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 Overlap of Kidney Failure in Extrapulmonary Sarcoidosis in Children-Case Report and Review of Literature.

Sarcoidosis is a non-necrotizing granulomatous inflammatory multisystemic disorder of unknown etiology. In children, as in adults, it can involve a few or all organ systems to a varying extent and degree, entailing multisystemic manifestations. Kidney involvement in pediatric-onset adult-type sarcoidosis is rare, with a wide range of renal manifestations, most of them related to calcium metabolism. Children with renal sarcoidosis tend to be more symptomatic than adults, although male patients have a higher prevalence. We present the case of a 10-year-old boy who presented with advanced renal failure with nephrocalcinosis and important hepatosplenomegaly. The diagnosis was established by histopathological examination, with consequent cortisone therapy and hemodialysis. This review emphasizes that sarcoidosis should be considered in the differential diagnosis of pediatric patients with acute kidney insufficiency or chronic kidney disease of an unknown etiology. As far as we know, this is the first study regarding extrapulmonary sarcoidosis in children from Romania.

Unusual Association of Diamond-Blackfan Anemia and Severe Sinus Bradycardia in a Six-Month-Old White Infant: A Case Report and Literature Review.

Diamond-Blackfan anemia is a rare (6-7 million live births), inherited condition manifesting as severe anemia due to the impaired bone marrow production of red blood cells. We present the unusual case of a six month old infant with a de novo mutation of the RPS19 gene causing Diamond-Blackfan anemia who additionally suffers from severe sinus bradycardia. The infant was diagnosed with this condition at the age of four months; at the age of 6 months, she presents with severe anemia causing hypoxia which, in turn, caused severe dyspnea and polypnea, which had mixed causes (hypoxic and infectious) as the child was febrile. After correction of the overlapping diarrhea, metabolic acidosis, and severe anemia (hemoglobin < 3 g/dL), she developed severe persistent sinus bradycardia immediately after mild sedation (before central venous catheter insertion), not attributable to any of the more frequent causes, with a heart rate as low as 49 beats/min on 24 h Holter monitoring, less than the first percentile for age, but with a regular QT interval and no arrhythmia. The echocardiogram was unremarkable, showing a small interatrial communication (patent foramen ovale with left-to-right shunting), mild left ventricular hypertrophy, normal systolic and diastolic function, and mild tricuspid regurgitation. After red cell transfusion and appropriate antibiotic and supportive treatment, the child's general condition improved dramatically but the sinus bradycardia persisted. We consider this a case of well-tolerated sinus bradycardia and foresee a good cardiologic prognosis, while the hematologic prognosis remains determined by future corticoid response, treatment-related complications and risk of leukemia.

Paroxysmal Supraventricular Tachycardia in Wolff-Parkinson-White Syndrome in a Newborn-Case Report and Mini-Review.

Wolff-Parkinson-White (WPW) syndrome is a rare abnormal condition frequently associated with paroxysmal supraventricular tachycardia (PSVT) and is described as an arrhythmia under the form of increased heartbeat. Currently, there are various possible treatments going from medicines such as adenosine and beta-blockers to cardioversion. The unknown causes of this condition together with the different responses to treatment in each patient make it difficult to establish the best therapeutic approach. In this context, in the current paper, we were interested in reporting the therapeutic options and their efficiency in the case of associated heart or inflammatory conditions in a 13-day-old patient.

Upper gastrointestinal bleeding in children from a hospital center of Northeast Romania.

BACKGROUND: The aim of this study was to investigate the common etiologies, clinical and biological patterns of upper gastrointestinal bleeding (UGIB) in children from a hospital center in Northeast Romania. METHODS: This seven-year retrospective study was performed from 2007 to 2013 in St. Mary Children's Emergency Hospital, Jassy, Romania and included all children who referred to our center with UGIB exteriorized by hematemesis or melena. Endoscopy was performed under conscious sedation/general anesthesia after the informed consent was obtained. RESULTS: One hundred and three patients aged 1-18 years were included in this study. There were 57 males and 46 females with male to female ratio 1.2:1; 43.69% presented with hematemesis, 31.07% had melena and 25.24% had both. The most common causes of UGIB were erosive gastritis (33.98%), followed by esophagitis (14.56%), duodenitis (11.65%), duodenal ulcer (10.68%), gastric ulcer (5.83%), esophageal varices (4.85%), Mallory-Weiss syndrome (1.94%); multiple etiologies counted for 16.50% cases. A certain bleeding source was found in 34.95% cases, a possible one in 39.81% of the patients; the source could not be ascertained in 25.24% of cases. Nonsteroidal anti-inflammatory drug (NSAID) consumption was documented in in 17.51% of patients. The incidence of H. pylori infection was 36.89%. CONCLUSIONS: The most common cause of of upper GI bleeding in our series was gastritis, followed by oesophagitis and duodenitis. Most of the patients presented with hematemesis; previous consumption of NSAIDs and H. pylori infection were associated with gastroduodenal ulceration and bleeding. Early endoscopy was associated with a higher detection rate of the bleeding source.

Unraveling chronic kidney disease in children: a surprising manifestation of celiac disease.

Celiac disease, firstly described in children, is a type of T-cell enteropathy that occurs in individuals genetically predisposed to gluten exposure. The estimated global prevalence of celiac disease is continuously increasing. Although, traditionally, celiac disease was diagnosed in children with failure to thrive and digestive issues, it is now recognized that may present with a wide range of symptoms beyond gastrointestinal ones. Celiac disease continues to pose significant challenges due to the continuous advancement of knowledge in understanding its pathophysiology, diagnosing the condition, managing its effects, and exploring potential therapeutic approaches. The prevalence of celiac disease is increased among individuals with chronic kidney disease, also. The most frequent associations are with diabetic nephropathy, IgA nephropathy and urolithiasis. A gut-kidney axis has been recognized to play a significant role in chronic kidney diseases. This literature review aims to review the chronic renal pathology associated with celiac disease, with emphasis on childhood.

SARS-CoV-2 Possible Etiology of Cerebral Venous Thrombosis in a Teenager: Case Report and Review of Literature.

Cerebral venous thrombosis in pediatric patient has a varied etiology. The authors present the case of a teenager who, since the debut of SARS-CoV-2 infection, has accused intermittent right side hemicrania, which has become persistent in association with nausea and vomiting since the 5th day of quarantine. She was hospitalized in the 9th day since the debut. Neuroimaging revealed extended venous cerebral thrombosis affecting the right sigmoid sinus, the transverse sinus bilaterally, the confluence of the transverse sinuses and the right internal jugular vein. The evolution was favorable under anticoagulant and symptomatic treatment. Laboratory tests excluded other etiological causes for the cerebral venous thrombosis, thus the authors consider that cerebral thrombosis is a possible complication of SARS-CoV-2 infection in teenagers.

Epidemiological Characteristics of Helicobacter pylori Infection in Children in Northeast Romania.

(1) Background: Although gastritis has been associated with multiple etiologies, in pediatrics the main etiology is idiopathic. Many studies have reported mild-to-severe gastritis Helicobacter pylori (H. pylori) as an etiological factor. We evaluated the distribution of the infection with H. pylori by age, gender and place of living; (2) Methods: A retrospective study was conducted over a period of 3 years, over a cohort of 1757 patients of both sexes, aged between 1 and 18 years, admitted to a regional gastroenterology center in Iasi, Romania, with clinical signs of gastritis which underwent upper gastrointestinal endoscopy. The research was based on the analysis of data from patient observation charts and hospital discharge tickets, as well as endoscopy result registers; (3) Results: Out of the 1757 children, in 30.8% of cases the H. pylori infection was present. Out of them, 26.8% were males and 73.2% females. The average age of children with an H. pylori infection was higher (14.1 + 2.8 DS), compared with children without H. pylori (12.8 + 3.7 SD), an average difference of 1.3 years (95% confidence interval 0.96 to 1.66; p < 0.001). By place of living, children with H. pylori infection were from urban areas at 24.7% and from rural areas at 75.3%; (4) Conclusions: H. pylori infection incidence is still high in children, especially in teenagers, so extensive prevention and treatment programs are needed.

Difficulties in Adaptation of the Mother and Newborn via Cesarean Section versus Natural Birth-A Narrative Review.

Birth is a physiological act that is part of the morpho-functional economy of the maternal body. Each stage in the act of birth has a predetermined pathway that is neurohormonally induced and morpho-functionally established through specific and characteristic adaptations. Like maternity, childbirth also has an important impact on the maternal body as a biological structure and psycho-emotional behavior. Cesarean section performed at the request of the mother with no medical underlying conditions besides the prolonged hospitalization risk can also cause breathing problems in children, delayed breastfeeding, and possible complications in a future pregnancy. Vaginal birth remains the path of choice for a physiological evolution pregnancy. Although erroneously considered safe and easy today, cesarean section delivery must remain an emergency procedure or a procedure recommended for pregnancies where birth is a risk to the mother and to the child, as cesarean section itself is a risk factor for negative outcomes for both mother and baby. This review summarizes the impact that both cesarean section and natural birth have on mother and newborn in their attempt to adapt to postpartum events and extrauterine life.

Palm-Plant Pain, Sign of a Severe Systemic Disease? Case Report and Review of Literature.

Fabry disease is an X-linked lysosomal storage disease, second in prevalence after Gaucher disease. The onset of symptoms occurs in childhood or adolescence with palmo-plantar burning pains, hypo hidrosis, angiokeratomas, and corneal deposits. In the absence of diagnosis and treatment, the disease will progress to the late phase, characterized by progressive cardiac, cerebral and renal damage, and possible death. We present the case of an 11-year-old male boy who was transferred to the Pediatric Nephrology Department for palmo-plantar burning pain and end stage renal disease. Following the evaluations for the etiology of end stage renal disease we excluded the vasculitis, the neurologic diseases, extrapulmonary tuberculosis. Because of suggestive aspect at CT scan and lack of etiologic diagnosis of renal insufficiency we performed lymph node and kidney biopsy, with a surprising result for storage disease. The specific investigation confirmed the diagnosis.

Pediatric Systemic Lupus Erythematous in COVID-19 Era.

Pediatric systemic lupus erythematosus is a chronic autoimmune disorder with a highly variable course and prognosis. It results in functional abnormalities in the immune system due to intrinsic factors and the use of immunosuppressive therapies associated with underlying comorbidities seem to increase the risk of severe COVID-19 and poor outcomes of the disease in pediatric systemic lupus erythematosus (SLE) patients. The aim of this review is to obtain a better understanding of the existing link between this new viral infection and pediatric lupus. We have analyzed the characteristics of newly diagnosed cases of pediatric SLE following COVID-19 which have been reported in the literature and which describe the impact that COVID-19 has on patients already suffering with pediatric SLE.

Predictor Factors for Chronicity in Immune Thrombocytopenic Purpura in Children.

(1) Background: Immune thrombocytopenia (ITP) is an acute autoimmune blood disorder that is the main cause of thrombocytopenia in children. It is characterized by a decrease in platelets below 100 × 109/L, and limited evolution with severe complications such as intracranial hemorrhage. The chronic form is defined by the persistence of thrombocytopenia more than 12 months after diagnosis. (2) Methods: We performed a retrospective study over a period of 10 years (1 January 2011-31 December 2020) at the Emergency Clinical Hospital for Children "Sf. Maria", Iasi. The aim of the study was to describe the clinical characteristics and to determine the prognostic factors in immune thrombocytopenia in children. (3) Results: In this study we included 271 children with ITP, comprising 123 females (45.4%) and 148 males (54.6%). The remission rate was higher in males, being 68.9% compared to 56.1% in females. Children with ITP under 9 years of age had a higher remission rate. Children with a platelet count > 10 × 109/L at diagnosis had a higher likelihood-of-remission rate compared to patients who presented initial platelet count below this value. (4) Conclusions: The risk factors highly suggestive for chronicity are: age at diagnosis, female sex, and the number of platelets at the onset of the disease.

Pitfalls of Thrombotic Microangiopathies in Children: Two Case Reports and Literature Review.

Thrombotic microangiopathy can present itself in the form of several clinical entities, representing a real challenge for diagnosis and treatment in pediatric practice. Our article aims to explore the evolution of two rare cases of pediatric thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS) with extremely similar clinical pictures, which, coincidentally, presented at approximately the same time in our hospital. These cases and our literature review demonstrate the multiple facets of thrombotic microangiopathy, which can produce various determinations and salient manifestations even among the pediatric population. TTP and aHUS may represent genuine diagnostic pitfalls through the overlap of their clinical and biological findings, although they develop through fundamentally different mechanisms that require different therapeutic approaches. As a novelty, we underline that COVID-19 infection cannot be excluded as potential trigger for TTP and aHUS in our patients and we predict that other reports of such an association will follow, raising a complex question of COVID-19's implication in the occurrence and evolution of thrombotic microangiopathies. On this matter, we conducted literature research that resulted in 15 cases of COVID-19 pediatric infections associated with either TTP or aHUS. Taking into consideration the morbidity associated with TTP and aHUS, an elaborate differential diagnosis and prompt intervention are of the essence.

A 10-year retrospective single-center study of alpha-fetoprotein and beta-human chorionic gonadotropin in Romanian children with (para)gonadal tumors and cysts.

OBJECTIVES: Malignant tumor is a top-ranking cause of pediatric (>1-year) mortality in America and Europe. Among pediatric tumors, germ cell tumors (GCT) and gonadal tumors rank fourth (6%) by the Surveillance, Epidemiology, and End Results (SEER) program (seer.cancer.gov). Continuous research on tumor markers harnesses their full potential in tumor detection and management. We evaluated the effectiveness of beta-human chorionic gonadotropin (ß-hCG) and Alpha-fetoprotein (AFP) in Romanian children with (para)gonadal tumors and cysts, determining their accuracy in detecting malignancy, tumor-type, stage, complications, prognosis, and treatment response. METHODS: A 10-year retrospective study of AFP and ß-hCG in 134 children with cysts and (para)gonadal tumors aged one month to 17 years was performed. RESULTS: AFP/ß-hCG was unelevated in patients with cysts and nonmalignant tumors. Forty-eight/86 patients (43 GCT and 5 non-GCT) with malignant tumors had elevated AFP/ß-hCG, 3/48 patients had recurrences, and 25/48 had mixed-GCT (68% had elevated AFP + ß-hCG). All 30 patients with Yolk sac tumors (YST) or their components had elevated AFP. Area under the curve, sensitivity and specificity for GCT were: AFP + ß-hCG- 0.828, 67.2%, 100%; AFP- 0.813, 64.1%, 100%; and ß-hCG- 0.664, 32.8%, 100%. Two patients whose AFP/ß-hCG levels remained elevated died. Common mixed-GCT components were YST-80% and embryonal carcinoma-72%. Thirty of 34 metastasis cases were GCT, with 26/34 patients having elevated AFP/ß-hCG. CONCLUSIONS: AFP/ß-hCG detects malignant GCT and can determine tumor-type. GCT patients with markedly elevated AFP + ß-hCG had poor prognosis, especially if recurrence or metastasis was present. Recurrence is unrelated to elevated AFP/ß-hCG. The tumor components and quantity present determine AFP/ß-hCG values in mixed-GCT.

The Relationship between Anemia and Helicobacter Pylori Infection in Children.

(1) Background: Many studies suggest that Helicobacter pylori (H. pylori) infection is associated with a higher prevalence of anemia. The aim of this study is to explore this fact for a pediatric population from the northeast of Romania; (2) Methods: A correlational retrospective study between infection with H. pylori and anemia was performed on a group of 542 children in a pediatric gastroenterology regional center in Northeast Romania; (3) Results: Out of 542 children with confirmed H. pylori infection, microcytic hypochromic anemia was present in 48 children, of whom 7 (14.5%) also had iron deficiency.; (4) Conclusions: The study results demonstrate a significant association of H. pylori infection with iron-deficiency anemia and iron deficiency in children in accordance with the results established in the published literature. Although the direct relationship between them it is not clear yet, prevention represents one of the first clinical measures that need to be implemented when encountering a refractory moderate to severe iron-deficiency anemia and, especially, when associated with gastrointestinal tract symptoms.

Current Antithrombotic Therapy Strategies in Children with a Focus on Off-Label Direct Oral Anticoagulants-A Narrative Review.

(1) Background: The incidence of thromboembolic events is relatively low in the general population, but it increases in hospitalized children and those who underwent thrombogenic procedures. Although the evidence regarding direct oral anticoagulants (DOACs) in children with venous thromboembolism (VTE) is growing, DOACs were excluded from existing guidelines due to the lack of reliable data at that moment. Therefore, current evidence on VTE management in children needs to be critically reviewed. (2) Methods: We have conducted a literature search in the Scopus, EMBASE, and MEDLINE databases using prespecified keywords to retrieve studies published between 2010 and 2022. (3) Results: Clinical trials highlighted that rivaroxaban and dabigatran had predictable pharmacokinetic and pharmacodynamic profiles in children, similar to those observed in adults. Dabigatran and rivaroxaban had a similar safety profile to standard therapy but improved thrombotic burden and resolution during follow-up. Most studies involving apixaban and edoxaban are ongoing, and results are awaited. (4) Conclusions: Dabigatran and rivaroxaban could be valid therapeutic options for VTE management in children. In the case of apixaban and edoxaban, results from ongoing clinical studies are required before using them in pediatric VTE.

Challenges in the Pharmacotherapeutic Management of Pediatric Asthma.

Bronchial asthma is one of the most common chronic conditions in pediatric practice, with increasing prevalence hampered by poor socioeconomic impacts, leading to major public health issues. Considered as a complex heterogeneous syndrome, not a single disease, the management of the disease is a real challenge, impacting medical staff, patients and caregivers. Over the decades, a significant number of diagnostic and treatment regimen have been developed to achieve good standards, sustaining balanced control of the disease. This paper attempts a review on the establishment of new trends in the management of bronchial asthma in the pediatric age group.

Acute Otitis Media in Children-Challenges of Antibiotic Resistance in the Post-Vaccination Era.

Acute otitis media (AOM) is a leading cause of antibiotic prescriptions in children worldwide, even in the era of pneumococcal conjugate vaccines. We aimed to assess the bacterial spectrum of AOM in children and to investigate the antimicrobial resistance profile in culture-positive cases. We performed a retrospective, tympanocentesis-based analysis of antimicrobial resistance patterns in children with AOM hospitalized in "St Mary" Emergency Hospital for Children Iasi, Romania, between January 2013 and December 2021. A total of 147 samples have been assessed, 97 (65.98%) of which had positive cultures, with Streptococcus pneumoniae and Haemophilus influenzae as the most common microorganisms. A worrying proportion, 82.85% (58/70), of the Streptococcus pneumoniae strains were multidrug-resistant. The World Health Organization included Streptococcus pneumoniae and Haemophilus influenzae on the medium priority group due to penicillin non-susceptibility and ampicillin-resistant strains, respectively. Consequently, strategies to address the threats of antimicrobial resistance are needed to reduce the potential negative effects on hospitalization costs.

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.

Non-Cardiac Cause of Death in Selected Group Children with Cardiac Pathology: A Retrospective Single Institute Study.

BACKGROUND: Pediatricians and pediatric surgeons often face children with cardiomegaly and dilatative or hypertrophic cardiomyopathies presenting with or without symptoms. Some of these patients have already been diagnosed and received medication, and some present with completely unrelated pathologies. METHODS: We performed a 4-year retrospective study on the causes and mechanisms of death of children with cardiac pathology who died outside the cardiology clinic of our hospital by studying the hospital charts and necropsy reports. All children who were in this situation in our hospital were included. RESULTS: Most children in our study group were infants (81.82%), most were boys (81.82%), and in most cases, the cause or mechanism of death was unrelated to their heart condition, whether it had already been diagnosed or not (one case probably died as a result of a malignant ventricular arrhythmia). Additionally, 27.27% of children died as a consequence of bronchopneumonia, the same percentage died as a consequence of an acquired non-pulmonary disease or after surgery, and 18.18% died as a consequence of congenital malformations. CONCLUSIONS: Cardiac disease needs to be thoroughly investigated using multiple tools for all children presenting with heart failure symptoms, those with heart murmurs, and children scheduled for surgery of any type. The intensive care specialist and surgeon need to be aware of any heart pathology before non-cardiac surgical interventions.