Pediatric Acute Lymphoblastic Leukemia Emerging Therapies-From Pathway to Target.

Over the past 40 years, the 5-years-overall survival rate of pediatric cancer reached 75-80%, and for acute lymphoblastic leukemia (ALL), exceeded 90%. Leukemia continues to be a major cause of mortality and morbidity for specific patient populations, including infants, adolescents, and patients with high-risk genetic abnormalities. The future of leukemia treatment needs to count better on molecular therapies as well as immune and cellular therapy. Advances in the scientific interface have led naturally to advances in the treatment of childhood cancer. These discoveries have involved the recognition of the importance of chromosomal abnormalities, the amplification of the oncogenes, the aberration of tumor suppressor genes, as well as the dysregulation of cellular signaling and cell cycle control. Lately, novel therapies that have already proven efficient on relapsed/refractory ALL in adults are being evaluated in clinical trials for young patients. Tirosine kinase inhibitors are, by now, part of the standardized treatment of Ph+ALL pediatric patients, and Blinatumomab, with promising results in clinical trials, received both FDA and EMA approval for use in children. Moreover, other targeted therapies such as aurora-kinase inhibitors, MEK-inhibitors, and proteasome-inhibitors are involved in clinical trials that include pediatric patients. This is an overview of the novel leukemia therapies that have been developed starting from the molecular discoveries and those that have been applied in pediatric populations.

The Role of Phytosterols in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease is now recognized as the most common cause of chronic liver disease with an increasing prevalence in both adults and children. Although the symptoms are absent or poorly expressed in most cases, some patients may progress to end-stage liver disease. The pathogenesis of NAFLD is known to be multifactorial. Current therapeutic recommendations focus on lifestyle changes in order to reduce the incidence of risk factors and drugs targeting major molecular pathways potentially involved in the development of this disease. Given that a pharmacological treatment, completely safe and effective, is not currently known in recent years more research has been done on the effects that some bio-active natural compounds, derived from plants, have in preventing the onset and progression of NAFLD. Numerous studies, in animals and humans, have shown that phytosterols (PSs) play an important role in this pathology. Phytosterols are natural products that are found naturally in plant. More than 250 phytosterols have been identified, but the most common in the diet are stigmasterol, ß-sitosterol, and campesterol. Consumption of dietary PSs can reduce serum cholesterol levels. Due to these properties, most studies have focused on their action on lipid metabolism and the evolution of NAFLD. PSs may reduce steatosis, cytotoxicity oxidative stress, inflammation, and apoptosis. The purpose of this review is to provide an overview of the importance of dietary phytosterols, which are a window of opportunity in the therapeutic management of NAFLD.

The Perspectives of Biomarkers in Predicting the Survival of the Renal Graft.

Kidney transplantation (KT) is currently the elective approach for patients with end-stage renal disease. Although it is a safe choice for these patients, the early complications can lead to graft dysfunction. One of the most redoubtable complications is delayed graft function (DGF), having no specific treatment. The effects of DGF on the graft survival are large enough to justify the formulation of specific biological protocols. Therefore, discovering biomarkers of acute impairment in renal transplanted patients is required. Creatinine is a poor marker to establish the kidney injury. Estimated glomerular filtration rate together with creatinine is ready to approximately measure the kidney function. Different serum and urine proteins are being studied as possible predictive biomarkers for delayed graft function. This review will concentrate on recent and existing research which provide insight concerning the contribution of some molecules for the estimation and evaluation of graft function after kidney transplantation. Further studies examining various aspects of DGF after KT are urgently needed to address a hitherto less-known clinical question.

Variations in Biochemical Values under Stress in Children with SARS-CoV-2 Infection.

In the case of SARS-CoV-2 infection, children seem to be less affected than adults, but data regarding epidemiologic characteristics and biochemical values are poor and essentially based on limited case series. The aim of our study is to highlight the predictive value of some biochemical markers at hospitalization, for the correct classification of the patient in the form of disease. Methods: We performed an analytical retrospective study on 82 pediatric patients diagnosed with COVID-19 in the emergency department, with moderate or severe form of disease, and treated in our tertiary hospital. We analyzed the epidemiologic characteristics, symptomatology and biochemical values and compare the data according to the form of disease. Results: The mean age at admission was 4.5 years (median 1 year) and the masculine/feminine ratio was 1.5. Comparing the data between the two groups of patients (42 severe/40 moderate), we observed that the severe form presented with a lower pH at admission (p = 0.02), hyperglycemia (p = 0.01), increased values of transaminases (p = 0.01 and 0.02) and hypoproteinemia (p = 0.01). Also, the severe form was statistically significantly associated with comorbidities, acute respiratory distress, rising of the inflammatory markers during hospitalization. Hyperlactatemia (Lactate > 1.5 mmol/L) was significantly associated with the age under one year (p < 0.001). Mortality rate was 9.75% and the median age at death was 3 months. Univariate logistic regression model shows that the presence of anemia increased the probability of death 88 times, comorbidities 23.3 times and ketoacidosis 16.4 times. Conclusions: Metabolic acidosis, hyperlactatemia, hyperglycemia, modified hepatic values and hypoproteinemia are biochemical markers associated with the severe form of disease in SARS-CoV-2 infection in children. Presence of anemia, comorbidities and ketoacidosis are important risk factors for death of pediatric patients with SARS-CoV-2 infection.

Gastroesophageal Reflux in Children with Asthma.

Background: Nowadays it is considered that a specific causal relationship exists between asthma and gastroesophageal reflux (GER), because of the aspiration of gastric refluate which leads to and maintain spasticity even real crisis of paroxystic expiratory dyspnea. This study explores this relationship and evaluates the results after treatment. Methods: 56 children diagnosed with asthma, hospitalized in a regional center of pediatric gastroenterology in Northeast Romania, underwent 24-hour continuous esophageal pH monitoring in order to establish the presence of GER. The Boix-Ochoa score was used to interpret the results. Proton pump inhibitors were administered to those with GER and the patients were reevaluated after 2 months. Results: 39 patients (69.64%) had GER, with a Boix-Ochoa score above normal (N < 11.99), and 17 patients (30.36%) had normal score. After administering proton pump inhibitors for 2 months, 7 patients still had high Boix-Ochoa score (17.95%). The result of this analysis shows that the presence of asthma increases the chance of GER by 2.86 times. Conclusions: In children with asthma we have to look for GER in order to treat, because it can help the treatment of asthma or even solve some cases resistant to standard treatment.

Long term follow-up in a patient with prune-belly syndrome - a care compliant case report.

RATIONALE: Malformative uropathies represent a major cause of Chronic Kidney Disease (CKD) in children. Genitourinary system is the most frequent and sever affected in Prune-Belly syndrome cases. That is why the findings of early diagnosis and vigilant monitoring for these situations remain a major challenge for the medical team. PATIENT CONCERNS: We present the clinical course of a 10 years old child with diagnosis of Prune-Belly syndrome. A urinary tract abnormality was suspected starting 25 weeks of gestation, when a routine ultrasound showed oligohydramnios, increased size urinary bladder, bilateral hydronephrosis and megaureters, thin abdominal wall. DIAGNOSIS: Prenatal suspicion of Prune-Belly syndrome plays a deciding role in renal disease progression. A detailed clinical exam at birth established the diagnosis of Prune-Belly syndrome. Renal ultrasound confirmed bilateral grade III hydronephrosis and megaureters, with empty bladder, suggesting an obstruction at this level. A persistent urachus was confirmed by catheterization. Later it was used for imaging study that showed bilateral high grade reflux. INTERVENTIONS: The main goal of any treatment is to preserve kidney function. Treatment options depend on the clinical picture. The pregnancy was closely monitorized, but fetal distress appeared so early labor was induced at 32 weeks. At beginning a temporary catheter was placed into the urachus which expressed urine. The urachus drain was left in place until the age of 6 weeks, when a bilateral ureterostomy was performed. Skeletal and genital malformations were present too; the child has undergone several surgeries to solve these abnormalities. OUTCOMES: At the age of 10 years, he is a well-adapted child. He has had fewer than 3 urinary tract infections per year. Long term follow-up showed a relatively slow decline in the estimated Glomerular Filtration Rate in our child (62 ml/1.73m/min). LESSONS: This case suggests that induced early labor could prove beneficial for early upper urinary tract decompression through earlier access to surgery. This is an option especially in situations or region where vesicoureteric or vesicoamniotic shunt placement is not available.

Correlation between esophageal pH-metry and esophagitis in gastroesophageal reflux disease in children.

Gastroesophageal reflux (GER) is the intermittent or permanent passage of stomach content into the esophagus and gastroesophageal reflux disease (GERD) is the reflux which triggers a whole set of symptoms or complications. The study compares the 24-hours esophageal pH-metry, used for diagnosis of the GERD, with the esophagitis degree observed at the upper digestive endoscopy.72 children were included, aged over 4 years old, admitted in a pediatric gastroenterology regional center in Northeast Romania, diagnosed with GERD by 24 hours pH-metry (with a positive Boix-Ochoa score), which also underwent the upper digestive endoscopy.Out of the 72 children diagnosed with GERD, 47 (65.28%) had grade A esophagitis and 25 (34.72%) grade B esophagitis. In GERD associated with grade B esophagitis the Boix-Ochoa score is statistically significant higher, compared with the GERD associated with grade A esophagitis (F = 9.76, P = .0036, 95% CI).Upper digestive endoscopy performed in patients with gastroesophageal reflux disease shows the constant presence of esophagitis at all patients. There were only grade A and B esophagitis due to the fact that they are young patients with a relative short history of the disease. The correlation tests show a perfect parallel between the pH-metry scores and the endoscopic lesion. The correlation is so accurate that the pH-metry scores can be sufficient to prove GERD and the grade of esophagitis, the upper digestive endoscopy being reserved only for the cases that does not respond to the medical treatment or have other complications.

A case report of pediatric calciphylaxis-a rare and potentially fatal under diagnosed condition.

RATIONALE: Though to be rare, calcific uremic arteriolophathy (CUA) is an ectopic calcification entity causing pain and disabilities in patients with chronic renal insufficiency, thus increasing the morbidity and mortality. PATIENT CONCERN: We report a case of four years old boy admitted with acute respiratory failure. Physical examination revealed: irritability, purple subcutaneous hard nodules, tachypnea, dry spasmodic cough, respiratory rate 45/min, heart rate 110/min, blood pressure 100/60 mmHg, with normal heart sounds, no murmurs, hepatomegaly with hepato-jugular reflux. He was diagnosed at 2 years old with stage 5 chronic kidney disease due to untreated posterior urethral valve, and subsequently started peritoneal dialysis. He developed severe renal osteodystrophy, refractory to standard phosphate binders. DIAGNOSES: Pathology examination revealed the presence of diffuse calcifications involving the skin, brain, heart, lung, kidney, stomach and pancreas, consistent with the underlying diagnosis of CUA. INTERVENTION: Apart from standard treatment for end stage renal disease and associated co-morbidities, intensive care procedures have been initiated: oxygen therapy, continuous positive airway pressure, inotropic medication (Dopamine, Dobutamine), anticonvulsants (Diazepam), and antiedematous therapy (Dexamethasone). OUTCOME: His pulmonary function rapidly deteriorated up to the severe hypoxemia, seizures and cardio-respiratory arrest, despite the initiation of intensive care measures. LESSONS: A careful follow up of small children might detect in time an abnormal urinary pattern. The diagnosis of growth failure should also trigger urgent further investigation.

Focal segmental glomerulosclerosis in children complicated by posterior reversible encephalopathy syndrome.

An uncommon side effect of cyclosporine A (CsA) use is posterior reversible encephalopathy syndrome (PRES). PRES usually develops because of disturbed capacity of posterior cerebral blood flow to autoregulate an acute rise in blood pressure. We present the case of a 10-year-old girl who was previously diagnosed in our department with focal segmental glomerulosclerosis. She was treated with CsA and developed seizures, progressive loss of consciousness, and visual disturbance on the 7th day of treatment. Brain magnetic resonance imaging showed degeneration of white matter with diffuse demyelination in the parietal and posterior occipital lobes, consistent with the diagnosis of PRES. Cases of PRES reported in children are usually secondary to immunosuppressive therapy in oncological and haematological diseases. Our case is the fifth reported case of focal segmental glomerulosclerosis in children treated with CsA and complicated by PRES. Rapid recognition of PRES and stopping neurotoxic therapy early are essential for a good prognosis.

Different evolution in the treatment of a severe persistent asthma in 2 twins: Case report and review of the literature.

RATIONALE: Asthma is a multifactorial disease with complex genetic inheritance. In children under the age of 5 years, the diagnosis of asthma is a challenge. PATIENT CONCERN: We present the case of twin sisters under the same treatment for persistent asthma, but with different evolution over the time. DIAGNOSES: One of the sister is diagnosed with severe persistent bronchial asthma associated with bronchiectasis and dyslipidemia and the other one only with mild persistent asthma. INTERVENTIONS: At each admission the treatment for the exacerbations and the underlying respiratory infections was represented by antibiotics, short-acting ß2 agonists, and, sometimes, oxygen and systemic corticosteroids. As chronic treatment, they received in the last period inhaled corticosteroids associated with long-acting ß2 agonist. OUTCOMES: Until the age of 6.5 years, they had similar diagnoses and treatment; from this point one was asymptomatic, with normal pulmonary function tests. The other one had a more complicated evolution which led to a severe crisis by the age of 10 years old. LESSONS: Although asthma is a multifactorial disease with complex genetic inheritance, the genetics has its limits. Our twins had a similar onset with the same genetic inheritance, with the same risk factors, with the same comorbidities and with the same treatment. In this context, different evolutions of severe persistent asthma require more extensive genetic investigations. PATIENT CONCERN: We present the case of twin sisters under the same treatment for persistent asthma, but with different evolution over the time.

"Message from a turtle": otitis with Salmonella arizonae in children: Case report.

RATIONALE: Salmonella enterica subsp arizonae is a common gut inhabitant of reptiles (snakes are the most common reservoir, but it also occurs in turtles). Alhough human cases owing to this organism are exceedingly rare, it may occasionally infect young infants and immunocompromised individuals with a history of intimate associations with reptiles. Our case is the 20th one among the infections with S arizonae in children, but the 2nd one of otitis and the first of mastoiditis. The other cases had different anatomical locations, such as gastroenteritis, osteomyelitis, meningitis, ankle infection, wound infection, and sinusitis. PATIENT CONCERNS AND DIAGNOSIS: We report a rare case of otitis with Salmonella in a previously healthy adolescent, which was most likely acquired after bathing in a lake. The ear infection was complicated with mastoiditis. Audiometric testing showed a moderately conductive hearing loss (60 dB on pure-tone average). INTERVENTION: Standard therapy for S arizonae was initiated. The surgery revealed a "hidden" cholesteatoma. Surgical management comprised of canal wall up mastoidectomy with attico-antrotomy and posterior tympanotomy followed by tympanoplasty. OUTCOMES: Daily postoperative dressing care of the incision, along with antibiotic lavage of the external auditory canal packing, ensured a favorable evolution. The functional gain was important; the 1-month postsurgical pure tone audiogram indicated nearly normal hearing (a mean of 25 dB for air conduction thresholds). LESSON: Salmonella enterica serotype arizonae is a rare cause of human infection, being a common organism in reptiles, like snakes and turtles. Young children are at a particular risk for acquiring such infections. Our study might encourage further epidemiologic investigations into these infections to generate a more effective strategy among public health agencies.

Posterior reversible encephalopathy syndrome in children with kidney disease.

Posterior reversible encephalopathy syndrome (PRES) has been described as a neurological condition observed in a variety of clinical settings and is characterized by focal neurological deficits, seizures, headaches, altered mental status, and visual impairment, associated with transient typical lesions on neuroimaging, predominantly in the posterior part of the brain. The most common risk factors for PRES are hypertension, renal diseases, and the use of calcineurin inhibitors. The incidence of PRES in children with renal disorders varies between 4 and 9%, according to different reports. Vasogenic cerebral edema is considered the major pathophysiological mechanism of PRES. There are two main theories regarding the genesis of this edema: (1) hyperperfusion, due to autoregulatory failure of the cerebral vasculature, and (2) hypoperfusion, due to vasoconstriction of the cerebral arteries. In addition, PRES might also be the result of a systemic inflammatory state causing endothelial dysfunction. The management of PRES includes BP control, treatment of seizures, and removal of or reduction in calcineurin inhibitors. Intravenous administration of antihypertensive therapy is preferred, and various drugs have been used in this regard, including nicardipine, labetalol, sodium nitroprusside, and hydralazine. The prognosis of PRES is usually benign, except for rare cases with intracranial hemorrhage.

Magnesium in Pediatric Nephrotic Syndrome.

Aim: In the present study, we aimed to evaluate serum Mg concentration in children with nephrotic syndrome and highlight the relationship between Mg concentration and acute nephropathy. Material and Methods: We conducted a clinical study in 27 patients, aged 2 to 17 years, admitted to the Nephrology clinic of the Iasi "Sf. Maria" Children's Hospital between 2011-2015, with the diagnosis of idiopathic nephrotic syndrome (NS), first episode or relapse. In each patient, we investigated serum urea and creatinine, total cholesterol, total serum proteins, serum magnesium, urinary proteins, creatinine clearance and renal histopathology. We also used a control group of 14 children with normal renal function. Results: 12 patients had NS in the acute phase, 6 steroid responsive and 6 steroid resistant. The remaining 15 patients were in the remission phase of NS, 7 steroid responsive and 8 steroid resistant. Significantly decreased serum Mg levels were found in NS active group compared to control group. Renal histopathological analysis in steroid responsive patients revealed the following pathological aspects: optically normal glomeruli (1 case), minimal mesangial changes (5 cases), IgM nephropathy (4 cases), mesangioproliferative glomerulonephritis (4 cases). Conclusions: The variations of serum and urinary Mg levels in children with acute nephropathy may be useful for early diagnosis and improving therapy.

[Characteristic features of urinary tract infection in malnourished children]. / Particularitatile infectiei urinare la malnutriti.

UNLABELLED: The aim of this study is to prove a relationship between urinary tract infection and malnutrition in children 0-3 years old, hospitalized in the IVI Pediatric Clinic, Hospital St. Mary Iasi, between January 2000 and December 2004. MATERIAL AND METHODS: We have made a retrospective study for 298 infant and young children with urinary tract infection, 237 eutrophic and 61 malnourished. We studied comparatively the both groups with urinary tract infection (UTI), and we applied statistic methods for results. RESULTS: The statistic methods prove that relative risk for UTI increases in malnutrition, predictive positive value is 72.5%. The clinical manifestation is similar in malnourished and eutrophic, but many co morbidities were associated with dystrophic status. Malformation of urinary tract was associate two times more in malnourished child. The etiology of infection was dominated by Escherichia coli, Proteus and Klebsiella pneumoniae. In malnourished children 5% of UTI was determinate by opportunist etiological agents like: Enterobacter, Enterococcus, Acinetobacter. More frequently, bacterium develops resistance of antibiotics like amino-penicilina, Trimethoprim and Cephalosporin. CONCLUSION: Accurate and fast diagnosis and treatment of UTI in infant and child with malnutrition is the best way for nutritional rehabilitation and prevention of serious consequence.

[Nutrition of low birth weight infants]. / Nutritia copilului cu greutate mica la nastere.

The low birth weight infant's (LBW) nutrition needs special attention. Energy requirements are increased due to a high metabolic rate and a low thermogenesis. Increased protein requirements are, easy to be absorbed (from lacto-serum). Lipids, as important energetic source requires an appropriate content in essential fatty acids and medium chain triglycerides (TGM) which are easy absorbed in absence of lipase and deficit of bile salt secretion. The carbohydrates should be represented by lactose or equivalents like di-, oligo or polysaccharides. The addition of maltodextrin avoid an exaggerate supply and incomplete digestion of lactose. Sodium requirement are increased due to exaggerated loss consequence of renal immaturity. The rapid rate of growth impose the addition of Calcium, Phosphorus, Iron, Copper, and vitamins, especially Vitamin D, E and Folic acid. The appropriate nutrition of LBW must cover his special needs to maintain the homeostasis and rapid growth. Precise nutrient requirements are, however, difficult to establish.

[Urinary tract infections in children--aspects of microbiological diagnosis]. / Infectia urinara la copil aspecte ale diagnosticului bacteriologic.

UNLABELLED: Urinary tract infection (UTI) is one of the most common bacterial infections of childhood, with the incidence range between 1-1.5% in boys and 3-8% in girls. AIM: To estimate the value of urine analysis (bacteriology and biochemistry) for diagnostic of UTI in children. MATERIAL AND METHOD: The method was to observe 700 urinary specimens collected from patients hospitalized in 4th Clinic of Pediatric Nephrology between October 2004 and February 2005, the urinalysis (UA) being performed in the Microbiology laboratory of "St. Maria" Emergency Children Hospital Iasi. The sample collection was made from the midstream urine flow, direct microscopy and standard culture were performed immediately after collection. We applied a diagnostic strategy study in order to evaluate sensitivity and specificity of UA for prediction of UTI. The data was assessed according to the Receiver Operator Characteristic Curve. RESULTS AND DISCUSSION: We analysed the relation between leukocituria and positive urine culture and we find a sensitivity equal to 56%, with CI 95% = 0.56 +/- 0.07, and a specificity equal to 10%, with CI 95% = 0.10 +/- 0.02. The likelihood of UTI with negative UA result has been calculated as a negative likelihood ratio = 4.4. If we supplement a number of culture (2-3) we have obtain a sensitivity 97% +/- 0.02%, and the predictive negative value 97% (that mean the possibility to lose UTI in just 3% cases), and a specificity 35%, with a predictive positive value 61% (that mean a decrease of possibility to over-measure UTI). CONCLUSIONS: The sensitivity of UA increase if we correlate more than leukocyturie and the significantly positive urine culture. We must to supplement a number of urine culture for increase the chance to obtain a positive diagnostic of UTI, and to exclude a possibility to over-measure UTI. Through increase a sensibility of method for diagnostic, decrease the possibility to loose and no treaty UTI with serious consequence.