Did pediatric drug development advance epilepsy treatment in young patients?It is time for new research goals

Modern drugs have changed epilepsy,which affects people of all ages.However,for young people with epilepsy,the framework of drug development has stalled.In the wake of the thalidomide catastrophe,the misconception emerged that for people<18 years of age drugs,including antiseizure medications(ASMs),need separate proof of efficacy and safety,overall called"pediatric drug development".For ASMs,this has changed to some degree.Authorities now accept that ASMs are effective in<18 years as well,but they still require"extrapolation of efficacy,"as if minors were another species.As a result,some of the pediatric clinical epilepsy research over the past decades was unnecessary.Even more importantly,this has hampered research on meaningful research goals.We do not need to confirm that ASMs work before as they do after the 18th birthday.Instead,we need to learn how to prevent brain damage in young patients by preventing seizures and optimize ASMs’uses.Herein we discuss how to proceed in this endeavor.

Dose escalation of adalimumab as a strategy to overcome anti-drug antibodies:A case report of infantile-onset inflammatory bowel disease

BACKGROUND Treatment of infantile-onset inflammatory bowel disease(IO-IBD)is often challenging due to its aggressive disease course and failure of standard therapies with a need for biologics.Secondary loss of response is frequently caused by the production of anti-drug antibodies,a well-known problem in IBD patients on biologic treatment.We present a case of IO-IBD treated with therapeutic drug monitoring(TDM)-guided high-dose anti-tumor necrosis factor therapy,in which dose escalation monitoring was used as a strategy to overcome anti-drug antibodies.CASE SUMMARY A 5-mo-old boy presented with a history of persistent hematochezia from the 10th d of life,as well as relapsing perianal abscess and growth failure.Hypoalbuminemia,anemia,and elevated inflammatory markers were also present.Endoscopic assessment revealed skip lesions with deep colic ulcerations,inflammatory anal sub-stenosis,and deep fissures with persistent abscess.A diagnosis of IO-IBD Crohn-like was made.The patient was initially treated with oral steroids and fistulotomy.After the perianal abscess healed,adalimumab(ADA)was administered with concomitant gradual tapering of steroids.Clinical and biochemical steroid-free remission was achieved with good trough levels.After 3 mo,antibodies to ADA(ATA)were found with undetectable trough levels;therefore,we optimized the therapy schedule,first administering 10 mg weekly and subsequently up to 20 mg weekly(2.8 mg/kg/dose).After 2 mo of high-dose treatment,ATA disappeared,with concomitant high trough levels and stable clinical and biochemical remission of the disease.CONCLUSION TDM-guided high-dose ADA treatment as a monotherapy overcame ATA production.This strategy could be a good alternative to combination therapy,especially in very young patients.

Comparison of 2D and 4D Flow MRI Measurements for Hemodynamic Evaluation of the Fontan Palliation

Background:The assessment of Fontan circuit’sflow is traditionally evaluated by multiple through-plane phase-contrast MRI acquisitions(2Dflow),while recently,a single volumetric 4D-flow MRI acquisition is emerging as a comprehensive tool for the hemodynamic evaluation in congenital heart diseases.Purpose:To compare 2D and 4D-flow MRI measurements in patients after Fontan palliation and to evaluate parameters affecting potential dis-agreement.Methods:39 patients after Fontan palliation(23 males,age 22±11 years)who underwent cardiac MRI with 2D and 4D-flow MRI acquisition were included in the study.In all patients,bloodflow quantification in the Fontan circuit and aorta by 2Dflow and by 4Dflow MRI acquisition blinding to the 2D results was per-formed.The agreement between 2D and 4D-flow MRI was calculated as the intraclass correlation coefficient(ICC).The mean absolute differences between 4D and 2Dflows were analyzed using linear regression models.Results:4D-flow MRI acquisition time was slightly lower than 2D(7.6±1.8 min vs.9.4±3.3 min,p=0.03).Flow was slightly predominant in the right pulmonary artery(58%of total pulmonaryflow).Conduit/tunnel-pul-monary arteriesflow accounted for 60%of the Fontan circuit.Agreement between 2D and 4D was overall good-to-excellent from ICC:0.81795%CI:0.637–0.907 to 0.93295%CI:0.866–0.965.There was no significant influ-ence of evaluated parameters on the agreement on 4D and 2Dflow.Conclusions:4D-flow MRI represents a valid tool in Fontan’sflow quantification.Further larger studies are needed to confirm our results and to evaluate the impact of advanced 4D-flow MRI parameters on the prognostic stratification in patients after Fontan palliation.

Gastrointestinal and liver infections in children undergoing antineoplastic chemotherapy in the years 2000

AIM: To review gastrointestinal and liver infections in children undergoing antineoplastic chemotherapy. To look at gut microflora features in oncology children.METHODS: We selected studies published after year 2000, excluding trials on transplanted pediatric patients. We searched English language publications in MEDLINE using the keywords: "gastrointestinal infection AND antineoplastic chemotherapy AND children", "gastrointestinal infection AND oncology AND children", "liver infection AND antineoplastic chemotherapy AND children", "liver abscess AND chemotherapy AND child", "neutropenic enterocolitis AND chemotherapy AND children", "thyphlitis AND chemotherapy AND children", "infectious diarrhea AND children AND oncology", "abdominal pain AND infection AND children AND oncology", "perianal sepsis AND children AND oncology", "colonic pseudo-obstruction A N D o n c o l o g y A N D c h i l d A N D c h e m o t h e r a p y ", "microflora AND children AND malignancy", "microbiota AND children AND malignancy", "fungal flora AND children AND malignancy". We also analysed evidence from several articles and book references.RESULTS: Gastrointestinal and liver infections represent a major cause of morbidity and mortality in children undergoing antineoplastic chemotherapy. Antineoplastic drugs cause immunosuppression in addition to direct toxicity, predisposing to infections, although the specific risk is variable according to disease and host features. Common pathogens potentially induce severe diseases whereas opportunistic microorganisms may attack vulnerable hosts. Clinical manifestations can be subtle and not specific. In addition, several conditions are rare and diagnostic process and treatments are not standardized. Diagnosis may be challenging, however early diagnosis is needed for quick and appropriate interventions. Interestingly, the source of infectionin those children can be exogenous or endogenous. Indeed, mucosal damage may allow the penetrance of endogenous microbes towards the bowel wall and their translocation into the bloodstream. However, only limited knowledge of intestinal dysbiosis in oncology children is available. CONCLUSION: The diagnostic work-up requires a multimodal approach and should be implemented(also by further studies on new biomarkers) for a prompt and individualized therapy.

Minimally invasive surgery for paediatric inflammatory bowel disease: Personal experience and literature review

The incidence of paediatric inflammatory bowel disease(PIBD) has dramatically increased in the last 20 years. Although first reported in mid 1970s',diagnostic laparoscopy has started to be routinely adopted in paediatric surgical practice since late 1990s'. Minimally invasive surgery was first limited to diagnostic purposes. After 2002 it was also applied to the radical treatment of PIBD,either Crohn's disease(CD) or Ulcerative colitis. During the last decade minimally invasive approaches to PIBD have gained popularity and have recently became the "gold standard" for the treatment of such invalidating and troublesome chronic diseases. The authors describe and track the historical evolution of minimally invasive surgery for PIBD and address all available opportunities,including most recent advancements such as robotic surgery,single port approaches and minimally invasive treatment of perianal fistulising CD. A systematic review of all series of PIBD treated with minimally invasive approaches published so far is provided in order to determine the incidence and type of patients' complications reported up to present days. The authors also describe their experience with minimally invasive surgery for PIBD and will report the results of 104 laparoscopic procedures performed in a series of 61 patients between January 2006 and December 2014.

Eye reflux:an ocular extraesophageal manifestation of gastric reflux

AIM： To suspect laryngopharyngeal reflux（LPR） in patients with ocular surface disease（OSD）. METHODS： The present study evaluated a group of subjects with OSD assessing the Ocular Surface Disease Index（OSDI） and the Reflux Symptom Index（RSI） to detect patients with suspected LPR and define a possible relationship between tests.RESULTS： Two hundred and ninety subjects（175 females, mean age： 60.41±15.68y） were consecutively visited at ophthalmologist offices. One hundred and one（34%） patients had pathological RSI（〉13） and consequently a suspected LPR.CONCLUSION： The current study shows that suspected LPR may be common（34%） in patients with OSD and a suspected LPR may be considered in OSD patients when RSI score is 〉13 and OSDI score is 〉42.

Pancreatic metastasis from mycosis fungoides mimicking primary pancreatic tumor

Mycosis fungoides(MF) is a cutaneous T-cell lymphoma that can undergo local progression with possible systemic dissemination. We report a case of a patient affected by MF with a pancreatic mass that was a diagnostic challenge between primitive tumor and pancreatic metastasis from MF. Clinical setting findings and imaging studies raised the suspicion of a pancreatic primary neoplasm. A diagnostic clue was provided by the combined histomorphologic/immunohistochemical study of pancreatic and cutaneous biopsies, which revealed a pancreatic localization of MF. Considering the rarity of metastatic localization of MF to the pancreas, we next investigated whether chemokinechemokine receptor interactions could be involved in the phenomenon to provide new insight into the possible mechanisms underlying metastatic localization of MF to the pancreas. Histological analyses of archival pancreatic tissue demonstrated that glucagon-secreting cells of the pancreatic islets expressed the CCL27 chemokine, which may have attracted in our case metastatic MF cells expressing the complementary receptor CCR10.

Exosomes:Key tools for cancer liquid biopsy

Precision medicine is based on the identification of biomarkers of tumor development and progression.Liquid biopsy is at the forefront of the ability to gather diagnostic and prognostic information on tumors,as it can be noninvasively performed prior or during treatment.Liquid biopsy mostly utilizes circulating tumor cells,or free DNA,but also exosomes.The latter are nanovesicles secreted by most cell types,found in any body fluid that deliver proteins,nucleic acids and lipids to nearby and distant cells with a unique homing ability.Exosomes function in signalling between the tumor microenvironment and the rest of the body,promoting metastasis,immune remodelling and drug resistance.Exosomes are emerging as a key tool in precision medicine for cancer liquid biopsy,as they efficiently preserve their biomarker cargo.Moreover,exosomes strongly resemble the parental cell,which can help in assessing the oxidative and metabolic state of the donor cell.In this respect,exosomes represent one of the most promising new tools to fight cancer.This review will discuss the clinical applications of profiling exosomal proteins and lipids by high-throughput proteomics and metabolomics,and nucleic acids by next generation sequencing,as well as how this may allow cancer diagnosis,therapy response monitoring and recurrence detection.

Endothelial impairment evaluation by peripheral arterial tonometry in pediatric endocrinopathies:A narrative review

Endothelial dysfunction(ED)is characterized by an imbalance between vasodilator and vasoconstriction agents.Several pathological conditions clinically diagnosed in childhood and adolescence are characterized by ED and increased risk for early development of microangiopathic and macroangiopathic impairment,in particular type 1 diabetes mellitus(T1DM),T2DM,obesity,metabolic syndromeand pituitary dysfunction associated to various endocrinopathies.More recently insulin resistance following chemotherapy or radiotherapy for tumors,bone marrow transplantation for hematological malignancies(i.e.,cancer survivors),or immunosuppressive treatment for solid organ transplantation has been observed.Assessment of ED by means of non-invasive techniques is the gold standard for early ED detection before clinical manifestation.It is aimed to recognize patients at risk and to avoid the development and progression of more serious illnesses.Reactive hyperemia-peripheral artery tonometry is a noninvasive technique to assess peripheral endothelial function by measuring modifications in digital pulse volume during reactive hyperemia,and represents a non-invasive,reproducible and operator-independent tool able to detect precocious ED.This narrative review aimed to provide an overview of the most important papers regarding ED detection by EndoPat 2000 in children and adolescents with different endocrine diseases.A comprehensive search of English language articles was performed in the MEDLINE database without using other search filters except the publication interval between 2005 and 2020.

提供服务及临床观察推动分子遗传学研究——一个新型的连锁低磷酸血症佝偻病及全结肠无神经节细胞症的基因定位

一、X连锁肌萎缩的遗传服务 Dystrophin基因的缺失突变可引起病情严重的DMD或病情较轻的BMD,有两个高频缺失区(HFDR)分别位于dystro-phin基因5’端下游500及1200kb处。我们改进了在文献中已报道了的三种PCR反应,使我们实验室能分析dystrophin基因的30个外显子。用这些PCR方法查出了Sou-thern印迹法及cDNA探针在152个患者中查出的96种缺失中的95种,唯一一种未查出的缺失为外显子22到25,但产生了一个接头片段。

RET in breast cancer:pathogenic implications and mechanisms of drug resistance

Initiation,progression,outcome and sensibility to therapies in breast cancer(BC),the most frequent cancer in women,are driven by somatic and germline mutations.Although the effectiveness of hormonal therapies is well-founded,it is prescribed for cancers which express steroid hormone receptors,such as estrogen receptor(ER).RET is a proto-oncogene encoding a transmembrane tyrosine kinase receptor that is activated by one of its four ligands(GDNF,neurturin,artemin or persephin)and one of its coreceptors(Gfrα1-4).Loss-of-function mutations in RET are responsible for Hirschsprung disease,while gain-of-function mutations for multiple endocrine neoplasia type 2.In addition,deregulation of its intracellular signaling,due to mutations,gene rearrangements,overexpression or transcriptional upregulation,can cause several neuroendocrine and epithelial tumors.In BC,amplification of receptor tyrosine kinases,such as ERBB2,EGFR,IGFR and FGFR1,and/or their upregulation contribute to cancer initiation and progression.RET can also have an important role in BC,but only in the subset of ER-positive(ER+)tumors,where it is found overexpressed.Targeting the RET pathway and shedding light on molecular basis of the resistance to hormone therapy may lead to new therapies in ER+BC,improving treatment outcome and preventing tumor-related events.Thus,here,we review the state of the art of RET biology in BC and agents targeting RET tested in the clinical trials and discuss the specificity of the still available RET inhibitors and the molecular mechanisms underlying the BC resistance to endocrine therapy.

The good and bad sides of exosomes:pre-metastatic niche formation,cancer biomarker and therapy carriers

Exosomes,nanovesicles of endocytic origin,are secreted by most cell types;cancer cells representing no exception.Exosomes facilitate intercellular communication as they deliver diverse proteins,mRNA,miRNA and lipids.In this review,we discuss how exosomes represent one of the main risks associated with cancer but also one of the most promising new tools to fight it.Exosomes appear to function as signalling molecules between the tumour microenvironment,i.e.,the complex of both cancer and stromal cells,and the rest of the body.Cancerderived exosomes have been shown to drive the initiation and progression of metastasis,by transporting their cargoes to target tissues.In this respect,exosomes are implicated in cancer progression,dissemination and therapy resistance.However,exosomes are also emerging as a key tool in precision medicine,pivotal for cancer liquid biopsy in early diagnosis and for assessing when there is a recurrence.Profiling exosomal cancer-derived nucleic acids by ultrasensitive next-generation sequencing along with mapping the protein profile utilizing highthroughput proteomics will allow earlier cancer detection,therapeutic stratification and monitoring of response to therapy.Exosomes are also a promising new tool for cancer immunotherapy.Clinically utilizing exosomes for these applications in cancer diagnosis and therapeutics will be the next challenge.