survival (DFS) based on the extracted features from PET and CT images in a training set (n = 470), and then validated it on a test set (n = 237). Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were applied to evaluate the discriminatory ability of radiomics nomogram, and compare radiomics signatures with plasma Epstein-Barr virus (EBV) DNA.

Results: A total of 18 features were selected to construct CT-based and PET-based signatures, which were significantly associated with DFS (P < 0.001). Using these signatures, we proposed a radiomics nomogram with a C-index of 0.754 [95% confidence interval (95% CI), 0.709-0.800] in the training set and 0.722 (95% CI, 0.652-0.792) in the test set. Consequently, 206 (29.1%) patients were stratified as high-risk group and the other 501 (70.9%) as low-risk group by the radiomics nomogram, and the corresponding 5-year DFS rates were 50.1% and 87.6%, respectively (P < 0.0001). High-risk patients could benefit from IC while the low-risk could not. Moreover, radiomics nomogram performed significantly better than the EBV DNA-based model (C-index: 0.754 vs. 0.675 in the training set and 0.722 vs. 0.671 in the test set) in risk stratification and guiding IC.

Conclusions: Deep learning PET/CT-based radiomics could serve as a reliable and powerful tool for prognosis prediction and may act as a potential indicator for individual IC in advanced NPC.

©2019 American Association for Cancer Research.

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7
Review
Int J Urol




. 2019 Dec;26(12):1099-1105. doi: 10.1111/iju.14090. Epub 2019 Aug 22.
Quality of life outcomes after low dose-rate brachytherapy for localized prostate cancer: Current status and future perspectives
Yasukiyo Murakami 1, Takefumi Satoh 1 2, Hideyasu Tsumura 1, Ken-Ichi Tabata 1, Kazumasa Matsumoto 1, Hiromichi Ishiyama 3, Masatsugu Iwamura 1
Affiliations expand
PMID: 31441133
DOI: 10.1111/iju.14090

Abstract


The present review summarizes data from studies reporting on health-related quality of life after brachytherapy and competing modalities. There are various therapeutic modalities for localized prostate cancer, including radical surgery, external beam radiotherapy and active surveillance. Advances in surgical and radiation treatment have entered clinical practice in the form of robot-assisted surgery or intensity-modulated radiotherapy. Brachytherapy remains the main treatment option for patients with localized prostate cancer, with 10-year survival data showing favorable outcomes. Because each treatment modality has achieved favorable survival outcomes, focus in determining appropriate treatment has shifted toward health-related quality of life, where each treatment has a different profile and/or adverse symptoms. The development of health-related quality of life assessment tools has allowed the creation of a pool of specific health-related quality of life data across many studies. The present article reviews the impact of brachytherapy and other modalities on quality of life, as well as future directions.

Keywords: brachytherapy; comparative effectiveness; patient reported outcome; prostatic neoplasms; quality of life.

© 2019 The Japanese Urological Association.

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8
Comparative Study
Cells




. 2019 Nov 22;8(12):1491. doi: 10.3390/cells8121491.
Mesenchymal Stem/Stromal Cells Derived from Dental Tissues: A Comparative In Vitro Evaluation of Their Immunoregulatory Properties Against T cells
María Del Pilar De la Rosa-Ruiz 1 2, Marco Antonio Álvarez-Pérez 3, Víctor Adrián Cortés-Morales 1, Alberto Monroy-García 4, Héctor Mayani 5, Gladis Fragoso-González 6, Sara Caballero-Chacón 7, Daniel Diaz 8, Fernando Candanedo-González 9, Juan José Montesinos 1
Affiliations expand
PMID: 31766697
PMCID: PMC6953107
DOI: 10.3390/cells8121491Free PMC article

Abstract


Bone marrow mesenchymal stem/stromal cells (BM-MSCs) have immunoregulatory properties and have been used as immune regulators for the treatment of graft-versus-host disease (GVHD). Human dental tissue mesenchymal stem cells (DT-MSCs) constitute an attractive alternative to BM-MSCs for potential clinical applications because of their accessibility and easy preparation. The aim of this in vitro study was to compare MSCs from dental pulp (DP-MSCs), gingival tissue (G-MSCs), and periodontal ligament (PDL-MSCs) in terms of their immunosuppressive properties against lymphoid cell populations enriched for CD3+ T cells to determine which MSCs would be the most appropriate for in vivo immunoregulatory applications. BM-MSCs were included as the gold standard. Our results demonstrated, in vitro, that MSCs from DP, G, and PDL showed immunoregulatory properties similar to those from BM, in terms of the cellular proliferation inhibition of both CD4+- and CD8+-activated T-cells. This reduced proliferation in cell co-cultures correlated with the production of interferon-γ and tumor necrosis factor alpha (TNF-α) and the upregulation of programmed death ligand 1 (PD-L1) in MSCs and cytotoxic T-cell-associated Ag-4 (CTLA-4) in T-cells and increased interleukin-10 and prostaglandin E2 production. Interestingly, we observed differences in the production of cytokines and surface and secreted molecules that may participate in T-cell immunosuppression in co-cultures in the presence of DT-MSCs compared with BM-MSCs. Importantly, MSCs from four sources favored the generation of T-cell subsets displaying the regulatory phenotypes CD4+CD25+Foxp3+ and CD4+CD25+CTLA-4+. Our results in vitro indicate that, in addition to BM-MSCs, MSCs from all of the dental sources analyzed in this study might be candidates for future therapeutic applications.

Keywords: T cells; dental pulp; gingival tissue; immunoregulation; mesenchymal stem/stromal cells; periodontal ligament.

Conflict of interest statement


The authors declare no conflict of interest.

Cited by 1 article
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9
Clin Cancer Res




. 2019 Jul 15;25(14):4413-4421. doi: 10.1158/1078-0432.CCR-19-0006. Epub 2019 Apr 16.
Multidrug Cancer Therapy in Metastatic Castrate-Resistant Prostate Cancer: An Evolution-Based Strategy
Jeffrey B West 1, Mina N Dinh 1 2, Joel S Brown 1, Jingsong Zhang 3, Alexander R Anderson 1, Robert A Gatenby 4
Affiliations expand
PMID: 30992299
PMCID: PMC6665681
DOI: 10.1158/1078-0432.CCR-19-0006Free PMC article

Abstract


Purpose: Integration of evolutionary dynamics into systemic therapy for metastatic cancers can prolong tumor control compared with standard maximum tolerated dose (MTD) strategies. Prior investigations have focused on monotherapy, but many clinical cancer treatments combine two or more drugs. Optimizing the evolutionary dynamics in multidrug therapy is challenging because of the complex cellular interactions and the large parameter space of potential variations in drugs, doses, and treatment schedules. However, multidrug therapy also represents an opportunity to further improve outcomes using evolution-based strategies.

Experimental design: We examine evolution-based strategies for two-drug therapy and identify an approach that divides the treatment drugs into primary and secondary roles. The primary drug has the greatest efficacy and/or lowest toxicity. The secondary drug is applied solely to reduce the resistant population to the primary drug.

Results: Simulations from the mathematical model demonstrate that the primary-secondary approach increases time to progression (TTP) compared with conventional strategies in which drugs are administered without regard to evolutionary dynamics. We apply our model to an ongoing adaptive therapy clinical trial of evolution-based administration of abiraterone to treat metastatic castrate-resistant prostate cancer. Model simulations, parameterized with data from individual patients who progressed, demonstrate that strategic application of docetaxel during abiraterone therapy would have significantly increased their TTP.

Conclusions: Mathematical models can integrate evolutionary dynamics into multidrug cancer clinical trials. This has the potential to improve outcomes and to develop clinical trials in which these mathematical models are also used to estimate the mechanism(s) of treatment failure and explore alternative strategies to improve outcomes in future trials.

©2019 American Association for Cancer Research.

Conflict of interest statement


Disclosure of Potential Conflicts of Interest

J. Zhang reports receiving speakers bureau honoraria from Sanofi. No potential conflicts of interest were disclosed by the other authors.

Comment in
An adaptive approach to therapy.
Stone L.Nat Rev Urol. 2019 Jul;16(7):388. doi: 10.1038/s41585-019-0197-z.PMID: 31110276 No abstract available.

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10
Case Reports
Cancer Genet




. 2020 Feb;241:51-56. doi: 10.1016/j.cancergen.2019.12.006. Epub 2019 Dec 25.
Rapid progressive lung cancers harbouring multiple clonal driver mutations with big bang evolution model
Kei Kunimasa 1, Yosuke Hirotsu 2, Harumi Nakamura 3, Motohiro Tamiya 4, Yuki Iijima 5, Hiroto Ishida 6, Yuichiro Hamamoto 3, Tomohiro Maniwa 7, Toru Kimura 7, Kazumi Nishino 4, Taichiro Goto 8, Kenji Amemiya 2, Hitoshi Mochizuki 2, Toshio Oyama 9, Shin-Ichi Nakatsuka 3, Toru Kumagai 4, Jiro Okami 7, Masahiko Higashiyama 7, Fumio Imamura 10, Masao Omata 11
Affiliations expand
PMID: 31917104
DOI: 10.1016/j.cancergen.2019.12.006

Abstract


Introduction: Next-generation sequencing (NGS) of multiple metastases in an advanced cancer patient reveals the evolutional history of the tumor. The evolutionary model is clinically valuable because it reflects the future course of the tumorigenic process and prognosis of the patient.

Materials and methods: We experienced two lung cancer patients whose clinical courses were abruptly deteriorating resulting in very poor prognosis. To investigate the evolutionary model of these patients, we performed targeted sequencing covering whole exons of 53 significantly mutated genes associated with lung cancer of multiple metastases by autopsy. We conducted PyClone analysis to infer subclonal archtecture of multi-lesional samples.

Results: The NGS analysis revealed both patients harboring multiple clonal driver mutations. In Case.1, KRAS Q61H, KEAP1 G333C, STK11 K312*, RBM10 Q320* and MGA I1429V and in Case.2, TP53 R337L, TP53 Q192*, PTEN W274C, RB1 P29fs and CREBBP P696L with high allele fraction were detected in all lesions. These mutations were clustered and occupied major population across multi-lesional tumor samples. Our data suggested their lung cancers progressed with punctuated and big bang evolutional model.

Conclusion: We should pay attention to clinical course of lung cancer patients harboring multiple clonal driver mutations in their primary lesions. Their punctuated and big bang evolutionary process could develop systemic clinically undetectable metastases with an unexpected speed.

Keywords: Cancer evolution model; Multiple clonal driver mutation; Next generation sequence.

Copyright © 2019. Published by Elsevier Inc.

Conflict of interest statement


Declaration of Competing Interest The authors have no conflicts of interest to disclose concerning the study.
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11
Review
ANZ J Surg




. 2019 Oct;89(10):1224-1229. doi: 10.1111/ans.15074. Epub 2019 Mar 28.
Clinical implications of the genetics of sporadic colorectal cancer
Jesse Fischer 1, Logan C Walker 2, Bridget A Robinson 3 4, Frank A Frizelle 1 5, James M Church 6, Tim W Eglinton 1 5
Affiliations expand
PMID: 30919552
DOI: 10.1111/ans.15074

Abstract


Colorectal cancer (CRC) is common and at least 80% of cases are sporadic, without any significant family history. Prognostication and treatment have been relatively empirical for what has become increasingly identified as a genetically heterogeneous disease. There are three main genetic pathways in sporadic CRC: the chromosomal instability pathway, the microsatellite instability pathway and the CpG island methylator phenotype pathway. There is significant overlap between these complex molecular pathways and this limits the clinical application of CRC genetics. Recent Australian and New Zealand guidelines recommend routine testing of mismatch repair (MMR) status for new cases of CRC and selective KRAS and BRAF testing on the basis of diagnostic, prognostic and therapeutic implications. It is important that all clinicians treating CRC have an understanding of the importance of and basis for identifying key genetic features of CRC. It is likely that in the future better molecular characterization such as that allowed by the consensus molecular subtype classification will allow improved prognostication and targeted therapy in order to deliver more personalized treatment for CRC.

Keywords: colorectal cancer; colorectal cancer guidelines; epigenetics; genetics; molecular testing.

© 2019 Royal Australasian College of Surgeons.

Cited by 3 articles
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12
Arch Iran Med




. 2019 Jun 1;22(6):279-285.
Tabari Cohort Profile and Preliminary Results in Urban Areas and Mountainous Regions of Mazandaran, Iran
Motahareh Kheradmand 1, Mahmood Moosazadeh 1, Majid Saeedi 2, Hossein Poustchi 3 4, Sareh Eghtesad 3 5, Ravanbakhsh Esmaeili 6, Reza Alizadeh-Navaei 7, Akbar Hedayatizadeh-Omran 7, Roja Nikaeein 8, Alireza Rafiei 9, Ghasem Janbabaee 7, Zahra Kashi 10, Mehrnoush Sohrab 10, Mahboobeh Shirzad AhooDashti 11, Mahdi Afshari 12, Bahareh Golpour 8, Mohsen Aarabi 13, Iradj Maleki 14, Hafez Tirgar Fakheri 14, Ali Ghaemian 15, Mehran Zarghami 16, Alireza Ghaemi 17
Affiliations expand
PMID: 31356093Free article

Abstract


Background: The Tabari cohort study (TCS), part of the Prospective Epidemiological Research Studies in IrAN (PERSIAN), is a large longitudinal prospective cohort designed to better understand the risk factors associated with major non-communicable diseases (NCDs) across two urban and mountainous regions in north of Iran.

Methods: The enrollment phase of TCS started in June 2015 and ended in November 2017. During this phase, individuals aged 35-70 years from urban and mountainous regions of Sari township (Mazandaran province) were invited to the cohort center by health volunteers (urban regions) and Behvarz (mountainous areas) using census information. Data was collected based on the PERSIAN cohort study protocols. Hypertension was defind as systolic blood pressure ≥140 mm Hg or a diastolic blood pressure ≥90 mm Hg or history of diagnosis with hypertension or taking antihypertensive medications among participants free from cardiovascular diseases. Diabetes was defined as fasting blood sugar ≥126 mg/dL or a history of diagnosis or taking glucoselowering medications among all participants.

Results: A total of 10,255 participants were enrolled in TCS, 59.5% of whom were female. Among the total population, 7,012 participants were urban residents (68.4%). The prevalence of daily smoking in the total population was 9.1%. Body mass index in 75.9% of participants was ≥25 kg/m2. The prevalence of hypertension, diabetes, and thyroid disorders were 22.2%, 17.2%, and 10.5%, respectively.

Conclusion: The Tabari cohort is different from other cohorts in terms of levels of risk factors associated with NCDs. This study has certain important strengths including its population-based design and large sample size that provides a valid platform for conducting future investigations and trials. A biobank that has been designed to store blood, nail, hair and urine samples for future research is another strength of this study. Researchers who are interested in using the information can refer to the following web page: http://persiancohort.com.

Keywords: Cancer; Cardiovascular; Cohort; Mazandaran; PERSIAN; Risk factor; Tabari cohort.

© 2019 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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13
Sci Rep




. 2019 Feb 21;9(1):2514. doi: 10.1038/s41598-019-38986-w.
Cardiac molecular pathways influenced by doxorubicin treatment in mice
Ben F Bulten 1 2, Martina Sollini 3 4, Roberto Boni 5 4, Katrin Massri 6 4, Lioe-Fee de Geus-Oei 7 8, Hanneke W M van Laarhoven 9, Riemer H J A Slart 7 10, Paola A Erba 4 10
Affiliations expand
PMID: 30792528
PMCID: PMC6385261
DOI: 10.1038/s41598-019-38986-wFree PMC article

Abstract


Doxorubicin (DOX) is a potent chemotherapeutic with distinct cardiotoxic properties. Understanding the underlying cardiotoxic mechanisms on a molecular level would enable the early detection of cardiotoxicity and implementation of prophylactic treatment. Our goal was to map the patterns of different radiopharmaceuticals as surrogate markers of specific metabolic pathways induced by chemotherapy. Therefore, cardiac distribution of 99mTc-sestamibi, 99mTc-Annexin V, 99mTc-glucaric acid and [18F]FDG and cardiac expression of Bcl-2, caspase-3 and -8, TUNEL, HIF-1α, and p53 were assessed in response to DOX exposure in mice. A total of 80 mice (64 treated, 16 controls) were evaluated. All radiopharmaceuticals showed significantly increased uptake compared to controls, with peak cardiac uptake after one (99mTc-Annexin V), two (99mTc-sestamibi), three ([18F]FDG), or four (99mTc-glucaric acid) cycles of DOX. Strong correlations (p < 0.01) were observed between 99mTc-Annexin V, caspase 3 and 8, and TUNEL, and between [18F]FDG and HIF-1α. This suggests that the cardiac DOX response starts with apoptosis at low exposure levels, as indicated by 99mTc-Annexin V and histological apoptosis markers. Late process membrane disintegration can possibly be detected by 99mTc-sestamibi and 99mTc-glucaric acid. [18F]FDG signifies an early adaptive response to DOX, which can be further exploited clinically in the near future.

Conflict of interest statement


The authors declare no competing interests.

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14
Review
Curr Opin Oncol




. 2020 May;32(3):210-215. doi: 10.1097/CCO.0000000000000624.
Recent progress in treating advanced prostate cancer
Theodore Gourdin 1
Affiliations expand
PMID: 32209821
DOI: 10.1097/CCO.0000000000000624

Abstract


Purpose of review: Summarize recent advances in the treatment of advanced prostate cancer.

Recent findings: Recent randomized data suggest a survival advantage to early use of novel androgen receptor inhibitors in combination with androgen deprivation therapy both in the setting of hormone-sensitive metastatic prostate cancer and nonmetastatic castration-resistant disease. While ongoing analyses examine optimal sequencing of existing agents for treatment of advanced prostate cancer, additional research focuses on expanding treatment options through development of novel genomically targeted therapies, antibody-drug conjugates, and immune therapy combinations.

Summary: In this review, we summarize the recent data supporting the early use of novel androgen receptor inhibitors in advanced prostate cancer and aim to also frame how these drugs may fit within the existing context of docetaxel and abiraterone. We present recent series examining sequencing of approved therapies while searching for predictive biomarkers. Finally, we examine trials evaluating novel agents that target certain biological pathways to highlight the likely future directions for progress in the clinical management of advanced prostate cancer.
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15
Review
Curr Opin Oncol




. 2020 May;32(3):203-209. doi: 10.1097/CCO.0000000000000623.
Immune escape mechanisms in head and neck squamous cell carcinoma and implication for new immunotherapy approach
Marco C Merlano 1 2, Nerina Denaro 1, Ornella Garrone 1
Affiliations expand
PMID: 32195680
DOI: 10.1097/CCO.0000000000000623

Abstract


Purpose of review: The aim of this review is to describe the major steps leading to the immunosuppressive tumor microenvironment and to summarize some of the new immunotherapies that interfere with these mechanisms.

Recent findings: Immunotherapy has improved the outcome of relapsed/metastatic head and neck squamous cell carcinoma (HNSCC). However, most patients still do not respond to treatment and median overall survival remains short with a modest rate of long-term survivors. There is a growing awareness that tumor immune-escape is a complex process that involves many redundant mechanisms other than immune check-points. They interfere with the innate immune response, activation of adaptive immune response, homing of effector T cells, their clonal expansion, viability, and efficiency. This abundance of immunosuppressive mechanisms explains the limited results achieved by immune checkpoint inhibitors. Combined treatments targeting different mechanisms of escape are in development to further improve the outcome of patients with HNSCC.

Summary: Many mechanisms favor tumor immune-escape. Each tumor exploits preferably some of them and the challenge is to understand which are the best targets in each tumor. This knowledge is an important tool to design future combination strategies based on strong biological rationales, which could offer better results than simple empirical combinations.
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16
Review
Anticancer Drugs




. 2019 Mar;30(3):308-312. doi: 10.1097/CAD.0000000000000707.
Clinical management of localized undifferentiated sinonasal carcinoma: our experience and review of the literature
Francesco Perri 1, Giuseppina Della Vittoria Scarpati 2, Franco Ionna 3, Francesco Longo 3, Massimo Montano 1, Paolo Muto 4, Vincenzo Ravo 4, Mario Giuliano 5 6, Francesco Caponigro 1
Affiliations expand
PMID: 30779722
DOI: 10.1097/CAD.0000000000000707

Abstract


Undifferentiated sinonasal carcinoma (SNUC) is defined as a small round blue cell tumor that is immunohistochemically distinct from other sinonasal malignancies, such as lymphoma, mucosal melanoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, and olfactory neuroblastoma. SNUCs are very aggressive malignancies, provoking quick destruction of the splanchnocranium structures. Being a very rare neoplasm, there are no prospective clinical trials assessing their treatment strategies, so lots of data are derived by small retrospective trials. Tri-modality treatments (namely those treatments which use together surgery, radiation therapy and chemotherapy) are now considered the best of care for this category of poor prognosis tumors, and whenever possible they should be employed. Despite the tri-modality treatments and the multidisciplinary management, SNUCs are characterized by poor prognosis with a median overall survival reaching 14 months. Ameliorating radiotherapy techniques and performing therapies adapted to the genetics of the disease could represent a promising strategy of therapy in the near future. In this report, we have presented our experience, describing the treatment and the prognosis of four patients seen at our Institution. Moreover, we have performed a review of the literature analyzing the now available therapy options and the possible future strategies.

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17
Review
Mutat Res




. Apr-Jun 2020;784:108299. doi: 10.1016/j.mrrev.2020.108299. Epub 2020 Feb 25.
Rogue versus chromothriptic cell as biomarker of cancer
Aleksandra Fucic 1, Vladimir Druzhinin 2, Anna Aghajanyan 3, Predrag Slijepcevic 4, Marina Bakanova 2, Elizaveta Baranova 2, Varvara Minina 2, Tatiana Golovina 2, Kirill Kourdakov 2, Anna Timofeeva 2, Victor Titov 5
Affiliations expand
PMID: 32430100
DOI: 10.1016/j.mrrev.2020.108299

Abstract


New molecular cytogenetic biomarkers may significantly contribute to biodosimetry, whose application is still globally diverse and not fully standardized. In 2011, a new term, chromothripsis, was introduced raising great interest among researchers and soon motivating further investigations of the phenomenon. Chromothripsis is described as a single event in which one or more chromosomes go through severe DNA damage very much resembling rogue cells (RC) described more than 50 years ago. In this review, we for the first time compare these two multi-aberrant cells types, RC versus chromothriptic cells, giving insight into the similarities of the mechanisms involved in their etiology. In order to make a better comparison, data on RC in 3366 subjects from studies on cancer patients, Chernobyl liquidators, child victims of the Chernobyl nuclear plant accident, residentially and occupationally exposed population have been summarized for the first time. Results of experimental and epidemiological analysis show that chromothriptic cells and RC may be caused by exposure to high LET ionizing radiation. Experience and knowledge collected on RC may be used in future for further investigations of chromothripsis, introducing a new class of cells which include both chromothriptic and RC, and better insight into the frequency of chromothriptic cell per subject, which is currently absent. Both cell types are relevant in investigations of cancer etiology, biomonitoring of accidentally exposed population to ionizing radiation and biomonitoring of astronauts due to their exposure to high LET ionizing radiation during interplanetary voyages.

Keywords: Biomarker; Chromothripsis; Ionizing radiation; Rogue cell.

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

Conflict of interest statement


Declaration of Competing Interest None declared.
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18
Review
Curr Opin Oncol




. 2020 May;32(3):187-195. doi: 10.1097/CCO.0000000000000622.
The emerging data on choice of optimal therapy for locally advanced nasopharyngeal carcinoma
Edwin Pun Hui 1, Brigette B Y Ma, Anthony T C Chan
Affiliations expand
PMID: 32175925
DOI: 10.1097/CCO.0000000000000622

Abstract


Purpose of review: We focus on the emerging data from randomized clinical trials for optimal integration of induction, concurrent, and/or adjuvant chemotherapy with intensity-modulated radiotherapy in locally advanced nasopharyngeal carcinoma (NPC), and the use of plasma Epstein-Barr virus (EBV) DNA for risk stratification.

Recent findings: Several phase 3 trials have shown that induction chemotherapy followed by concurrent chemoradiation (CRT) improved overall survival or disease-free survival when compared to CRT alone in stage III/IV NPC who is at high risk of distant metastases. The benefit of adjuvant chemotherapy following CRT when compared to CRT alone is uncertain. There are increasing clinical data supporting the use of plasma EBV DNA for risk stratification. There are growing clinical data supporting the integration of immune checkpoint inhibitors into the induction, concurrent, and/or adjuvant/maintenance phase of treatment in locally advanced NPC.

Summary: Concurrent chemoradiation remains the standard treatment backbone in locally advanced NPC. There is level 1 evidence for induction chemotherapy followed by CRT in stage III/IV NPC. There is increasing evidence against the indiscriminate use of adjuvant chemotherapy following CRT. With the increasing treatment intensification, future treatment algorithm in NPC should incorporate plasma EBV DNA and other biomarkers for risk stratification and treatment selection.
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19
Review
Cancers (Basel)




. 2020 Sep 17;12(9):E2651. doi: 10.3390/cancers12092651.
Cellular and Molecular Progression of Prostate Cancer: Models for Basic and Preclinical Research
Sirin Saranyutanon 1 2, Sachin Kumar Deshmukh 1 2, Santanu Dasgupta 1 2, Sachin Pai 3, Seema Singh 1 2 4, Ajay Pratap Singh 1 2 4
Affiliations expand
PMID: 32957478
DOI: 10.3390/cancers12092651Free article

Abstract


We have witnessed noteworthy progress in our understanding of prostate cancer over the past decades. This basic knowledge has been translated into efficient diagnostic and treatment approaches leading to the improvement in patient survival. However, the molecular pathogenesis of prostate cancer appears to be complex, and histological findings often do not provide an accurate assessment of disease aggressiveness and future course. Moreover, we also witness tremendous racial disparity in prostate cancer incidence and clinical outcomes necessitating a deeper understanding of molecular and mechanistic bases of prostate cancer. Biological research heavily relies on model systems that can be easily manipulated and tested under a controlled experimental environment. Over the years, several cancer cell lines have been developed representing diverse molecular subtypes of prostate cancer. In addition, several animal models have been developed to demonstrate the etiological molecular basis of the prostate cancer. In recent years, patient-derived xenograft and 3-D culture models have also been created and utilized in preclinical research. This review is an attempt to succinctly discuss existing information on the cellular and molecular progression of prostate cancer. We also discuss available model systems and their tested and potential utility in basic and preclinical prostate cancer research.

Keywords: oncogenes; prostate cancer; research model; tumor suppressor genes.
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20
Review
Anticancer Res




. 2020 Sep;40(9):4829-4841. doi: 10.21873/anticanres.14486.
The Future of ER+/HER2- Metastatic Breast Cancer Therapy: Beyond PI3K Inhibitors
Athina Stravodimou 1, Ioannis A Voutsadakis 2 3
Affiliations expand
PMID: 32878771
DOI: 10.21873/anticanres.14486

Abstract


Most breast cancers express the estrogen receptor (ER) receptor and are negative for the human epidermal growth factor receptor 2 (HER2) receptor. ER+/HER2- cancers are treated with hormone-based therapies in the adjuvant setting and derive significant survival benefit from these therapies in the metastatic setting. However, hormone resistance develops in most metastatic patients. An increased understanding of the biology of ER+/HER2- breast cancers has led to the development of new therapies for this disease including CDK4/6 inhibitors and PI3K inhibitors. Several other neoplastic processes are targeted by novel drugs in clinical development, addressing cancer vulnerabilities. These include newer ways to block the ER and targeting the HER2 receptors in ER+/HER2- cancers expressing HER2 in low levels not qualifying for clinical positivity. In addition, promising therapeutic options include targeting other surface receptors or their downstream pathways, as well as targeting the apoptotic machinery and boosting the immune response which is initially insufficient in these cancers. A selection of new drugs in advanced development for ER+/HER2- breast cancer will be discussed in this review.

Keywords: ER positive; ER targeting; FGFR inhibitors; breast cancer; elacestrant; review; venetoclax.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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21
Placenta




. 2020 Sep 15;101:124-131. doi: 10.1016/j.placenta.2020.09.010. Online ahead of print.
Maternal altitude and risk of low birthweight: A systematic review and meta-analyses
Lin Yang 1, Veronika Helbich-Poschacher 2, Chao Cao 3, Katrin Klebermass-Schrehof 4, Thomas Waldhoer 5
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PMID: 32956874
DOI: 10.1016/j.placenta.2020.09.010

Abstract


Background: Previous studies conducted in high altitude regions showed that maternal altitude was associated with low birth weight. The effect size of birth weight reduction is inclusive with unknown effects due to preterm birth. We systematically reviewed the literature and synthesize evidence on associations between altitude elevation from sea level and birth weight.

Method: We searched MEDLINE/PubMed, Embase, Scopus, Web of Science, and Cochrane database, from inception to May 5, 2020 for studies that reported maternal altitude and birth weight. Bayesian multilevel effect models were employed to estimate the effect size on birth weight (and gestational age) associated with altitude. Bayesian multilevel effect models were employed to estimate the effect size on birth weight (and gestational age) associated with altitude.

Results: The systematic search identified 1020 articles, with 52 articles meeting the inclusion criteria providing 207 estimates for the association of altitude and birth weight (n = 4,428,563), and with 22 articles providing 71 estimates for gestational age (n = 2,149,627). A reduction in mean birth weight of 96.98 g was associated with every 1000 m increase in altitude across 52 studies. A statistically significant but numerically minimal effect of maternal altitude elevation was observed on the gestational age (0.3 days), corresponding to a negligible estimation of 5 g lower birth weight. A relatively high heterogeneity of between-study association (I2>84.1%) and small study effect was found.

Conclusion: A clinically meaningful birth weight reduction was associated with maternal altitude elevation beginning from sea level. Future longitudinal studies are needed to elucidate the causal association and to understand the late effect of maternal altitude.

Keywords: Bayesian multilevel model; Birth weight; Maternal altitude; meta-Analyses.

Copyright © 2020 Elsevier Ltd. All rights reserved.
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22
Otolaryngol Head Neck Surg




. 2020 Sep 22;194599820960146. doi: 10.1177/0194599820960146. Online ahead of print.
Association Between Immunosuppression and Outcomes in Oral Cavity Squamous Cell Carcinoma
Julia Chang 1, John B Sunwoo 1, Jennifer Lobo Shah 2, Wendy Hara 3, Jison Hong 4, A Dimitrios Colevas 5, Vasu Divi 1
Affiliations expand
PMID: 32957854
DOI: 10.1177/0194599820960146

Abstract


Objective: To assess the effect of immunosuppression on recurrence and mortality outcomes in oral cavity squamous cell carcinoma (SCC) after initial surgical treatment.

Study design: Retrospective cohort study.

Setting: A single academic tertiary referral center.

Methods: Patients with oral cavity SCC treated with initial surgery were included. Immunosuppressed versus nonimmunosuppressed groups were compared. Primary end points were 5-year overall recurrence and all-cause mortality. Secondary end points were recurrence subtypes (local, regional, and distant) and disease-specific mortality.

Results: Of 803 patients with oral cavity SCC, 71 (9%) were immunosuppressed from therapeutic drug use (n = 48) or systemic disease (n = 23). The immunosuppressed group consisted of patients with a history of transplant (21%), autoimmune or pulmonary disorder (45%), hematologic malignancy or myeloproliferative disorder (30%), and HIV infection (3%). After adjusting for baseline variables of age, sex, comorbidities, pathologic tumor characteristics, and adjuvant treatment, all recurrence and mortality outcomes were worse in the immunosuppressed group. The multivariate-adjusted hazard ratio for overall recurrence was 2.16 (95% CI, 1.50-3.12; P < .01), and all-cause mortality was 1.79 (95% CI, 1.15-2.78; P < .01) in Cox regression analysis. The 2 groups were then matched in a 1:5 ratio according to the same baseline variables. All end points apart from disease-specific mortality were significantly worse in the immunosuppressed group after matching.

Conclusion: This study demonstrates that immunosuppression is associated with poor outcomes in oral cavity SCC, with an approximate 2-fold increase in rates of recurrence and mortality. Future studies are needed to assess the risks and benefits of adjusting therapeutic immunosuppression in this population.

Keywords: head and neck cancer; immunosuppression; oral cavity squamous cell carcinoma; recurrence outcomes; survival outcomes.
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23
Blood Adv




. 2020 Sep 22;4(18):4574-4583. doi: 10.1182/bloodadvances.2020002947.
Systems-based hematology: highlighting successes and next steps
Jori E May 1, Patrick C Irelan 2, Kailee Boedeker 2, Emily Cahill 2, Steven Fein 3, David A Garcia 4, Lisa K Hicks 5, Janice Lawson 6, Ming Y Lim 7, Colleen T Morton 8, Anita Rajasekhar 9, Satish Shanbhag 10, Marc S Zumberg 9, Robert M Plovnick 2, Nathan T Connell 11
Affiliations expand
PMID: 32960959
PMCID: PMC7509880
DOI: 10.1182/bloodadvances.2020002947Free PMC article

Abstract


Systems-based hematology is dedicated to improving care delivery for patients with blood disorders. First defined by the American Society of Hematology in 2015, the idea of a systems-based hematologist arose from evolving pressures in the health care system and increasing recognition of opportunities to optimize the quality and cost effectiveness of hematologic care. In this review, we begin with a proposed framework to formalize the discussion of the range of initiatives within systems-based hematology. Classification by 2 criteria, project scope and method of intervention, facilitates comparison between initiatives and supports dialogue for future efforts. Next, we present published examples of successful systems-based initiatives in the field of hematology, including efforts to improve stewardship in the diagnosis and management of complex hematologic disorders (eg, heparin-induced thrombocytopenia and thrombophilias), the development of programs to promote appropriate use of hematologic therapies (eg, blood products, inferior vena cava filters, and anticoagulation), changes in care delivery infrastructure to improve access to hematologic expertise (eg, electronic consultation and disorder-specific care pathways), and others. The range of projects illustrates the broad potential for interventions and highlights different metrics used to quantify improvements in care delivery. We conclude with a discussion about future directions for the field of systems-based hematology, including extension to malignant disorders and the need to define, expand, and support career pathways.

© 2020 by The American Society of Hematology.

Conflict of interest statement


Conflict-of-interest disclosure: S.F. has served as medical director for HemeOnc Call, LLC, which has a section on telemedicine. A.R. has served on advisory boards for Alexion, Baxter, Bayer, and Kedrion Biopharma Octapharma Plasma, and her institution has received research support on her behalf from Alnylam (Sanofi Genzyme), Baxalta (Shire), Biomarin, Dimensions Therapeutics, Genetech, Janssen Pharmaceuticals, and Roche. M.S.Z. has served as a member of the American Board of Internal Medicine’s Hematology Board and provided consultancy for Novartis and legal case review. The remaining authors declare no competing financial interests.

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24
Review
J Pain Symptom Manage




. 2020 Sep 19;S0885-3924(20)30754-5. doi: 10.1016/j.jpainsymman.2020.09.022. Online ahead of print.
Clinical aspects of palliative sedation in prospective studies. A systematic review
Maria Arantzamendi 1, Alazne Belar 2, Sheila Payne 3, Maaike Rijpstra 4, Nancy Preston 3, Johan Menten 5, Michael Van der Elst 5, Lukas Radbruch 6, Jeroen Hasselaar 4, Carlos Centeno 7
Affiliations expand
PMID: 32961218
DOI: 10.1016/j.jpainsymman.2020.09.022

Abstract


Context: Near the end of life when patients experience refractory symptoms, palliative sedation may be considered as a last treatment. Clinical guidelines have been developed, but they are mainly based on expert opinion or retrospective chart reviews. Therefore, evidence for the clinical aspects of palliative sedation is needed.

Objectives: To explore clinical aspects of palliative sedation in recent prospective studies.

Methods: Systematic review conducted following PRISMA guidelines and registered at PROSPERO. PubMed, CINAHL, Cochrane, Medline and Embase were searched (January 2014-December 2019), combining "sedation", "palliative care", "prospective". Article quality was assessed.

Results: Ten prospective articles were included, involving predominantly cancer patients. Most frequently reported refractory symptoms were delirium (41-83%), pain (25-65%), and dyspnoea (16-59%). In some articles, psychological and existential distress were mentioned (16-59%). Only a few articles specified the tools used to assess symptoms. Level of sedation assessment tools were: the Richmond Agitation Sedation Scale, Ramsay Sedation Scale, Glasgow Coma Scale and Bispectral Index Monitoring. The palliative sedation practice shows an underlying need for proportionality in relation to symptom intensity. Midazolam was the main sedative used. Other reported medications were phenobarbital, promethazine and anaesthetic medication- propofol. The only study that reported level of patient's discomfort as a palliative sedation outcome showed a decrease in patient discomfort.

Conclusions: Assessment of refractory symptoms should include physical evaluation with standardised tools applied and interviews for psychological and existential evaluation by expert clinicians working in teams. Future research needs to evaluate the effectiveness of palliative sedation for refractory symptom relief.

Keywords: deep sedation; hospice care; palliative care; palliative medicine; palliative sedation; prospective studies; sedation; systematic review; terminal care; terminally ill.

Copyright © 2020. Published by Elsevier Inc.
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25
Eur J Cancer




. 2020 Sep 18;139:27-36. doi: 10.1016/j.ejca.2020.07.024. Online ahead of print.
Tobacco-related cancers in Europe: The scale of the epidemic in 2018
Ivana Kulhánová 1, David Forman 2, Jerome Vignat 2, Carolina Espina 2, Hermann Brenner 3, Hans H Storm 4, Linda Bauld 5, Isabelle Soerjomataram 2
Affiliations expand
PMID: 32957011
DOI: 10.1016/j.ejca.2020.07.024

Abstract


Background: Tobacco smoking is the major preventable cause of cancer. Despite the longstanding decline in smoking prevalence, lung cancer remains one of the most frequently diagnosed cancers in both sexes. We aimed to estimate the current cancer burden attributable to smoking in Europe.

Methods: Smoking-related cancer incidence by country, cancer type, sex and age in Europe was estimated from GLOBOCAN 2018. We applied a modified version of the indirect method to estimate the population attributable fraction (PAF) for lung cancer and applied Levin's formula to estimate the PAF for other smoking-related cancer sites.

Results: In Europe in 2018, 572,000 and 186,000 cancer cases were attributable to tobacco smoking in males and females respectively, accounting for 28% (males) and 10% (females) of all cancer cases. By region, the largest and the lowest PAF due to smoking in males occurred in Eastern Europe (35% of all cancer cases) and Northern Europe (21%), respectively. Among women, this pattern was reversed (16% in Northern Europe and 6% in Eastern Europe). Lung cancer accounted for more than half of the total cancer burden attributable to smoking (382,000). Other major contributors to the total PAF were lip, oral cavity and pharynx, bladder and laryngeal cancers in men (27% out of total PAF) and colorectal, pancreatic, oral cavity and pharyngeal cancers (21%) in women.

Conclusions: Tobacco smoking was responsible for one in five cancer cases in Europe in 2018. The introduction and robust implementation of tobacco control programmes are critical to reduce this cancer burden in the future.

Keywords: Cancer; Europe; Population attributable fraction; Smoking.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Conflict of interest statement


Conflict of interest statement No conflict of interest is declared.
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26
Exp Hematol




. 2020 Sep 19;S0301-472X(20)30558-0. doi: 10.1016/j.exphem.2020.09.193. Online ahead of print.
THE OLD AND THE NEW: DNA AND RNA METHYLATION IN NORMAL AND MALIGNANT HEMATOPOIESIS
Andrew A Guirguis 1, Brian J Liddicoat 2, Mark A Dawson 3
Affiliations expand
PMID: 32961299
DOI: 10.1016/j.exphem.2020.09.193

Abstract


Whilst DNA cytosine methylation is the oldest and most well studied epigenetic modification, basking in its glory days, it may be soon overshadowed by the new kid on the block: RNA adenosine methylation. This juxtaposition is indeed superficial and a deep exploration towards the fundamental requirements for these essential epigenetic marks provides a clear perspective on their converging and synergistic roles. The recent discovery that both of these modifications are essential for preventing inappropriate activation of the intracellular innate immune responses to endogenous transcripts has provided a lot of interest in targeting them therapeutically as a means to improve cancer immunogenicity. Here we discuss the potential physiological function for DNA and RNA methylation in normal hematopoiesis, how these pervasive epigenetic marks are exploited in cancer, and provide suggestions for future research with a focus on leveraging this knowledge to uncover novel therapeutic targets.

Copyright © 2020. Published by Elsevier Inc.
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27
Support Care Cancer




. 2020 Sep 21. doi: 10.1007/s00520-020-05756-8. Online ahead of print.
'I don't talk about my distress to others; I feel that I have to suffer my problems...' Voices of Indian women with breast cancer: a qualitative interview study
Sunitha Daniel 1 2, Chitra Venkateswaran 3, Ann Hutchinson 4, Miriam J Johnson 4
Affiliations expand
PMID: 32955655
DOI: 10.1007/s00520-020-05756-8

Abstract


Background: Breast cancer is the commonest form of cancer among women globally, including in India. The rising incidence in the developing world is thought to be due to increased life expectancy, urbanisation, and adoption of western lifestyles. A recent systematic review found that Indian women living in India or as immigrants in Canada experienced a range of psychological distresses both ameliorated and exacerbated by cultural issues personally, within the family, within their community, and in the context of faith, and only two of the five qualitative studies explored the experience of women with breast cancer living in India. Distress may also affect treatment compliance.

Aim: The aim of the study was to explore the psychological distresses experienced by Indian women with breast cancer living in Kerala, South India, during and after treatment and to understand better what helped to relieve or increase these distresses.

Methods: In-depth interviews were conducted with 20 consenting women undergoing treatment for breast cancer. Purposive sampling was used to obtain maximum variation in sociodemographic and clinical characteristics. Interviews were verbatim transcribed, translated into English, and back-translated to Malayalam to ensure that the meaning had not been lost. English data were analysed using thematic frame work analysis and synthesised to provide a deeper understanding of the individuals' experience.

Results: Three major themes emerged from the data. The first major theme was 'far-reaching psychological distress'. This included anxiety, guilt, anger, and depression in response to the disease and physical side effects of treatment and issues relating to body image, especially hair loss and sexuality. The second major theme was 'getting on with life'. Women tried to make sense of the disease, by actively seeking information, the role of medical professionals, and their practical adaptations. Many found a new future and a new way to live normal. The third major theme was the 'support system' strongly based on family, friends, faith, and the community which affect them positively as well as negatively.

Conclusion: Psychological concerns related to disease and treatment are common in Indian women with particular emphasis on body image issues associated with hair loss. Family and faith were key support systems for almost all the women, although it could also be the causes of distress.

Keywords: Body image; Breast neoplasms; Distress; Hair loss; Indian; Psychological; Stress.
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28
Comparative Study
BMC Surg




. 2020 May 6;20(1):93. doi: 10.1186/s12893-020-00760-5.
Robotic, laparoscopic or open hemihepatectomy for giant liver haemangiomas over 10 cm in diameter
Minggen Hu 1, Kuang Chen 1, Xuan Zhang 1, Chenggang Li 1, Dongda Song 1, Rong Liu 2
Affiliations expand
PMID: 32375738
PMCID: PMC7204244
DOI: 10.1186/s12893-020-00760-5Free PMC article

Abstract


Background: To evaluate the clinical efficacy of robotic, laparoscopic, and open hemihepatectomy for giant liver haemangiomas.

Methods: From April 2011 to April 2017, consecutive patients who underwent hemihepatectomy for giant liver haemangiomas were included in this study. According to the type of operation, these patients were divided into the robotic hemihepatectomy (RH) group, the laparoscopic hemihepatectomy (LH) group, and the open hemihepatectomy (OH) group. The perioperative and short-term postoperative outcomes were compared among the three groups. The study was reported following the STROCSS criteria.

Results: There were no significant differences in age, sex, tumour location, body surface area (BSA), future liver remnant volume (FLR), standard liver volume (SLV), liver haemangioma volume, FLR/SLV, resected normal liver volume/resected volume, hepatic disease, rates of blood transfusion, liver function after 24 h of surgery, operative morbidity and mortality among the three groups. Compared with patients in the RH group (n = 19) and the LH group (n = 13), patients in the OH group (n = 25) had a significantly longer postoperative hospital stay (P < 0.05), time to oral intake (P < 0.05), and time to get-out-of-bed (P < 0.05); a higher VAS score after 24 h of surgery (P < 0.05); and a shorter operative time (P < 0.05). There were no significant differences in these postoperative outcomes (P>0.05) between the RH group and the LH group. When the setup time in the RH group was excluded, the operative time in the RH group was significantly shorter than that in the LH group (P<0.05). There was no significant difference in the operative time between the RH group and the OH group (P>0.05). The amount of intraoperative blood loss in the RH group was the lowest among the three groups (P<0.05), and the amount of intraoperative blood loss in the LH group was less than that in the OH group (P<0.05).

Conclusion: Robotic and laparoscopic hemihepatectomies were associated with less intraoperative blood loss,better postoperative recovery and lower pain score. Compared with laparoscopic hemihepatectomy, robotic hemihepatectomy was associated with significantly less intraoperative blood loss and a shorter operative time.

Keywords: Clinical effects; Giant liver haemangioma; Hemihepatectomy; Laparoscopic liver resection; Robotic liver resection.

Conflict of interest statement


The authors declare that they have no competing interests.

Cited by 1 article
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29
Clinical Trial
BMC Cancer




. 2020 Jan 21;20(1):52. doi: 10.1186/s12885-020-6547-7.
Intrafractional vaginal dilation in anal cancer patients undergoing pelvic radiotherapy (DILANA) - a prospective, randomized, 2-armed phase-II-trial
Nathalie Arians 1 2 3, Matthias Häfner 4 5 6, Johannes Krisam 7, Kristin Lang 4 5 6, Antje Wark 4 5 6, Stefan A Koerber 4 5 6, Adriane Hommertgen 4 5 6, Jürgen Debus 4 5 6 8 9 10
Affiliations expand
PMID: 31964381
PMCID: PMC6974962
DOI: 10.1186/s12885-020-6547-7Free PMC article

Abstract


Background: The incidence of anal cancer is rising in the last decades and more women are affected than men. The prognosis after chemoradiation is very good with complete remission rates of 80-90%. Thus, reducing therapy-related toxicities and improving quality of life are of high importance. With the development of new radiotherapy techniques like IMRT (Intensity-modulated radiotherapy), the incidence of acute and chronic gastrointestinal toxicities has already been reduced. However, especially in female anal cancer patients genital toxicities like vaginal fibrosis and stenosis are of great relevance, too. Up to now, there are no prospective data reporting incidence rates, techniques of prevention or impact on quality of life. The aim of the DILANA trial is to evaluate the incidence and grade of vaginal fibrosis, to optimize radiotherapy by reducing dose to the vaginal wall to minimize genital toxicities and improve quality of life of anal cancer patients.

Methods: The study is designed as a prospective, randomized, two-armed, open, single-center phase-II-trial. Sixty patients will be randomized into one of two arms, which differ only in the diameter of a tampon used during treatment. All patients will receive standard (chemo) radiation with a total dose of 45-50.4 Gy to the pelvic and inguinal nodes with a boost to the anal canal up to 54-60 Gy. The primary objective is the assessment of the incidence and grade of vaginal fibrosis 12 months after (chemo) radiation depending on the extent of vaginal dilation. Secondary endpoints are toxicities according to the CTC AE version 5.0 criteria, assessment of clinical feasibility of daily use of a tampon, assessment of compliance for the use of a vaginal dilator and quality of life.

Discussion: Prospective studies are needed evaluating the incidence and grade of vaginal fibrosis after (chemo) radiation in female anal cancer patients. Furthermore, the assessment of techniques to reduce the incidence of vaginal fibrosis like intrafractional vaginal dilation as well as other radiotherapy-independent methods like using a vaginal dilator are essential. Additionally, implementation of a systematic assessment of vaginal stenosis is necessary to grant reproducibility and comparability of future data.

Trial registration: The trial is registered with clinicaltrials.gov (NCT04094454, 19.09.2019).

Conflict of interest statement


The authors declare that they have no competing interests.

32 references
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30
J Med Internet Res




. 2020 Sep 12. doi: 10.2196/22550. Online ahead of print.
Crystal Bone: Predicting Short-Term Fracture Risk From Electronic Health Records With Deep Learning
Yasmeen Adar Almog 1, Angshu Rai 1, Patrick Zhang 1, Amanda Moulaison 1, Ross Powell 1, Anirban Mishra 1, Kerry Weinberg 1, Celeste Hamilton 2, Mary Oates 3, Eugene McCloskey 4, Steven R Cummings 5
Affiliations expand
PMID: 32956069
DOI: 10.2196/22550Free article

Abstract


Background: Fractures due to osteoporosis and low bone mass are common and give rise to significant clinical, personal, and economic burden. Even after a fracture occurs, high fracture risk remains widely underdiagnosed and undertreated. Common fracture risk assessment tools utilize a subset of clinical risk factors for prediction, and often require manual data entry. Furthermore, these tools predict risk over the long term, and do not explicitly provide short-term risk estimates necessary to identify patients likely to experience a fracture in the next 1-2 years.

Objective: The goal of this study was to develop and evaluate an algorithmic approach to the identification of patients at risk of fracture in the next 1-2 years. In order to address the aforementioned limitations of current prediction tools, this approach focuses on a short-term timeframe, automated data entry, and the use of longitudinal data to inform the predictions.

Methods: Using electronic health record (EHR) data from over 1M patients, we developed Crystal Bone, a method that applies machine learning techniques from Natural Language Processing to the temporal nature of patient histories to generate short-term fracture risk predictions. Similar to how language models predict the next word in a given sentence or the topic of a document, Crystal Bone predicts whether a patient's future trajectory might contain a fracture event, or whether the "signature" of the patient's journey is similar to that of a typical future fracture patient.

Results: The proposed models accurately predict fracture risk in the next 1-2 years for patients aged over 50 years (area under the receiver operating characteristics curve [AUROC]=0.81 in a holdout set with 192,590 patients). These algorithms outperform the experimental baselines (AUROC=0.67) and have shown meaningful improvements when compared to a retrospective approximation of human-level performance, such as correctly identifying 9649 of 13,765 (70%) at-risk patients who did not receive any preventative bone-health-related medical interventions from their physicians.

Conclusions: These findings indicate that it is possible to use a patient's unique medical history as it changes over time to predict the risk of short-term fracture. Validating and applying such a tool within the healthcare system could enable automated and widespread prediction of this risk and may help with identification of patients at very high risk of fracture.
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31
Cancer Chemother Pharmacol




. 2020 Sep 22. doi: 10.1007/s00280-020-04146-5. Online ahead of print.
A preliminary assessment of oral monepantel's tolerability and pharmacokinetics in individuals with treatment-refractory solid tumors
Anna Mislang 1, Richard Mollard 2 3, Gonzalo Tapia Rico 1 4, W Douglas Fairlie 5 6 7, Erinna F Lee 5 6 7, Tiffany J Harris 5, Roger Aston 8, Michael P Brown 9 10 11 12
Affiliations expand
PMID: 32960289
DOI: 10.1007/s00280-020-04146-5

Abstract


Purpose: Monepantel is an approved veterinary anthelmintic with a strong safety profile. Preclinical evidence suggests novel mTOR pathway-associated anticancer activity. An open-label Phase I trial assessed tolerability, pharmacokinetics, pharmacodynamics and PET-CT imaging following oral Zolvix® monepantel administration to adults with treatment refractory, progressing and unresectable solid tumors.

Methods: Subjects were scheduled to daily home-based monepantel administration for 28 days in a 3 + 3 dose escalation study (5.0, 25.0 and 62.5 mg/kg bw).

Results: Of 41 reported drug-related AEs, 68% were Grade 1 and 24% were Grade 2; 35 AEs related to gastrointestinal effects including very poor palatability. DLT and MTD could not be determined due to early termination. Myelosuppression was not observed at the lowest level tested. Three of four Cohort 1 subjects had reduced mTOR pathway marker p-RPS6KB1 levels in PBMCs and achieved RECISTv1.1 SD by CT; one had progressive bony metastases by FDG-PET. One subject recorded PD on day 28, correlating with no detectable plasma monepantel from day 7. Monepantel sulfone dominated monepantel in pharmacokinetics. Both Cohort 2 subjects withdrew early due to AEs and the trial was terminated.

Conclusions: Short-term 5 mg/kg bw monepantel administration provides a combined steady-state trough plasma monepantel and monepantel sulfone concentration of 0.5 μM. Gastrointestinal AEs including very poor palatability are concerning and suggested to be resolved by future drug product reformulation. RECISTv1.1, p-RPS6KB1 and plasma tumor marker outcomes provide preliminary evidence of anticancer activity.

Keywords: Anthelmintic; Monepantel; Phase I study; Treatment-refractory cancer.
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32
Blood Adv




. 2020 Sep 22;4(18):4560-4572. doi: 10.1182/bloodadvances.2020002475.
HRI depletion cooperates with pharmacologic inducers to elevate fetal hemoglobin and reduce sickle cell formation
Scott A Peslak 1 2, Eugene Khandros 2, Peng Huang 2, Xianjiang Lan 2, Carly L Geronimo 2, Jeremy D Grevet 2, Osheiza Abdulmalik 2, Zhe Zhang 3, Belinda M Giardine 4, Cheryl A Keller 4, Junwei Shi 5, Ross C Hardison 4, Gerd A Blobel 2
Affiliations expand
PMID: 32956454
DOI: 10.1182/bloodadvances.2020002475

Abstract


Increasing fetal hemoglobin (HbF) provides clinical benefit in patients with sickle cell disease (SCD). We recently identified heme-regulated inhibitor (HRI, EIF2AK1), as a novel HbF regulator. Because HRI is an erythroid-specific protein kinase, it presents a potential target for pharmacologic intervention. We found that maximal HbF induction required >80% to 85% HRI depletion. Because it remains unclear whether this degree of HRI inhibition can be achieved pharmacologically, we explored whether HRI knockdown can be combined with pharmacologic HbF inducers to achieve greater HbF production and minimize potential adverse effects associated with treatments. Strongly cooperative HbF induction was observed when HRI depletion was combined with exposure to pomalidomide or the EHMT1/2 inhibitor UNC0638, but not to hydroxyurea. Mechanistically, reduction in the levels of the HbF repressor BCL11A reflected the cooperativity of HRI loss and pomalidomide treatment, whereas UNC0638 did not modulate BCL11A levels. In conjunction with HRI loss, pomalidomide maintained its HbF-inducing activity at 10-fold lower concentrations, in which condition there were minimal observed detrimental effects on erythroid cell maturation and viability, as well as fewer alterations in the erythroid transcriptome. When tested in cells from patients with SCD, combining HRI depletion with pomalidomide or UNC0638 achieved up to 50% to 60% HbF and 45% to 50% HbF, respectively, as measured by high-performance liquid chromatography, and markedly counteracted cell sickling. In summary, this study provides a foundation for the exploration of combining future small-molecule HRI inhibitors with additional pharmacologic HbF inducers to maximize HbF production and preserve erythroid cell functionality for the treatment of SCD and other hemoglobinopathies.

© 2020 by The American Society of Hematology.
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33
Transl Lung Cancer Res




. 2020 Aug;9(4):1053-1066. doi: 10.21037/tlcr-19-396.
Predictive and prognostic significance of M descriptors of the 8th TNM classification for advanced NSCLC patients treated with immune checkpoint inhibitors
Sangtian Liu 1 2, Fei Zhou 1, Zhiyu Liu 3, Anwen Xiong 1, Yijun Jia 1, Sha Zhao 1, Chao Zhao 2, Xuefei Li 2, Tao Jiang 1, Ruoshuang Han 1, Meng Qiao 1, Yiwei Liu 1, Yayi He 1, Jiayu Li 1, Wei Li 1, Guanghui Gao 1, Shengxiang Ren 1, Chunxia Su 1, Caicun Zhou 1
Affiliations expand
PMID: 32953484
PMCID: PMC7481592
DOI: 10.21037/tlcr-19-396Free PMC article

Abstract


Background: A strong association between M descriptors and prognosis of non-small cell lung cancer (NSCLC) has been demonstrated recently. However, its predictive and prognostic significance for advanced NSCLC patients treated with immune checkpoint inhibitors (ICIs) remain unclear. In this study, we aimed at investigating the impact of M descriptors on clinical outcomes in those patients.

Methods: A retrospective analysis was conducted. Patients treated with more than two cycles of ICIs were included. Detailed characteristics and clinical response after immunotherapy were recorded. M descriptors were classified into M1a, M1b, and M1c according to the 8th TNM classification.

Results: A total of 103 patients were enrolled, including 42 with M1a disease, 16 with M1b disease and 45 with M1c disease. Patients with M1a disease demonstrated significant longer median progress-free survival (PFS) (11.9 vs. 4.1 and 3.2 months, respectively, P=0.0002) and overall survival (OS) (35 vs. 22.1 and 12 months, P=0.02) than those with M1b and M1c disease. Patients with M1a disease showed higher objective response rate (ORR) (28.6% vs. 14.8%, P=0.08) and disease control rate (DCR) (81% vs. 59%, P=0.02) compared with those with M1b and M1c disease. Multivariate analysis identified M1a stage as being independently associated with prolonged PFS and had better OS than those with M1c disease (P=0.05) but not M1b disease (P=0.06).

Conclusions: The current study demonstrated a clear association between M descriptors and the therapeutic response to ICIs and confirmed its prognostic role in advanced patients treated with ICIs monotherapy. M descriptors may need to be stratified in future study design.

Keywords: Immune checkpoint inhibitors (ICIs); M descriptors; M1a stage; non-small-cell lung cancer (NSCLC).

2020 Translational Lung Cancer Research. All rights reserved.

Conflict of interest statement


Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-19-396). TJ serves as an unpaid editorial board member of Translational Lung Cancer Research from Feb 2018 to Jan 2021. YH serves as an unpaid editorial board member of Translational Lung Cancer Research from Jan 2020 to Dec 2021. CZ serves as an unpaid editorial board member of Translational Lung Cancer Research from Mar 2012 to Mar 2022. The other authors have no conflicts of interest to declare.

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34
Review
Zhongguo Fei Ai Za Zhi




. 2020 Feb 20;23(2):111-117. doi: 10.3779/j.issn.1009-3419.2020.02.06.
[Advances and Challenges of Local Thermal Ablation in Non-small Cell Lung Cancer]
[Article in Chinese]
Qing Gou 1, Zejian Zhou 1, Mingfang Zhao 2, Xiaoming Chen 1, Qing Zhou 3
Affiliations expand
PMID: 32093455
PMCID: PMC7049787
DOI: 10.3779/j.issn.1009-3419.2020.02.06Free PMC article

Abstract
in English, Chinese


Non-small cell lung cancer (NSCLC) is the most common pathological type of primary lung cancer. Currently, main treatment approaches for NSCLC patients include surgical resection, radiotherapy, chemotherapy, targeted therapy and so on. In recent years, thermal ablation has received increasing attention in the treatment of various stages of NSCLC. As a safe and efficient local treatment, thermal ablation may bring potential clinical benefits to NSCLC patients. However, many issues remain unsolved and further investigation is needed in the clinical application of thermal ablation in NSCLC. In this review, we aim to summarize the applications of thermal ablation in NSCLC and further discuss the emerging controversies as well as future research directions.

Keywords: Local treatment; Lung neoplasms; Thermal ablation.

41 references
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35
Pediatr Blood Cancer




. 2020 Sep 22;e28401. doi: 10.1002/pbc.28401. Online ahead of print.
Gliomas, germ cell tumors, and craniopharyngioma
Paul Aridgides 1, Geert O Janssens 2, Steve Braunstein 3, Shauna Campbell 4, Matthew Poppe 5, Erin Murphy 6, Shannon MacDonald 7, Matthew Ladra 8, Claire Alapetite 9, Daphne Haas-Kogan 10
Affiliations expand
PMID: 32960496
DOI: 10.1002/pbc.28401

Abstract


This report summarizes the current multimodality treatment approaches for children with low- and high-grade gliomas, germinoma, and nongerminomatous germ cell tumors, and craniopharyngiomas used in the Children's Oncology Group (COG) and the International Society of Pediatric Oncology (SIOP). Treatment recommendations are provided in the context of historical approaches regarding the roles of surgery, radiation, and chemotherapy. Future research strategies for these tumors in both COG and SIOP are also discussed.

Keywords: chemotherapy; craniopharyngioma; germ cell tumors; gliomas; protons; radiation therapy; surgery.

© 2020 Wiley Periodicals, Inc.

99 references
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36
Editorial
Int J Radiat Oncol Biol Phys




. 2020 Oct 1;108(2):438-443. doi: 10.1016/j.ijrobp.2020.07.006.
Opportunities in Telemedicine, Lessons Learned After COVID-19 and the Way Into the Future
May Abdel-Wahab 1, Eduardo Rosenblatt 2, Ben Prajogi 2, Eduardo Zubizarretta 2, Miriam Mikhail 2
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PMID: 32890528
PMCID: PMC7462967
DOI: 10.1016/j.ijrobp.2020.07.006Free PMC article
No abstract available

68 references
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37
Editorial
Future Oncol




. 2020 Sep;16(25):1879-1881. doi: 10.2217/fon-2020-0501. Epub 2020 Jun 21.
A clinical dilemma amid COVID-19 pandemic: missed or encountered diagnosis of cancer?
Emre Yekedüz 1 2, Ayşe Müge Karcıoğlu 3, Güngör Utkan 1 2, Yüksel Ürün 1 2
Affiliations expand
PMID: 32564611
PMCID: PMC7307743
DOI: 10.2217/fon-2020-0501Free PMC article
No abstract available

14 references
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38
J Cancer Res Ther




. 2020;16(2):301-308. doi: 10.4103/jcrt.JCRT_898_19.
Time to untreatable progression is an appropriate surrogate endpoint for overall survival in patients with hepatocellular carcinoma after transarterial chemoembolization
Hongyu Wang 1, Bin Li 2, Yu Wang 1, Jiang Zhang 3, Yanqin Wu 1, Wenzhe Fan 1, Jiaping Li 1
Affiliations expand
PMID: 32474517
DOI: 10.4103/jcrt.JCRT_898_19Free article

Abstract


Aims: The aim of the study was to determine whether the time to progression (TTP) or time to untreatable progression (TTUP) is an appropriate surrogate endpoint for overall survival (OS) in patients with hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE).

Materials and methods: Eighty-four patients with Barcelona clinic liver cancer (BCLC) stage B or C HCC underwent TACE. The correlations of TTP and TTUP with OS were evaluated after a log transformation of the indicated values. After identifying independent prognostic factors of TTP, TTUP, and OS, the partial correlations of TTP and TTUP with OS were analyzed in all patients and subgroups. Subsequently, the prognostic value of TTP and TTUP was compared by the multivariate survival analysis of OS.

Results: Both the BCLC stage and tumor number were correlated with TTP and TTUP. In addition, the BCLC stage, initial treatment failure, and sorafenib administration were associated with OS. In all patients, the correlation coefficients of TTP and TTUP with OS were 0.559 and 0.789, respectively. Adjustment for independent prognostic factors yielded partial correlation coefficients which were 0.433 and 0.697, respectively. Furthermore, OS was found to be associated with TTUP (P = 0.003; hazard ratio: 0.253; 95% confidence interval: 0.10-0.63) but not with TTP.

Conclusion: Untreatable progression is more representative of clinical progression in patients with HCC who underwent TACE. In the current study, TTUP is a more appropriate surrogate endpoint for OS than TTP. Future studies should explore whether untreatable progression is a valuable endpoint event in clinical trials or an indicator of the need for second-line therapy.

Keywords: Hepatocellular carcinoma; overall survival; surrogate endpoint; time to untreatable progression; transarterial chemoembolization.

Conflict of interest statement


None
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39
J Cutan Med Surg




. 2020 Sep 21;1203475420960426. doi: 10.1177/1203475420960426. Online ahead of print.
Socioeconomic Status and Melanoma in Canada: A Systematic Review
Heidi Oi-Yee Li 1, Adrian Joseph-Michel Bailey 1, Elysia Grose 1, James Ted McDonald 2, Alexandra Quimby 3, Stephanie Johnson-Obaseki 3, Carolyn Nessim 4
Affiliations expand
PMID: 32955341
DOI: 10.1177/1203475420960426

Abstract


As melanoma is one of the leading cancers in average years of life lost per death from disease, screening and early diagnosis are imperative to decrease morbidity and mortality. Socioeconomic status (SES) has been shown to be associated with melanoma incidence. However, it is unclear if this association holds true in universal healthcare systems where screening, diagnostic, and treatment services are available to all patients. The objective of this systematic review was to evaluate the evidence on the association of SES and melanoma incidence in Canada. A comprehensive search of PubMed and EMBASE yielded 7 studies reporting on melanoma incidence or outcomes with respect to SES in Canada. High SES was associated with increased melanoma incidence across all studies, which encompassed all Canadian provinces, and time periods spanning from 1979 to 2012. Studies also reported an increasing incidence of melanoma over time. There were substantial discrepancies in melanoma incidence across Canadian provinces, after controlling for SES and demographic characteristics. Populations of lower SES and living within certain healthcare regions had increased risks of advanced melanoma at diagnosis. This review highlights the potential for inequities in access to care even within a universal healthcare system. Future research is needed to characterize specific risk factors within different patient groups and within the universal health system context in order to implement targeted strategies to lower melanoma incidence, morbidity, and mortality.

Keywords: health disparities; health equity; healthcare system; melanoma; social determinants; social inequality; socioeconomic status; systematic review; universal healthcare.
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40
Editorial
Int J Radiat Oncol Biol Phys




. 2020 Oct 1;108(2):362-363. doi: 10.1016/j.ijrobp.2020.05.039.
The Importance of Temporary Telehealth Parity Laws to Improve Public Health During COVID-19 and Future Pandemics
Brian C Baumann 1, Kelly M MacArthur 2, Jeff M Michalski 3
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PMID: 32890513
PMCID: PMC7462835
DOI: 10.1016/j.ijrobp.2020.05.039Free PMC article
No abstract available

1 reference
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41
J Gastrointest Oncol




. 2020 Aug;11(4):654-662. doi: 10.21037/jgo-20-191.
Impact of immunotherapy use in patients with stage IV pancreatic carcinoma
Achuta K Guddati 1, Takefumi Komiya 2, Sunny J Patel 1, Neil Sharma 3, Emily Powell 4
Affiliations expand
PMID: 32953149
PMCID: PMC7475322
DOI: 10.21037/jgo-20-191Free PMC article

Abstract


Background: Most patients with pancreatic cancer have non-resectable disease at the time of diagnosis and usually die within 6-12 months. Despite indications in other solid tumors, the role of immunotherapy (IO) is unknown for late stage, advanced pancreatic cancer.

Methods: Using the National Cancer Database (NCDB), cases of Stage IV pancreatic cancers diagnosed in the period of 2014-2016 with at least 30-day follow up were retrospectively analyzed. The following clinical demographics were included: age (younger than 70 vs. older than 70), sex (male vs. female), race (whites vs. others), insurance (uninsured vs. insured), type of institution (academic vs. nonacademic), liver metastasis (yes vs. no), lung metastasis (yes vs. no), external beam radiation (yes vs. no), systemic chemotherapy (yes vs. no) and IO (yes vs. no). survival analysis was performed using Kaplan-Meier curves and Log-rank tests. Multivariable Cox proportional hazard models and propensity score matching analysis were also utilized. A P value <0.05 was considered significant.

Results: Among 25,596 eligible cases, 163 patients were treated with IO. A significant association between the use of IO and several clinical demographics (age <70, academic institution, adenocarcinoma, lung metastasis, radiation, chemotherapy) was noted. Chemotherapy was administered in 133 (82%) and 16,342 (64%) of cases in the IO and non-IO groups, respectively. Use of IO was associated with improved overall survival (OS) in both univariate and multivariate analyses (P<0.0001 for each). Median OS (in months) was 12.2 in the IO group vs. 5.8 in the non-IO group. Landmark analysis in the IO group showed 12 and 24-month survival of 51.0% and 20.0% respectively, as compared with 28.2% and 11.9% in the non-IO group. Propensity score matching analysis also demonstrated a trend toward improved OS in IO group (P=0.0753). Median survival was 12.2 and 8.9 months, respectively.

Conclusions: This retrospective data analysis using a large cancer database suggests that use of IO could improve survival in patients with advanced pancreatic cancer. More studies will be needed in the future to validate these results.

Keywords: Immunotherapy (IO); PD-1; pancreatic cancer; propensity score matching.

2020 Journal of Gastrointestinal Oncology. All rights reserved.

Conflict of interest statement


Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at: http://dx.doi.org/10.21037/jgo-20-191). The authors have no conflicts of interest to declare.

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42
Minerva Stomatol




. 2020 Sep 22. doi: 10.23736/S0026-4970.20.04430-1. Online ahead of print.
Psychological reactions to COVID-19 and epidemiological aspects of dental practitioners during lockdown in Italy
Pierantonio Bellini 1, Vittorio Checchi 2, Cristina Liani 3, Davide Bencivenni 1, Ugo Consolo 1
Affiliations expand
PMID: 32960524
DOI: 10.23736/S0026-4970.20.04430-1

Abstract


Background: Due to droplet production and exposure to saliva and blood, dental practitioners are at high risk of COVID-19 contagion during their routine procedures. The aim of this study is to investigate the behavior of Italian dentists and to analyze their reactions in relation to Sars-CoV-2 pandemic professional restrictive measures.

Methods: An online structured survey composed of 40 questions has been sent to dental practitioners all over Italy to investigate their behavior and to analyze their reactions in relation to Sars-CoV-2 pandemic restrictive measures introduced by the Italian national administrative order of 10 March 2020 (DM-10M20).

Results: 1109 dentists replied. To assess concerns and psychological responses the sample was divided into two groups based on the number of cases registered in their work area. In the first group were included all the responders working in the Italian regions that had more than 15,000 confirmed cases of COVID-19 as of April 29, 2020. The second group included responders working in the Italian regions that had less than 15,000 confirmed cases. The 45.2% of the respondents showed minimal anxiety, 34.5% showed mild anxiety, 13.9% showed moderate anxiety, while 6.4% showed a score indicative of a severe level of anxiety.

Conclusions: The COVID-19-related emergency condition had a highly negative impact on dental practices in Italy. Those who completed the survey reported practice closure or reduction during the lockdown, and a high level of concern about the professional future for all dental practitioners. Concerns related to professional activity were accompanied by severe anxiety levels.
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43
Review
Vaccines (Basel)




. 2020 Sep 17;8(3):E537. doi: 10.3390/vaccines8030537.
Electroporation as the Immunotherapy Strategy for Cancer in Veterinary Medicine: State of the Art in Latin America
Felipe Maglietti 1, Matías Tellado 2, Mariangela De Robertis 3 4, Sebastián Michinski 5, Juan Fernández 2, Emanuela Signori 6, Guillermo Marshall 5
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PMID: 32957424
DOI: 10.3390/vaccines8030537Free article

Abstract


Electroporation is a technology that increases cell membrane permeability by the application of electric pulses. Electrochemotherapy (ECT), the best-known application of electroporation, is a very effective local treatment for tumors of any histology in human and veterinary medicine. It induces a local yet robust immune response that is responsible for its high effectiveness. Gene electrotransfer (GET), used in research to produce a systemic immune response against cancer, is another electroporation-based treatment that is very appealing for its effectiveness, low cost, and simplicity. In this review, we present the immune effect of electroporation-based treatments and analyze the results of the vast majority of the published papers related to immune response enhancement by gene electrotransfer in companion animals with spontaneous tumors. In addition, we present a brief history of the initial steps and the state of the art of the electroporation-based treatments in Latin America. They have the potential to become an essential form of immunotherapy in the region. This review gives insight into the subject and helps to choose promising research lines for future work; it also helps to select the adequate treatment parameters for performing a successful application of this technology.

Keywords: cancer; companion animals; electrochemotherapy; gene electrotransfer; gene therapy; immune response; tumor.
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44
Transl Lung Cancer Res




. 2020 Aug;9(4):1202-1211. doi: 10.21037/tlcr-19-675.
Impact of time-to-treatment on overall survival of non-small cell lung cancer patients-an analysis of the national cancer database
Trisari Anggondowati 1, Apar Kishor Ganti 2, K M Monirul Islam 3
Affiliations expand
PMID: 32953498
PMCID: PMC7481622
DOI: 10.21037/tlcr-19-675Free PMC article

Abstract


Background: The association between time-to-treatment and outcomes for lung cancer has not been conclusively established. In this study, we evaluated the effect of time-to-treatment on the overall 5-year survival of patients with non-small cell lung cancer (NSCLC) with cancer stage at diagnosis.

Methods: We analyzed data in the National Cancer Data Base for adult patients newly diagnosed with NSCLC in 2003-2011 (N=693,554). Extended Cox regression with counting process was used to model the effect of time-to-treatment on survival, adjusted for demographic and clinical factors. Multivariable analyses were performed separately for the groups with different stages at diagnosis. Time-to-treatment was defined as the interval between diagnosis and treatment initiation, with the categories of (I) 0 day, (II) 1 day-4 weeks, (III) 4.1-6.0 weeks, and (IV) >6 weeks (the 1 day-4 weeks group was considered the reference group).

Results: Compared to treatment initiated between 1 day and 4 weeks after diagnosis, time-to-treatment at 4.1-6.0 weeks was associated with a lower risk of death for patients with early-stage cancer [adjusted HR (aHR), 0.84 (95% CI, 0.82-0.85)], with locally advanced cancer [aHR, 0.82 (95% CI, 0.80-0.83)], and with metastatic cancer [aHR, 0.75 (95% CI, 0.74-0.76)]. Similarly, a lower risk of death was associated with time-to-treatment longer than 6 weeks for patients with any cancer stage at diagnosis. However, a subset analysis for early-stage patients who received surgery only showed that extended time-to-surgery was associated a higher risk of death [aHR 4.1-6.0 weeks, 1.06 (95% CI, 1.03-1.09); aHR>6 weeks 1.17 (95% CI, 1.14-1.20)].

Conclusions: The findings show that, although time-to-treatment should not be compromised, it is imperative to ensure that patients receive optimal pre-treatment assessments rather than rushing the treatment. Future research should focus on examining clinical characteristics to determine an optimal time-to-treatment to achieve the best possible survival for NSCLC patients.

Keywords: Non-small cell lung cancer (NSCLC); survival; time-to-treatment; waiting time.

2020 Translational Lung Cancer Research. All rights reserved.

Conflict of interest statement


Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-19-675). AKG reports non-financial support from Takeda, grants from Apexigen, grants and personal fees from AstraZeneca, personal fees from Roche, grants from Novartis, grants from Merck, outside the submitted work. The other authors have no conflicts of interest to declare.

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45
Biol Blood Marrow Transplant




. 2020 Sep 18;S1083-8791(20)30579-6. doi: 10.1016/j.bbmt.2020.09.014. Online ahead of print.
Impact of reduced-intensity conditioning regimens on outcomes in diffuse large B-cell lymphoma undergoing allogeneic transplantation
Narendranath Epperla 1, Kwang W Ahn 2, Manoj Khanal 2, Carlos Litovich 3, Sairah Ahmed 4, Nilanjan Ghosh 5, Timothy S Fenske 6, Mohamed A Kharfan-Dabaja 7, Anna Sureda 8, Mehdi Hamadani 9
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PMID: 32956819
DOI: 10.1016/j.bbmt.2020.09.014

Abstract


Background: Reduced-intensity conditioning (RIC) regimens are frequently used for allogeneic hematopoietic cell transplantation (allo-HCT) in diffuse large B-cell lymphoma (DLBCL). However, the RIC regimen with the best risk/benefit profile for allo-HCT in DLBCL is not known. This is particularly important, as patients with DLBCL undergoing allo-HCT in the future would be enriched for those whose lymphoma has failed chimeric antigen receptor T-cell (CAR-T) therapy or other novel immunotherapies, with potentially more advanced disease and suboptimal performance scores. Using the CIBMTR database, we report the outcomes of the three most commonly used allo-HCT RIC regimens in DLBCL.

Methods: 562 adult DLBCL patients in the CIBMTR registry undergoing allo-HCT using matched related or unrelated donors, between 2008-2016 were included in the analysis. Patients received one of the three RIC regimens: fludarabine/i.v. busulfan (∼6•4mg/kg) (Flu/Bu), fludarabine/melphalan (140mg/m2) (Flu/Mel140) or BCNU/etoposide/cytarabine/melphalan (BEAM).

Findings: The study cohort was divided into three groups: Flu/Bu (n=151), Flu/Mel140 (n=296) and BEAM (n=115). Relative to Flu/Bu, the Flu/Mel140 (HR=2.33, 95%CI=1.42-3.82; p=0.001) and BEAM (HR=2.54, 95%CI=1.34-4.80; p=0.004) regimens were associated with a higher non-relapse mortality (NRM) risk. Although the risk of relapse with Flu/Mel140 was lower compared to Flu/Bu (HR=0.70, 95%CI=0.52-0.95; p=0.02), this did not translate in an improvement in progression-free (HR=1.04) or overall survival (HR=1.30). There was a significantly higher risk of grade 3-4 acute graft-versus-host disease with BEAM (HR=2.19, 95%CI=1.10-4.35; p=0.03) compared to Flu/Bu. In the chemosensitive subset, multivariate analysis showed a significantly higher mortality risk with Flu/Mel140 (HR=1.48, 95%CI=1.07-2.04, p=0.02) relative to Flu/Bu conditioning.

Conclusions: In the largest analysis comparing the impact of various RIC conditioning regimens on the survival of DLBCL patients undergoing allo-HCT, our results suggest that Flu/Bu is a better RIC choice in less fit or heavily pretreated patients due to lowest NRM risk.

Keywords: Reduced-intensity conditioning; allogeneic hematopoietic cell transplant; diffuse large B-cell lymphoma; survival.

Copyright © 2020. Published by Elsevier Inc.

Conflict of interest statement


Declaration of Competing Interest The authors do not have any relevant competing interests pertaining to the manuscript
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46
Future Oncol




. 2020 Sep 21. doi: 10.2217/fon-2020-0415. Online ahead of print.
USP44 hypermethylation promotes cell proliferation and metastasis in breast cancer
Xin Chen 1, Xiaotang Wu 2, Wen Lei 3
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PMID: 32956592
DOI: 10.2217/fon-2020-0415

Abstract


Aim: The methylation and expression levels of USP44 in breast cancer were investigated and their effects on tumor cells were researched. Materials & Methods: Bioinformatics was employed to identify the target gene from TCGA database. Sodium bisulfite and decitabine were used for DNA modification and demethylation, and methylation-specific PCR and reverse transcriptase PCR were performed to assess USP44 methylation and expression levels. Tumor cell behaviors were assayed via several in vitro experiments. Results: USP44 was hypermethylated, which caused its poor expression in breast cancer, whereas its overexpression significantly suppressed cancer cell proliferation, migration and invasion and induced apoptosis. Conclusion: USP44 negatively functions in cancer progression upon overexpression, indicating its potential as a therapeutic target for clinical treatment of breast cancer.

Keywords: DAC; DNA methylation; USP44; apoptosis; breast cancer; epigenetics; invasion; migration; overexpression; proliferation.
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47
J Oncol Pharm Pract




. 2020 Sep 22;1078155220959428. doi: 10.1177/1078155220959428. Online ahead of print.
Neurotrophic tyrosine kinase inhibitors: A review of implications for patients, clinicians and healthcare services
Andrew Walker 1
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PMID: 32957860
DOI: 10.1177/1078155220959428

Abstract


Neurotrophic tyrosine receptor kinase (NTRK) inhibitors represent the latest advancement as a treatment option in targeted therapies for malignant disease. NTRK gene fusions involving NTRK1, 2 or 3 are implicated as genetics drivers for a number of tumour types which arise within adult and paedatric patients. NTRK inhibitors (Larotrectinib and Entrectinib) are effective agents which have demonstrated clinical benefit in the treatment of NTRK fusion positive solid tumours. Larotrectinib represents the first targeted agent to receive approval from international authorisation and commissioning bodies for the treatment of a specific genetic expression indiscriminate of the site from which the tumour has arisen. As such NTRK inhibitors could pave the way for international healthcare bodies to adopt a similar approach for future targeted therapies thereby altering the manner in which healthcare providers and patients are able to access and utilise innovative, targeted treatment options in future. The potential implications of this new approach are likely to impact upon several aspects of the traditional authorisation and commissioning pathways with potential changes to the design of clinical trials, the review and approval process by regulatory bodies and immunohistopathology services.

Keywords: Neurotrophic tyrosine receptor kinase; entrectinib; larotrectinib; neurotrophic tyrosine receptor kinase inhibitor; oncology.
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48
Am J Surg




. 2020 Sep 15;S0002-9610(20)30580-8. doi: 10.1016/j.amjsurg.2020.09.013. Online ahead of print.
Multi-Disciplinary Trauma Evaluation and Management Simulation (MD-TEAMS) training for emergency medicine and general surgery residents
Katharine E Caldwell 1, Al Lulla 2, Collyn T Murray 2, Rahul R Handa 3, Ernesto J Romo 2, Jason W Wagner 2, Paul E Wise 3, Jennifer M Leonard 3, Michael M Awad 3
Affiliations expand
PMID: 32958156
DOI: 10.1016/j.amjsurg.2020.09.013

Abstract


Background: Successful trauma resuscitation relies on multi-disciplinary collaboration. In most academic programs, general surgery (GS) and emergency medicine (EM) residents rarely train together before functioning as a team.

Methods: In our Multi-Disciplinary Trauma Evaluation and Management Simulation (MD-TEAMS), EM and GS residents completed manikin-based trauma scenarios and were evaluated on resuscitation and communication skills. Residents were surveyed on confidence surrounding training objectives.

Results: Residents showed improved confidence running trauma scenarios in multi-disciplinary teams. Residents received lower communication scores from same-discipline vs cross-discipline faculty. EM residents scored higher in evaluation and planning domains; GS residents scored higher in action processes; groups scored equally in team management. Strong correlation existed between team leader communication and resuscitative skill completion.

Conclusion: MD-TEAMS demonstrated correlation between communication and resuscitation checklist item completion and communication differences by resident specialty. In the future, we plan to evaluate training-related resident behavior changes and specialty-specific communication differences by residents.

Keywords: Communication; Multi-disciplinary; Simulation; Surgical education; Trauma.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Conflict of interest statement


Declaration of competing interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Salary support for KEC was provided by the Washington University School of Medicine Surgical Oncology Basic Science and Translational Research Training Program grant T32CA009621, from the National Cancer Institute (NCI). All other authors declare no relevant conflicts of interest.
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49
Review
Cell Mol Bioeng




. 2020 Jun 15;13(4):341-357. doi: 10.1007/s12195-020-00625-0. eCollection 2020 Aug.
Organoids as Complex In Vitro Models for Studying Radiation-Induced Cell Recruitment
Benjamin C Hacker 1, Marjan Rafat 1 2 3
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PMID: 32952734
PMCID: PMC7479086 (available on 2021-06-15)
DOI: 10.1007/s12195-020-00625-0

Abstract


Patients with triple negative breast cancer (TNBC) typically receive chemotherapy, surgery, and radiation therapy. Although this treatment improves prognosis for most patients, some patients continue to experience recurrence within 5 years. Preclinical studies have shown that immune cell infiltration at the irradiated site may play a significant role in tumor cell recruitment; however, little is known about the mechanisms that govern this process. This lack of knowledge highlights the need to evaluate radiation-induced cell infiltration with models that have controllable variables and maintain biological integrity. Mammary organoids are multicellular three-dimensional (3D) in vitro models, and they have been used to examine many aspects of mammary development and tumorigenesis. Organoids are also emerging as a powerful tool to investigate normal tissue radiation damage. In this review, we evaluate recent advances in mammary organoid technology, consider the advantages of using organoids to study radiation response, and discuss future directions for the applications of this technique.

Keywords: Cell–cell interactions; immune cell co-culture; ionizing radiation; organoid models; radiotherapy; recurrence; triple negative breast cancer.

© Biomedical Engineering Society 2020.
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50
Transl Lung Cancer Res




. 2020 Aug;9(4):1343-1360. doi: 10.21037/tlcr-19-638.
PD-L1 as a prognostic biomarker in surgically resectable non-small cell lung cancer: a meta-analysis
Stephanie Tuminello 1, Daniel Sikavi 2, Rajwanth Veluswamy 1 3, Cesar Gamarra 1, Wil Lieberman-Cribbin 1, Raja Flores 4, Emanuela Taioli 1 4 5
Affiliations expand
PMID: 32953509
PMCID: PMC7481631
DOI: 10.21037/tlcr-19-638Free PMC article

Abstract


Background: PD-L1 tumor expression has been associated with poor prognosis in a variety of solid tumors, including lung cancer, and represents a validated target for immune checkpoint inhibition in advanced malignances. It remains unknown, however, if PD-L1 can be used to predict survival in early stage, surgically treated cancers. This meta-analysis compares PD-L1 tumor expression and long term survival after surgical resection in early non-small cell lung cancer (NSCLC).

Methods: PubMed was searched to identify eligible studies that compared survival of surgically resected stage I-III NSCLC patients according to PD-L1 tumor expression. Included studies were grouped according to measurement criteria of PD-L1 expression: 1%, 5%, 50% cutoffs or H-score. Meta-analysis was performed using a linear mixed-effects model to determine overall survival (OS). I2 was used as a measure of heterogeneity.

Results: There were 40 eligible studies, including 10,380 patients. Regardless of cut-off used, higher PD-L1 tumor expression was associated with worse OS [hazard ratio (HR)1%: 1.59, 95% confidence interval (CI), 1.17-2.17; HR5%: 1.44, 95% CI, 1.03-2.00; HR50%: 1.52, 95% CI, 1.02-2.25, HRH-score: 1.34, 95% CI, 1.04-1.73]. Study heterogeneity was low and not statistically significant under all PD-L1 cutoffs.

Conclusions: PD-L1 expression is consistently associated with worse survival, regardless of how it is quantified. In addition to acting as a prognostic biomarker, PD-L1 may also be used in future as a predictive biomarker for patients most likely to benefit from adjuvant immunotherapy.

Keywords: Carcinoma; costimulatory protein; immunotherapy; non-small cell lung; programmed death-ligand 1 (PD-L1).

2020 Translational Lung Cancer Research. All rights reserved.

Conflict of interest statement


Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-19-638). Dr. Veluswamy has received research funding from the Lung Cancer Research Foundation; has received a CTSA KL2 Scholars Award and a BMS IIT grant; has participated on scientific advisory boards for Merck, BMS, and AstraZeneca; and was on the Speakers Bureau (unbranded) for AstraZeneca. The other authors have no conflicts of interest to declare.

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