Targeted Treatment and Immunotherapy in High-risk and Relapsed/ Refractory Pediatric Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia is the most frequent pediatric malignancy in children, comprising 30% of all pediatric malignancies; adult ALL comprises 5% of all ALL cases, which have a 186.6 per 1 million incidence. In pediatric ALL (pALL), on which this review focuses, approximately 1 in 285 children are diagnosed with cancer before the age of 20, and approximately 1 in 530 young adults between the ages of 20 and 39 years old is a childhood cancer survivor. The survival probability in pALL is now very high, approximately 80-90%. Thus, the most important is to improve supportive care and treatment based on relapse risk, optimally being based on the genetic feature of malignant cells. Improvements made by now are mainly the classifying of subgroups based on genetic characteristics such as aneuploidy or translocation and aligning them with treatment response. Relevant genetic changes in ALL pathogenesis are transcription regulators of lymphoid development (PAX5, IKZF1, EBF1, and LEF1) and/or coactivators (TBL1XR1 and ERG), lymphoid signaling (BTLA, and CD200 TOX), and tumor suppressor genes (CDKN2A, CDKN2B, RB1, and TP53). This review aims to summarize treatment strategies inhibiting tyrosine kinases, influencing different signaling pathways, BCL inhibitors, and anti-CD therapy (anti-cluster differentiation therapy) in pALL. CAR T-cell therapy (chimeric antigen receptors T-cell therapy) is under research and requires further development.

Case Report: Identification of likely recurrent CEP290 mutation in a child with Joubert syndrome and cerebello-retinal-renal features.

Background. Joubert syndrome (JS) is a rare autosomal recessive ciliopathy with an estimated prevalence of 1 in 100,000. JS is characterized by hyperpnoea, hypotonia, ataxia, developmental delay and various neuropathological abnormalities in the brain including cerebellar hypoplasia and cerebellar vermis aplasia. JS can also have variable multi-organ involvement, including the retina, kidneys, liver, and musculoskeletal system. Methods and Results. Here we report a clinical description of two-year-old girl presenting with breathing difficulties, hyperechoic kidneys with loss of corticomedullary differentiation. Brain magnetic resonance imaging revealed the typical molar tooth sign consistent with a clinical diagnosis of JS and retinal examination showed severe retinal dystrophy leading to blindness. Molecular genetic analysis using whole exome sequencing and Sanger sequence confirmation demonstrated a homozygous mutation (c.5493delA, p.(A1832fs*19) in CEP290 which segregated from either parent and was consistent with the multisystem ciliopathy phenotype. This precise variant has been described previously in 2 families from the Kosovar-Albanian region suggesting this allele is a recurrent mutation in this population. Conclusions. Mutations in CEP290 lead to multisystem ciliopathy syndromes and molecular genetic diagnostics of such cases allows precise diagnosis, screening of at risk relatives and appropriate management.

Joubert syndrome: Molecular basis and treatment.

Joubert syndrome (JS; MIM PS213300) is a rare genetic autosomal recessive disease characterized by cerebellar vermis hypoplasia, a distinctive malformation of the cerebellum and the so-called "molar tooth sign." Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes. Such pleiotropic characteristics are typical of many disorders involving primary cilium aberrations, providing a significant overlap between JS and other ciliopathies such as nephronophthisis, Meckel syndrome, and Bardet-Biedl syndrome. This review will describe some characteristics of JS associated with changes in 35 genes, and will also address subtypes of JS, clinical diagnosis, and the future of therapeutic developments.

Type II Pleuropulmonary Blastoma in a 4 Month Old Infant with Negative Dicer1 Mutation on Next Generation Sequencing.

INTRODUCTION: Pleuropulmonary blastoma (PPB) is a rare, but aggressive tumor in the pediatric population. PPB is a dysontogenetic neoplasm of childhood that involves the lungs and/or pleura. Young relatives of children with PPB have an increased incidence of neoplasias and dysplasias. According to tumor tissue histopathology, PPB evolves from a cystic to solid state over time. PPBs can be sub-classified as type I (purely cystic), type II (having both cystic and solid elements), and type III (completely solid). Type II and type III tumors may be associated with metastasis, with the brain being the most common metastatic site. Due to the primitive nature of cells in the tumor mass, PPBs are very aggressive tumors that are resistant to therapy. The prognosis depends on the histopathology content and tumor type. Respiratory problems are the main complaint and diagnosis can be made only after additional examinations. Genetic relations through family members are associated with mutations in the DICER1 gene; between 60-80% of patients with PPBs are positive for DICER1 mutations. Mosaicism has also been reported. AIM: The aim was to present a case of a 4 month-old infant with type II PPB, who had a negative result for DICER1 mutation in next generation sequencing. To detail the clinical presentation of this patient, we present radiographic and ultrasound findings and results of histopathological analysis, as well as genetic and scintigraphic findings and chemotherapy treatment. CASE REPORT: Here we describe the genetic analysis of a patient with PPB who was negative for mutations in DICER1 and who had no relatives with disease. This patient underwent radical resection of the tumor and began therapy, but subsequently died after developing leukopenia and sepsis. CONCLUSION: This case provides an example of a patient with PPB who was negative for DICER1 mutation upon genetic analysis and emphasizes the potential for disease that does not involve mutation of this gene.

Gallbladder ascariasis in Kosovo - focus on ultrasound and conservative therapy: a case series.

BACKGROUND: Ascaris lumbricoides is one of the most common intestinal infections in developing countries, including Kosovo. In contrast to migration to the bile duct, migration of the worm to the gallbladder, due to the narrow and tortuous nature of the cystic duct, is rare. When it does occur, it incites acalculous cholecystitis. CASE PRESENTATIONS: This case series describes a 16-month-old Albanian girl, a 22-month-old Albanian girl, a 4-year-old Albanian girl, and a 10-year-old Albanian boy. Here we report our experience with gallbladder ascariasis including clinical manifestations, diagnostic procedures, and treatment. Fever, diarrhea and vomiting, dehydration, pale appearance, and weakness were the manifestations of the primary disease. In all patients, a physical examination revealed reduced turgor and elasticity of the skin. Abdomen was at the level of the chest, soft, with minimal palpatory pain. The liver and spleen were not palpable. A laboratory examination was not specific except for eosinophilia. There were no pathogenic bacteria in coproculture but Ascaris was found in all patients. At an ultrasound examination in all cases we found single, long, linear echogenic structure without acoustic shadowing containing a central, longitudinal anechoic tube with characteristic movement within the gallbladder. Edema of the gallbladder wall was suggestive of associated inflammation. There were no other findings on adjacent structures and organs. All patients received mebendazole 100 mg twice a day for 3 days. They also received symptomatic therapy for gastroenteritis. Because of elevated markers of inflammation all patients were treated with antibiotics, assuming acute cholecystitis, although ultrasound was able to confirm cholecystitis in only two of our four patients. Since the length of stay was dependent on the primary pathology it was 7 to 10 days. At control ultrasounds on 14th day, third and sixth month, all patients were free of ascariasis. CONCLUSIONS: Gallbladder ascariasis should be considered in all patients presenting with abdominal pain, distension, colic, nausea, anorexia, and intermittent diarrhea associated with jaundice, nausea, vomiting, fever, and severe radiating pain. Eosinophilia, ova, and parasites on stool examination as well as an anechogenic tube with characteristic movement within the bile duct found on abdominal ultrasound are conclusive for diagnosis. Mebendazole is an effective drug for the treatment. Surgical treatment is rarely needed.

Dental Caries Among Kosovar Children with Type 1 Diabetes Mellitus

Objective: To evaluate the oral health status in children with type 1 diabetes mellitus. Material and Methods: Dental examinations, based on World Health Organization caries diagnostic criteria for DMFT index for permanent dentition and survey were performed among 160 children, aged 10-15-year-old, divided into two groups. The first group consisted of 80 children with type 1 diabetes mellitus (41 females, 39 males), and in the second group, consisted 80 healthy children (49 females, 31 males). Frequency, odds ratio and Mann-Whitney U test were used in the statistical analyses. The level of significance was set at 5%. Results: The higher mean of the DMFT index was found among children with type 1 diabetes compared to the healthy group. The mean DMFT index for diabetic children was 6.56 ± 3.56 and for the healthy group was 4.21 ± 2.63. Moreover, the frequency of decayed teeth was higher in children with type 1 diabetes than in the healthy group. The higher risk of caries was found in diabetic children compared with healthy for 1.35 times. A higher proportion of children, 61.25% with type 1 diabetes mellitus, reported that they brush their teeth once per day, 22.50% twice per day, and 16.25% rarely. From the healthy group, 46.25% of children brush their teeth once per day, and 42.50% twice per day and 11.25% rarely brush their teeth per day. Conclusion: Diabetic children are at higher risk for caries than are healthy children.

Thrombocytopenia absent radius (TAR) syndrome.

AIM: The aim of the work was a presentation of one case with Thrombocytopenia absent radius (TAR) syndrome. METHODS: Diagnosis of TAR syndrome has been established on the basis of pedigree, laboratory findings (hemogram, platelet count, peripheral smear), bone marrow biopsy, radiological examination and karyotype. RESULTS: A patient was a two months old female child, hospitalized due petechial bleeding, upper limb anomalies and diarrhea. LABORATORY FINDINGS: red blood cell count was 2.1 x 1012/L, hemoglobin value was 62 g/L, white blood cell count indicated the existence of leukemoid reaction (40.0 x 109/L), the eosinophyle count at the leukocyte formula was increased (3%), bleeding time was prolonged (10'). The platelets at the peripheral blood smear were rarely present, whereas the megacaryocytes appeared in the bone marrow aspiration in the decreased number, or did not appear at all. At the radiological examination of the upper limbs, radius was absent in both shoulders. CONCLUSION: TAR syndrome is a rare hereditary disease. Obligatory clinical manifestations are: thrombocytopenia and bilateral absence of the radius. Prenatal diagnosis can be established during the 16th week of gestation by ultrasound and if it is continued with the pregnancy it is preferred that the platelet transfusion be given intrauterine. The mortality rate depends on the age of the patient and the platelet count.

Choice of surgical procedure for ptosis correction.

PURPOSE: the ideal procedure for ptosis management is not available until now. In many ptosis cases there is a doubt which procedure will give the best results and patient satisfaction. The aim of this paper was to present our point of view in this topic. METHOD: retrospective review and analysis of 350 ptosis cases operated by a single surgeon was done. Primary outcome measure was cosmetic appearance, secondary outcome measures includes the need for reoperation and specific complications for each operation: central picking of operated eyelid for Fasanella-Servat operation, presence and degree of lid-lag phenomenon and lagophthalmos for levator muscle resection and frontalis muscle suspension. RESULTS: 350 cases of ptosis are operated by a single consultant surgeon. Among them, Fasanella-Servat procedure was done in 119 cases (reoperation rate was 8.4%), levator muscle resection in 112 (reoperation rate was 10.7%), frontalis muscle suspension in 116 (reoperation rate was 10.3%) and Mc. Cord procedure in 3 cases. CONCLUSION: levator muscle function is a key determining factor in choosing the appropriate operating procedure for ptosis correction regardless of the degree and etiology of ptosis.