Publications by authors named "Antonio Ruggiero"

140 Publications

131-I-metaiodobenzylguanidine and chemotherapy for advanced neuroblastoma.

Expert Rev Clin Pharmacol 2021 Jul 27. Epub 2021 Jul 27.

Pediatric Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Sacro Cuore, Largo A. Gemelli 8, Rome, Italy 00168.

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http://dx.doi.org/10.1080/17512433.2021.1960821DOI Listing
July 2021

hTERT Transduction Extends the Lifespan of Primary Pediatric Low-Grade Glioma Cells While Preserving the Biological Response to NGF.

Pathol Oncol Res 2021 2;27:612375. Epub 2021 Apr 2.

UOC di Oncologia Pediatrica, "Fondazione Policlinico Universitario A. Gemelli", IRCCS, Rome, Italy.

The neurotrophin nerve growth factor (NGF) modulates the growth of human gliomas and is able to induce cell differentiation through the engagement of tropomyosin receptor kinase A (TrkA) receptor, although the role played in controlling glioma survival has proved controversial. Unfortunately, the slow growth rate of low-grade gliomas (LGG) has made it difficult to investigate NGF effects on these tumors in preclinical models. In fact, patient-derived low-grade human astrocytoma cells duplicate only a limited number of times in culture before undergoing senescence. Nevertheless, replicative senescence can be counteracted by overexpression of hTERT, the catalytic subunit of telomerase, which potentially increases the proliferative potential of human cells without inducing cancer-associated changes. We have extended, by hTERT transduction, the proliferative potential of a human LGG cell line derived from a pediatric pilocytic astrocytoma (PA) surgical sample. Remarkably, the hTERT-transduced LGG cells showed a behavior similar to that of the parental line in terms of biological responses to NGF treatment, including molecular events associated with induction of NGF-related differentiation. Therefore, transduction of LGG cells with hTERT can provide a valid approach to increase the life-span of patient-derived astrocytoma primary cultures, characterized by a finite proliferative potential.
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http://dx.doi.org/10.3389/pore.2021.612375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262147PMC
April 2021

Cardiac Surveillance for Early Detection of Late Subclinical Cardiac Dysfunction in Childhood Cancer Survivors After Anthracycline Therapy.

Front Oncol 2021 14;11:624057. Epub 2021 May 14.

Unit of Pediatrics, Pediatric Cardiology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Background: In childhood cancer survivors (CCSs) anthracycline-related cardiotoxicity is an important cause of morbidity and late mortality, but the optimal modality of cardiac surveillance still remains to be defined. The aim of this study was to assess whether non-invasive echocardiography-based functional cardiac measures can detect early subclinical myocardial changes in long-term pediatric cancer survivors who received anthracycline therapy.

Methods: Twenty anthracycline-treated long-term CCSs and 20 age, sex, and body surface area matched healthy controls were enrolled in this study. Among cancer survivors, mean age at diagnosis was 6.5 ± 4.4 years, and the mean cumulative anthracycline dose was 234.5 ± 87.4 mg/m. All subjects underwent a comprehensive functional echocardiographic protocol study including two-dimensional echocardiography (2D Echo), tissue Doppler imaging (TDI), speckle tracking (STE) and three-dimensional echocardiography (3D Echo). Patients were studied at a mean follow-up time of 6.5 ± 2.8 years from the end of therapy.

Results: No significant differences in two-dimensional left ventricle ejection fraction (LVEF), diastolic parameters and speckle tracking (STE)-derived myocardial strain were observed between patients treated with anthracyclines and controls. Myocardial performance index was significantly prolonged (p = 0.005) and three-dimensional LVEF was significantly reduced (p = 0.002) in CCSs compared to controls, even though most values were within the normal range. There were no significant correlations between 2D, STE, and 3D echocardiographic parameters and age at diagnosis or duration of follow-up. No significant differences in echocardiographic parameters were found when stratifying cancer patients according to established risk factors for anthracycline cardiomyopathy.

Conclusions: This study found significantly reduced three-dimensional LVEF in CCSs compared with controls, despite no significant differences in two-dimensional LVEF and longitudinal strain values. These findings suggest that long-term CCSs who had received anthracycline therapy may be found to have subclinical features of myocardial dysfunction. However, further studies are needed to demonstrate the validity of new imaging techniques, including STE and 3D Echo, to identify patients at risk for cardiomyopathy in the long-term follow-up of CCSs.
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http://dx.doi.org/10.3389/fonc.2021.624057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162652PMC
May 2021

ALK-rearranged histiocytosis: Report of two cases with involvement of the central nervous system.

Neuropathol Appl Neurobiol 2021 May 28. Epub 2021 May 28.

Pathology Unit, Department of Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Aims: Histiocytoses are a heterogeneous group of localized or disseminated diseases. Clinical presentation and patients' outcome vary greatly, ranging from mild to life-threatening disorders. Rare cases of systemic or localized histiocytosis harboring ALK rearrangement have been reported.

Methods: Two cases of CNS histiocytosis were thoroughly investigated by implementing multiple molecular tests, i.e. FISH, RT-qPCR, NGS analysis.

Results: In a 10-month old girl (patient #1), MRI showed two left hemispheric lesions and a right fronto-mesial lesion histologically consisting of a moderately cellular infiltrative proliferation, composed by CD68(PGM1)+/CD163+ spindle cells. ALK 5'/3'-imbalance and a KIF5B(exon 24)-ALK(exon 20) fusion were documented by RT-qPCR and NGS analysis, respectively. A subsequent CT scan showed multiple hepatic and pulmonary lesions. The patient was started on chemotherapy (vinblastine) associated to an ALK-inhibitor (Alectinib) with remarkable response. In a 11-year-old girl (patient #2), MRI showed a right frontal 1.5 cm lesion. Neuropathological examination revealed a histiocytic proliferation composed by medium sized CD68(PGM1)+/HLA-DR+ cells, showing moderate ALK1 positivity. ALK rearrangement and a KIF5B(exon 24)-ALK(exon 20) fusion were demonstrated also in this case. Subsequent CT, 18F-FDG-PET and MRI scans showed the presence of a single right femoral lesion, proved to be a fibrous cortical defect.

Conclusions: In ALK-histiocytoses, CNS involvement may occur as part of a systemic disease or, rarely, as its only primary disease localization, which could remain otherwise asymptomatic. The diagnosis often relies on neuropathological examination of brain biopsy, which may pose a diagnostic challenge due to the variable histopathological features. An integrated histological and molecular approach in such cases is recommended.
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http://dx.doi.org/10.1111/nan.12739DOI Listing
May 2021

Vincristine-Induced Peripheral Neuropathy (VIPN) in Pediatric Tumors: Mechanisms, Risk Factors, Strategies of Prevention and Treatment.

Int J Mol Sci 2021 Apr 16;22(8). Epub 2021 Apr 16.

Pediatric Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Sacro Cuore, 00168 Rome, Italy.

Vincristine-induced peripheral neurotoxicity (VIPN) is a very common side effect of vincristine chemotherapy among pediatric patients with cancer. Neuropathy may be sensory, motor and/or autonomic, with consequent reduction, delay or discontinuation of vincristine-chemotherapy, but also pain, disability, reduced quality of life of patients and an increase in medical costs. Vincristine acts out its antineoplastic function by altering the normal assembly and disassembly of microtubules, with their consequent mitosis block and death. Vincristine leads to VIPN through a complex mechanism of damage, which occurs not only on the microtubules, but also on the endothelium and the mitochondria of nerve cells. Furthermore, both patient-related risk factors (age, race, ethnicity and genetic polymorphisms) and treatment-related risk factors (dose, time of infusion and drug-drug interactions) are involved in the pathogenesis of VIPN. There is a lack of consensus about the prophylaxis and treatment of VIPN among pediatric oncologic patients, despite several molecules (such as gabapentin, pyridoxine and pyridostigmine, glutamic acid and glutamine) having been already investigated in clinical trials. This review describes the molecular mechanisms of VIPN and analyzes the risk factors and the principal drugs adopted for the prophylaxis and treatment of VIPN in pediatric patients with cancer.
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http://dx.doi.org/10.3390/ijms22084112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073828PMC
April 2021

Pediatric ERCP with a single-use duodenoscope in an immunocompromised child.

VideoGIE 2021 Apr 23;6(4):176-177. Epub 2021 Jan 23.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Digestive Endoscopy Unit, Rome, Italy.

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http://dx.doi.org/10.1016/j.vgie.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058260PMC
April 2021

Management of Oral Mucositis in Children With Malignant Solid Tumors.

Front Oncol 2021 30;11:599243. Epub 2021 Mar 30.

Unità di Oncologia Pediatrica, Fondazione Policlinico Universitario Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.

Introduction: In recent years, the use of intensive regimens for the treatment of pediatric cancer has led to a marked improvement in patient survival. However, these treatments are associated with an increase in toxic effects. Among these side effects, mucositis (inflammation of the oral cavity) significantly affect the success of treatment. The aim of this study was to assess the prevalence of mucositis in a pediatric population with solid tumor and undergoing chemotherapy, identify the risk factors that influence its occurrence, and verify the usefulness of pain rating scales.

Methods: We registered episodes of mucositis which occurred in a sample of 84 consecutive children with solid tumors between 1 January, 2012 and 30 April, 2018. The World Health Organization (WHO) oral mucositis grading scale and the modified Wong-Baker FACES Pain Rating Scale (WBS) were used to assess the severity of each episode. Moreover, data on the treatments used and blood count results were collected.

Results: The prevalence of mucositis in our population was 50%, without statistically significant difference according to sex and a higher prevalence observed in patients aged >10 years. The presence of neutropenia, higher number of cycles of chemotherapy, and co-existence of lymphomas and sarcomas were identified as factors favoring the occurrence of mucositis. The WBS showed results superimposed on the WHO oral mucositis grading scale in choosing the intensity and duration of mucositis treatment.

Conclusion: Oral mucositis is a common complication of chemotherapy against childhood malignancies. The WHO oral mucositis scale is a valuable tool for assessing its severity in pediatric patients. Furthermore, WBS can be used as an assessment tool to establish the therapy to be adopted for patients in whom direct evaluation of the oral cavity is not possible.
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http://dx.doi.org/10.3389/fonc.2021.599243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042390PMC
March 2021

Management of chronic musculoskeletal pain in veterans: a systematic review.

Acta Biomed 2021 03 31;92(S2):e2021011. Epub 2021 Mar 31.

School of Nursing Science and Midwifery, Sapienza University of Rome, A.O. S. Camillo-Forlanini Hospital, Rome, Italy.

Background And Aim Of The Work: Veterans are military with health problems due to military conditions. The improved body armor and operational conditions has reduced the number of deaths, but increased the number of veterans with severe injuries, affected by musculoskeletal pain and associated syndromes, such as post-traumatic stress disorder. Multimodal approaches are considered in USA the gold standard for the treatment of these problems, while in Europe and Italy the data are unknown. The aim of this review was to describe and summarize multimodal therapeutic approaches that apply to the veteran population for chronic musculoskeletal pain and relate syndromes management.

Methods: A comprehensive systematic review of the literature on Cochrane Library, PubMed, CINAHL e PsycINFO databases was conducted, from 2001 to 2020.

Results: 228 papers have been found, 134 were selected after the first screening. 24 quantitative studies were included in the review, all from USA. Different multimodal interventions with different kind of treatment types emerged. The analyzed studies' sample size was 11 million (mean age = 57.67 years; SD=±11.94). The multimodal approaches showed a significant improvement in all outcomes (pain reduction and control, opioid therapy reduction, psychosocial outcomes) compared to traditional therapy.

Conclusions: Multimodal therapeutic approaches seem to guarantee a good management chronic musculoskeletal pain and related mental disorders, and the reduction and control to opioid use. Military nurses emerged as professionals who have a central role in this approach. European and Italian authorities should consider veterans, in order to assess their expected increase in the future.
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http://dx.doi.org/10.23750/abm.v92iS2.11352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138808PMC
March 2021

The Multidimensional Assessment for Pediatric Patients in Radiotherapy (M.A.P.-RT) Tool for Customized Treatment Preparation: RADAR Project.

Front Oncol 2021 29;11:621690. Epub 2021 Mar 29.

UOC di Radioterapia Oncologica, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.

Pediatric patients may experience considerable distress during radiotherapy. Combining psychological interventions with standard therapies can reduce the need for sedation. The RADAR Project aims to use a systematic method of recording data that can reveal patients' difficulties and fragility during treatment. In this context, the aim of our study was to investigate the ability of a multidimensional assessment tool (M.A.P.-RT schedule) to predict the need for sedation during radiotherapy. The schedule, which is administered during the first evaluation, was created to collect information on patients and their families in a standardized way. The study enrolled pediatric patients (aged 0-18 years or 18-21 with cognitive impairment). Data were collected by means of the M.A.P.-RT module; this explores various thematic areas, and is completed by the radiation oncologist, psychologist and nurse during their first evaluation. Features were selected by means of the Boruta method (random forest classifier), and the totals of the significant partial scores on each subsection of the module were inserted into a logistic model in order to test for their correlation with the use of anesthesia and with the frequency of psychological support. The results of logistic regression (LR) were used to identify the best predictors. The AUC was used to identify the best threshold for the scores in the evaluation. A total of 99 patients were considered for this analysis. The feature that best predicted both the need for anesthesia and the frequency of psychological support was the total score (TS), the AUC of the ROC being 0.9875 for anesthesia and 0.8866 for psychological support. During the first evaluation, the M.A.P.-RT form can predict the need for anesthesia in pediatric patients, and is a potential tool for personalizing therapeutic and management procedures.
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http://dx.doi.org/10.3389/fonc.2021.621690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039366PMC
March 2021

The BET Inhibitor OTX015 Exhibits In Vitro and In Vivo Antitumor Activity in Pediatric Ependymoma Stem Cell Models.

Int J Mol Sci 2021 Feb 13;22(4). Epub 2021 Feb 13.

UOC Pediatric Oncology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.

Childhood ependymomas are heterogenous chemoresistant neoplasms arising from aberrant stem-like cells. Epigenome deregulation plays a pivotal role in ependymoma pathogenesis, suggesting that epigenetic modifiers hold therapeutic promise against this disease. Bromodomain and extraterminal domain (BET) proteins are epigenome readers of acetylated signals in histones and coactivators for oncogenic and stemness-related transcriptional networks, including MYC/MYCN (Proto-Oncogene, BHLH Transcritpion Factor)-regulated genes. We explored BET inhibition as an anticancer strategy in a panel of pediatric patient-derived ependymoma stem cell models by OTX015-mediated suppression of BET/acetylated histone binding. We found that ependymoma tissues and lines express BET proteins and their targets MYC and MYCN. In vitro, OTX015 reduced cell proliferation by inducing G0/G1-phase accumulation and apoptosis at clinically tolerable doses. Mechanistically, inhibitory p21 and p27 increased in a p53-independent manner, whereas the proliferative driver, phospho-signal transducer and activator of transcription 3 (STAT3), decreased. Upregulation of apoptosis-related proteins and survivin downregulation were correlated with cell line drug sensitivity. Minor alterations of MYC/MYCN expression were reported. In vivo, OTX015 significantly improved survival in 2/3 orthotopic ependymoma models. BET proteins represent promising targets for pharmaceutical intervention with OTX015 against ependymoma. The identification of predictive determinants of sensitivity may help identify ependymoma molecular subsets more likely to benefit from BET inhibitor therapies.
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http://dx.doi.org/10.3390/ijms22041877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918371PMC
February 2021

Contactless: a new personalised telehealth model in chronic pediatric diseases and disability during the COVID-19 era.

Ital J Pediatr 2021 Feb 12;47(1):29. Epub 2021 Feb 12.

Pediatric Neurology Unit, Fondazione Policlinico A Gemelli -IRCCS, Università Cattolica del Sacro Cuore, Largo Gemelli 8, 00168, Rome, Italy.

Background: Suspending ordinary care activities during the COVID-19 pandemic made it necessary to find alternative routes to comply with care recommendations not only for acute health needs but also for patients requiring follow-up and multidisciplinary visits. We present the 'Contactless' model, a comprehensive operational tool including a plurality of services delivered remotely, structured according to a complexity gradient, aimed to cover diagnostic procedures and monitor disease progression in chronic pediatric patients.

Methods: A multidisciplinary and multiprofessional project team was recruited, in collaboration with patients' associations, to map a panel of available Evidence-Based solutions and address individual needs in full respect of the concept of personalized medicine. The solutions include a number of services from videoconsultations to more structure videotraining sessions.

Results: A modular framework made up of four three Macro-levels of complexity - Contactless Basic, Intermediate and Advanced - was displayed as an incremental set of services and operational planning establishing each phase, from factors influencing eligibility to the delivery of the most accurate and complex levels of care.

Conclusion: The multimodal, multidisciplinary 'Contactless' model allowed the inclusion of all Units of our Pediatric Department and families with children with disability or complex chronic conditions. The strengths of this project rely on its replicability outside of pediatrics and in the limited resources needed to practically impact patients, caregivers and professionals involved in the process of care. Its implementation in the future may contribute to reduce the duration of hospital admissions, money and parental absence from work.
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http://dx.doi.org/10.1186/s13052-021-00975-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880513PMC
February 2021

Intranasal drugs for analgesia and sedation in children admitted to pediatric emergency department: a narrative review.

Ann Transl Med 2021 Jan;9(2):189

Dipartimento di Pediatria, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy.

Acute pain is one of the most common symptoms in children admitted to the Pediatric Emergency Department (PED) and its management represents a real clinical challenge for pediatricians. Different painful procedures can be very stressful for young children and their perception of pain can be enhanced by emotional factors, such as anxiety, distress, or anger. Adequate procedural sedation reduces anxiety and emotional trauma for the patient, but it reduces also stress for operators and the time for procedures. We have reviewed the literature on this topic and the drugs covered in these papers were: midazolam, fentanyl, ketamine, and dexmedetomidine. There are several routes of administering for these drugs to provide analgesia and anxiolysis to children: oral, parenteral, or intranasal (IN). Intravenous (IV) sedation, since it involves the use of needles, can be stressful; instead, IN route is a non-invasive procedure and generally well tolerated by children and it has become increasingly widespread. Some medications can be administered by a mucosal atomizer device (MAD) or by drops. The benefits of the atomized release include less drug loss in the oropharynx, higher cerebrospinal fluid levels, better patient acceptability, and better sedative effects. IN midazolam has a sedative, anxiolytic and amnesic effect, but without analgesic properties. Fentanyl and ketamine are mainly used for pain control. Dexmedetomidine has anxiolytic and analgesic properties. In conclusion, IN analgo-sedation is a simple, rapid and painless option to treat pain and anxiety in the PED requiring brief training on the administration process and experience in sedation.
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http://dx.doi.org/10.21037/atm-20-5177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867955PMC
January 2021

Narrative review of intrathecal drug delivery (IDD): indications, devices and potential complications.

Ann Transl Med 2021 Jan;9(2):186

Unità di Oncologia Pediatrica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Sacro Cuore, Rome, Italy.

The management of chronic refractory pain (non-neoplastic and cancer-related pain) remains a therapeutic challenge. The continuous intrathecal (IT) administration of drugs may play an important role in the possible management options. Intrathecal drug delivery devices (IDDDs) may be effective for patients with refractory chronic pain. Therefore, they may be adopted for non-oncologic pain in patients with compression fractures, spondylolisthesis, spondylosis, back surgery failure syndrome and spinal stenosis. Oncologic patients can benefit from these treatments in a variable way according to tumor characteristics, prognosis, periprocedural imaging and risk of disease progression. In this review, we describe the most commonly used drugs (opioids and non-opioids), their pharmacokinetic and pharmacodynamic features and indications of use. The most used drugs are morphine, hydromorphone, fentanyl, methadone, bupivacaine, clonidine, and ketamine. Patient evaluation before the device implantation should be based on clinical examination, medical records assessment and psychometric evaluation. The infusion pumps available on the market are both non-programmable (with continuous IT deliver of drugs) and programmable (with variable deliver of drugs according to their flow rate). Moreover, we describe the procedure of implantation and the potential complications of IT drug delivery (such as bleeding, infection, loss of cerebrospinal fluid, wound seroma, loss of catheter pump propellant).
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http://dx.doi.org/10.21037/atm-20-3814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867880PMC
January 2021

Opioid transdermal delivery system: a useful method for pain management in children.

Ann Transl Med 2021 Jan;9(2):185

Pediatric Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Sacro Cuore, Rome, Italy.

Transdermal delivery system (TDDS) is a non-invasive and less expensive method for drug delivery. Despite its feasibility, only a restricted group of drugs can be delivered by TDDS, because of the little permeability of skin. Moreover, TDDS is limited to lipophilic drugs with small molecular masses and it is not indicated for peptides, macromolecules and hydrophilic drugs. Among opioids, fentanyl and buprenorphine are suitable for transdermal administration only for chronic pain management (not for acute pain). However, opioid TDDS still remains off-label for chronic pain management in children. In this review, we describe the main features of the adhesive TDDS and the main characteristics of pediatric skin and the differences from the adult one. Moreover, we focus on fentanyl and buprenorphine patches and their non-invasive mechanism of action, and on the main aspects that make them suitable for pain management among the pediatric population.
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http://dx.doi.org/10.21037/atm-20-2619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867936PMC
January 2021

Editorial for the series on pain therapy.

Authors:
Antonio Ruggiero

Ann Transl Med 2021 Jan;9(2):184

Pediatric Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Universita' Cattolica del Sacro Cuore, Rome, Italy. (Email:

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http://dx.doi.org/10.21037/atm-2020-pt-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867957PMC
January 2021

Managing children with brain tumors during the COVID-19 era: Don't stop the care!

Comput Struct Biotechnol J 2021 12;19:705-709. Epub 2021 Jan 12.

Pediatric Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Sacro Cuore, Rome, Italy.

The COVID-19 pandemic has substantially stressed health care systems globally, subsequently reducing cancer care services and delaying treatments. Pediatric populations infected by COVID-19 have shown mild clinical symptoms compared to adults, perhaps due to decreased susceptibility. Several scientific societies and governments have released information on the management of patients with cancer, wherein they warn against exposure to SARS-CoV-2 infection and suggest continuing treatment. To determine the best diagnostic and therapeutic approach, multidisciplinary tumor boards should convene regularly, including through conference calls and telematics platforms. A prompt diagnostic workup may reduce children's suffering and prevent loss of confidence in the health care system among parents. Moreover, ensuring adequate support and information regarding measures for preventing SARS-CoV-2 infection in pediatric patients and their families is essential for avoiding panic and excessive stress, allowing early reporting of any suspected symptoms of cancer and, in turn, facilitating early diagnosis and prompt modulation of treatment.
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http://dx.doi.org/10.1016/j.csbj.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817528PMC
January 2021

Targeting the mitogen‑activated protein kinase kinase and protein kinase A pathways overcomes acquired resistance to Selumetinib in low‑grade glioma cells.

Oncol Rep 2021 02 25;45(2):752-763. Epub 2020 Nov 25.

Pediatric Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, I‑00168 Rome, Italy.

The Ras/Raf/MEK/MAPK signaling cascade is frequently activated in human cancer and serves a crucial role in the oncogenesis of pediatric low‑grade gliomas (PLGGs). Therefore, drugs targeting kinases among the mitogen‑activated protein kinase (MAPK) effectors of receptor tyrosine kinase signaling may represent promising candidates for the treatment of PLGGs. The aim of the present study was to elucidate the anticancer effects of the MEK inhibitor Selumetinib on two low‑grade glioma cell lines and the possible underlying effects on intracellular signal transduction. The two cancer cell lines displayed different levels of sensitivity to Selumetinib, as Res186 cells were resistant (IC50>1 µM), whereas Res259 cells were sensitive (IC50≤1 µM) to MEK inhibition. Despite the different levels of sensitivity, Selumetinib mediated the phosphorylation of AKT and MEK in both cell lines and suppressed the phosphorylated MAPK cascades. In addition, Selumetinib induced cell cycle arrest at the G0/G1 phase by downregulating the expression levels of cyclin D1 and p21 and upregulating those of p27 compared with those in the control cells. A Res259 cell line with acquired resistance to Selumetinib (Res259/R) was next established and biologically and molecularly characterized, and it was demonstrated that addition of a selective cAMP‑dependent protein kinase A inhibitor to Selumetinib overcame drug resistance in Res 259/R cells. In conclusion, the results of the present study provided three low‑grade glioma cell line models characterized by sensitivity, intrinsic and acquired resistance to Selumetinib, which may be usuful tools to study new mechanisms of chemoresistance to MEK inhibitors and to explore alternative therapeutic strategies in low‑grade gliomas for personalization of treatment.
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http://dx.doi.org/10.3892/or.2020.7867DOI Listing
February 2021

Second series by the Italian Association of Pediatric Hematology and Oncology of children and adolescents with intracranial ependymoma: an integrated molecular and clinical characterization with a long-term follow-up.

Neuro Oncol 2021 05;23(5):848-857

Departments of Neurology and Psychiatric, La Sapienza University, Rome, Italy.

Background: A prospective 2002-2014 study stratified 160 patients by resection extent and histological grade, reporting results in 2016. We re-analyzed the series after a median of 119 months, adding retrospectively patients' molecular features.

Methods: Follow-up of all patients was updated. DNA copy number analysis and gene-fusion detection could be completed for 94/160 patients, methylation classification for 68.

Results: Progression-free survival (PFS) and overall survival (OS) at 5/10 years were 66/58%, and 80/73%. Ten patients had late relapses (range 66-126 mo), surviving after relapse no longer than those relapsing earlier (0-5 y). On multivariable analysis a better PFS was associated with grade II tumor and complete surgery at diagnosis and/or at radiotherapy; female sex and complete resection showed a positive association with OS. Posterior fossa (PF) tumors scoring ≥0.80 on DNA methylation analysis were classified as PFA (n = 41) and PFB (n = 9). PFB patients had better PFS and OS. Eighteen/32 supratentorial tumors were classified as RELA, and 3 as other molecular entities (anaplastic PXA, LGG MYB, HGNET). RELA had no prognostic impact. Patients with 1q gain or cyclin-dependent kinase inhibitor 2A (CDKN2A) loss had worse outcomes, included significantly more patients >3 years old (P = 0.050) and cases of dissemination at relapse (P = 0.007).

Conclusions: Previously described prognostic factors were confirmed at 10-year follow-up. Late relapses occurred in 6.2% of patients. Specific molecular features may affect outcome: PFB patients had a very good prognosis; 1q gain and CDKN2A loss were associated with dissemination. To draw reliable conclusions, modern ependymoma trials need to combine diagnostics with molecular risk stratification and long-term follow-up.
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http://dx.doi.org/10.1093/neuonc/noaa257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099475PMC
May 2021

Impact of COVID-19 in paediatric early-phase cancer clinical trials in Europe: A report from the Innovative Therapies for Children with Cancer (ITCC) consortium.

Eur J Cancer 2020 12 9;141:82-91. Epub 2020 Oct 9.

Center for Child Health Research, Tampere University and Department of Pediatrics, Tampere University Hospital, Tampere, Finland, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Introduction: Data regarding real-world impact on cancer clinical research during COVID-19 are scarce. We analysed the impact of the COVID-19 pandemic on the conduct of paediatric cancer phase I-II trials in Europe through the experience of the Innovative Therapies for Children with Cancer (ITCC).

Methods: A survey was sent to all ITCC-accredited early-phase clinical trial hospitals including questions about impact on staff activities, recruitment, patient care, supply of investigational products and legal aspects, between 1st March and 30th April 2020.

Results: Thirty-one of 53 hospitals from 12 countries participated. Challenges reported included staff constraints (30% drop), reduction in planned monitoring activity (67% drop of site initiation visits and 64% of monitoring visits) and patient recruitment (61% drop compared with that in 2019). The percentage of phase I, phase II trials and molecular platforms closing to recruitment in at least one site was 48.5%, 61.3% and 64.3%, respectively. In addition, 26% of sites had restrictions on performing trial assessments because of local contingency plans. Almost half of the units suffered impact upon pending contracts. Most hospitals (65%) are planning on improving organisational and structural changes.

Conclusion: The study reveals a profound disruption of paediatric cancer early-phase clinical research due to the COVID-19 pandemic across Europe. Reported difficulties affected both patient care and monitoring activity. Efforts should be made to reallocate resources to avoid lost opportunities for patients and to allow the continued advancement of oncology research. Identified adaptations to clinical trial procedures may be integrated to increase preparedness of clinical research to futures crises.
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http://dx.doi.org/10.1016/j.ejca.2020.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546235PMC
December 2020

Cisplatin-induced nephrotoxicity in children: what is the best protective strategy?

J Oncol Pharm Pract 2021 Jan 29;27(1):180-186. Epub 2020 Sep 29.

Pediatric Oncology Unit, Fondazione Policlinico Universitario A.Gemelli IRCCS, Università Cattolica Sacro Cuore, Rome, Italy.

Introduction: Platinum compounds, which are considerably effective for the treatment of childhood malignancies, have significantly contributed to the increase in long-term survival of children with cancer. Unfortunately, children receiving cisplatin-based chemotherapy have been known to be at risk for severe disabling adverse effects, such as nephrotoxicity.

Methods: A literature research of the MEDLINE PubMed database was conducted to identify articles published between 1980 and 2019 reviewing "Cisplatin AND mannitol."

Results: The primary pharmacodynamics and clinical characteristics of cisplatin were described, focusing on its renal toxic effects and potential preventive strategies, in order to improve clinical outcomes among children with cancer aged 1 to 14 years. Currently, selecting either hydration alone or hydration plus mannitol for preventing nephrotoxicity has been controversial considering the lack of guidelines to provide treatment recommendations both among adults and children.

Conclusions: Appropriate knowledge regarding the pharmacokinetics and toxicological profile of cisplatin may help physicians prevent renal toxicity. Unfortunately, published data regarding the nephroprotective utility of adding mannitol appear to be inconclusive. As such, appropriate hydration remains the main fundamental strategy for reducing the risk of cisplatin-induced nephrotoxicity. Considering the increasing number of children safely cured of their tumours, it is imperative that those treated with cisplatin receive the most appropriate nephroprotective strategy for reducing the negative impact of platinum compounds on quality of life.
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http://dx.doi.org/10.1177/1078155220961550DOI Listing
January 2021

Bone and Soft Tissue Sarcoma.

Authors:
Antonio Ruggiero

Cancers (Basel) 2020 Sep 12;12(9). Epub 2020 Sep 12.

Pediatric Oncology Unit, Fondazione Policlinico Universitario A.Gemelli IRCCS, Universita' Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy.

Bone and soft-tissue sarcomas are relatively rare tumors both in children and adults [...].
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http://dx.doi.org/10.3390/cancers12092609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564470PMC
September 2020

Diffuse Intrinsic Pontine Glioma (DIPG): Breakthrough and Clinical Perspective.

Curr Med Chem 2021 ;28(17):3287-3317

Department of Pharmacy and Pharmaceutical Sciences, University of Bari, Via E. Orabona 4, 70125 Bari, Italy.

Diffuse intrinsic pontine glioma (DIPG) mainly affects children with a median age of 6-7 years old. It accounts for 10% of all pediatric tumors. Unfortunately, DIPG has a poor prognosis, and the median survival is generally less than 16-24 months independently from the treatment received. Up to now, children with DIPG are treated with focal radiotherapy alone or in combination with antitumor agents. In the last decade, ONC201 known as dopamine receptor antagonist was uncovered, by a high throughput screening of public libraries of compounds, to be endowed with cytotoxic activity against several cancer cell lines. Efforts were made to identify the real ONC201 target, responsible for its antiproliferative effect. The hypothesized targets were the Tumor necrosis factor-Related Apoptosis-Inducing Ligand stimulation (TRAIL), two oncogenic kinases (ERK/AKT system) that target the same tumor-suppressor gene (FOXO3a), dopamine receptors (DRD2 and DRD3 subtypes) and finally the mitochondrial Caseynolitic Protease P (ClpP). ONC201 structure-activity relationship is extensively discussed in this review, together with other two classes of compounds, namely ADEPs and D9, already known for their antibiotic activity but noteworthy to be discussed and studied as potential "leads" for the development of new drugs to be used in the treatment of DIPG. In this review, a detailed and critical description of ONC201, ADEPs, and D9 pro-apoptotic activity is made, with particular attention to the specific interactions established with its targets that also are intimately described. Pubmed published patents and clinical trial reports of the last ten years were used as the bibliographic source.
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http://dx.doi.org/10.2174/0929867327666200806110206DOI Listing
June 2021

CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models.

Cancers (Basel) 2020 Jul 16;12(7). Epub 2020 Jul 16.

Group of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain.

Pediatric ependymoma (EPN) is a highly aggressive tumor of the central nervous system that remains incurable in 40% of cases. In children, the majority of cases develop in the posterior fossa and can be classified into two distinct molecular entities: EPN posterior fossa A (PF-EPN-A) and EPN posterior fossa B (PF-EPN-B). Patients with PF-EPN-A have poor outcome and are in demand of new therapies. In general, PF-EPN-A tumors show a balanced chromosome copy number profile and have no recurrent somatic nucleotide variants. However, these tumors present abundant epigenetic deregulations, thereby suggesting that epigenetic therapies could provide new opportunities for PF-EPN-A patients. In vitro epigenetic drug screening of 11 compounds showed that histone deacetylase inhibitors (HDACi) had the highest anti-proliferative activity in two PF-EPN-A patient-derived cell lines. Further screening of 5 new brain-penetrating HDACi showed that CN133 induced apoptosis in vitro, reduced tumor growth in vivo and significantly extended the survival of mice with orthotopically-implanted EPN tumors by modulation of the unfolded protein response, PI3K/Akt/mTOR signaling, and apoptotic pathways among others. In summary, our results provide solid preclinical evidence for the use of CN133 as a new therapeutic agent against PF-EPN-A tumors.
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http://dx.doi.org/10.3390/cancers12071922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409080PMC
July 2020

Data acquired by wearable sensors for the evaluation of the flexion-relaxation phenomenon.

Data Brief 2020 Aug 3;31:105957. Epub 2020 Jul 3.

Department of Information Engineering (DII), Università Politecnica delle Marche, 60131 Ancona, Italy.

The relationship between flexibility and the pattern formed by the surface electromyography activity of the back muscles while performing a dynamic trunk flexion-extension task is not yet thoroughly understood, although many previous studies have adopted it as their focus in the literature. Additionally, several studies have proposed technologies and algorithms to analyse the flexion-relaxation phenomenon, which is defined by myoelectric silence that occurs when the subject's torso exceeds a certain flexion angle. Before participating in the flexion-relaxation test, subjects involved in the data collection underwent medical examinations, in which their physical condition, perceived pain, and level of disability were reported in their anamnesis. During the flexion-relaxation test, which was conducted with 25 subjects with and without low back pain, subjects wore four surface electromyography electrodes positioned over the back muscles, as well as an inertial sensor to estimate trunk inclination.
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http://dx.doi.org/10.1016/j.dib.2020.105957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358657PMC
August 2020

Phase II results from a phase I/II study to assess the safety and efficacy of weekly nab-paclitaxel in paediatric patients with recurrent or refractory solid tumours: A collaboration with the European Innovative Therapies for Children with Cancer Network.

Eur J Cancer 2020 08 15;135:89-97. Epub 2020 Jun 15.

Gustave Roussy, Villejuif, France.

Background: The phase I component of a phase I/II study defined the recommended phase II dose and established the tolerability of nab-paclitaxel monotherapy in paediatric patients with recurrent or refractory solid tumours. The activity and safety of nab-paclitaxel monotherapy was further investigated in this phase II study.

Patients And Methods: Paediatric patients with recurrent or refractory Ewing sarcoma, neuroblastoma or rhabdomyosarcoma received 240 mg/m of nab-paclitaxel on days 1, 8 and 15 of each 28-day cycle. The primary end-point was the overall response rate (ORR; complete response [CR] + partial response [PR]). Secondary end-points included duration of response, disease control rate (DCR; CR + PR + stable disease [SD]), progression-free survival, 1-year overall survival, safety and pharmacokinetics.

Results: Forty-two patients were enrolled, 14 each with Ewing sarcoma, neuroblastoma and rhabdomyosarcoma. The ORRs were 0%, 0% and 7.1% (1 confirmed PR), respectively. The DCRs were 30.8% (4 SD), 7.1% (1 SD) and 7.1% (1 confirmed PR and 0 SD) in the Ewing sarcoma, neuroblastoma and rhabdomyosarcoma groups, respectively. The median progression-free survival was 13.0, 7.4 and 5.1 weeks, respectively, and the 1-year overall survival rates were 48%, 25% and 15%, respectively. The most common grade III/4IVadverse events were haematologic (neutropenia [50%] and anaemia [48%]), and grade III/IV peripheral neuropathy occurred in 2 patients (14%) in the rhabdomyosarcoma group. Pharmacokinetics analyses revealed that paclitaxel tissue distribution was both rapid and extensive.

Conclusions: In this phase II study, limited activity was observed; however, the safety of nab-paclitaxel in paediatric patients was confirmed.

Trial Registration: NCT01962103 and EudraCT 2013-000144-26.
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http://dx.doi.org/10.1016/j.ejca.2020.04.031DOI Listing
August 2020

Temozolomide and oral etoposide in children with recurrent malignant brain tumors.

Drugs Context 2020 2;9. Epub 2020 Jun 2.

Pediatric Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Sacro Cuore, Rome, Italy.

Despite advances in the treatment of brain tumors, the prognosis of children with recurrent malignant brain tumors remains poor. Etoposide (VP-16), an inhibitor of nuclear enzyme deoxyribonucleic acid (DNA)-topoisomerase II, has shown activity in brain tumors. Its efficacy appears schedule dependent but, to date, the most effective schedule of administration has not been well defined. Temozolomide (TMZ), like VP-16, penetrates the blood-brain barrier and has activity against malignant brain tumors. This novel alkylating agent is rapidly absorbed and is highly bioavailable after oral administration. The antitumor activity of TMZ has been shown to be schedule dependent. Based on the evidence of different mechanisms of cytotoxicity, TMZ and VP-16 have been utilized in combination in patients with malignant brain tumors. This review evaluates the results derived from the combination use of TMZ and oral VP-16. The reported data suggest potential activity of oral VP-16 and TMZ alone or in combination. Further clinical trials are needed to explore and confirm their promising activity in relapsed brain neoplasms.
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http://dx.doi.org/10.7573/dic.2020-3-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271709PMC
June 2020

Diagnosis of COVID-19 infection in children: Less nasopharyngeal swabs, more saliva.

Acta Paediatr 2020 09 1;109(9):1913-1914. Epub 2020 Jul 1.

Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.

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http://dx.doi.org/10.1111/apa.15397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300614PMC
September 2020

Can we optimise doxorubicin treatment regimens for children with cancer? Pharmacokinetic simulations and a Delphi consensus procedure.

BMC Pharmacol Toxicol 2020 05 28;21(1):37. Epub 2020 May 28.

Department of Paediatric Haematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer-Campus 1, A1, 48149, Muenster, Germany.

Background: Despite its cardiotoxicity doxorubicin is widely used for the treatment of paediatric malignancies. Current treatment regimens appear to be suboptimal as treatment strategies vary and do not follow a clear pharmacological rationale. Standardisation of dosing strategies in particular for infants and younger children is required but is hampered by scarcely defined exposure-response relationships. The aim is to provide a rational dosing concept allowing for a reduction of variability in systemic therapy intensity and subsequently unforeseen side effects.

Methods: Doxorubicin plasma concentrations in paediatric cancer patients were simulated for different treatment schedules using a population pharmacokinetic model which considers age-dependent differences in doxorubicin clearance. Overall drug exposure and peak concentrations were assessed. Simulation results were used to support a three round Delphi consensus procedure with the aim to clarify the pharmacological goals of doxorubicin dosing in young children. A group of 28 experts representing paediatric trial groups and clinical centres were invited to participate in this process.

Results: Pharmacokinetic simulations illustrated the substantial differences in therapy intensity associated with current dosing strategies. Consensus among the panel members was obtained on a standardised a priori dose adaptation that individualises doxorubicin doses based on age and body surface area targeting uniform drug exposure across children treated with the same protocol. Further, a reduction of peak concentrations in very young children by prolonged infusion was recommended.

Conclusions: An approach to standardise current dose modification schemes in young children is proposed. The consented concept takes individual pharmacokinetic characteristics into account and involves adaptation of both the dose and the infusion duration potentially improving the safety of doxorubicin administration.
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http://dx.doi.org/10.1186/s40360-020-00417-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254632PMC
May 2020

Facing the COVID-19 outbreak in children with cancer.

Drugs Context 2020 12;9. Epub 2020 May 12.

Pediatric Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.

Europe is now the epicenter of the COVID-19 outbreak. Many concerns have arisen about the management and treatment of children with cancer while researchers are wondering how to deal with this devastating pandemic. In view of the epidemiological and clinical characteristics of the COVID-19 outbreak, it is fundamental to stress that the behavior and hygiene rules adopted by children with cancer must be respected and implemented in order to continue to safeguard their health for the current pandemic.
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http://dx.doi.org/10.7573/dic.2020-4-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224358PMC
May 2020

Assessment and Management of Platinum-Related Ototoxicity in Children Treated for Cancer.

Cancers (Basel) 2020 May 17;12(5). Epub 2020 May 17.

Pediatric Oncology Unit, Fondazione Policlinico Universitario A.Gemelli IRCCS, Universita' Cattolica Sacro Cuore, 00168 Rome, Italy.

Platinum compounds are a group of chemotherapeutic agents included in many pediatric and adult oncologic treatment protocols. The main platinum compounds are cisplatin, carboplatin, and oxaliplatin. Their use in clinical practice has greatly improved long-term survival of pediatric patients, but they also cause some toxic effects: ototoxicity, myelosuppression, nephrotoxicity, and neurotoxicity. Hearing damage is one of the main toxic effects of platinum compounds, and it derives from the degeneration of hair cells of the ear, which, not having self-renewal capacity, cannot reconstitute themselves. Hearing loss from platinum exposure is typically bilateral, sensorineural, and permanent, and it is caused by the same mechanisms with which platinum acts on neoplastic cells. According to available data from the literature, the optimal timing for the audiological test during and after treatment with platinum compounds is not well defined. Moreover, no substances capable of preventing the onset of hearing loss have been identified.
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http://dx.doi.org/10.3390/cancers12051266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281210PMC
May 2020
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