Oncology

Review
Cancer Epidemiol Biomarkers Prev




. 2019 Oct;28(10):1563-1579. doi: 10.1158/1055-9965.EPI-19-0221.
Cancer Progress and Priorities: Lung Cancer
Matthew B Schabath 1 2, Michele L Cote 3 4
Affiliations expand
PMID: 31575553
PMCID: PMC6777859
DOI: 10.1158/1055-9965.EPI-19-0221Free PMC article

Abstract


In the United States, lung cancer is the second most common diagnosed cancer and the leading cause of cancer-related death. Though tobacco smoking is the major risk factor accounting for 80 to 90% of all lung cancer diagnoses, there are numerous other risk factors that have been identified as casually associated with lung cancer etiology. However, there are few causally-linked risk factors for lung cancer diagnosed among never smokers which, if considered a unique reportable category, is the 11th most common cancer and the 7th leading cause of cancer-related death. Lung cancer survival has only marginally improved over the last several decades, but the availability of screening and early detection by low-dose computer tomography and advances in targeted treatments and immunotherapy will likely decrease mortality rates and improve patient survival outcomes in the near future.

Cited by 5 articles
10 figures
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2
Cell Death Dis




. 2019 Sep 17;10(10):682. doi: 10.1038/s41419-019-1897-2.
Metadherin enhances vulnerability of cancer cells to ferroptosis
Jianling Bi 1, Shujie Yang 2 3, Long Li 1, Qun Dai 4 5, Nicholas Borcherding 3 6, Brett A Wagner 7, Garry R Buettner 3 7, Douglas R Spitz 3 7, Kimberly K Leslie 1 3, Jun Zhang 8 9 10 11, Xiangbing Meng 12 13 14
Affiliations expand
PMID: 31527591
PMCID: PMC6746770
DOI: 10.1038/s41419-019-1897-2Free PMC article

Abstract


Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death driven by lipid hydroperoxides within biological membranes. Although therapy-resistant mesenchymal-high cancers are particularly vulnerable to ferroptosis inducers, especially phospholipid glutathione peroxidase 4 (GPx4) inhibitors, the underlying mechanism is yet to be deciphered. As such, the full application of GPx4 inhibitors in cancer therapy remains challenging. Here we demonstrate that metadherin (MTDH) confers a therapy-resistant mesenchymal-high cell state and enhanced sensitivity to inducers of ferroptosis. Mechanistically, MTDH inhibited GPx4, as well as the solute carrier family 3 member 2 (SLC3A2, a system Xc- heterodimerization partner), at both the messenger RNA and protein levels. Our metabolomic studies demonstrated that MTDH reduced intracellular cysteine, but increased glutamate levels, ultimately decreasing levels of glutathione and setting the stage for increased vulnerability to ferroptosis. Finally, we observed an enhanced antitumor effect when we combined various ferroptosis inducers both in vitro and in vivo; the level of MTDH correlated with the ferroptotic effect. We have demonstrated for the first time that MTDH enhances the vulnerability of cancer cells to ferroptosis and may serve as a therapeutic biomarker for future ferroptosis-centered cancer therapy.

Conflict of interest statement


The authors declare that they have no conflict of interest.

Cited by 1 article
44 references
8 figures
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3
Front Immunol




. 2019 May 8;10:1016. doi: 10.3389/fimmu.2019.01016. eCollection 2019.
Hematopoietic-Specific Deletion of Foxo1 Promotes NK Cell Specification and Proliferation
Pei Huang 1, Fangjie Wang 1, Yao Yang 1, Wenjing Lai 1, Meng Meng 1, Shuting Wu 2, Hongyan Peng 2, Lili Wang 2, Rixing Zhan 3, Saber Imani 4, Jianhua Yu 5, Bingbo Chen 6, Xiaohui Li 1, Youcai Deng 1
Affiliations expand
PMID: 31139183
PMCID: PMC6519137
DOI: 10.3389/fimmu.2019.01016Free PMC article

Abstract


We previously reported that deletion of Foxo1, via Ncr1-iCre mice from the expression of NKp46 onward, led to enhanced natural killer (NK) cell maturation and effector function. In this model, however, the role of Foxo1 in regulating NK cell specification and early development remains exclusive. Herein, we utilized a murine model of hematopoietic-specific deletion of Foxo1 before lymphoid specification, by crossing mice carrying floxed Foxo1 alleles (Foxo1 fl/fl) with Vav1-iCre mice, to revisit the role of Foxo1 on NK cell specification and early development. The data showed that hematopoietic-specific deletion of Foxo1 resulted in increased proportion and numbers of common lymphoid progenitors (CLP) (Lin-CD127+c-Kit+Sca-1+), pre-pro NK b cells (Lin-Sca-1+c-Kit-CD135-CD127+), as well as committed Lin-CD122+ cells and CD3-CD19-NKp46+ NK cells in bone marrow. Hematopoietic-specific deletion of Foxo1 also promoted NK cells proliferation in a cell-intrinsic manner, indicated by increased Ki-67 expression and more expansion of NK cell after ex vivo stimulation with IL-15. The reason for Foxo1 suppressing NK cell proliferation might be its direct transcription of the cell-cycle inhibitory genes, such as p21 cip1, p27 kip1, p130, Gadd45a, and Ccng2 (cyclin G2) in NK cells, supported by the evidence of decreased mRNA expression of p21 cip1, p27 kip1, p130, Gadd45a, and Ccng2 in Foxo1-deficient NK cells and direct binding of Foxo1 on their promoter region. Furthermore, hematopoietic-specific deletion of Foxo1 resulted in increased ratio of mature NK subsets, such as CD11b+CD27- and CD43+KLRG1+ NK cells, but decreased ratio of immature NK subsets, such as CD27+CD11b- and CD27+CD11b+ NK cells, consistent with the findings in the murine model of Ncr1-iCre mediated Foxo1 deletion. Conclusively, Foxo1 not only acts as a negative checkpoint on NK cell maturation, but also represses NK cell specification and proliferation. The relative higher expression of Foxo1 in CLP and early NK precursors may also contribute to the later NK cell proliferation and responsiveness, which warranties another separate study in the future.

Keywords: Foxo1; NK proliferation; NK specification; cell cycle; natural killer cell.

Cited by 2 articles
43 references
4 figures
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4
Eur J Nucl Med Mol Imaging




. 2019 Dec;46(13):2790-2799. doi: 10.1007/s00259-019-04495-1. Epub 2019 Sep 4.
Prediction of outcome in anal squamous cell carcinoma using radiomic feature analysis of pre-treatment FDG PET-CT
P J Brown 1, J Zhong 2, R Frood 2, S Currie 2 3, A Gilbert 3 4, A L Appelt 3 4, D Sebag-Montefiore 3 4, A Scarsbrook 2 3
Affiliations expand
PMID: 31482428
PMCID: PMC6879433
DOI: 10.1007/s00259-019-04495-1Free PMC article

Abstract


Purpose: Incidence of anal squamous cell carcinoma (ASCC) is increasing, with curative chemoradiotherapy (CRT) as the primary treatment of non-metastatic disease. A significant proportion of patients have locoregional treatment failure (LRF), but distant relapse is uncommon. Accurate prognostication of progression-free survival (PFS) would help personalisation of CRT regimens. The study aim was to evaluate novel imaging pre-treatment features, to prognosticate for PFS in ASCC.

Methods: Consecutive patients with ASCC treated with curative intent at a large tertiary referral centre who underwent pre-treatment FDG-PET/CT were included. Radiomic feature extraction was performed using LIFEx software on baseline FDG-PET/CT. Outcome data (PFS) was collated from electronic patient records. Elastic net regularisation and feature selection were used for logistic regression model generation on a randomly selected training cohort and applied to a validation cohort using TRIPOD guidelines. ROC-AUC analysis was used to compare performance of a regression model encompassing standard clinical prognostic factors (age, sex, tumour and nodal stage-model A), a radiomic feature model (model B) and a combined radiomic/clinical model (model C).

Results: A total of 189 patients were included in the study, with 145 in the training cohort and 44 in the validation cohort. Median follow-up was 35.1 and 37. 9 months, respectively for each cohort, with 70.3% and 68.2% reaching this time-point with PFS. GLCM entropy (a measure of randomness of distribution of co-occurring pixel grey-levels), NGLDM busyness (a measure of spatial frequency of changes in intensity between nearby voxels of different grey-level), minimum CT value (lowest HU within the lesion) and SMTV (a standardized version of MTV) were selected for inclusion in the prognostic model, alongside tumour and nodal stage. AUCs for performance of model A (clinical), B (radiomic) and C (radiomic/clinical) were 0.6355, 0.7403, 0.7412 in the training cohort and 0.6024, 0.6595, 0.7381 in the validation cohort.

Conclusion: Radiomic features extracted from pre-treatment FDG-PET/CT in patients with ASCC may provide better PFS prognosis than conventional staging parameters. With external validation, this might be useful to help personalise CRT regimens in the future.

Keywords: Anal squamous cell carcinoma (ASCC); FDG-PET/CT; Outcome prediction; Radiomic feature analysis.

Conflict of interest statement


The authors declare that they have no conflict of interest.

Cited by 2 articles
44 references
2 figures
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5
J Natl Cancer Inst




. 2020 Mar 1;112(3):278-285. doi: 10.1093/jnci/djz113.
Comparative Validation of Breast Cancer Risk Prediction Models and Projections for Future Risk Stratification
Parichoy Pal Choudhury 1, Amber N Wilcox 2 3, Mark N Brook 4, Yan Zhang 1, Thomas Ahearn 2 3, Nick Orr 1 5 6 7, Penny Coulson 4, Minouk J Schoemaker 4, Michael E Jones 4, Mitchell H Gail 2 3, Anthony J Swerdlow 4 6, Nilanjan Chatterjee, Montserrat Garcia-Closas 2 3
Affiliations expand
PMID: 31165158
PMCID: PMC7073933
DOI: 10.1093/jnci/djz113Free PMC article

Abstract


Background: External validation of risk models is critical for risk-stratified breast cancer prevention. We used the Individualized Coherent Absolute Risk Estimation (iCARE) as a flexible tool for risk model development and comparative model validation and to make projections for population risk stratification.

Methods: Performance of two recently developed models, one based on the Breast and Prostate Cancer Cohort Consortium analysis (iCARE-BPC3) and another based on a literature review (iCARE-Lit), were compared with two established models (Breast Cancer Risk Assessment Tool and International Breast Cancer Intervention Study Model) based on classical risk factors in a UK-based cohort of 64 874 white non-Hispanic women (863 patients) age 35-74 years. Risk projections in a target population of US white non-Hispanic women age 50-70 years assessed potential improvements in risk stratification by adding mammographic breast density (MD) and polygenic risk score (PRS).

Results: The best calibrated models were iCARE-Lit (expected to observed number of cases [E/O] = 0.98, 95% confidence interval [CI] = 0.87 to 1.11) for women younger than 50 years, and iCARE-BPC3 (E/O = 1.00, 95% CI = 0.93 to 1.09) for women 50 years or older. Risk projections using iCARE-BPC3 indicated classical risk factors can identify approximately 500 000 women at moderate to high risk (>3% 5-year risk) in the target population. Addition of MD and a 313-variant PRS is expected to increase this number to approximately 3.5 million women, and among them, approximately 153 000 are expected to develop invasive breast cancer within 5 years.

Conclusions: iCARE models based on classical risk factors perform similarly to or better than BCRAT or IBIS in white non-Hispanic women. Addition of MD and PRS can lead to substantial improvements in risk stratification. However, these integrated models require independent prospective validation before broad clinical applications.

Published by Oxford University Press 2019. This work is written by US Government employees and is in the public domain in the US.

Cited by 8 articles
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6
Review
Curr Opin Urol




. 2020 Mar;30(2):208-212. doi: 10.1097/MOU.0000000000000730.
Human papillomavirus vaccination and prevention of intraepithelial neoplasia and penile cancer: review article
João F da Costa Nunes 1, Sanarelly Pires, Daher C Chade
Affiliations expand
PMID: 31972636
DOI: 10.1097/MOU.0000000000000730

Abstract


Purpose of review: The objective of the current article is to promote a literature revision of the relationship between the prevention of intraepithelial neoplasms (PeIN) and invasive penile cancer, and human papillomavirus (HPV) vaccination, aiming to enumerate the pros and cons of immunization.

Recent findings: The immunization against the HPV is sufficiently safe and many countries have incorporated the vaccine to their immunization calendar. Compared with men, the sampling size and the evidence quality of scientific researches among the female population are more robust. Some randomized and nonrandomized studies suggest that vaccination reduces the incidence of genital warts and no PeIN and penile cancer cases were developed in the vaccinal group. However, 70% of patients can evolve with the neoplasia despite having been immunized and even among HPV infected patients, only 1% will develop cancer.

Summary: The studies about vaccination against HPV and prevention on penile cancer are conflicting and the main academic urology societies still have not incorporated vaccination of men in their guidelines. Future studies are necessary to confirm the efficiency and cost-benefit of the vaccine in men to prevent intraepithelial neoplasms and invasive penile cancer.
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7
Adv Exp Med Biol




. 2020;1268:53-114. doi: 10.1007/978-3-030-46227-7_4.
Vitamin D Receptor Polymorphisms and Cancer
Patrizia Gnagnarella 1, Sara Raimondi 2, Valentina Aristarco 3, Harriet Ann Johansson 3, Federica Bellerba 2, Federica Corso 2, Sara Gandini 4
Affiliations expand
PMID: 32918214
DOI: 10.1007/978-3-030-46227-7_4

Abstract


Increasing scientific evidence supports the link between vitamin D and cancer risk. The active metabolite 1,25(OH)2D exerts its activity by binding to the vitamin D receptor (VDR), an intracellular receptor that mediates transcriptional activation and repression of target genes. The binding of 1,25(OH)2D to VDR is able to regulate hundreds of different genes. VDR is active in virtually all tissues including the colon, breast, lung, ovary, bone, kidney, parathyroid gland, pancreatic b-cells, monocytes, T lymphocytes, melanocytes, keratinocytes, and also cancer cells.The relevance of VDR gene restriction fragment length polymorphisms for various types of cancer has been investigated by a great number of studies.We have carried out a systematic review of the literature to analyze the relevance of more VDR polymorphisms (Fok1, Bsm1, Taq1, Apa1, and Cdx2) for individual malignancies considering ethnicity as a key factor for heterogeneity.Up to December 2018, we identified 176 independent studies with data to assess the risk of breast, prostate, colorectal, skin (melanoma and non-melanoma skin cancer), lung, ovarian, kidney, bladder, gallbladder, esophageal, thyroid, head and neck, liver and pancreatic cancer, oral squamous cell carcinoma, non-Hodgkin lymphoma, multiple myeloma and sarcoma.Significant associations with VDR polymorphisms have been reported for prostate (Fok1, Bsm1, Taq1, Apa1, Cdx2), breast (Fok1, Bsm1, Taq1, Apa1, CdX2), colorectal (Fok1, Bsm1, Taq1, Apa1), and skin cancer (Fok1, Bsm1, Taq1). Very few studies reported risk estimates for the other cancer sites.Conflicting data have been reported for most malignancies, and at present, it is still not possible to make any definitive statements about the importance of the VDR genotype for cancer risk. It seems probable that other factors such as ethnicity, phenotype, 25(OH)D plasma levels, and UV radiation exposure play a role as confounding factors and introduce heterogeneity.To conclude, there is some indication that VDR polymorphisms may modulate the risk of some cancer sites and in future studies VDR genetic variation should be integrated also with assessment of vitamin D status and stratified by ethnicity.

Keywords: 25-Hydroxyvitamin D; Apa1; Basal cell carcinoma; Breast cancer; Bsm1; Cancer; Cdx2; Colon-rectum cancer; Esophageal adenocarcinoma; Fok1; Head and neck cancer; Hepatocellular carcinoma; Melanoma; Meta-analysis; Nasopharyngeal carcinoma; Non-Hodgkin lymphoma; Oral squamous cell carcinoma; Prostate cancer; Renal cell carcinoma; Risk estimates; Squamous cell carcinoma; Taq1; Thyroid carcinoma; Ultraviolet; VDR polymorphisms; Vitamin D.
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8
Cancer Epidemiol Biomarkers Prev




. 2019 Oct;28(10):1559-1562. doi: 10.1158/1055-9965.EPI-19-0043. Epub 2019 Aug 28.
Addressing Challenges in Converting Grant-Funded Infrastructures to Broadly Used Research Resources
Betsy Rolland 1, Ann M Geiger 2
Affiliations expand
PMID: 31462397
DOI: 10.1158/1055-9965.EPI-19-0043

Abstract


The NCI invests heavily in research resources to serve the research community, including datasets, biospecimen banks, and networks of institutions in which clinical trials and other human subjects research are conducted. These resources often begin as grant-funded infrastructure initiated by scientists based on their own scientific interests, with a subsequent recognition of additional scientific uses. Although converting existing project-specific research activities into research resources may appear efficient in terms of time and financial investment, challenges can arise that undermine this efficiency and jeopardize future use. Here, we describe three challenges in the conversion process: (i) project-based infrastructure versus a research resource for a broader research community; (ii) complexity versus ease of use; and (iii) individual professional goals versus research resource priorities. We use our experience with the NCI-funded Cancer Research Network, particularly the Virtual Data Warehouse, to illustrate each challenge, concluding with strategies to mitigate each one. As studies grow in size and complexity, an ever-increasing volume of data, biospecimens, and human subjects research networks will be available for conversion to resources for scientific questions beyond those originally proposed. Addressing likely challenges thoughtfully can result in a more efficient conversion process and ultimately greater scientific impact.

©2019 American Association for Cancer Research.
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9
Review
Can Respir J




. 2020 Sep 5;2020:1401053. doi: 10.1155/2020/1401053. eCollection 2020.
Tuberculosis and COVID-19: Lessons from the Past Viral Outbreaks and Possible Future Outcomes
Radu Crisan-Dabija 1, Cristina Grigorescu 2, Cristina-Alice Pavel 3, Bogdan Artene 4, Iolanda Valentina Popa 5 6, Andrei Cernomaz 7, Alexandru Burlacu 4 6
Affiliations expand
PMID: 32934758
PMCID: PMC7479474
DOI: 10.1155/2020/1401053Free PMC article

Abstract


Background: The threat of contagious infectious diseases is constantly evolving as demographic explosion, travel globalization, and changes in human lifestyle increase the risk of spreading pathogens, leading to accelerated changes in disease landscape. Of particular interest is the aftermath of superimposing viral epidemics (especially SARS-CoV-2) over long-standing diseases, such as tuberculosis (TB), which remains a significant disease for public health worldwide and especially in emerging economies.

Methods and results: The PubMed electronic database was systematically searched for relevant articles linking TB, influenza, and SARS-CoV viruses and subsequently assessed eligibility according to inclusion criteria. Using a data mining approach, we also queried the COVID-19 Open Research Dataset (CORD-19). We aimed to answer the following questions: What can be learned from other coronavirus outbreaks (focusing on TB patients)? Is coinfection (TB and SARS-CoV-2) more severe? Is there a vaccine for SARS-CoV-2? How does the TB vaccine affect COVID-19? How does one diagnosis affect the other? Discussions. Few essential elements about TB and SARS-CoV coinfections were discussed. First, lessons from past outbreaks (other coronaviruses) and influenza pandemic/seasonal outbreaks have taught the importance of infection control to avoid the severe impact on TB patients. Second, although challenging due to data scarcity, investigating the pathological pathways linking TB and SARS-CoV-2 leads to the idea that their coexistence might yield a more severe clinical evolution. Finally, we addressed the issues of vaccination and diagnostic reliability in the context of coinfection.

Conclusions: Because viral respiratory infections and TB impede the host's immune responses, it can be assumed that their lethal synergism may contribute to more severe clinical evolution. Despite the rapidly growing number of cases, the data needed to predict the impact of the COVID-19 pandemic on patients with latent TB and TB sequelae still lies ahead. The trial is registered with NCT04327206, NCT01829490, and NCT04121494.

Copyright © 2020 Radu Crisan-Dabija et al.

Conflict of interest statement


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

69 references
2 figures
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10
Review
Crit Rev Oncol Hematol




. 2020 Sep;153:103062. doi: 10.1016/j.critrevonc.2020.103062. Epub 2020 Jul 17.
Anaplastic Astrocytoma: State of the art and future directions
Mario Caccese 1, Marta Padovan 2, Domenico D'Avella 3, Franco Chioffi 4, Marina Paola Gardiman 5, Franco Berti 6, Fabio Busato 6, Luisa Bellu 6, Eleonora Bergo 2, Marco Zoccarato 7, Matteo Fassan 5, Vittorina Zagonel 2, Giuseppe Lombardi 2
Affiliations expand
PMID: 32717623
DOI: 10.1016/j.critrevonc.2020.103062

Abstract


Anaplastic Astrocytoma(AA) is a malignant, diffusely infiltrating, primary brain tumor. According to the WHO 2016 classification of central-nervous-system tumors, AA has been described as a glial tumor with no co-deletion of 1p/19q, and is divided into IDH mutated tumor, characterized by better prognosis, and IDH wild-type form, with worse prognosis. The standard of care is maximal safe resection followed by radiotherapy and chemotherapy with temozolomide. Several efforts have been made to evaluate, according to molecular selection, which is the best post-surgical treatment. At recurrence, the treatment remains challenging and some trials are ongoing to evaluate new potential drugs, alone or in combination with chemotherapy. We performed a description of the status of the art on diagnosis, molecular characteristics and treatment of AA. In particular, we focused our details on new drugs; indeed, a deeper knowledge of the molecular characteristics of gliomas could lead to to development of active personalized treatments according with precision medicine.

Keywords: Anaplastic astrocytoma; Glioma; New drugs.

Copyright © 2020 Elsevier B.V. All rights reserved.
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11
J Oral Maxillofac Surg




. 2020 Jul;78(7):1193-1202. doi: 10.1016/j.joms.2020.01.032. Epub 2020 Feb 5.
Oral Lichen Planus-Associated Oral Cavity Squamous Cell Carcinoma Is Associated With Improved Survival and Increased Risk of Recurrence
David L Best 1, Curtis Herzog 2, Corey Powell 3, Thomas Braun 4, Brent B Ward 5, Justine Moe 6
Affiliations expand
PMID: 32114008
DOI: 10.1016/j.joms.2020.01.032

Abstract


Purpose: We investigated the overall survival (OS), disease-specific survival (DSS), and disease-free survival among patients with oral lichen planus-associated oral cavity squamous cell carcinoma (OLP-OCSCC). The secondary objective was to assess the annual risk of tumor recurrence or second primary tumor (SPT).

Materials and methods: A comparative retrospective study was performed of patients with OLP-OCSCC presenting between June 2007 and December 2018 to the Department of Oral and Maxillofacial Surgery, Michigan Medicine (Ann Arbor, MI) and patients with OCSCC in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database (1973 to 2015).

Results: A total of 87 patients with OLP-OCSCC met the inclusion criteria, and 55,165 patients with OCSCC from the SEER database were included. The proportion of women was greater in the OLP group than in the SEER group (56.3 vs 38.0%; P < .001). In the OLP group, 47.1% had no smoking history and 43.7% had no alcohol history. Most patients in the OLP group had presented with stage I disease (46.0%) compared with 31.7% in the SEER group (P = .004). Overall, the OS and DSS were significantly greater in the OLP group than in the SEER group at all points from 1 to 5 years (P ≤ .01). In the OLP group, 46 patients (52.9%) had at least 1 recurrence or SPT. At 10 years, the predicted mean number of recurrences was 1.93 per patient (95% confidence interval, 1.56 to 2.39).

Conclusions: OLP-OCSCC frequently affects women, nonsmokers, and nondrinkers and presents with localized disease at a high frequency. Patients with OLP-OCSCC have increased OS and DSS and a greater risk of tumor recurrence or SPT compared with OCSCC in the general population. Lifelong, frequent surveillance is recommended for patients with OLP-OCSCC owing to the risk of late recurrence. Future studies are needed to understand the pathophysiology of OLP-OCSCC.

Copyright © 2020 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.
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12
Review
Int J Public Health




. 2020 Sep;65(7):1205-1216. doi: 10.1007/s00038-020-01463-7. Epub 2020 Sep 4.
The psychosocial impact of flu influenza pandemics on healthcare workers and lessons learnt for the COVID-19 emergency: a rapid review
Serena Barello 1 2, Anna Falcó-Pegueroles 3, Debora Rosa 4, Angela Tolotti 5, Guendalina Graffigna 6 7, Loris Bonetti 8 9
Affiliations expand
PMID: 32888048
PMCID: PMC7472941
DOI: 10.1007/s00038-020-01463-7Free PMC article

Abstract


Objectives: During a pandemic, healthcare workers (HCWs) are essential to the health system response. Based on our knowledge, little information is available regarding the psychosocial impact on HCWs or interventions for supporting them during pandemics. Therefore, the study aimed to assess available literature on perceived stress and psychological responses to influenza pandemics in HCWs and identify implications for healthcare practice and future research.

Methods: This is a rapid review of the literature. The review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis.

Results: Across all the studies-both qualitative and quantitative-HCWs working during the epidemic reported frequent concerns regarding their own health and the fear of infecting their families, friends and colleagues. Moreover, social isolation, uncertainty, fears of stigmatization and reluctance to work or considering absenteeism were frequently reported. Moreover, many studies highlighted a high prevalence of high levels of stress, anxiety and depression symptoms, which could have long-term psychological implications in HCWs.

Conclusions: This rapid review offers an overview of the major concerns regarding HCWs' psychosocial well-being and possible preventive strategies, which could be useful for the current COVID-19 outbreak and similar future pandemics. Studies suggested to invest on preventive psychological, social, family and physical support and to guaranteeing reasonable work conditions and others in order to protect HCWs from the long-lasting psychological effect of the COVID-19 pandemic.

Keywords: COVID-19; Health personnel; Nurse; Pandemics; Physician; Psychology.

Conflict of interest statement


The authors declare that they have no conflict of interest.

54 references
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13
Review
Cancers (Basel)




. 2020 Sep 19;12(9):E2679. doi: 10.3390/cancers12092679.
Adjuvant Chemotherapy for Stage III Colon Cancer
Julien Taieb 1 2, Claire Gallois 1 2
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PMID: 32961795
DOI: 10.3390/cancers12092679Free article

Abstract


In patients with stage III colon cancer (CC), adjuvant chemotherapy with the combination of oxapliplatin to a fluoropyrimidine (FOLFOX or CAPOX) is a standard of care. The duration of treatment can be reduced from 6 months to 3 months, depending on the regimen, for patients at low risk of recurrence, without loss of effectiveness and allowing a significant reduction in the risk of cumulative sensitive neuropathy. However, our capacity to identify patients that do really need this doublet adjuvant treatment remains limited. In fact, only 30% at the most will actually benefit from this adjuvant treatment, 50% of them being already cured by the surgery and 20% of them experiencing disease recurrence despite the adjuvant treatment. Thus, it is necessary to be able to better predict individually for each patient the risk of recurrence and the need for adjuvant chemotherapy together with the need of new treatment approaches for specific subgroups. Many biomarkers have been described with their own prognostic weight, without leading to any change in clinical practices for now. In this review, we will first discuss the recommendations for adjuvant chemotherapy, and then the different biomarkers described and the future perspectives for the management of stage III CC.

Keywords: adjuvant chemotherapy; colon cancer; prognosis.
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14
Review
Asia Pac J Clin Oncol




. 2020 Sep 24. doi: 10.1111/ajco.13449. Online ahead of print.
Role and mechanism of autophagy-regulating factors in tumorigenesis and drug resistance
Rana Muhammad Usman 1, Faryal Razzaq 2, Arshia Akbar 3, Arafat Ali Farooqui 4, Ahmad Iftikhar 5, Azka Latif 6, Hamza Hassan 7, Jianjun Zhao 8, Jennifer S Carew 5, Steffan T Nawrocki 5, Faiz Anwer 8
Affiliations expand
PMID: 32970929
DOI: 10.1111/ajco.13449

Abstract


A hallmark feature of tumorigenesis is uncontrolled cell division. Autophagy is regulated by more than 30 genes and it is one of several mechanisms by which cells maintain homeostasis. Autophagy promotes cancer progression and drug resistance. Several genes play important roles in autophagy-induced tumorigenesis and drug resistance including Beclin-1, MIF, HMGB1, p53, PTEN, p62, RAC3, SRC3, NF-2, MEG3, LAPTM4B, mTOR, BRAF and c-MYC. These genes alter cell growth, cellular microenvironment and cell division. Mechanisms involved in tumorigenesis and drug resistance include microdeletions, genetic mutations, loss of heterozygosity, hypermethylation, microsatellite instability and translational modifications at a molecular level. Disrupted or altered autophagy has been reported in hematological malignancies like lymphoma, leukemia and myeloma as well as multiple solid organ tumors like colorectal, hepatocellular, gall bladder, pancreatic, gastric and cholangiocarcinoma among many other malignancies. In addition, defects in autophagy also play a role in drug resistance in cancers like osteosarcoma, ovarian and lung carcinomas following treatment with drugs such as doxorubicin, paclitaxel, cisplatin, gemcitabine and etoposide. Therapeutic approaches that modulate autophagy are a novel future direction for cancer drug development that may help to prevent issues with disease progression and overcome drug resistance.

Keywords: Autophagy-related genes; autophagy; drug resistance; hydroxychloroquine; tumorigenesis.

© 2020 John Wiley & Sons Australia, Ltd.

149 references
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15
Review
Crit Care




. 2020 Sep 16;24(1):559. doi: 10.1186/s13054-020-03273-y.
Comparison of published guidelines for management of coagulopathy and thrombosis in critically ill patients with COVID 19: implications for clinical practice and future investigations
Adam Flaczyk 1, Rachel P Rosovsky 2, Clay T Reed 3, Brittany K Bankhead-Kendall 4, Edward A Bittner 1, Marvin G Chang 5
Affiliations expand
PMID: 32938471
DOI: 10.1186/s13054-020-03273-yFree article

Abstract


Critically ill patients with COVID-19 are at increased risk for thrombotic complications which has led to an intense debate surrounding their anticoagulation management. In the absence of data from randomized controlled clinical trials, a number of consensus guidelines and recommendations have been published to facilitate clinical decision-making on this issue. However, substantive differences exist between these guidelines which can be difficult for clinicians. This review briefly summarizes the major societal guidelines and compares their similarities and differences. A common theme in all of the recommendations is to take an individualized approach to patient management and a call for prospective randomized clinical trials to address important anticoagulation issues in this population.

Keywords: Anticoagulation; COVID-19; Coronavirus; Hematologic monitoring; Therapeutic anticoagulation; Thrombosis; Venous thromboembolism.
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16
Review
Curr Opin Urol




. 2020 Mar;30(2):223-228. doi: 10.1097/MOU.0000000000000714.
Management of the penile squamous cell carcinoma patient after node positive radical inguinal lymph node dissection: current evidence and future prospects
Hielke M de Vries 1, Sarah R Ottenhof 1, Michiel S van der Heijden 2, Floris J Pos 3, Simon Horenblas 1, Oscar R Brouwer 1
Affiliations expand
PMID: 31895078
DOI: 10.1097/MOU.0000000000000714

Abstract


Purpose of review: The level of evidence for current (adjuvant) treatment strategies after node positive inguinal lymphadenectomy is relatively low because of a paucity of prospective studies and controversy exist between the two major guidelines. The present review aims to provide a review of current literature on the available treatment options of patients after a tumor positive inguinal lymph node dissection.

Recent findings: Patients without inguinal extranodal extension or less than two tumor positive inguinal nodes are at low risk of ipsilateral pelvic nodal disease. Patients with pN1 disease are unlikely to benefit from adjuvant treatment, whereas patients with pN2 disease might benefit from adjuvant radiotherapy. For patients with high risk of pelvic nodal disease, prophylactic pelvic lymph node dissection (PLND) is advised by current guidelines. The InPACT study investigates whether adjuvant chemoradiotherapy could be used instead of prophylactic PLND. Subgroup analyses of retrospective cohorts suggest that patients with pN3 disease based on tumor positive pelvic nodes may benefit from adjuvant radiotherapy or chemotherapy. Given the weak level of evidence and substantial toxicity associated with current regimens, adjuvant chemotherapy cannot be generally recommended.

Summary: Despite current treatment strategies, patients with pN2-pN3 disease still have a poor prognosis. Prospective international multicenter studies are necessary to identify the best treatment options for patients with advanced node positive penile squamous cell carcinoma.
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17
Sci Rep




. 2019 Mar 11;9(1):4155. doi: 10.1038/s41598-019-40697-1.
Computational analysis of the evolutionarily conserved Missing In Metastasis/Metastasis Suppressor 1 gene predicts novel interactions, regulatory regions and transcriptional control
Petar Petrov 1, Alexey V Sarapulov 2, Lel Eöry 3, Cristina Scielzo 4 5, Lydia Scarfò 4 5 6, Jacqueline Smith 3, David W Burt 7, Pieta K Mattila 8
Affiliations expand
PMID: 30858428
PMCID: PMC6411742
DOI: 10.1038/s41598-019-40697-1Free PMC article

Abstract


Missing in Metastasis (MIM), or Metastasis Suppressor 1 (MTSS1), is a highly conserved protein, which links the plasma membrane to the actin cytoskeleton. MIM has been implicated in various cancers, however, its modes of action remain largely enigmatic. Here, we performed an extensive in silico characterisation of MIM to gain better understanding of its function. We detected previously unappreciated functional motifs including adaptor protein (AP) complex interaction site and a C-helix, pointing to a role in endocytosis and regulation of actin dynamics, respectively. We also identified new functional regions, characterised with phosphorylation sites or distinct hydrophilic properties. Strong negative selection during evolution, yielding high conservation of MIM, has been combined with positive selection at key sites. Interestingly, our analysis of intra-molecular co-evolution revealed potential regulatory hotspots that coincided with reduced potentially pathogenic polymorphisms. We explored databases for the mutations and expression levels of MIM in cancer. Experimentally, we focused on chronic lymphocytic leukaemia (CLL), where MIM showed high overall expression, however, downregulation on poor prognosis samples. Finally, we propose strong conservation of MTSS1 also on the transcriptional level and predict novel transcriptional regulators. Our data highlight important targets for future studies on the role of MIM in different tissues and cancers.

Conflict of interest statement


The authors declare no competing interests.

Cited by 1 article
99 references
6 figures
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18
Review
Int J Mol Sci




. 2020 Sep 19;21(18):E6885. doi: 10.3390/ijms21186885.
Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies
Ingrid Lilienthal 1, Nikolas Herold 1 2
Affiliations expand
PMID: 32961800
DOI: 10.3390/ijms21186885Free article

Abstract


Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure. Introduction of combination chemotherapy in the 1970s, however, dramatically increased overall survival rates from 20% to approximately 70%. Unfortunately, large clinical trials aiming to intensify treatment in the past decades have failed to achieve higher cure rates. In this review, we revisit how the heterogenous nature of osteosarcoma as well as acquired and intrinsic resistance to chemotherapy can account for stagnation in therapy improvement. We summarise current osteosarcoma treatment strategies focusing on molecular determinants of treatment susceptibility and resistance. Understanding therapy susceptibility and resistance provides a basis for rational therapy betterment for both identifying patients that might be cured with less toxic interventions and targeting resistance mechanisms to sensitise resistant osteosarcoma to conventional therapies.

Keywords: chemoresistance; cisplatin; combination chemotherapy; doxorubicin; drug synergy; ifosfamide; immunotherapy; methotrexate; osteosarcoma; tumour microenvironment.
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19
Oral Dis




. 2020 Sep 22. doi: 10.1111/odi.13648. Online ahead of print.
Acute and cumulative benefits of Photobiomodulation for xerostomia: a systematic review and meta-analysis
Noelia Galiano-Castillo 1 2 3 4, Lizhou Liu 5, Mario Lozano-Lozano 1 2 3 4, Steve Tumilty 5, Irene Cantarero-Villanueva 1 2 3 4, George David Baxter 5
Affiliations expand
PMID: 32964596
DOI: 10.1111/odi.13648

Abstract


The objective was to explore the effectiveness of photobiomodulation therapy for treating patients who suffer xerostomia and/or hyposalivation due to the most prevalent clinical diagnoses. We searched PubMed, Scopus, Web of Science, CINAHL, and Cochrane Library for randomised or clinical controlled trials published until 31 October 2019. Risk of bias assessment and meta-analysis were conducted using the Cochrane tools. A total of 274 records were retrieved and 11 met the inclusion criteria. Interventions whose parameters ranged between wavelengths of 790-830nm (infrared), 30-120mW of power, and an energy density below 30J/cm-2 were associated with improvements in xerostomia/hyposalivation. As for the assessment of methodological quality, 10 of the 11 articles included had a high risk of overall bias. Only 3 articles provided sufficient information to conduct a meta-analysis for quality of life, compared with placebo in patients with burning mouth syndrome, showing a standardised mean difference between groups from baseline of -0.90 (-1.48;-0.32). The present review and meta-analysis suggest that photobiomodulation therapy is an effective, non-invasive and safe approach in patients with xerostomia. However, despite the potential, it is not possible to reach a reliable consensus on the parameters to be used, and future studies should be conducted by standardising intervention protocols.

Keywords: Low-Level Light Therapy; Meta-Analysis; Systematic Review; Xerostomia.

This article is protected by copyright. All rights reserved.
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20
Biochem Biophys Res Commun




. 2020 Mar 19;523(4):947-953. doi: 10.1016/j.bbrc.2020.01.048. Epub 2020 Jan 18.
Quercetin pretreatment enhances the radiosensitivity of colon cancer cells by targeting Notch-1 pathway
Yana Li 1, Zhicheng Wang 2, Jingji Jin 3, Shuang-Xi Zhu 4, Gan-Qing He 5, Sui-Hui Li 6, Jianfeng Wang 7, Yong Cai 8
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PMID: 31964531
DOI: 10.1016/j.bbrc.2020.01.048

Abstract


Cancer stem-like cells are rare immortal cells within tumor, which are thought to play important roles in ionizing radiation (IR) therapy-resistance. Quercetin is a natural flavonoid with potential anti-cancer properties without significant cytotoxicity in normal tissues. In this study, we demonstrated that quercetin-IR combination treatment exhibited more dramatic anti-cancer effect than either quercetin or IR treatment alone via targeting colon cancer stem cells (CSCs) and inhibiting the Notch-1 signaling. These effects were further verified by in vivo studies which showed remarkable decrease of the CSCs markers and the expression of Notch-1 signaling proteins in human colon cancer xenografts in nude mice. Co-treatment with quercetin and low dose of radiation significantly reduced the expressions of all five proteins of γ-secretase complex in HT-29 and DLD-1 cells. In addition, ectopic expression of the Notch intracellular domain (NICD) partly reversed the inhibition effects by the combination therapy. In conclusion, our results indicated that the combination of quercetin (20 μM) and IR (5Gy) might be a promising therapeutic strategy for colon cancer treatment by targeting colon cancer stem-like cells and inhibiting the Notch-1 signaling. In future studies, we intend to further explore the potential therapeutic efficacy of the quercetin-radiation combination treatment in clinical trials.

Keywords: Colon cancer; Notch-1; Quercetin; Radiotherapy.

Copyright © 2020 Elsevier Inc. All rights reserved.

Conflict of interest statement


Declaration of competing interest The following authors declared that they do not have anything to disclose regarding conflict of interest with respect to this manuscript:

Cited by 1 article
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21
Neurooncol Adv




. 2020 Aug 8;2(1):vdaa094. doi: 10.1093/noajnl/vdaa094. eCollection Jan-Dec 2020.
Long-term cognitive deficits in pediatric low-grade glioma (LGG) survivors reflect pretreatment conditions-report from the German LGG studies
Thomas Traunwieser 1, Daniela Kandels 1, Franz Pauls 2, Torsten Pietsch 3, Monika Warmuth-Metz 4, Brigitte Bison 4, Juergen Krauss 5, Rolf-Dieter Kortmann 6, Beate Timmermann 7, Ulrich-Wilhelm Thomale 8, Peggy Luettich 9, Anne Neumann-Holbeck 10, Tanja Tischler 10, Pablo Hernáiz Driever 11, Olaf Witt 9, Astrid K Gnekow 1
Affiliations expand
PMID: 32968720
PMCID: PMC7497816
DOI: 10.1093/noajnl/vdaa094Free PMC article

Abstract


Background: Disease and treatment contribute to cognitive late effects following pediatric low-grade glioma (LGG). We analyzed prospectively collected neuropsychological data of German pediatric LGG survivors and focused on the impact of hydrocephalus at diagnosis, neurofibromatosis type 1 (NF1) status, and extent of surgery.

Methods: We used the Neuropsychological Basic Diagnostic screening tool based on the Cattell-Horn-Carroll model for intelligence and the concept of cross-battery assessment at 2 and 5 years from diagnosis for 316 patients from the German pediatric LGG study and LGG registry (7.1 years median age; 45 NF1; cerebral hemispheres 16%, supratentorial midline 39%, infratentorial 45%). Hydrocephalus was classified radiologically in 137 non-NF1 patients with infratentorial tumors (95/137 complete/subtotal resection).

Results: Patients with NF1 versus non-NF1 exhibited inferior verbal short-term memory and visual processing (P < .001-.021). In non-NF1 patients, infratentorial tumor site and complete/subtotal resection were associated with sequelae in visual processing, psychomotor speed, and processing speed (P < .001-.008). Non-NF1 patients without surgical tumor reduction and/or nonsurgical treatment experienced similar deficits. Degree of hydrocephalus at diagnosis had no further impact. Psychomotor and processing speed were impaired comparably following chemo-/radiotherapy (P < .001-.021). Pretreatment factors such as NF1 or tumor site were relevant at multivariate analysis.

Conclusions: All pediatric LGG survivors are at risk to experience long-term cognitive impairments in various domains. Even surgical only management of cerebellar LGG or no treatment at all, that is, biopsy only/radiological diagnosis did not protect cognitive function. Since pattern and extent of deficits are crucial to tailor rehabilitation, neuropsychological and quality of survival assessments should be mandatory in future LGG trials.

Keywords: hydrocephalus; neurofibromatosis; neuropsychology; pediatric low-grade glioma; resection.

© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

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22
Oncology (Williston Park)




. 2020 Sep 15;34(9):377-378. doi: 10.46883/ONC.2020.3409.0377.
Is Telehealth Here To Stay
No authors listed
PMID: 32965670
DOI: 10.46883/ONC.2020.3409.0377

Abstract


The telehealth explosion was facilitated by the onset of the coronavirus disease 2019 (COVID-19) pandemic, but what happens when the crisis is over? Will there be lasting changes to the practice of medicine and delivery of care, or will providers and patients alike be eager to go back to the "old way" of doing things? Jeremy Gabrysch, MD, a physician and CEO of Remedy, an on-demand urgent care service that delivers doctors right to your front door, discusses what the future of telehealth may hold.
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23
Comparative Study
Microvasc Res




. 2020 Jul;130:104008. doi: 10.1016/j.mvr.2020.104008. Epub 2020 Apr 21.
Profiling the endothelial function using both peripheral artery tonometry (EndoPAT) and Laser Doppler Flowmetry (LD) - Complementary studies or waste of time?
Maciej Jakubowski 1, Aleksandra Turek-Jakubowska 2, Ewa Szahidewicz-Krupska 2, Karolina Gawrys 2, Jakub Gawrys 2, Adrian Doroszko 2
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PMID: 32330479
DOI: 10.1016/j.mvr.2020.104008

Abstract


Endothelial dysfunction (ED) plays a key role in developing of cardiovascular diseases and is an important predictor of future cardiovascular events. Nevertheless, there is no established method assessing endothelial function in general population. The most popular protocol includes the ultrasound-flow-mediated-dilation, but its repeatability is operator-dependent. We intended to compare the two other operator-independent methods assessing endothelial function - the EndoPAT and Laser Doppler flowmetry (LD), and we endeavored to place them on current individual profile of biochemical cardiovascular risk and endothelial function. A total of 61 clinically healthy subjects (aged 29 ± 1y) were investigated. The blood was collected for conventional cardiovascular risk markers, the NO-pathway metabolites (ADMA, L-arginine, SDMA), oxidative-stress-markers (MDA, thiol-index) as well as endothelial and platelet activation markers (sICAM1, sVCAM1, PAI-1, sE-selectin, sP-selectin, VEGF). Subsequently, all participants underwent examination by both EndoPAT and LD. There was a poor correlation between EndoPAT and LD results. No significant differences between participants with preserved and impaired endothelial function regarding endothelial activation nor cardiovascular risk markers were observed. Both methods assess endothelial function independently from the profile of endothelial pro/anti-inflammatory status and conventional risk factors, therefore further prospective studies are needed in order to verify their additional value in the cardiovascular risk stratification.

Keywords: Endothelial function assessment; Laser doppler; Peripheral artery tonometry.

Copyright © 2020 Elsevier Inc. All rights reserved.
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24
Aging Clin Exp Res




. 2020 Sep 22. doi: 10.1007/s40520-020-01712-y. Online ahead of print.
Urinary incontinence and quality of life: a systematic review and meta-analysis
Damiano Pizzol 1, Jacopo Demurtas 2 3, Stefano Celotto 4, Stefania Maggi 5, Lee Smith 6, Gabriele Angiolelli 7, Mike Trott 6, Lin Yang 8 9, Nicola Veronese 10 11
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PMID: 32964401
DOI: 10.1007/s40520-020-01712-y

Abstract


Background: Urinary incontinence (UI) and low quality of life (QoL) are two common conditions. Some recent literature proposed that these two entities can be associated. However, no attempt was made to collate this literature. Therefore, the aim of this study was to conduct a systematic review and meta-analysis of existing data to estimate the strength of the association between UI and QoL.

Methods: An electronic search of major databases up to 18th April 2020 was carried out. Meta-analysis of cross-sectional and case-control studies comparing mean values in QoL between patients with UI and controls was performed, reporting random-effects standardized mean differences (SMDs) ± 95% confidence intervals (CIs) as the effect size. Heterogeneity was assessed with the I2.

Results: Out of 8279 articles initially screened, 23 were finally included for a total of 24,983 participants, mainly women. The mean age was ≥ 50 years in 12/23 studies. UI was significantly associated with poor QoL as assessed by the short-form 36 (SF-36) total score (n = 6 studies; UI: 473 vs. 2971 controls; SMD = - 0.89; 95% CI - 1.3 to - 0.42; I2 = 93.5) and by the sub-scales of SF-36 and 5/8 of the domains included in the SF-36. Similar results were found using other QoL tools. The risk of bias of the studies included was generally high.

Conclusions: UI is associated with a poor QoL, with a strong level of certainty. This work, however, mainly based on cross-sectional and case-control studies, highlights the necessity of future longitudinal studies for better understanding the importance of UI on QoL.

Keywords: Meta-analysis; Quality of life; Urinary incontinence.
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25
Neurol Sci




. 2020 Sep 24. doi: 10.1007/s10072-020-04723-9. Online ahead of print.
COVID-19 and neurological training in Europe: from early challenges to future perspectives
Matthijs van der Meulen 1, Nina N Kleineberg 2 3, David R Schreier 4, David García-Azorin 5, Francesco Di Lorenzo 6
Affiliations expand
PMID: 32970238
DOI: 10.1007/s10072-020-04723-9

Abstract


The worldwide SARS-CoV-2 pandemic is dramatically affecting health systems with consequences also for neurological residency training. Here we report early experiences and challenges that European neurologists and residents faced. The breadth of the pandemic and the social restrictions induced substantial modifications in both inpatient and outpatient clinical care and academic activities as well, adversely affecting our residency training. On the other hand we see also opportunities, such as gaining more clinical and professional skills. All these drastic and sudden changes lead us to reconsider some educational aspects of our training program that need to be improved in order to better prepare the neurologists of the future to manage unexpected and large emergency situations like the one we are living in these days. A reconsideration of the neurological training program could be beneficial to guarantee high standard level of the residency training in this period and beyond.

Keywords: COVID-19; Residency training; Telemedicine.
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26
Review
Strahlenther Onkol




. 2020 May;196(5):421-443. doi: 10.1007/s00066-020-01583-2. Epub 2020 Mar 24.
Technological quality requirements for stereotactic radiotherapy : Expert review group consensus from the DGMP Working Group for Physics and Technology in Stereotactic Radiotherapy
Daniela Schmitt 1, Oliver Blanck 2, Tobias Gauer 3, Michael K Fix 4, Thomas B Brunner 5, Jens Fleckenstein 6, Britta Loutfi-Krauss 7, Peter Manser 4, Rene Werner 8, Maria-Lisa Wilhelm 9, Wolfgang W Baus 10, Christos Moustakis 11
Affiliations expand
PMID: 32211939
PMCID: PMC7182540
DOI: 10.1007/s00066-020-01583-2Free PMC article

Abstract


This review details and discusses the technological quality requirements to ensure the desired quality for stereotactic radiotherapy using photon external beam radiotherapy as defined by the DEGRO Working Group Radiosurgery and Stereotactic Radiotherapy and the DGMP Working Group for Physics and Technology in Stereotactic Radiotherapy. The covered aspects of this review are 1) imaging for target volume definition, 2) patient positioning and target volume localization, 3) motion management, 4) collimation of the irradiation and beam directions, 5) dose calculation, 6) treatment unit accuracy, and 7) dedicated quality assurance measures. For each part, an expert review for current state-of-the-art techniques and their particular technological quality requirement to reach the necessary accuracy for stereotactic radiotherapy divided into intracranial stereotactic radiosurgery in one single fraction (SRS), intracranial fractionated stereotactic radiotherapy (FSRT), and extracranial stereotactic body radiotherapy (SBRT) is presented. All recommendations and suggestions for all mentioned aspects of stereotactic radiotherapy are formulated and related uncertainties and potential sources of error discussed. Additionally, further research and development needs in terms of insufficient data and unsolved problems for stereotactic radiotherapy are identified, which will serve as a basis for the future assignments of the DGMP Working Group for Physics and Technology in Stereotactic Radiotherapy. The review was group peer-reviewed, and consensus was obtained through multiple working group meetings.

Keywords: FSRT; Radiosurgery; Recommendations; SBRT; SRS; Technique.

Conflict of interest statement


D. Schmitt, O. Blanck, T. Gauer, M. K. Fix, T.B. Brunner, J. Fleckenstein, B. Loutfi-Krauss, P. Manser, R. Werner, M.-L. Wilhelm, W. W. Baus, and C. Moustakis declare that they have no competing interests.

Cited by 2 articles
223 references
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27
Oncol Lett




. 2020 Nov;20(5):199. doi: 10.3892/ol.2020.12060. Epub 2020 Sep 4.
Negative regulation between the expression levels of receptor for hyaluronic acid-mediated motility and hyaluronan leads to cell migration in pancreatic cancer
Xiao-Bo Cheng 1, Shuwen Wang 1, Hua Yang 1, Hanxing Tong 2, Guodong Shi 1, Lili Wu 3, Jian Zhou 1, Lei Shi 1, Hongwei Li 1, Songtao Ren 1, Yuhong Zhou 4, Norihiro Sato 5
Affiliations expand
PMID: 32963605
PMCID: PMC7491089
DOI: 10.3892/ol.2020.12060Free PMC article

Abstract


Receptor for hyaluronic acid (HA)-mediated motility (RHAMM) expression is upregulated in pancreatic ductal adenocarcinoma (PDAC). In the present study, small interfering RNA knockdown was used to investigate the regulatory mechanism and function of RHAMM in PDAC cells. Reverse transcription-quantitative PCR was used to measure the mRNA expression levels of RHAMM, hyaluronan synthases (HAS1, HAS2 and HAS3) and hyaluronidases (HYAL1, HYAL2 and HYAL3) in eight PDAC cell lines. Cell migration was assessed using a Transwell assay, while HA concentration was measured using an ELISA. The results revealed that RHAMM-knockdown significantly increased migration in two PDAC cell lines, significantly decreased migration in one cell line and did not affect migration in the other cell lines, and was positively associated with changes in HA production. There was a linear negative correlation between RHAMM mRNA expression and HA concentration in PDAC cells and tissues. The negative correlation between RHAMM mRNA expression and HA concentration was demonstrated in other models, including SUIT2 cells treated with an HA inhibitor or stimulator and a system involving co-culture of SUIT2 cells and stromal fibroblasts. The present findings demonstrated a negative correlation between RHAMM mRNA expression and HA production in a subset of PDAC cell lines. The efficacy of a therapeutic strategy targeting RHAMM should be carefully evaluated in future studies.

Keywords: HA; HAS; HYAL; PDAC; RHAMM-knockdown.

Copyright: © Cheng et al.

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28
J Am Med Inform Assoc




. 2020 Sep 23;ocaa177. doi: 10.1093/jamia/ocaa177. Online ahead of print.
Remote symptom monitoring integrated into electronic health records: A systematic review
Julie Gandrup 1, Syed Mustafa Ali 1, John McBeth 1 2, Sabine N van der Veer 3, William G Dixon 1 2 4
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PMID: 32968785
DOI: 10.1093/jamia/ocaa177

Abstract


Objective: People with long-term conditions require serial clinical assessments. Digital patient-reported symptoms collected between visits can inform these, especially if integrated into electronic health records (EHRs) and clinical workflows. This systematic review identified and summarized EHR-integrated systems to remotely collect patient-reported symptoms and examined their anticipated and realized benefits in long-term conditions.

Materials and methods: We searched Medline, Web of Science, and Embase. Inclusion criteria were symptom reporting systems in adults with long-term conditions; data integrated into the EHR; data collection outside of clinic; data used in clinical care. We synthesized data thematically. Benefits were assessed against a list of outcome indicators. We critically appraised studies using the Mixed Methods Appraisal Tool.

Results: We included 12 studies representing 10 systems. Seven were in oncology. Systems were technically and functionally heterogeneous, with the majority being fully integrated (data viewable in the EHR). Half of the systems enabled regular symptom tracking between visits. We identified 3 symptom report-guided clinical workflows: Consultation-only (data used during consultation, n = 5), alert-based (real-time alerts for providers, n = 4) and patient-initiated visits (n = 1). Few author-described anticipated benefits, primarily to improve communication and resultant health outcomes, were realized based on the study results, and were only supported by evidence from early-stage qualitative studies. Studies were primarily feasibility and pilot studies of acceptable quality.

Discussion and conclusions: EHR-integrated remote symptom monitoring is possible, but there are few published efforts to inform development of these systems. Currently there is limited evidence that this improves care and outcomes, warranting future robust, quantitative studies of efficacy and effectiveness.

Keywords: digital health, mobile health, patient-generated health data; electronic health record; long-term conditions; remote monitoring.

© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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29
JCO Oncol Pract




. 2020 Sep 24;OP2000520. doi: 10.1200/OP.20.00520. Online ahead of print.
Telehealth for Cancer Care in Veterans: Opportunities and Challenges Revealed by COVID
Cindy Y Jiang 1, Nadeem T El-Kouri 2, David Elliot 3, Jenna Shields 2, Megan E V Caram 4 5, Timothy L Frankel 6, Nithya Ramnath 4 5, Vida A Passero 2
Affiliations expand
PMID: 32970512
DOI: 10.1200/OP.20.00520

Abstract


The Veterans Health Administration system is one of the largest integrated health care providers in the United States, delivering medical care to > 9 million veterans. Barriers to delivering efficient health care include geographical limitations as well as long wait times. Telehealth has been used as a solution by many different health care services. However, it has not been as widely used in cancer care. In 2018, the US Department of Veterans Affairs (VA) Pittsburgh Healthcare System expanded the use of telehealth to provide antineoplastic therapies to rural patients by creating a clinical video telehealth clinic of the Virtual Cancer Care Network. This allows oncologists located at the tertiary center to virtually deliver care to remote sites. The recent COVID-19 pandemic forced oncologists across the VA system to adopt telehealth to provide continuity of care. On the basis of our review and personal experience, we have outlined opportunities for telehealth to play a role in every step of the cancer care journey from diagnosis to therapy to surveillance to clinical trials for medical, surgical, and radiation oncology. There are many advantages, such as decreased travel time and potential cost savings; however, there continues to be challenges with veterans having access to devices and the Internet as well as understanding how to use telehealth equipment. The lessons learned from this assessment of the VA telehealth system for cancer care can be adopted and integrated into other health systems. In the future, there needs to be evaluation of how telehealth can be further incorporated into oncology, satisfaction of veterans using telehealth services, overcoming telehealth barriers, and defining metrics of success.
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30
Review
Cancers (Basel)




. 2020 Sep 21;12(9):E2692. doi: 10.3390/cancers12092692.
Prognostic and Predictive Value of Tumor-Infiltrating Immune Cells in Urothelial Cancer of the Bladder
Sandra van Wilpe 1 2, Eveline C F Gerretsen 2, Antoine G van der Heijden 3, I Jolanda M de Vries 2, Winald R Gerritsen 1 2, Niven Mehra 1 2
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PMID: 32967190
DOI: 10.3390/cancers12092692Free article

Abstract


The prognosis and responsiveness to chemotherapy and checkpoint inhibitors differs substantially among patients with bladder cancer (BC). There is an unmet need for biomarkers that can accurately predict prognosis and treatment outcome. Here, we describe the available literature on the prognostic and predictive value of tumor-infiltrating immune cells in BC. Current evidence indicates that a high density of tumor-infiltrating CD8+ T cells is a favorable prognostic factor, whereas PD-L1 expression and tumor-associated macrophages are unfavorable prognostic features. While PD-L1 expression appears unsuccessful as a biomarker for the response to checkpoint inhibitors, there are some indications that high CD8+ T cell infiltration, low transforming growth factor-beta signaling and low densities of myeloid-derived suppressor cells are associated with response. Future studies should focus on combinations of biomarkers to accurately predict survival and response to treatment.

Keywords: biomarkers; checkpoint inhibitors; chemotherapy; prognosis; urothelial cancer.
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31
Review
Cancers (Basel)




. 2020 Sep 21;12(9):E2703. doi: 10.3390/cancers12092703.
Extraskeletal Myxoid Chondrosarcoma: State of the Art and Current Research on Biology and Clinical Management
Silvia Stacchiotti 1, Giacomo Giulio Baldi 2, Carlo Morosi 3, Alessandro Gronchi 4, Roberta Maestro 5
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PMID: 32967265
DOI: 10.3390/cancers12092703Free article

Abstract


Extraskeletal myxoid chondrosarcoma (EMC) is an ultra-rare mesenchymal neoplasm with uncertain differentiation, which arises mostly in the deep soft tissue of proximal extremities and limb girdles. EMC is marked by a translocation involving the NR4A3 gene, which can be fused in-frame with different partners, most often EWSR1 or TAF1. Although EMC biology is still poorly defined, recent studies have started shedding light on the specific contribution of NR4A3 chimeric proteins to EMC pathogenesis and clinical outcome. Standard treatment for localized disease is surgery, plus or minus radiation therapy with an expected prolonged survival even though the risk of relapse is about 50%. In advanced cases, besides the standard chemotherapy currently used for soft tissue sarcoma, antiangiogenic agents have recently shown promising activity. The aim of this review is to provide the state of the art of treatment for localized and advanced disease, with a focus on pharmacological treatments available for EMC. The biological basis of current research and future perspectives will be also discussed.

Keywords: NR4A3 fusions; antiangiogenics; chemotherapy; chondrosarcoma; sarcoma.
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32
Int J Technol Assess Health Care




. 2020 Sep 23;1-8. doi: 10.1017/S0266462320000677. Online ahead of print.
Cost-effectiveness of treating head and neck cancer using intensity-modulated radiation therapy: implications for cancer control program in India
Akashdeep Singh Chauhan 1, Shankar Prinja 1, Sushmita Ghoshal 2, Roshan Verma 3
Affiliations expand
PMID: 32962782
DOI: 10.1017/S0266462320000677

Abstract


Background: The newer cancer treatment technologies hold the potential of providing improved health outcomes at an additional cost. So it becomes obligatory to assess the costs and benefits of a new technology, before defining its clinical value. We assessed the cost-effectiveness of intensity-modulated radiotherapy (IMRT) as compared to 2-dimensional radiotherapy (2-DRT) and 3-dimensional radiotherapy (3D-CRT) for treating head and neck cancers (HNC) in India. The cost-effectiveness of 3-DCRT as compared to 2-DRT was also estimated.

Methods: A probabilistic Markov model was designed. Using a disaggregated societal perspective, lifetime study horizon and 3 percent discount rate, future costs and health outcomes were compared for a cohort of 1000 patients treated with any of the three radiation techniques. Data on health system cost, out of pocket expenditure, and quality of life was assessed through primary data collected from a large tertiary care public sector hospital in India. Data on xerostomia rates following each of the radiation techniques was extracted from the existing randomized controlled trials.

Results: IMRT incurs an incremental cost of $7,072 (2,932-13,258) and $5,164 (463-10,954) per quality-adjusted life year (QALY) gained compared to 2-DRT and 3D-CRT, respectively. Further, 3D-CRT as compared to 2-DRT requires an incremental cost of $8,946 (1,996-19,313) per QALY gained.

Conclusion: Both IMRT and 3D-CRT are not cost-effective at 1 times GDP per capita for treating HNC in India. The costs and benefits of using IMRT for other potential indications (e.g. prostate, lung) require to be assessed before considering its introduction in India.

Keywords: 2-Dimensional radiotherapy; 3-Dimensional conformal radiotherapy; Cost-effectiveness analysis; Head and neck cancers; Intensity-modulated radiation therapy.
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33
J Glob Antimicrob Resist




. 2020 Sep 21;S2213-7165(20)30230-7. doi: 10.1016/j.jgar.2020.08.022. Online ahead of print.
Italian Young Doctors' knowledge, attitude and practices on antibiotic use and resistance: A national cross-sectional survey
F Di Gennaro 1, C Marotta 1, M Amicone 2, D F Bavaro 3, F Bernaudo 4, E M Frisicale 5, P K Kurotschka 6, A Mazzari 7, N Veronese 8, R Murri 9, M Fantoni 9
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PMID: 32971291
DOI: 10.1016/j.jgar.2020.08.022

Abstract


Objectives: Antimicrobial resistance (AMR) is one of the major health issues world-wide. Clinicians should play a central role to fight AMR, and medical training is a pivotal issue to contrast it; therefore, assessing levels of knowledge, attitudes and practices among young doctors is essential for future antimicrobial stewardship (AMS) programs.

Methods: A national-wide cross-sectional, multicentre survey was conducted. A descriptive analysis of knowledge and attitudes was performed, along with a univariate and multivariate analysis of their determinants.

Results: Overall, 1179 young doctors accessed the survey and 1055 completed all sections (89.5%). As for the knowledge section of the questionnaire, almost all the participants declared to know the different species of bacteria proposed, however, the percentage of participants who correctly responded to clinical quizzes was of 23% for the question on vancomycin-resistant enterococci (VRE), 42% the one about carbapenem-resistant Enterobacteriaceae (CRE), 32% on extended-spectrum-beta-lactamases (ESBL) producing bacteria and of 27% (285) on methicillin-resistant Staphilococcus aureus (MRSA). Similarly, 81% of participants disagreed in stating that, during their medical training, AMR was adequately addressed and 70% disagreed that they received the right example from their tutors. Finally, a high rate of agreement with the proposed actions to contrast AMR was documented; in particular, percentages of agreement were 75% of respondents who agreed to be part of an active surveillance system or AMS programs.

Conclusions: Tackling AMR should be a priority for politicians and for all health workers. The inclusion of competencies in antibiotic use in all specialty curricula is urgently needed.

Keywords: antimicrobial resistance; antimicrobial stewardship; attitudes; knowledge; multidrug resistance; practice; survey.

Copyright © 2020. Published by Elsevier Ltd.
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34
Int J Rheum Dis




. 2020 Sep 23. doi: 10.1111/1756-185X.13972. Online ahead of print.
The impact of single nucleotide polymorphisms in ADORA2A and ADORA3 genes on the early response to methotrexate and presence of therapy side effects in children with juvenile idiopathic arthritis: Results of a preliminary study
Justyna Roszkiewicz 1, Dominika Michałek 2, Aleksandra Ryk 2, Zbigniew Swacha 3, Bartosz Szmyd 4, Elżbieta Smolewska 1
Affiliations expand
PMID: 32969158
DOI: 10.1111/1756-185X.13972

Abstract


Aim: Methotrexate (MTX) administered at the dose 10-15 mg/m2 is recommended as the first-line therapy in most juvenile idiopathic arthritis (JIA) subtypes. The disease-modifying effect of methotrexate is associated with release of adenosine and mediated via binding to adenosine receptor A2A (ADORA2A) and 3 (ADORA3). The aim of our study was to determine the association between single nucleotide polymorphisms in ADORA2A (rs2236624, rs2298383) and ADORA3 (rs3393) receptor genes on the disease activity and presence of MTX therapy side effects in patients with JIA.

Methods: One hundred children with JIA of all subtypes treated with MTX were recruited to the study. Demographic and clinical parameters were collected at the baseline of MTX therapy and on a control visit 4-6 months after starting MTX. Single nucleotide polymorphism genotyping was performed using genomic DNA isolated from peripheral blood samples.

Results: The polymorphic variant of ADORA2A rs2236624 was associated with ~3.5 times higher odds of gastrointestinal side effects occurrence (odds ratio: 3.59, 95% CI: 1.15-11.22, P = 0.0282). Children with the ADORA3 rs3393 polymorphic variants (CT/CC) after 6 months of MTX treatment had significantly lower number of joints with active arthritis (median: 0.00 vs 1.00, P = 0.0400) and value of C-reactive protein (0.60 vs 2.40, P = 0.0242) in comparison to TT variant.

Conclusion: Although future studies are needed to verify our findings, polymorphisms in ADORA2A and ADORA3 genes may become the determinants of MTX treatment efficacy and gastrointestinal toxicity in children with JIA.

Keywords: juvenile idiopathic arthritis; methotrexate; single nucleotide polymorphism.

© 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

30 references
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35
PLoS One




. 2020 Sep 23;15(9):e0239438. doi: 10.1371/journal.pone.0239438. eCollection 2020.
Adding the temporal domain to PET radiomic features
Wyanne A Noortman 1 2, Dennis Vriens 1, Cornelis H Slump 3, Johan Bussink 4, Tineke W H Meijer 4, Lioe-Fee de Geus-Oei 1 2, Floris H P van Velden 1
Affiliations expand
PMID: 32966313
DOI: 10.1371/journal.pone.0239438Free article

Abstract


Background: Radiomic features, extracted from positron emission tomography, aim to characterize tumour biology based on tracer intensity, tumour geometry and/or tracer uptake heterogeneity. Currently, radiomic features are derived from static images. However, temporal changes in tracer uptake might reveal new aspects of tumour biology. This study aims to explore additional information of these novel dynamic radiomic features compared to those derived from static or metabolic rate images.

Methods: Thirty-five patients with non-small cell lung carcinoma underwent dynamic [18F]FDG PET/CT scans. Spatial intensity, shape and texture radiomic features were derived from volumes of interest delineated on static PET and parametric metabolic rate PET. Dynamic grey level cooccurrence matrix (GLCM) and grey level run length matrix (GLRLM) features, assessing the temporal domain unidirectionally, were calculated on eight and sixteen time frames of equal length. Spearman's rank correlations of parametric and dynamic features with static features were calculated to identify features with potential additional information. Survival analysis was performed for the non-redundant temporal features and a selection of static features using Kaplan-Meier analysis.

Results: Three out of 90 parametric features showed moderate correlations with corresponding static features (ρ≥0.61), all other features showed high correlations (ρ>0.7). Dynamic features are robust independent of frame duration. Five out of 22 dynamic GLCM features showed a negligible to moderate correlation with any static feature, suggesting additional information. All sixteen dynamic GLRLM features showed high correlations with static features, implying redundancy. Log-rank analyses of Kaplan-Meier survival curves for all features dichotomised at the median were insignificant.

Conclusion: This study suggests that, compared to static features, some dynamic GLCM radiomic features show different information, whereas parametric features provide minimal additional information. Future studies should be conducted in larger populations to assess whether there is a clinical benefit of radiomics using the temporal domain over traditional radiomics.

Conflict of interest statement


The authors have declared that no competing interests exist.
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36
Int J Radiat Oncol Biol Phys




. 2020 Sep 20;S0360-3016(20)34302-9. doi: 10.1016/j.ijrobp.2020.09.030. Online ahead of print.
Behavioral determinants of Canadian radiation oncologists' use of single fraction palliative radiation therapy for uncomplicated bone metastases
Janet E Squires 1, Sarah Asad 2, Melissa Demery Varin 3, Kristin Dorrance 4, Edward Chow 5, Alysa Fairchild 6, Rebecca Wong 7, Ian D Graham 8, Jeremy M Grimshaw 9, Kristopher Dennis 10
Affiliations expand
PMID: 32966890
DOI: 10.1016/j.ijrobp.2020.09.030

Abstract


Background: A mainstay therapy for pain relief from uncomplicated bone metastases is external beam radiation therapy. Single fraction radiation therapy (SFRT) is more convenient and cost-effective, causes fewer acute side effects, and is equivalent to multiple fraction radiation therapy for pain relief. Despite these advantages, radiation oncologists seldom prescribe SFRT.

Purpose: To identify the behavioral determinants to Canadian radiation oncologists' use of SFRT for uncomplicated bone metastases.

Methods and materials: Semi-structured interviews were conducted with 38 radiation oncologists from all 10 Canadian provinces. The interview guide and analysis were guided by the Theoretical Domains Framework (TDF). Transcripts were analyzed using a five-phase thematic content analysis process: coding, generation of belief statements, generation of themes within TDF domains, generation of overarching themes, and classification of themes as barriers or facilitators to SFRT use, or as divergent (a barrier or facilitator depending on the participant).

Results: Thirteen overarching themes were identified of which two were barriers, seven were facilitators and four were divergent. The most commonly identified theme was the facilitator 'most radiation oncologists are aware of evidence and guidelines on the use SFRT' (n=38, 100%). The three next most reported themes (n=37, 97.4%) were: 1) 'radiation oncologists' use of SFRT can influence their colleagues' use of it (divergent), 2) experience with SFRT can increase its use (facilitator), and 3) SFRT is convenient for patients (facilitator). The most commonly identified barrier (n=31, 81.6%) was 'SFRT is associated with a higher risk of retreatment'.

Conclusions: Our use of the TDF to explore the behavioral determinants of Canadian radiation oncologists' use of SFRT for uncomplicated bone metastases identified a range of factors that are perceived to encourage and discourage its use. Our results will inform the design of future interventions to increase the use of SFRT.

Copyright © 2020 Elsevier Inc. All rights reserved.
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37
Curr Opin Ophthalmol




. 2020 Sep 21. doi: 10.1097/ICU.0000000000000711. Online ahead of print.
History through the eyes of a pandemic
Veronica Kon Graversen 1, Sophia El Hamichi 2, Aaron Gold 2, Timothy G Murray 2
Affiliations expand
PMID: 32969843
DOI: 10.1097/ICU.0000000000000711

Abstract


Purpose: This review provides a historic perspective of the impact that major pandemics have had on human and their relationship with ophthalmology. The novel coronavirus epidemic is also analyzed, highlighting the relevance of the eye as a possible source of transmission, infection, and prognosis for the disease.

Results: Smallpox is suspected to be present for more than 12 000 years. However, trachoma seems to be the first recorded ophthalmological infectious disease. The deadliest pandemics include the bubonic plague, smallpox, and Spanish flu. The CoVID-19 epidemic is still developing and measures need to be implemented to prevent further escalation of the crisis.

Summary: Understanding the current facts in light of earlier historical evidence may help us prepare better to minimize the spread of infections in the future.
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38
Br J Cancer




. 2020 Sep 23. doi: 10.1038/s41416-020-01081-3. Online ahead of print.
Examination of potential novel biochemical factors in relation to prostate cancer incidence and mortality in UK Biobank
Aurora Perez-Cornago 1, Georgina K Fensom 2, Colm Andrews 2, Eleanor L Watts 2, Naomi E Allen 3, Richard M Martin 4 5 6, Mieke Van Hemelrijck 7 8, Timothy J Key 2, Ruth C Travis 2
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PMID: 32963348
DOI: 10.1038/s41416-020-01081-3

Abstract


Background: Although prostate cancer is a leading cause of cancer death, its aetiology is not well understood. We aimed to identify novel biochemical factors for prostate cancer incidence and mortality in UK Biobank.

Methods: A range of cardiovascular, bone, joint, diabetes, renal and liver-related biomarkers were measured in baseline blood samples collected from up to 211,754 men at recruitment and in a subsample 5 years later. Participants were followed-up via linkage to health administrative datasets to identify prostate cancer cases. Hazard ratios (HRs) and 95% confidence intervals were calculated using multivariable-adjusted Cox regression corrected for regression dilution bias. Multiple testing was accounted for by using a false discovery rate controlling procedure.

Results: After an average follow-up of 6.9 years, 5763 prostate cancer cases and 331 prostate cancer deaths were ascertained. Prostate cancer incidence was positively associated with circulating vitamin D, urea and phosphate concentrations and inversely associated with glucose, total protein and aspartate aminotransferase. Phosphate and cystatin-C were the only biomarkers positively and inversely, respectively, associated with risk in analyses excluding the first 4 years of follow-up. There was little evidence of associations with prostate cancer death.

Conclusion: We found novel associations of several biomarkers with prostate cancer incidence. Future research will examine associations by tumour characteristics.
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39
Cancer Med




. 2020 Sep 24. doi: 10.1002/cam4.3481. Online ahead of print.
Integrated genomic analysis identifies a genetic mutation model predicting response to immune checkpoint inhibitors in melanoma
Junjie Jiang 1, Yongfeng Ding 2, Mengjie Wu 1, Yanyan Chen 1, Xiadong Lyu 1, Jun Lu 1, Haiyong Wang 1, Lisong Teng 1
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PMID: 32969604
DOI: 10.1002/cam4.3481Free article

Abstract


Several biomarkers such as tumor mutation burden (TMB), neoantigen load (NAL), programmed cell-death receptor 1 ligand (PD-L1) expression, and lactate dehydrogenase (LDH) have been developed for predicting response to immune checkpoint inhibitors (ICIs) in melanoma. However, some limitations including the undefined cut-off value, poor uniformity of test platform, and weak reliability of prediction have restricted the broad application in clinical practice. In order to identify a clinically actionable biomarker and explore an effective strategy for prediction, we developed a genetic mutation model named as immunotherapy score (ITS) for predicting response to ICIs therapy in melanoma, based on whole-exome sequencing data from previous studies. We observed that patients with high ITS had better durable clinical benefit and survival outcomes than patients with low ITS in three independent cohorts, as well as in the meta-cohort. Notably, the prediction capability of ITS was more robust than that of TMB. Remarkably, ITS was not only an independent predictor of ICIs therapy, but also combined with TMB or LDH to better predict response to ICIs than any single biomarker. Moreover, patients with high ITS harbored the immunotherapy-sensitive characteristics including high TMB and NAL, ultraviolet light damage, impaired DNA damage repair pathway, arrested cell cycle signaling, and frequent mutations in NF1 and SERPINB3/4. Overall, these findings deserve prospective investigation in the future and may help guide clinical decisions on ICIs therapy for patients with melanoma.

Keywords: biomarker; durable clinical benefit; immune checkpoint inhibitors; melanoma.

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

54 references
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40
Med Phys




. 2020 Sep 22. doi: 10.1002/mp.14491. Online ahead of print.
Intensity-Modulated Proton Therapy (IMPT) Interplay Effect Evaluation of Asymmetric Breathing with Simultaneous Uncertainty Considerations in Patients with Non-Small Cell Lung Cancer
Jie Shan 1, Yunze Yang 1, Steven E Schild 1, Thomas B Daniels 1, William W Wong 1, Mirek Fatyga 1, Martin Bues 1, Terence T Sio 1, Wei Liu 1
Affiliations expand
PMID: 32964474
DOI: 10.1002/mp.14491

Abstract


Purpose: Intensity-modulated proton therapy (IMPT) is sensitive to uncertainties from patient setup and proton beam range, as well as interplay effect. In addition, respiratory motion may vary from cycle to cycle, and also from day to day. These uncertainties can severely degrade the original plan quality and potentially affect patient's outcome. In this work, we developed a new tool to comprehensively consider the impact of all these uncertainties and provide plan robustness evaluation under them.

Methods: We developed a comprehensive plan robustness evaluation tool that considered both uncertainties from patient setup and proton beam range, as well as respiratory motion simultaneously. To mimic patients' respiratory motion, the time spent in each phase was randomly sampled based on patient-specific breathing pattern parameters as acquired during the 4D-CT simulation. Spots were then assigned to one specific phase according to the temporal relationship between spot delivery sequence and patients' respiratory motion. Dose in each phase was calculated by summing contributions from all the spots delivered in that phase. The final 4D dynamic dose was obtained by deforming all doses in each phase to the maximum exhalation phase. Three hundred (300) scenarios (10 different breathing patterns with 30 different setup and range uncertainty scenario combinations) were calculated for each plan. The dose-volume histograms (DVHs) band method was used to assess plan robustness. Benchmarking the tool as an application's example, we compared plan robustness under both 3D and 4D robustly optimized IMPT plans for 10 non-randomly selected patients with non-small cell lung cancer.

Results: The developed comprehensive plan robustness tool had been successfully applied to compare the plan robustness between 3D and 4D robustly optimized IMPT plans for 10 lung cancer patients. In the presence of interplay effect with uncertainties considered simultaneously, 4D robustly optimized plans provided significantly better CTV coverage (D95% , p=0.002), CTV homogeneity (D5% -D95% , p=0.002) with less target hot spots (D5% , p=0.002), and target coverage robustness (CTV D95% bandwidth, p=0.004) compared to 3D robustly optimized plans. Superior dose sparing of normal lung (lung Dmean , p=0.020) favoring 4D plans and comparable normal tissue sparing including esophagus, heart, and spinal cord for both 3D and 4D plans were observed. The calculation time for all patients included in this study was 11.4±2.6 minutes.

Conclusion: A comprehensive plan robustness evaluation tool was successfully developed and benchmarked for plan robustness evaluation in the presence of interplay effect, setup and range uncertainties. The very high efficiency of this tool marks its clinical adaptation highly practical and versatile, including possible real-time intra-fractional interplay effect evaluation as a potential application for future use.

This article is protected by copyright. All rights reserved.
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41
Int J Radiat Oncol Biol Phys




. 2020 Sep 21;S0360-3016(20)34304-2. doi: 10.1016/j.ijrobp.2020.09.032. Online ahead of print.
Combination of Olaparib and radiotherapy for triple negative breast cancer: preliminary results of the RADIOPARP phase I trial
Pierre Loap 1, Delphine Loirat 2, Frederique Berger 2, Francesco Ricci 2, Anne Vincent-Salomon 2, Cyrine Ezzili 2, Veronique Mosseri 2, Alain Fourquet 2, Monia Ezzalfani 2, Youlia Kirova 2
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PMID: 32971187
DOI: 10.1016/j.ijrobp.2020.09.032

Abstract


Purpose: Preclinical studies have evidenced that triple-negative breast cancer (TNBC) cell lines are more sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. This provides a strong rational for developing a new therapeutic approach for TNBC management based on PARP inhibition. The primary goal of the XXXXXXXXX phase-I trial was to evaluate the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of Olaparib (O) combined with loco-regional radiotherapy (RT).

Methods and materials: XXXXXXXXX was a single institutional phase I trial which evaluated Olaparib-radiotherapy combination in patients with inflammatory, locoregionally advanced or metastatic TNBC who received neoadjuvant chemotherapy. Radiotherapy delivered 50 Gy to the breast or to the chest wall. Lymph nodes could be included in target volumes according to local guidelines. The dose-finding toxicity-based study was conducted in sequential and adaptive Bayesian scheme with the method of Time-to-event Continual Reassessment, with four Olaparib dose levels (50mg, 100mg, 150mg and 200mg twice a day).

Results: Twenty-four patients with ECOG Performance Status of 0 or 1 were enrolled from September 2017 to November 2019. Twenty-one patients (87.5%) received the Olaparib-radiotherapy combination following breast surgery due to residual disease after neoadjuvant chemotherapy and the three other patients (12.5%) had unresectable tumors which were refractory to neo-adjuvant chemotherapy. All patients received full course combination treatment, as following: 4 patients (pts) at 50mgx2; 8 pts at 100mgx2; 7 pts at 150mgx2 and 5 pts at 200mgx2. No DLT was observed.

Conclusion: Olaparib was escalated to the maximum target dose of 200 mg twice a day without DLT. Further follow up is needed to evaluate the late toxicities. Pending the long-term results of the XXXXXXXXX trial, we suggest using Olaparib 200mg twice a day for future trials.

Copyright © 2020. Published by Elsevier Inc.
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42
Oncologist




. 2020 Sep 24. doi: 10.1002/onco.13540. Online ahead of print.
D-dimer enhances risk targeted thromboprophylaxis in ambulatory cancer patients
Vaibhav Kumar 1 2, Joseph Shaw 3, Nigel S Key 1 2, Anton Ilich 1 2, Ranjeeta Mallick 3, Phil Wells 3, Marc Carrier 3
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PMID: 32969580
DOI: 10.1002/onco.13540Free article

Abstract


Background: Thromboprophylaxis for ambulatory cancer patients is effective, although uncertainties remain on who should be targeted. Using D-dimer values from individuals enrolled to the AVERT trial, we sought to identify and validate a more efficient VTE risk threshold for thromboprophylaxis.

Methods: The AVERT trial compared thromboprophylaxis with apixaban to placebo among cancer patients with a Khorana Risk Score ≥ 2. The D-dimer measured at randomization was used to calculate an individualized 6-month VTE risk using the validated CATScore. A modified intention to treat analysis was used to assess efficacy (VTE) and safety (major and overall bleeding) in the a) complete cohort, b) ≥8% and <8% 6-month VTE risk thresholds.

Results: 574 patients were randomized in the AVERT trial, 466 (81%) with baseline D-dimer were included in the study. 237 subjects received apixaban, 229 received placebo. In the complete cohort, there were 13 (5·5%) VTE events in the apixaban arm compared to 26 (11·4%) events in the placebo arm (aHR-0·49 (0.25-0.95), p<0·05). Number needed to treat (NNT) to prevent one VTE=17. 82(35%) and 72(31%) patients in the apixaban and placebo arms, respectively had a 6-month VTE risk ≥8%. In this sub-group, 7(8·4%) VTE events occurred with apixaban and 19(26·3%) events with placebo (aHR-0·33 (0·14-0·81), p<0.05), NNT=6. Individuals with a VTE risk <8% derived no benefit from apixaban thromboprophylaxis (aHR-0·89 (0·30-2·65), p=0·84). Increased rates of overall bleeding were observed with apixaban in both the complete (aHR-2·11 (1·09-4·09), p<0.05) and ≥8% predicted risk cohorts (aHR-2·87 (0·91-9·13), p=0·07).

Conclusions: A 6-month VTE risk threshold of ≥8% increases the efficiency of risk targeted thromboprophylaxis in ambulatory cancer patients.

Implications for practice: Ambulatory cancer patients receiving chemotherapy have an increased risk of venous thromboembolism (VTE). A Khorana Risk Score (KRS) ≥2 is currently the suggested threshold for thromboprophylaxis. Using baseline D-dimer values from individuals enrolled to the AVERT trial, this retrospective validation study identifies a 6-month VTE risk of ≥8% as a more efficient threshold for thromboprophylaxis. At this threshold, the number needed to treat to prevent one VTE is 6 compared to 17 in with a KRS≥2. Conversely, individuals with a predicted risk of <8% derive no clinical benefit from thromboprophylaxis. Future prospective studies should validate this threshold for outpatient thromboprophylaxis.

Keywords: Apixaban; Cancer-associated thrombosis; D-dimer; Thromboprophylaxis; Venous Thromboembolism.

© AlphaMed Press 2020.
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43
Review
Pediatr Blood Cancer




. 2020 Sep 24;e28716. doi: 10.1002/pbc.28716. Online ahead of print.
Dexamethasone dosing for prevention of acute chemotherapy-induced vomiting in pediatric patients: A systematic review
Priya Patel 1, Ana Olteanu 2, Sandra Cabral 1, Nancy Santesso 3, Paula D Robinson 1, L Lee Dupuis 2 4
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PMID: 32970373
DOI: 10.1002/pbc.28716

Abstract


A systematic review was undertaken to describe dexamethasone doses studied for chemotherapy-induced vomiting (CIV) prophylaxis in pediatric patients and their effects on achieving complete acute CIV control. No dose-finding studies were identified. However, 16 studies assessing pediatric patients who received dexamethasone were included and classified according to the emetogenicity of chemotherapy administered. Eight different total daily dexamethasone doses were administered to patients on day 1 of highly emetogenic chemotherapy: three in conjunction with aprepitant/fosaprepitant plus a 5HT3 antagonist and five in conjunction with a 5HT3 antagonist. Five different total daily dexamethasone doses were administered in conjunction with a 5HT3 antagonist to patients on day 1 of moderately emetogenic chemotherapy. Due to the heterogeneity of studies identified, meta-analysis was not possible. The optimal dexamethasone dose to control acute CIV and to minimize harms in pediatric patients remains uncertain. This is a key area for future research.

Keywords: chemotherapy-induced nausea and vomiting; dexamethasone; pediatric oncology; supportive care.

© 2020 Wiley Periodicals LLC.

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44
Biomark Med




. 2020 Aug;14(12):1069-1084. doi: 10.2217/bmm-2019-0608.
Identification of hub genes and discovery of promising compounds in gastric cancer based on bioinformatics analysis
Jiani Huang 1 2, Fang Wen 1 3 4, Wenjie Huang 1 3 4, Yingfeng Bai 1 2, Xiaona Lu 1 3 4, Peng Shu 1 3 4
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PMID: 32969243
DOI: 10.2217/bmm-2019-0608

Abstract


Aim: To explore the mechanism of gastric carcinogenesis by mining potential hub genes and to search for promising small-molecular compounds for gastric cancer (GC). Materials & methods: The microarray datasets were downloaded from Gene Expression Omnibus database and the genes and compounds were analyzed by bioinformatics-related tools and software. Results: Six hub genes (MKI67, PLK1, COL1A1, TPX2, COL1A2 and SPP1) related to the prognosis of GC were confirmed to be upregulated in GC and their high expression was correlated with poor overall survival rate in GC patients. In addition, eight candidate compounds with potential anti-GC activity were identified, among which resveratrol was closely correlated with six hub genes. Conclusion: Six hub genes identified in the present study may contribute to a more comprehensive understanding of the mechanism of gastric carcinogenesis and the predicted potential of resveratrol may provide valuable clues for the future development of targeted anti-GC inhibitors.

Keywords: bioinformatics analysis; candidate compounds; differentially expressed genes; gastric cancer.
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45
Review
Asia Pac J Clin Oncol




. 2020 Sep 24. doi: 10.1111/ajco.13419. Online ahead of print.
Image-guided percutaneous microwave ablation of early-stage non-small cell lung cancer
Yang Ni 1, Hui Xu 2, Xin Ye 2
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PMID: 32969192
DOI: 10.1111/ajco.13419

Abstract


Although surgical lobectomy with systematic mediastinal lymph node evaluation is considered as the "gold standard" for management of early stage non-small cell lung cancer (NSCLC), image-guided percutaneous thermal ablation has been increasingly used for medically inoperable patients. Radiofrequency ablation (RFA) is a research-based technique that has the most studies for medically inoperable early-stage NSCLC. Other thermal ablation techniques used to treat pulmonary tumors include microwave ablation (MWA), cryoablation and laser ablation. MWA has several advantages over RFA including reduced procedural time, reduced heat-sink effect, large ablation zones, decreased susceptibility to tissue impedance, and simultaneous use of multiple antennae. This review article highlights the most relevant updates of MWA for the treatment of early-stage NSCLC, including mechanism of action, clinical outcomes, potential complications, the existing technique problems and future directions.

Keywords: early stage; microwave ablation; non-small cell lung cancer.

© 2020 John Wiley & Sons Australia, Ltd.

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46
Expert Opin Ther Targets




. 2020 Sep 24;1-17. doi: 10.1080/14728222.2020.1814738. Online ahead of print.
Targeting the intrinsically disordered architectural High Mobility Group A (HMGA) oncoproteins in breast cancer: learning from the past to design future strategies
Silvia Pegoraro 1, Gloria Ros 1, Michela Sgubin 1, Sara Petrosino 1, Alberto Zambelli 2, Riccardo Sgarra 1, Guidalberto Manfioletti 1
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PMID: 32970506
DOI: 10.1080/14728222.2020.1814738

Abstract


Introduction: Triple-negative breast cancer (TNBC) is the most difficult breast cancer subtype to treat because of its heterogeneity and lack of specific therapeutic targets. High Mobility Group A (HMGA) proteins are chromatin architectural factors that have multiple oncogenic functions in breast cancer, and they represent promising molecular therapeutic targets for this disease.

Areas covered: We offer an overview of the strategies that have been exploited to counteract HMGA oncoprotein activities at the transcriptional and post-transcriptional levels. We also present the possibility of targeting cancer-associated factors that lie downstream of HMGA proteins and discuss the contribution of HMGA proteins to chemoresistance.

Expert opinion: Different strategies have been exploited to counteract HMGA protein activities; these involve interfering with their nucleic acid binding properties and the blocking of HMGA expression. Some approaches have provided promising results. However, some unique characteristics of the HMGA proteins have not been exploited; these include their extensive protein-protein interaction network and their intrinsically disordered status that present the possibility that HMGA proteins could be involved in the formation of proteinaceous membrane-less organelles (PMLO) by liquid-liquid phase separation. These unexplored characteristics could open new pharmacological avenues to counteract the oncogenic contributions of HMGA proteins.

Keywords: High Mobility Group A; anticancer therapies; breast cancer; chemoresistance; stemness.
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47
BMC Med Inform Decis Mak




. 2020 Sep 22;20(1):241. doi: 10.1186/s12911-020-01265-0.
A data-driven approach to a chemotherapy recommendation model based on deep learning for patients with colorectal cancer in Korea
Jin-Hyeok Park 1, Jeong-Heum Baek 2, Sun Jin Sym 3, Kang Yoon Lee 4, Youngho Lee 5
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PMID: 32962726
DOI: 10.1186/s12911-020-01265-0Free article

Abstract


Background: Clinical Decision Support Systems (CDSSs) have recently attracted attention as a method for minimizing medical errors. Existing CDSSs are limited in that they do not reflect actual data. To overcome this limitation, we propose a CDSS based on deep learning.

Methods: We propose the Colorectal Cancer Chemotherapy Recommender (C3R), which is a deep learning-based chemotherapy recommendation model. Our model improves on existing CDSSs in which data-based decision making is not well supported. C3R is configured to study the clinical data collected at the Gachon Gil Medical Center and to recommend appropriate chemotherapy based on the data. To validate the model, we compared the treatment concordance rate with the National Comprehensive Cancer Network (NCCN) Guidelines, a representative set of cancer treatment guidelines, and with the results of the Gachon Gil Medical Center's Colorectal Cancer Treatment Protocol (GCCTP).

Results: For the C3R model, the treatment concordance rates with the NCCN guidelines were 70.5% for Top-1 Accuracy and 84% for Top-2 Accuracy. The treatment concordance rates with the GCCTP were 57.9% for Top-1 Accuracy and 77.8% for Top-2 Accuracy.

Conclusions: This model is significant, i.e., it is the first colon cancer treatment clinical decision support system in Korea that reflects actual data. In the future, if sufficient data can be secured through cooperation among multiple organizations, more reliable results can be obtained.

Keywords: Chemotherapy recommendation; Colorectal Cancer; Deep learning; Knowledge-based clinical decision support system (CDSS).
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48
Future Oncol




. 2020 Sep 23. doi: 10.2217/fon-2020-0464. Online ahead of print.
Alpelisib in the treatment of metastatic HR+ breast cancer with PIK3CA mutations
Athanasios Mavratzas 1, Frederik Marmé 1
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PMID: 32964734
DOI: 10.2217/fon-2020-0464

Abstract


Since the US FDA approval of everolimus/exemestane in July 2012, and of the first CDK 4/6 inhibitor, palbociclib, combined with endocrine treatment in February 2015, a third class of therapeutic compounds, the PI3K inhibitors, has been introduced to the arsenal of targeted therapies overcoming endocrine resistance in hormone receptor-positive metastatic breast cancer. Alpelisib (PIQRAY®) is the first of these novel agents yielding promising clinical results, giving an impetus to further development of tailored endocrine anticancer treatments. Herein, we review its pharmacodynamic and pharmacokinetic properties, safety and efficacy data, as well as Phase III SOLAR-1 trial, prompting FDA approval of alpelisib in hormone receptor-positive metastatic breast cancer harboring PIK3CA mutations. Furthermore, implications for clinical use and current research will also be discussed.

Keywords: PI3K pathway; PIK3CA mutations; alpelisib; metastatic hormone receptor-positive breast cancer.
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49
Future Oncol




. 2020 Sep 23. doi: 10.2217/fon-2020-0403. Online ahead of print.
Consensus paper: current state of first- and second-line therapy in advanced clear-cell renal cell carcinoma
Peter J Goebell 1, Philipp Ivanyi 2, Jens Bedke 3, Lothar Bergmann 4, Dominik Berthold 5, Martin Boegemann 6, Jonas Busch 7, Christian Doehn 8, Susanne Krege 9, Margitta Retz 10, Gunhild von Amsberg 11, Marc-Oliver Grimm 12, Viktor Gruenwald 13
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PMID: 32964728
DOI: 10.2217/fon-2020-0403Free article

Abstract


The therapy of advanced (clear-cell) renal cell carcinoma (RCC) has recently experienced tremendous changes. Several new treatments have been developed, with PD-1 immune-checkpoint inhibition being the backbone of therapy. Diverse immunotherapy combinations change current first-line standards. These changes also require new approaches in subsequent lines of therapy. In an expert panel, we discussed the new treatment options and how they change clinical practice. While first-line immunotherapies introduce a new level of response rates, data on second-line therapies remains poor. This scenario poses a challenge for clinicians as guideline recommendations are based on historical patient cohorts and agents may lack the appropriate label for their in guidelines recommended use. Here, we summarize relevant clinical data and consider appropriate treatment strategies.

Keywords: RCC; TKI; VEGFR inhibitor; advanced (clear-cell) renal cell carcinoma; checkpoint inhibition; mTOR inhibitor; tyrosine kinase inhibitor.
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50
Gastric Cancer




. 2020 Sep 24. doi: 10.1007/s10120-020-01124-x. Online ahead of print.
Prognostic significance of sarcopenia in microsatellite-stable gastric cancer patients treated with programmed death-1 inhibitors
Yeun-Yoon Kim 1 2, Jeeyun Lee 3, Woo Kyoung Jeong 4, Seung Tae Kim 3, Jae-Hun Kim 1, Jung Yong Hong 3, Won Ki Kang 3, Kyoung-Mee Kim 5, Insuk Sohn 6, Dongil Choi 1
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PMID: 32970267
DOI: 10.1007/s10120-020-01124-x

Abstract


Background: Sarcopenia has been underscored as a significant predictor of poor prognosis in cancer patients undergoing immunotherapy with programmed death-1 (PD-1) inhibitors. We aimed to investigate the prognostic significance of computed tomography (CT)-determined sarcopenia in patients with microsatellite-stable (MSS) gastric cancer (GC) treated with PD-1 inhibitors.

Methods: We retrospectively assessed patients with MSS GC who had been treated with PD-1 inhibitors from March 2016 to June 2019. Pre-treatment sarcopenic status was determined by analyzing L3 skeletal muscle index with abdominal CT. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and the differences in survival probability according to sarcopenic status were compared using the log-rank test. Cox proportional hazards regression analyses were performed to identify predictors of PFS and OS.

Results: Of 149 patients with MSS GC (mean age, 57.0 ± 12.3 years; 93 men), 79 (53.0%) had sarcopenia. Patients with sarcopenia had significantly shorter PFS than patients without sarcopenia (median, 1.4 months vs. 2.6 months; P = 0.026). Sarcopenia was independently associated with shorter PFS (adjusted hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.10-2.93; P = 0.020). Patients with sarcopenia had shorter OS than patients without sarcopenia (median, 3.6 months vs. 4.9 months; P = 0.052), but sarcopenia itself was not a significant prognostic factor for OS (adjusted HR, 1.01; 95% CI, 0.58-1.75; P = 0.974).

Conclusions: CT-determined sarcopenia is an independent prognostic factor for PFS in patients with MSS GC treated with PD-1 inhibitors.

Keywords: Gastric cancer; Nivolumab; Pembrolizumab; Sarcopenia.
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