Review Biol Blood Marrow Transplant
. 2019 Jul;25(7):1271-1280. doi: 10.1016/j.bbmt.2019.02.018. Epub 2019 Feb 22.
Risk Factors for Development of and Progression of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome
Selim Corbacioglu 1, Elias J Jabbour 2, Mohamad Mohty 3
Affiliations expand
PMID: 30797942 DOI: 10.1016/j.bbmt.2019.02.018
Free article
Abstract
Veno-occlusive disease, also known as sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of allogeneic or autologous hematopoietic stem cell transplantation (HSCT) most commonly associated with high-intensity chemotherapies. The development of VOD/SOS may be rapid and unpredictable, and the importance of identifying risk factors to facilitate prompt diagnosis and timely treatment has become increasingly recognized. The reporting of new retrospective study data for adults and children and the emergence of novel anticancer therapies that may increase the risk of VOD/SOD also necessitate updates on risk factors, as provided in this review. The latest studies reporting VOD/SOS risk factors support previously published data, although the importance of patient-related factors, such as acute kidney injury, increased international normalized ratio, female sex (in children), and platelet refractoriness, is given greater emphasis in the recent data. Non-transplantation-related chemotherapies associated with increased risk for VOD/SOS include oxaliplatin and 5-fluorouracil chemotherapies. The novel antibody drug conjugates gemtuzumab ozogamicin and inotuzumab ozogamicin are now reported in product labeling to pose risks for VOD/SOS based on clinical trial data; an expert consensus panel has issued recommendations for risk reduction measures with inotuzumab ozogamicin treatment, including VOD/SOS prophylaxis and limitation to ≤2 inotuzumab ozogamicin treatment cycles. A wide range of biomarkers, including genetic, hematologic, hepatic, and inflammatory factors, as well as novel diagnostic techniques such as thromboelastography and measures of liver stiffness, may further enhance future risk calculation for VOD/SOS, although none has been widely adopted. Continual monitoring for and recognition of VOD/SOS risk factors are essential for optimal management of this complication.

Keywords: Antibody drug conjugates; Biomarkers; Primary chemotherapy; Risk factors; Veno-occlusive disease/sinusoidal obstruction syndrome.

Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

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2
Multicenter Study Oncologist
. 2019 Nov;24(11):e1082-e1090. doi: 10.1634/theoncologist.2018-0672. Epub 2019 Mar 25.
Value of Tumor Growth Rate (TGR) as an Early Biomarker Predictor of Patients' Outcome in Neuroendocrine Tumors (NET)-The GREPONET Study
Angela Lamarca 1 2, Joakim Crona 3, Maxime Ronot 4, Marta Opalinska 5, Carlos Lopez Lopez 6, Daniela Pezzutti 7, Pavan Najran 8, Luciana Carvhalo 9, Regis Otaviano Franca Bezerra 10 11, Philip Borg 8, Naik Vietti Violi 12, Hector Vidal Trueba 13, Louis de Mestier 14, Niklaus Schaefer 15, Anders Sundin 16, Frederico Costa 9, Marianne Pavel 17, Clarisse Dromain 12, Knowledge Network
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PMID: 30910869 PMCID: PMC6853102 DOI: 10.1634/theoncologist.2018-0672
Free PMC article
Abstract in English , Chinese
Introduction: Tumor growth rate (TGR; percent size change per month [%/m]) is postulated to be an early radiological biomarker to overcome limitations of RECIST. This study aimed to assess the impact of TGR in neuroendocrine tumors (NETs) and potential clinical and therapeutic applications.

Materials and methods: Patients (pts) with advanced grade (G) 1/2 NETs from the pancreas or small bowel initiating systemic treatment (ST) or watch and wait (WW) were eligible. Baseline and follow-up scans were retrospectively reviewed to calculate TGR at pretreatment (TGR0), first follow-up (TGRfirst), and 3(±1) months of study entry (TGR3m).

Results: Out of 905 pts screened, 222 were eligible. Best TGRfirst (222 pts) cutoff was 0.8 (area under the curve, 0.74). When applied to TGR3m (103 pts), pts with TGR3m <0.8 (66.9%) versus TGR3m ≥ 0.8 (33.1%) had longer median progression-free survival (PFS; 26.3 m; 95% confidence interval [CI] 19.5-32.4 vs. 9.3 m; 95% CI, 6.1-22.9) and lower progression rate at 12 months (7.3% vs. 56.8%; p = .001). WW (vs. ST) and TGR3m ≥ 0.8 (hazard ratio [HR], 3.75; 95% CI, 2.21-6.34; p < .001) were retained as factors associated with a shorter PFS in multivariable Cox regression. TGR3m (HR, 3.62; 95% CI, 1.97-6.64; p < .001) was also an independent factor related to shorter PFS when analysis was limited to pts with stable disease (81 pts). Out of the 60 pts with TGR0 data available, 60% of pts had TGR0 < 4%/month. TGR0 ≥ 4 %/month (HR, 2.22; 95% CI, 1.15-4.31; p = .018) was also an independent factor related to shorter PFS.

Conclusion: TGR is an early radiological biomarker able to predict PFS and to identify patients with advanced NETs who may require closer radiological follow-up.

Implications for practice: Tumor growth rate at 3 months (TGR3m) is an early radiological biomarker able to predict progression-free survival and to identify patients with advanced neuroendocrine tumors who may require closer radiological follow-up. It is feasible to calculate TGR3m in clinical practice and it could be a useful tool for guiding patient management. This biomarker could also be implemented in future clinical trials to assess response to therapy.

Keywords: NET; Neuroendocrine tumor; Progression‐free survival; TGR; Tumor growth rate.

© AlphaMed Press 2019.

Conflict of interest statement
Disclosures of potential conflicts of interest may be found at the end of this article.

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3
Review Biol Blood Marrow Transplant
. 2019 Jul;25(7):e226-e246. doi: 10.1016/j.bbmt.2019.02.012. Epub 2019 Feb 14.
Hematopoietic Stem Cell Transplantation for Mucopolysaccharidoses: Past, Present, and Future
Madeleine Taylor 1, Shaukat Khan 2, Molly Stapleton 1, Jianmin Wang 3, Jing Chen 3, Robert Wynn 4, Hiromasa Yabe 5, Yasutsugu Chinen 6, Jaap Jan Boelens 7, Robert W Mason 1, Francyne Kubaski 8, Dafne D G Horovitz 9, Anneliese L Barth 9, Marta Serafini 10, Maria Ester Bernardo 11, Hironori Kobayashi 12, Kenji E Orii 13, Yasuyuki Suzuki 14, Tadao Orii 13, Shunji Tomatsu 15
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PMID: 30772512 PMCID: PMC6615945 DOI: 10.1016/j.bbmt.2019.02.012
Free PMC article
Abstract
Allogenic hematopoietic stem cell transplantation (HSCT) has proven to be a viable treatment option for a selected group of patients with mucopolysaccharidoses (MPS), including those with MPS types I, II, IVA, VI, and VII. Early diagnosis and timely referral to an expert in MPS are critical, followed by a complete examination and evaluation by a multidisciplinary team, including a transplantation physician. Treatment recommendations for MPS are based on multiple biological, sociological, and financial factors, including type of MPS, clinical severity, prognosis, present clinical signs and symptoms (disease stage), age at onset, rate of progression, family factors and expectations, financial burden, feasibility, availability, risks and benefits of available therapies such as HSCT, enzyme replacement therapy (ERT), surgical interventions, and other supportive care. International collaboration and data review are critical to evaluating the therapeutic efficacy and adverse effects of HSCT for MPS. Collaborative efforts to assess HSCT for MPS have been ongoing since the first attempt at HSCT in a patient with MPS reported in 1981. The accumulation of data since then has made it possible to identify early outcomes (ie, transplantation outcomes) and long-term disease-specific outcomes resulting from HSCT. The recent identification of predictive factors and the development of innovative regimens have significantly improved the outcomes of both engraftment failure and transplantation-related mortality. Assessment of long-term outcomes has considered a variety of factors, including type of MPS, type of graft, age at transplantation, and stage of disease progression, among others. Studies on long-term outcomes are considered a key factor in the use of HSCT in patients with MPS. These studies have shown the effects and limitations of HSCT on improving disease manifestations and quality of life. In this review, we summarize the efficacy, side effects, risks, and cost of HSCT for each type of MPS.

Keywords: Allogenic hematopoietic stem cell transplantation; Enzyme replacement therapy; Limitations; Mucopolysaccharidoses; Outcomes.

Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Conflict of interest statement
Conflict of Interest:

Madeleine Taylor, Shaukat Khan, Molly Stapleton, Jianmin Wang, Jing Chen, Robert Wynn, Hiromasa Yabe, Yasutsugu Chinen, Jaap Jan Boelens, Robert W. Mason, Francyne Kubaski, Dafne D.G Horovitz, Anneliese L. Barth, Marta Serafini, Alessandro Aiuti, Maria Ester Bernardo, Hironori Kobayashi, Kenji E. Orii, Yasuyuki Suzuki, Tadao Orii, and Shunji Tomatsu contributed to the Review Article and had no conflict of interest with any other party. All authors declare that they have no conflict of interests.

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4
Review Stem Cells Dev
. 2019 Aug 1;28(15):995-1003. doi: 10.1089/scd.2019.0025. Epub 2019 May 20.
Periodontal Ligament Stem Cells: Current Knowledge and Future Perspectives
Oriana Trubiani 1, Jacopo Pizzicannella 1 2, Sergio Caputi 1, Marco Marchisio 3, Emanuela Mazzon 4, Roberto Paganelli 3, Alessia Paganelli 5, Francesca Diomede 1
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PMID: 31017047 DOI: 10.1089/scd.2019.0025
Abstract
Teeth represent a fascinating area of study in regenerative medicine, because of their unique and complex developmental origin. Several types of mesenchymal stem cells (MSCs) have been characterized in the oral cavity, and those derived from the periodontal ligament (PDL) first isolated by our group in 2005, can be expanded in a xeno-free medium preserving morphological features and markers associated with pluripotency. These postnatal MSCs can be easily recovered by noninvasive procedures and cultured. This could facilitate the use of adult stem cells in human clinical regeneration therapy. In this review we summarize the results of our studies describing morphofunctional features, surface markers, and multilineage differentiation capacity in vitro of PDL MSCs obtained in our laboratories. In vivo characterization of PDL stem cell (PDLSC) location and heterogeneity are still lacking. However, we describe studies exploring the potential use of PDLSC to treat both periodontal diseases and regeneration of other tissues. These MSCs may have an advantage in possessing also angiogenetic, immunoregulatory, and anti-inflammatory properties. The secretome of such cells contains several interesting molecules mimicking the effects of the producer cells. We describe some recent studies from our group on the use of conditioned medium from PDL MSCs, and purified extracellular vesicles therein contained, in animal models of experimental autoimmune encephalomyelitis and their potential application to human disease.

Keywords: EAE; MSCs; inflammation; periodontal ligament; regenerative medicine; stem cells.

Cited by 7 articles
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5
Oncology (Williston Park)
. 2019 Sep 20;33(9):685003.
Biliary Cancer: Current Multimodality Treatment and Future Directions
Mehmet Sitki Copur, Shaheed Merani, Luciano M Vargas
PMID: 31571182
Free article
Abstract
Biliary cancer is a highly aggressive malignancy arising from the biliary tree, with its incidence increasing steadily on a global level. Most biliary cancers are diagnosed in the advanced and metastatic stages due to the paucity of signs and symptoms in the early presentation. Only about one-third of the patients can be treated with curative intent with an overall median survival of less than 24 months for all-comers from the time of diagnosis. This fact and the poor results of the currently available local and systemic therapies, are responsible for the disappointing outcome of biliary cancer patients. There is an unmet need for novel therapeutic approaches. Surgery, the backbone of curative treatments for biliary cancer, is effective in early, completely-resectable stages or in combination with neoadjuvant or adjuvant chemotherapy and/or radiation therapy for locally advanced stages. Systemic therapies in unresectable and recurrent cases are associated with poor outcomes. The introduction of next-generation sequencing technologies has opened new horizons for a better understanding of the molecular basis of this cancer with potential identification and evaluation of new treatment options.

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6
Clinical Trial Bone Marrow Transplant
. 2019 May;54(5):775-781. doi: 10.1038/s41409-018-0380-5. Epub 2018 Oct 30.
Effect of Bone Marrow CD34+cells and T-cell Subsets on Clinical Outcomes After Myeloablative Allogeneic Hematopoietic Cell Transplantation
Sagar S Patel 1, Lisa A Rybicki 2, Donna Corrigan 1, Carol Dumont 3, Brian Bolwell 1, Robert Dean 1, Priscilla Figueroa 3, Rabi Hanna 1, Hien Liu 4, Aaron T Gerds 1, Brian Hill 1, Deepa Jagadeesh 1, Matt Kalaycio 1, Brad Pohlman 1, Kristin Ricci 1, Ronald Sobecks 1, Wen Lu 3, Betty K Hamilton 1, Navneet S Majhail 5
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PMID: 30375493 DOI: 10.1038/s41409-018-0380-5
Abstract
Donor-derived T-cells mediate graft-versus-leukemia effect, immune reconstitution, and graft-versus-host-disease (GvHD) after allogeneic hematopoietic cell transplantation (HCT). We examined the association of donor cell subsets with outcomes in recipients of myeloablative allogeneic HCT using bone marrow (BM, N = 359) grafts from 2002 to 2014 with related or unrelated donors. Analysis considered pre-infusion graft total nucleated cell (TNC), CD34+ CD3+, CD4+, CD8+ doses. Most patients received busulfan-cyclophosphamide or etoposide-total body irradiation conditioning for acute leukemia or myelodysplastic syndrome. Calcineurin inhibitor-mycophenolate mofetil (CNI-MMF) (49%) or calcineurin inhibitor-methotrexate (CNI-MTX) (47%) were used for GvHD prophylaxis. In multivariable analysis, higher CD34+ dose was associated with platelet engraftment (P < 0.001) and lymphocyte recovery (P = 0.006). There was no association of donor cell subsets with donor chimerism or overall survival. In conclusion, BM graft composition is associated with myeloablative allogeneic HCT outcomes and future studies to evaluate optimal graft composition are needed.

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7
Review Onco Targets Ther
. 2020 Jun 8;13:5093-5112. doi: 10.2147/OTT.S193363. eCollection 2020.
Management of Refractory Pediatric Sarcoma: Current Challenges and Future Prospects
Deepam Pushpam # 1, Vikas Garg # 1, Sandip Ganguly 2, Bivas Biswas 2
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PMID: 32606731 PMCID: PMC7293381 DOI: 10.2147/OTT.S193363
Free PMC article
Abstract
Paediatric sarcomas are a heterogeneous group of disorders constituting bone sarcoma and various soft tissue sarcomas. Almost one-third of these presents with metastasis at baseline and another one-third recur after initial curative treatment. There is a huge unmet need in this cohort in terms of curative options and/or prolongation of survival. In this review, we have discussed the current treatment options, challenges and future strategies of managing relapsed/refractory paediatric sarcomas. Upfront risk-adapted treatment with multidisciplinary management remains the main strategy to prevent future recurrence or relapse of the disease. In the case of limited local and/or systemic relapse or late relapse, initial multimodality management can be administered. In treatment-refractory cases or where cure is not feasible, the treatment options are limited to novel therapeutics, immunotherapeutic approach, targeted therapies, and metronomic therapies. A better understanding of disease biology, mechanism of treatment refractoriness, identifications of driver mutation, the discovery of novel targeted therapies, cellular vaccine and adapted therapies should be explored in relapsed/refractory cases. Close national and international collaboration for translation research is needed to fulfil the unmet need.

Keywords: disease biology; immunotherapy; osteosarcoma; paediatric sarcoma; relapsed sarcoma; targeted therapy.

© 2020 Pushpam et al.

Conflict of interest statement
The authors report no conflicts of interest in this work.

199 references1 figure
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Review Onco Targets Ther
. 2020 Jun 11;13:5429-5441. doi: 10.2147/OTT.S254995. eCollection 2020.
The Role of Erastin in Ferroptosis and Its Prospects in Cancer Therapy
Yuechen Zhao 1, Yanqing Li 2, Ruifeng Zhang 1, Feng Wang 3, Tiejun Wang # 1, Yan Jiao # 4
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PMID: 32606760 PMCID: PMC7295539 DOI: 10.2147/OTT.S254995
Free PMC article
Abstract
Erastin was initially discovered as a small molecule compound that selectively kills tumor cells expressing ST and RASV12 and was later widely investigated as an inducer of ferroptosis. Ferroptosis is a recently discovered form of cell death caused by peroxidation induced by the accumulation of intracellular lipid reactive oxygen species (L-ROS) in an iron-dependent manner. Erastin can mediate ferroptosis through a variety of molecules including the cystine-glutamate transport receptor (system XC -), the voltage-dependent anion channel (VDAC), and p53. Erastin is able to enhance the sensitivity of chemotherapy and radiotherapy, suggesting a promising future in cancer therapy. We hope that this review will help to better understand the role of erastin in ferroptosis and lay the foundation for further research and the development of erastin-based cancer therapies in the future.

Keywords: VDAC; cancer; erastin; ferroptosis; p53; system XC−.

© 2020 Zhao et al.

Conflict of interest statement
The authors report no conflicts of interest in this work.

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9
Review J Eur Acad Dermatol Venereol
. 2020 Jun;34(6):1196-1201. doi: 10.1111/jdv.16515.
Dermatologists and SARS-CoV-2: The Impact of the Pandemic on Daily Practice
P Gisondi 1, S Piaserico 2, A Conti 3, L Naldi 4 5
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PMID: 32320091 PMCID: PMC7264567 DOI: 10.1111/jdv.16515
Free PMC article
Abstract
Since the first case of 'pneumonia of unknown aetiology' was diagnosed at the Wuhan Jinyintan Hospital in China on 30 December 2019, what was recognized thereafter as 'severe acute respiratory syndrome coronavirus 2' (SARS-CoV-2) has spread over the four continents, causing the respiratory manifestations of coronavirus disease-19 (COVID-19) and satisfying the epidemiological criteria for a label of 'pandemic'. The ongoing SARS-CoV-2 pandemic is having a huge impact on dermatological practice including the marked reduction of face-to-face consultations in favour of teledermatology, the uncertainties concerning the outcome of COVID-19 infection in patients with common inflammatory disorders such as psoriasis or atopic dermatitis receiving immunosuppressive/immunomodulating systemic therapies; the direct involvement of dermatologists in COVID-19 care for patient assistance and new research needs to be addressed. It is not known yet if skin lesions and derangement of the skin barrier could make it easier for SARS-CoV-2 to transmit via indirect contact; it remains to be defined if specific mucosal or skin lesions are associated with SARS-CoV-2 infection, although some unpublished observations indicate the occurrence of a transient varicelliform exanthema during the early phase of the infection. SARS-CoV-2 is a new pathogen for humans that is highly contagious, can spread quickly, and is capable of causing enormous health, economic and societal impacts in any setting. The consequences may continue long after the pandemic resolves, and new management modalities for dermatology may originate from the COVID-19 disaster. Learning from experience may help to cope with future major societal changes.

© 2020 European Academy of Dermatology and Venereology.

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10
Review Biomolecules
. 2020 Jun 28;10(7):E973. doi: 10.3390/biom10070973.
Mesothelin-Targeted Recombinant Immunotoxins for Solid Tumors
Brendan L Hagerty 1 2, Guillaume J Pegna 1 3, Jian Xu 1, Chin-Hsien Tai 1, Christine Alewine 1
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PMID: 32605175 DOI: 10.3390/biom10070973
Free article
Abstract
Mesothelin (MSLN) is a cell surface glycoprotein normally expressed only on serosal surfaces, and not found in the parenchyma of vital organs. Many solid tumors also express MSLN, including mesothelioma and pancreatic adenocarcinoma. Due to this favorable expression profile, MSLN represents a viable target for directed anti-neoplastic therapies, such as recombinant immunotoxins (iToxs). Pre-clinical testing of MSLN-targeted iTox's has yielded a strong body of evidence for activity against a number of solid tumors. This has led to multiple clinical trials, testing the safety and efficacy of the clinical leads SS1P and LMB-100. While promising clinical results have been observed, neutralizing anti-drug antibody (ADA) formation presents a major challenge to overcome in the therapeutic development process. Additionally, on-target, off-tumor toxicity from serositis and non-specific capillary leak syndrome (CLS) also limits the dose, and therefore, impact anti-tumor activity. This review summarizes existing pre-clinical and clinical data on MSLN-targeted iTox's. In addition, we address the potential future directions of research to enhance the activity of these anti-tumor agents.

Keywords: immunotoxin; mesothelin; mesothelioma; pancreatic adenocarcinoma.

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

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11
Review Int J Clin Oncol
. 2020 May;25(5):801-809. doi: 10.1007/s10147-020-01666-1. Epub 2020 Apr 3.
Rationale of Combination of anti-PD-1/PD-L1 Antibody Therapy and Radiotherapy for Cancer Treatment
Hiro Sato 1, Noriyuki Okonogi 2, Takashi Nakano 2
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PMID: 32246277 PMCID: PMC7192886 DOI: 10.1007/s10147-020-01666-1
Free PMC article
Abstract
Significant technological advances in radiotherapy have been made in the past few decades. High-precision radiotherapy has recently become popular and is contributing to improvements in the local control of the irradiated target lesions and the reduction of adverse effects. Accordingly, for long-term survival, the importance of systemic cancer control, including at non-irradiated sites, is growing. Toward this challenge, the treatment methods in which anti-PD-1/PD-L1 antibodies that exert systemic effects by restoring anti-tumour immunity are combined with radiotherapy has attracted attention in recent years. Previous studies have reported the activation of anti-tumour immunity by radiotherapy, which simultaneously elevates PD-L1 expression, suggesting a potential for combination therapy. Radiotherapy induces so-called 'immunogenic cell death', which involves cell surface translocation of calreticulin and extracellular release of high-mobility group protein box 1 (HMGB-1) and adenosine-5'-triphosphate (ATP). Furthermore, radiotherapy causes immune activation via MHC class I upregulation and cGAS-STING pathway. In contrast, induction of immunosuppressive lymphocytes and the release of immunosuppressive cytokines and chemokines by radiotherapy contribute to immunosuppressive reactions. In this article, we review immune responses induced by radiotherapy as well as previous reports to support the rationale of combination of radiotherapy and anti-PD-1/PD-L1 antibodies. A number of preclinical and clinical studies have shown the efficacy of radiotherapy combined with immune checkpoint inhibition, hence combination therapy is considered to be an important future strategy for cancer treatment.

Keywords: Immune checkpoint inhibitors; Immunogenic cell death; PD-1; PD-L1; Radiotherapy.

Conflict of interest statement
The authors declare no potential conflicts of interest.

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12
Adv Gerontol
. 2020;33(2):397-408.
[Theory and Practice of Aging Upon COVID-19 Pandemic]
[Article in Russian]
A G Golubev 1, A V Sidorenko 2
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PMID: 32593259
Abstract in English , Russian
Never before in history, aging was such a significant factor for epidemics as it is now for the current COVID-19 pandemic, which features a drastic shift of mortality towards older ages. Our analysis of data on COVID-19-related mortality in Spain, Italy, and Sweden has shown that, in the range of 30 to 90 years of age, each dependency of the logarithm of mortality upon age is linear, and all regression lines are strictly parallel to those related to the total mortality in accordance with the Gompertz law. In all cases, irrespective of the stage and place of epidemic, mortality doubling time in this age range is close to 7,5 years. The rates of being infected with the SARS-CoV-2 coronavirus and of being diagnosed due to the symptomatic manifestations of the infection are dependent on age to a far lesser degree. With account for these observations, three messages are put forth: 1) Older persons are the principal victims of both SARS-CoV-2 and measures undertaken to control its spread; 2) Older persons are not the principal driving force of SARS-CoV-2 spread; 3) Older persons can and should be engaged in combating the pandemic and its consequences; however, not via selective social distancing and other discriminative measures. People aged over 65 years constitute a significant part of the current population. They have specific interests and needs, which deserve no less respect than those of any other age group. This includes the right for the quality of life that remains sustained under the emergency conditions. Since the prospects for controlling the SARS-CoV-2 are dubious, those in charge of decisions concerning «people aged above 65» should mind that currently, unlike in the medieval ages, 65+ is the individual future of almost everyone.

Keywords: COVID-19; aging; epidemiology; geriatrics; gerontology.

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13
Neuro Oncol
. 2020 Jun 2;noaa130. doi: 10.1093/neuonc/noaa130. Online ahead of print.
European Genetic Ancestry Associated With Risk of Childhood Ependymoma
Chenan Zhang 1, Quinn T Ostrom 2 3, Helen M Hansen 4, Julio Gonzalez-Maya 4, Donglei Hu 5, Elad Ziv 5, Libby Morimoto 6, Adam J de Smith 7, Ivo S Muskens 7, Cassie N Kline 8 9, Zalman Vaksman 10, Hakon Hakonarson 11 12, Sharon J Diskin 10 12, Carol Kruchko 9, Jill S Barnholtz-Sloan 13, Vijay Ramaswamy 14, Francis Ali-Osman 15, Melissa L Bondy 2, Michael D Taylor 14, Catherine Metayer 6, Joseph L Wiemels 7, Kyle M Walsh 1 15
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PMID: 32607579 DOI: 10.1093/neuonc/noaa130
Abstract
Background: Ependymoma is a histologically defined central nervous system tumor most commonly occurring in childhood. Population-level incidence differences by race/ethnicity are observed, with individuals of European ancestry at highest risk. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk in US populations.

Methods: In a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among recently admixed Hispanic and African American subjects and estimated European admixture among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local ancestry. We also evaluated race/ethnicity-stratified ependymoma incidence data from the Central Brain Tumor Registry of the United States (CBTRUS).

Results: CBTRUS data revealed that African American and Native American children have 33% and 36%, respectively, reduced incidence of ependymoma compared with non-Hispanic whites. In genetic analyses, a 20% increase in European ancestry was associated with a 1.31-fold higher odds of ependymoma among self-reported Hispanics and African Americans (95% CI: 1.08-1.59, Pmeta = 6.7 × 10-3). Additionally, eastern European ancestral substructure was associated with increased ependymoma risk in non-Hispanic whites (P = 0.030) and in Hispanics (P = 0.043). Admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and targeted fine-mapping identified a lead variant at rs6039499 near RSPO4 (odds ratio = 1.99; 95% CI: 1.45-2.73; P = 2.2 × 10-5) but which was not validated in an independent set of posterior fossa type A patients.

Conclusions: Interethnic differences in ependymoma risk are recapitulated in the genomic ancestry of ependymoma patients, implicating regions to target in future association studies.

Keywords: disparities; ependymoma; ethnicity; genetic ancestry; pediatric cancer; race.

© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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14
Lancet Respir Med
. 2020 Jan;8(1):54-64. doi: 10.1016/S2213-2600(19)30269-3. Epub 2019 Sep 9.
Nicotine Patches Used in Combination With E-Cigarettes (With and Without Nicotine) for Smoking Cessation: A Pragmatic, Randomised Trial
Natalie Walker 1, Varsha Parag 2, Marjolein Verbiest 3, George Laking 4, Murray Laugesen 5, Christopher Bullen 2
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PMID: 31515173 DOI: 10.1016/S2213-2600(19)30269-3
Abstract
Background: Combination nicotine replacement therapy shows additive cessation benefits. We aimed to find out the effectiveness of combining nicotine patches with an e-cigarette (with and without nicotine) on six-month smoking abstinence.

Methods: We did a pragmatic, three-arm, parallel-group trial in New Zealand in adult smokers who were e-cigarette naive and motivated to quit smoking. Participants were recruited from the general population using national media advertising. Participants were randomly assigned (1:4:4), with the use of stratified block randomisation, to receive 14 weeks (2 weeks before the agreed quit date) of 21 mg, 24h nicotine patches, patches plus an 18 mg/L nicotine e-cigarette, or patches plus a nicotine-free e-cigarette. We advised participants to use one patch daily, with e-cigarette use as and when necessary or desired. Participants and researchers were masked to e-liquid nicotine content. We offered 6 weeks of telephone-delivered behavioural support. The primary outcome was exhaled carbon monoxide (CO)-verified continuous smoking abstinence 6 months after the agreed quit date. Primary analysis was by intention to treat, with sensitivity analysis by per protocol, treatment adherence, varying CO cutoffs, and complete case analysis. This paper presents the main analyses and is registered with ClinicalTrials.gov, NCT02521662.

Findings: Between March 17, 2016 and Nov 30, 2017, 1124 people were assigned to nicotine patches (patches only group, n=125), patches plus a nicotine e-cigarette (patches plus nicotine e-cigarette group, n=500), or patches plus a nicotine-free e-cigarette (patches plus nicotine-free e-cigarette group, n=499). 62 (50%) of 125 participants in the patches only group withdrew or were lost to follow-up by 6 months compared with 161 (32%) of 500 in the patches plus nicotine e-cigarette group and 162 (33%) of 499 in the patches plus nicotine-free e-cigarette group. 35 (7%) participants in the patches plus nicotine e-cigarette group had CO-verified continuous abstinence at 6 months compared with 20 (4%) in the patches plus nicotine-free e-cigarette group (risk difference [RD] 2·99 [95% CI 0·17-5·81]), and three (2%) people in the patches only group (RD 4·60 [1·11-8·09]). 18 serious adverse events occurred in 16 people in the patches plus nicotine e-cigarette group compared with 27 events in 22 people in the patches plus nicotine-free e-cigarette group and four events in three people in the patches only group. In the patches plus nicotine e-cigarette group, two life-threatening serious adverse events were reported (two separate heart attacks in the one participant). In the patches plus nicotine-free e-cigarette group, one death occurred (accidental drug overdose) and one life-threatening serious adverse event (heart attack). No significant between-group differences were noted for serious adverse events, and none were treatment-related.

Interpretation: Combining reduced-harm nicotine products, such as nicotine patches with a nicotine e-cigarette, can lead to a modest improvement in smoking cessation over and above that obtained from using patches plus a nicotine-free e-cigarette (or patches alone), with no indication of any serious harm in the short-term. Future e-cigarette trials should focus on their use alone or in combination with usual smoking cessation support, given issues with differential loss to follow-up and withdrawal if a usual care group is used as a comparator.

Funding: Health Research Council of New Zealand.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Comment in
E-cigarettes and dual nicotine replacement therapy for smoking cessation.
Benowitz NL.
Lancet Respir Med. 2020 Jan;8(1):7-8. doi: 10.1016/S2213-2600(19)30308-X. Epub 2019 Sep 9.
PMID: 31515174 No abstract available.
Cited by 6 articles
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15
Review ACS Cent Sci
. 2020 Jun 24;6(6):861-868. doi: 10.1021/acscentsci.0c00397. Epub 2020 May 15.
Nanoscale Metal-Organic Frameworks Generate Reactive Oxygen Species for Cancer Therapy
Kaiyuan Ni 1, Guangxu Lan 1, Wenbin Lin 1
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PMID: 32607433 PMCID: PMC7318063 DOI: 10.1021/acscentsci.0c00397
Free PMC article
Abstract
In the past 15 years, enormous progress has been made in cancer nanotechnology, and a several nanoparticles have entered clinical testing for cancer treatment. Among these nanoparticles are nanoscale metal-organic frameworks (nMOFs), a class of organic-inorganic hybrid nanomaterials constructed from metal binding sites and bridging ligands, which have attracted significant attention for their ability to integrate porosity, crystallinity, compositional and structural tunability, multifunctionality, and biocompatibility into a singular nanomaterial for cancer therapies. This Outlook article summarizes the progress on the design of nMOFs as nanosensitizers for photodynamic therapy (PDT), radiotherapy (RT), radiotherapy-radiodynamic therapy (RT-RDT), and chemodynamic therapy (CDT) via nMOF-mediated reactive oxygen species (ROS) generated under external energy stimuli or in the presence of endogenous chemical triggers. Inflammatory responses induced by nMOF-mediated ROS generation activate tumor microenvironments to potentiate cancer immunotherapy, extending the local treatment effects of nMOF-based ROS therapy to distant tumors via abscopal effects. Future research directions in nMOF-mediated ROS therapies and the prospect of clinical applications of nMOFs as cancer therapeutics are also discussed.

Copyright © 2020 American Chemical Society.

Conflict of interest statement
The authors declare the following competing financial interest(s): W.L. is founder and chairman of Coordination Pharmaceuticals, Inc., which licensed the nMOF technologies from the University of Chicago.

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16
Review J Clin Med
. 2020 Jun 26;9(6):E2004. doi: 10.3390/jcm9062004.
Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development
Karishma Dhuri 1, Clara Bechtold 1, Elias Quijano 2, Ha Pham 3, Anisha Gupta 4, Ajit Vikram 5, Raman Bahal 1
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PMID: 32604776 DOI: 10.3390/jcm9062004
Free article
Abstract
Antisense oligonucleotides (ASOs) bind sequence specifically to the target RNA and modulate protein expression through several different mechanisms. The ASO field is an emerging area of drug development that targets the disease source at the RNA level and offers a promising alternative to therapies targeting downstream processes. To translate ASO-based therapies into a clinical success, it is crucial to overcome the challenges associated with off-target side effects and insufficient biological activity. In this regard, several chemical modifications and diverse delivery strategies have been explored. In this review, we systematically discuss the chemical modifications, mechanism of action, and optimized delivery strategies of several different classes of ASOs. Further, we highlight the recent advances made in development of ASO-based drugs with a focus on drugs that are approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for clinical applications. We also discuss various promising ASO-based drug candidates in the clinical trials, and the outstanding opportunity of emerging microRNA as a viable therapeutic target for future ASO-based therapies.

Keywords: RNA; antisense oligonucleotides; chemical modifications; clinical trials.

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17
Review Trends Immunol
. 2020 Jun 27;S1471-4906(20)30130-7. doi: 10.1016/j.it.2020.06.006. Online ahead of print.
Cardiac Mast Cells: Underappreciated Immune Cells in Cardiovascular Homeostasis and Disease
Gilda Varricchi 1, Gianni Marone 2, Petri T Kovanen 3
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PMID: 32605802 DOI: 10.1016/j.it.2020.06.006
Abstract
Mast cells are multifarious immune cells with complex roles in tissue homeostasis and disease. They produce a plethora of mediators that play roles in inflammation, angiogenesis, lymphangiogenesis, and tissue remodeling. Recent insights into the heterogeneity of cardiac mast cell (CMC) subpopulations have renewed interest in their functional diversity in homeostasis and disease. They are located within the human heart in the myocardium, in atherosclerotic plaques, in the aortic valve, and in close proximity to nerves. Their plasticity enables different and even opposite functions in response to changing tissue contexts. These characteristics render CMCs intriguing, with a dichotomous role in protecting against, or accelerating, cardiovascular diseases. Future work should aim to identify CMC subsets, which could reveal novel therapeutic opportunities for cardiovascular disorders.

Keywords: allergy; atherosclerosis; cardiovascular diseases; eosinophils; mast cells; myocardial infarction; myocarditis.

Copyright © 2020 Elsevier Ltd. All rights reserved.

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18
Curr Colorectal Cancer Rep
. 2020 Aug;16(4):81-88. doi: 10.1007/s11888-020-00456-1. Epub 2020 Jun 5.
Immunotherapy in Colorectal Cancer: Potential of Fecal Transplant and Microbiota-augmented Clinical Trials
Robin Park 1, Shahid Umar 2, Anup Kasi 3
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PMID: 32607098 PMCID: PMC7325521 (available on 2021-08-01) DOI: 10.1007/s11888-020-00456-1
Abstract
Purpose of review: This review summarizes the role of the microbiome in colorectal cancer (CRC) in the setting of immunotherapy and emphasizes the potential of microbiota-influencing strategies with a focus on the use of fecal microbiota transplant (FMT).

Recent findings: Observations from preclinical and clinical studies suggest that the human gut microbiome is implicated in the CRC carcinogenesis and is integral in determining the clinical response and toxicity to immunotherapy. Among the therapeutic methods devised to exploit the microbiome, FMT is the most direct method and is backed by the highest level of evidence of efficacy in nonneoplastic disease settings. Furthermore, a favorable microbiome has the potential to overcome immunotherapy resistance and ameliorate immune-related adverse events (irAEs). To this end, clinical trials are underway to evaluate the potential of FMT and microbiota-augmented methods in the setting of immunotherapy in CRC.

Summary: Evidence from animal studies, retrospective studies, and smaller-scale prospective human studies have led to initiation of a number of microbiota-augmented clinical trials in CRC. Given the intimate relationship between the gut microbiota and the immune system as well as antitumor immune responses, potentiating immunotherapy and managing its toxicity are major areas of research in microbiota-augmented therapies in cancer. Therefore, evaluation of the patient microbiome as a routine part of clinical outcome analysis is warranted in future clinical trials.

Keywords: colorectal cancer; fecal microbiota transplant; immune-related adverse events; immunotherapy; microbiome.

Conflict of interest statement
Conflict of Interest Robin Park and Shahid Umar each declare no potential conflicts of interest.

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19
PLoS One
. 2020 Apr 2;15(4):e0230188. doi: 10.1371/journal.pone.0230188. eCollection 2020.
Exercise Experiences in Patients With Metastatic Lung Cancer: A Qualitative Approach
Pi-Hua Chang 1 2, Ching-Rong Lin 3 4, Yun-Hsiang Lee 2, Yi-Lin Liu 1, Gee-Chen Chang 5 6, Aasha I Hoogland 7, Yeur-Hur Lai 2 8
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PMID: 32240205 PMCID: PMC7117721 DOI: 10.1371/journal.pone.0230188
Free PMC article
Abstract
Background: Patients with metastatic lung cancer can have severe cancer-related symptoms and treatment-induced side effects. Exercise is beneficial for patients with metastatic lung cancer; however, little information is available on guiding patients how to perform exercise during hospitalization. The purpose of this qualitative study was to understand exercise experiences in patients with metastatic lung cancer.

Methods: Patients with metastatic lung cancer (n = 24) participated in face-to-face in-depth interviews at an inpatient ward of a medical center in central Taiwan. Interview transcripts were evaluated using narrative analysis to extract and validate themes.

Results: Three primary themes were identified: (1) modifying exercise to maximize physical functions; (2) living with symptoms and frustration, but still exercising; and (3) doing exercise to sustain hopes, inner power, and life. Secondary findings included: (1) adopting walking as their main form of exercise because of its convenience; and (2) among patients with severe symptoms, adjusting exercise towards shorter time durations and shorter distances, slower speeds, and higher frequencies.

Conclusions: The study found physically active lung cancer patients, although with metastatic condition, adjusted their exercise activities to balance disease and treatment-induced deteriorations and boost themselves to feel hope and fight for cancer. However, the results may not be applicable to physically inactive patients. Future research to explore experiences from those with even worse physical conditions and further helping them to take some mild exercise to enhance the positive side of cancer experiences are suggested.

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

71 references1 figure
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20
Cancer Med
. 2020 Jun 30. doi: 10.1002/cam4.3199. Online ahead of print.
Promising Survival Rate but High Incidence of Treatment-Related Mortality After Reduced-Dose Craniospinal Radiotherapy and Tandem High-Dose Chemotherapy in Patients With High-Risk Medulloblastoma
Ji Won Lee 1, Do Hoon Lim 2, Ki Woong Sung 1, Hee Won Cho 1, Hee Young Ju 1, Ju Kyung Hyun 1, Keon Hee Yoo 1, Hong Hoe Koo 1, Yeon-Lim Suh 3, Yoo-Sook Joung 4, Hyung Jin Shin 5
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PMID: 32608158 DOI: 10.1002/cam4.3199
Abstract
Background: In this study, we report the follow-up results of reduced dose of craniospinal radiotherapy (CSRT) followed by tandem high-dose chemotherapy (HDCT) in patients with high-risk medulloblastoma (MB).

Methods: Newly diagnosed high-risk MB patients (metastatic disease, postoperative residual tumor >1.5 cm2 , or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre-RT chemotherapy, radiotherapy (RT) including reduced-dose CSRT (23.4 or 30.6 Gy), four cycles of post-RT chemotherapy, and tandem HDCT were administered. NanoString and DNA sequencing were performed using archival tissues.

Results: In all, 40 patients were enrolled, and molecular subgrouping was possible in 21 patients (2 wingless, 3 sonic hedgehog, 8 Group 3, and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (5-year cumulative incidence [CI] 10.4 ± 0.3%). However, six patients died from treatment-related mortality (TRM) (four acute TRMs and two late TRMs) resulting in 18.5 ± 0.5% of 5-year CI. Taken together, the 5-year event-free survival and overall survival were 71.1 ± 8.0% and 73.2 ± 7.9%, respectively. Late effects were evaluated in 25 patients and high-tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common.

Conclusions: The strategy using tandem HDCT following reduced-dose CSRT showed promising results in terms of low relapse/progression rate; however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can benefit from HDCT will be needed in the future study.

Keywords: craniospinal radiotherapy; high-dose chemotherapy; long-term follow-up; medulloblastoma; treatment-related mortality.

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

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21
Review Infect Drug Resist
. 2020 Jun 16;13:1785-1806. doi: 10.2147/IDR.S238446. eCollection 2020.
Proteomic Applications in Antimicrobial Resistance and Clinical Microbiology Studies
Ehsaneh Khodadadi 1, Elham Zeinalzadeh 2 3, Sepehr Taghizadeh 1, Bahareh Mehramouz 3, Fadhil S Kamounah 4, Ehsan Khodadadi 5, Khudaverdi Ganbarov 6, Bahman Yousefi 7, Milad Bastami 7, Hossein Samadi Kafil 1
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PMID: 32606829 PMCID: PMC7305820 DOI: 10.2147/IDR.S238446
Free PMC article
Abstract
Sequences of the genomes of all-important bacterial pathogens of man, plants, and animals have been completed. Still, it is not enough to achieve complete information of all the mechanisms controlling the biological processes of an organism. Along with all advances in different proteomics technologies, proteomics has completed our knowledge of biological processes all around the world. Proteomics is a valuable technique to explain the complement of proteins in any organism. One of the fields that has been notably benefited from other systems approaches is bacterial pathogenesis. An emerging field is to use proteomics to examine the infectious agents in terms of, among many, the response the host and pathogen to the infection process, which leads to a deeper knowledge of the mechanisms of bacterial virulence. This trend also enables us to identify quantitative measurements for proteins extracted from microorganisms. The present review study is an attempt to summarize a variety of different proteomic techniques and advances. The significant applications in bacterial pathogenesis studies are also covered. Moreover, the areas where proteomics may lead the future studies are introduced.

Keywords: bacterial pathogenesis studies; drug resistance; pathogen; proteomics; virulence.

© 2020 Khodadadi et al.

Conflict of interest statement
The authors report no conflicts of interest in this work.

220 references1 figure
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22
Childs Nerv Syst
. 2020 Jun 30. doi: 10.1007/s00381-020-04731-2. Online ahead of print.
Current Status of MEK Inhibitors in the Treatment of Plexiform Neurofibromas
Andrea M Gross 1, Eva Dombi 1, Brigitte C Widemann 2
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PMID: 32607696 DOI: 10.1007/s00381-020-04731-2
Abstract
Background: Neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (pNF) can be debilitating and until recently, surgery was the only potentially effective therapy for these tumors.

Methods: We review critical steps in the path towards the FDA approval of the first medical therapy for NF1 pNF and the current status of MEK inhbitor therapy.

Results: Sustained efforts by the NF community have resulted in a detailed understanding of the natural history and biology of NF1-related peripheral nerve sheath tumors. This work provided the basis for the development of meaningful clinical trials targeting pNF. Inhibition of the RAS/MAPK signaling pathway with MEK inhibitors identified the first medical therapy which resulted in shrinkage in the majority of children with NF1 and large inoperable pNF. Based on this finding and subsequent demonstration of clinical benefit, the MEK inhibitor selumetinib recently received approval by the United States Food and Drug Administration (FDA) for children with symptomatic pNF.

Conclusions: Sustained efforts and collaborations have resulted in identification of MEK inhibitors as effective therapy for NF1 pNF. Future work work will be directed at prevention of pNF morbidity and deepening the reponse in symptomatic pNF.

Keywords: Clinical trial; MEK inhibitor; Neurofibromatosis 1; Plexiform neurofibroma; Trial design.

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23
Patient Prefer Adherence
. 2020 Jun 9;14:971-983. doi: 10.2147/PPA.S249079. eCollection 2020.
Development of the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) Medication Adherence Scale (PMAS)
John Devin Peipert # 1, Sherif M Badawy # 2, Sharon H Baik 1, Laura B Oswald 1, Fabio Efficace 3, Sofia F Garcia 1, Daniel K Mroczek 1, Michael Wolf 4, Karen Kaiser 1, Betina Yanez 1, David Cella 1
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PMID: 32606615 PMCID: PMC7293395 DOI: 10.2147/PPA.S249079
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Abstract
Poor medication adherence is associated with reduced drug effectiveness, poor health-related quality of life, increased morbidity and mortality, and increased healthcare utilization and cost. Including the patient's voice is essential in understanding barriers to adherence. Useful patient-reported adherence measures are brief, inexpensive, non-invasive; can indicate barriers to adherence; and can be incorporated in electronic health records. The NIH Patient-Reported Outcomes Measurement Information System (PROMIS®) includes high-quality, freely available patient-reported measures covering many important constructs in patient-centered research but does not include a medication adherence measure. To fill this gap, we developed the PROMIS Medication Adherence Scale (PMAS) using the rigorous PROMIS instrument development guidelines. To develop the PMAS, we first conducted a review of the reviews, which enabled us to identify content areas relevant to medication adherence behavior. Then, we conducted qualitative research to elicit patients' views of and experiences with medication adherence. This process identified the following important content areas to guide item writing: extent medication is taken, knowledge of medication regimen, beliefs about medication, remembering to take medication, skipping due to side effects, skipping due to feeling better, and cost of medications. Based on the results of these activities, we wrote items and aimed to retain 1-2 items per content area. The final item set included 9 total adherence items, which were then refined through intensive comprehension and translatability review, as well as cognitive interviews. Future steps include testing the PMAS's validity.

Keywords: PROMIS; medication adherence; patient-reported outcome.

© 2020 Peipert et al.

Conflict of interest statement
Dr John Devin Peipert reports grants from Pfizer, Bristol Myers Squibb, and Veloxis Pharmaceuticals and personal fees from AstraZeneca, outside the submitted work. Dr Fabio Efficace reports personal fees from Amgen, Bristol Myers Squibb, Orsenix, Incyte, Takeda, grants from Amgen, outside the submitted work. Dr Daniel K Mroczek reports personal fees from International Drug Development Institute, outside the submitted work. Dr Michael Wolf reports grants from Amgen, grants, personal fees from Merck, Sharpe & Dohme, Pfizer, personal fees from Sanofi, Luto UK, grants from Eli Lilly, outside the submitted work. Dr David Cella reports grants from the National Institutes of Health, during the conduct of the study. Dr Laura B Oswald is now affiliated with Health Outcomes and Behavior Program, Moffitt Cancer Center. The authors report no other conflicts of interest in this work.

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24
Cancer Manag Res
. 2020 Jun 17;12:4633-4643. doi: 10.2147/CMAR.S240275. eCollection 2020.
Icotinib as Adjuvant Treatment for Stage II-IIIA Lung Adenocarcinoma Patients With EGFR Mutation (ICWIP Study): Study Protocol for a Randomised Controlled Trial
Yu-Tao Liu 1, Xue-Zhi Hao 1, De-Ruo Liu 2, Gang Cheng 3, Shu-Cai Zhang 4, Wen-Hua Xiao 5, Yi Hu 6, Jun-Feng Liu 7, Ming He 7, Cui-Min Ding 8, Li Zhang 9, Jun Wang 10, Hui Li 11, Gui-Lan Dong 12, Xiu-Yi Zhi 13, Jian Li 14, Yuan-Kai Shi 1
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PMID: 32606956 PMCID: PMC7306474 DOI: 10.2147/CMAR.S240275
Free PMC article
Abstract
The efficacy and possible role of epidermal growth factor receptor tyrosine kinase inhibitors in treating early-stage non-small-cell lung cancer have yet to be established. Therefore, we aimed to explore the efficacy and safety of icotinib in completely resected EGFR-mutant stage II-IIIA lung adenocarcinoma patients who underwent standard chemotherapy. This is a randomised, double-blinded, placebo-controlled, multicentre, Phase III trial. A total of 124 patients aged 18-75 years who qualified the inclusion criteria were recruited. These patients were randomised (1:1) to receive either icotinib (125 mg 3 times per day) or placebo (the same dosage and frequency) for 36 months, followed by a further 36 months of observational window. The primary endpoint is disease-free survival (DFS), while the secondary endpoints are overall survival, 3-year and 5-year DFS, safety and tolerability of the medication, and health-related quality-of-life. Analyses will be conducted in a full analysis set and a per-protocol set as well. To our knowledge, the present study is the first randomised, double-blinded, placebo-controlled, multicenter trial designed to explore efficacy and safety of icotonib in this population. The results obtained in the near future may provide potential guidance in clinical practice. Trial Registration: This trial was registered on www.ClinicalTrail.gov as NCT02125240.

Keywords: EGFR mutation; adjuvant chemotherapy; icotinib; lung adenocarcinoma; non-small-cell lung cancer.

© 2020 Liu et al.

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

55 references1 figure
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25
Clinical Trial Cell Rep
. 2019 May 14;27(7):2022-2028.e3. doi: 10.1016/j.celrep.2019.04.064.
Functional Dominance of CHIP-Mutated Hematopoietic Stem Cells in Patients Undergoing Autologous Transplantation
Christina A Ortmann 1, Lena Dorsheimer 1, Khalil Abou-El-Ardat 2, Jennifer Hoffrichter 1, Birgit Assmus 3, Halvard Bonig 4, Anica Scholz 5, Heike Pfeifer 1, Hans Martin 1, Tobias Schmid 5, Bernhard Brüne 5, Sebastian Scheich 1, Björn Steffen 1, Julia Riemann 1, Stella Hermann 6, Alexandra Dukat 7, Gesine Bug 1, Christian H Brandts 8, Sebastian Wagner 2, Hubert Serve 2, Michael A Rieger 9
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PMID: 31091442 DOI: 10.1016/j.celrep.2019.04.064
Free article
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is caused by recurrent somatic mutations leading to clonal blood cell expansion. However, direct evidence of the fitness of CHIP-mutated human hematopoietic stem cells (HSCs) in blood reconstitution is lacking. Because myeloablative treatment and transplantation enforce stress on HSCs, we followed 81 patients with solid tumors or lymphoid diseases undergoing autologous stem cell transplantation (ASCT) for the development of CHIP. We found a high incidence of CHIP (22%) after ASCT with a high mean variant allele frequency (VAF) of 10.7%. Most mutations were already present in the graft, albeit at lower VAFs, demonstrating a selective reconstitution advantage of mutated HSCs after ASCT. However, patients with CHIP mutations in DNA-damage response genes showed delayed neutrophil reconstitution. Thus, CHIP-mutated stem and progenitor cells largely gain on clone size upon ASCT-related blood reconstitution, leading to an increased future risk of CHIP-associated complications.

Keywords: ASCT; CHIP; autologous stem cell transplantation; chemotherapy; clonal dominance; clonal hematopoiesis; hematopoietic stem cells; hematopoietic stress; leukemia; somatic mutations.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Cited by 2 articles
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26
Eur Urol Oncol
. 2020 Jun 27;S2588-9311(20)30082-1. doi: 10.1016/j.euo.2020.06.004. Online ahead of print.
The Value of Multiparametric Magnetic Resonance Imaging Sequences to Assist in the Decision Making of Muscle-invasive Bladder Cancer
Marco Bandini 1, Giuseppina Calareso 2, Daniele Raggi 3, Laura Marandino 3, Maurizio Colecchia 4, Andrea Gallina 1, Patrizia Giannatempo 3, Filippo Pederzoli 1, Giorgio Gandaglia 1, Nicola Fossati 1, Umberto Capitanio 1, Renzo Colombo 1, Andrea Salonia 5, Alberto Briganti 5, Francesco Montorsi 5, Francesco De Cobelli 6, Antonella Messina 2, Andrea Necchi 7
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PMID: 32605888 DOI: 10.1016/j.euo.2020.06.004
Abstract
Interim data from the PURE-01 study, using pembrolizumab before radical cystectomy in muscle-invasive bladder cancer (MIBC), suggested that multiparametric magnetic resonance imaging (mpMRI) was able to predict the pathologic response. Owing to the availability of novel effective therapies in MIBC, the possibility to assess tumor response easily has become exceedingly important. The primary objective of the present study was to evaluate the association between individual and combined MRI sequences, and the pathologic response in the final PURE-01 population. Images were internally evaluated and the diagnostic performance was analyzed for separate sequences, along with their combination. From February 2017 to December 2019, 143 patients were enrolled in PURE-01, and 123 with suitable paired imaging assessments before and after pembrolizumab tests (N = 246 mpMRI in total) were analyzed in relation to the pathologic response. The area under the curve (AUC) of the combination of all sequences to predict ypT0ypN0 response was 0.74. By excluding dynamic contrast enhancement (DCE) assessment, the AUC was 0.74. When looking at ypT1/a/is ypN0 response, the AUC was 0.87 in both cases. Without DCE, 95% of patients with no evidence of disease resulted in ypT1/a/is ypN0 and 65% ypT0ypN0 responders. In conclusion, the final results confirmed the reliability of mpMRI and suggested the opportunity to avoid intravenous gadolinium contrast to personalize bladder-sparing strategies in radiologically complete responders. PATIENT SUMMARY: We evaluated the reliability of multiparametric bladder magnetic resonance imaging to predict the pathologic response to pembrolizumab administered before radical cystectomy in muscle-invasive bladder cancer. We observed that this radiologic examination is promising in the attempt to identify opportunities to spare the bladder in selected, radiologically defined complete responders. We also observed that the use of intravenous gadolinium contrast can be avoided in future studies. ClinicalTrials.gov, number NCT02736266.

Keywords: Biparametric magnetic resonance imaging; Bladder magnetic resonance imaging; Dynamic contrast enhancement; Multiparametric magnetic resonance imaging; Muscle-invasive bladder cancer; Noninvasive response assessment.

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

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27
J Clin Med
. 2020 Jun 27;9(7):E2019. doi: 10.3390/jcm9072019.
Tumor Volume Dynamics as an Early Biomarker for Patient-Specific Evolution of Resistance and Progression in Recurrent High-Grade Glioma
Daniel J Glazar 1, G Daniel Grass 2 3, John A Arrington 3 4 5 6, Peter A Forsyth 3 7, Natarajan Raghunand 3 8, Hsiang-Hsuan Michael Yu 2 3, Solmaz Sahebjam 3 7, Heiko Enderling 1 2 3
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PMID: 32605050 DOI: 10.3390/jcm9072019
Free article
Abstract
Recurrent high-grade glioma (HGG) remains incurable with inevitable evolution of resistance and high inter-patient heterogeneity in time to progression (TTP). Here, we evaluate if early tumor volume response dynamics can calibrate a mathematical model to predict patient-specific resistance to develop opportunities for treatment adaptation for patients with a high risk of progression. A total of 95 T1-weighted contrast-enhanced (T1post) MRIs from 14 patients treated in a phase I clinical trial with hypo-fractionated stereotactic radiation (HFSRT; 6 Gy × 5) plus pembrolizumab (100 or 200 mg, every 3 weeks) and bevacizumab (10 mg/kg, every 2 weeks; NCT02313272) were delineated to derive longitudinal tumor volumes. We developed, calibrated, and validated a mathematical model that simulates and forecasts tumor volume dynamics with rate of resistance evolution as the single patient-specific parameter. Model prediction performance is evaluated based on how early progression is predicted and the number of false-negative predictions. The model with one patient-specific parameter describing the rate of evolution of resistance to therapy fits untrained data ( R 2 = 0.70 ). In a leave-one-out study, for the nine patients that had T1post tumor volumes ≥1 cm3, the model was able to predict progression on average two imaging cycles early, with a median of 9.3 (range: 3-39.3) weeks early (median progression-free survival was 27.4 weeks). Our results demonstrate that early tumor volume dynamics measured on T1post MRI has the potential to predict progression following the protocol therapy in select patients with recurrent HGG. Future work will include testing on an independent patient dataset and evaluation of the developed framework on T2/FLAIR-derived data.

Keywords: high-grade glioma; mathematical model; patient-specific; response prediction.

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28
Cell Rep
. 2020 Jun 30;31(13):107830. doi: 10.1016/j.celrep.2020.107830.
Senescence, Necrosis, and Apoptosis Govern Circulating Cell-free DNA Release Kinetics
Ariana Rostami 1, Meghan Lambie 1, Caberry W Yu 2, Vuk Stambolic 1, John N Waldron 3, Scott V Bratman 4
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PMID: 32610131 DOI: 10.1016/j.celrep.2020.107830
Abstract
The kinetics of circulating cell-free DNA (cfDNA) release may provide a real-time assessment of induced cell death. However, there is a limited understanding of the underlying biological rationale for cfDNA release following distinct treatments and cell death mechanisms. Here, we uncover a complex interplay between apoptosis, necrosis, and senescence in determining cfDNA release kinetics. Utilizing multiple in vitro and in vivo preclinical models, we show how cfDNA release is modulated through a combination of apoptotic and senescent triggers and inhibitors. Interestingly, we identify treatment-induced senescence as a previously unrecognized determinant of cfDNA kinetics that can counteract its release. Necrosis is the predominant cell death mechanism that consistently contributes to cfDNA release in response to ionizing radiation, and, surprisingly, apoptosis plays a comparatively minor role in some tumors. Based on our results, we propose a model to explain cfDNA release from cells over time, with important implications for future studies.

Keywords: apoptosis; circulating cell-free DNA; kinetics; liquid biopsy; navitoclax; necrosis; radiotherapy; senescence; treatment monitoring.

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Conflict of interest statement
Declaration of Interests S.V.B. provides consultation for Bristol-Myers Squibb, receives institutional research support from Nektar Therapeutics, and is a co-inventor on a patent relating to mutation-based ctDNA detection technology that has been licensed to Roche Molecular Diagnostics and on patent applications relating to methylation-based ctDNA detection technology.

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