ST2 and Reg3α: Can they predict aGvHD, steroid refractoriness and transplant-related mortality in pediatric patients after HSCT?

BACKGROUND/AIM: There are several complications of hematopoietic stem cell transplantation. Without any doubt, most important of these is aGvHD that increases transplant-related mortality. The aim of this study is to investigate whether ST-2 and Reg3α levels measured at an early stage in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation can be individual biomarkers identifying future GvHD and predicting treatment response. MATERIALS AND METHODS: From January 2019 to January 2021, 27 patients undergoing hematopoietic stem cell transplantation for primary immunodeficiency or hematopoietic diseases formed the study group. During their follow-up, the patients were classified into two groups as those developing and those not developing aGvHD. Nineteen healthy volunteers from a similar age group who needed their blood samples drawn for other reasons and who did not have any history of chronic disease, infection or medication use formed the control group. Blood samples of patients scheduled to have allogeneic HSCT were obtained before the administration of the preparative regimen, on Day +7 post-transplant and on the day of diagnosis if they developed aGvHD. Serum samples were stored at -20ºC until the day of processing. ST2 and Reg3α levels were measured using the ELISA method. RESULTS: For patients who developed aGvHD (n = 13), ST2 levels obtained before the transplantation, on Day +7 post-transplant and on the day of aGvHD diagnosis (in patients developing GvHD) were significantly higher compared to the healthy Control Group (p-value <0.05). As regards to the samples obtained on the same days, ST2 levels did not differ significantly among patients who developed and those who did not develop GvHD (n = 14; p-value >0.05). ST2 levels of samples obtained on the days that acute skin and gastrointestinal tract GvHD developed did not differ significantly between these two groups (p-value >0.05). Reg3α levels of the pre-transplant samples, on Day +7 after the transplantation and on the day of aGvHD diagnosis did not show any difference between any of the groups (p-value >0.05). As only two patients died after transplantation, thus correlation of ST2 and Reg3α levels with transplant-related mortality could not be proven. CONCLUSION: The results of this study suggest that ST2 and Reg3α levels are neither diagnostic nor prognostic or predictive biomarkers of aGvHD, steroid resistance or transplant-related mortality in pediatric patients. This study can be regarded as a pilot study because of the small patient population; more research involving a larger patient population is required.

Evaluation of the genotoxicity, cytotoxicity, and bioactivity of calcium silicate-based cements.

BACKGROUND: As calcium silicate-based cements (CSCs) have found success in various vital pulp therapy applications, several new CSC products have emerged. This study aimed to assess the genotoxicity, cytotoxicity, and bioactivity of four CSCs by comparing the newly introduced materials Bio MTA+ and MTA Cem with previously studied materials, Biodentine and NeoMTA. METHODS: Genotoxicity was evaluated using the micronucleus (MN) assay in human peripheral blood lymphocyte cells, measuring MN frequency and nuclear division index (NDI). Cytotoxicity was assessed in human dental pulp stem cells through the Water-Soluble Tetrazolium Salt-1 (WST-1) colorimetric assay. Bioactivity was determined by ELISA, measuring the levels of angiogenic and odontogenic markers (BMP-2, FGF-2, VEGF, and ALP). Statistical analyses included ANOVA, Dunnet and Sidak tests, and Wald chi-square test. (p < .05). RESULTS: The MN frequency in the groups was significantly lower than that in the positive control group (tetraconazole) (p < .05). NDI values decreased with increasing concentration (p < .05). Bio MTA+ and NeoMTA showed decreased cell viability at all concentrations in 7-day cultures (p < .01). All materials increased BMP-2, FGF-2, and VEGF levels, with Biodentine and NeoMTA showing the highest levels of BMP-2 and FGF-2 on day 7. Biodentine displayed the highest VEGF levels on day 7. Biodentine and NeoMTA groups exhibited significantly higher ALP activity than the Bio MTA+ and MTA Cem groups by day 7. CONCLUSION: Bio MTA+ and MTA Cem demonstrated no genotoxic or cytotoxic effects. Moreover, this study revealed bioactive potentials of Bio MTA+ and MTA Cem by enhancing the expression of angiogenic and osteogenic growth factors.

Thalassemia patients in transfussion dependent period and after hematopoietic stem cell transplantation: how are the psychiatric status and life quality of these patients?

Although hematopoietic stem cell transplantation (HSCT) has been widely used to treat patients with beta-thalassemia major, evidence showing whether this treatment improves mental health, self esteem and health-related quality of life (HRQoL) is limited. We aimed to describe psychiatric problems, HRQoL and self-esteem scores of patients who have thalassemia and compared with patients who underwent HSCT in the current study. A total of 24 patients with thalassemia major and 13 patients who underwent HSCT at least 2 years ago aged between 7-37 years were included. We used The Children's Depression Inventory, The Spielberger State-Trait Anxiety Inventory, and Pediatric Quality of LifeTM (PedsQL™) for assesment of children and Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), World Health Organization Quality of Life Scale Brief Version (WHOQOL-BREF) for assessment of adults. We also used Piers Harris Self Concept Scale for children and adults. Psychopathologies are common in both groups (50% in Thalassemia group and 69.2% in HSCT group). Popularity scores in Piers Haris scale of patients in HSCT group were significantly higher compared to thalassemia group (p = 0.03). Additionally, HSCT group had higher scores in physical health subscales of HRQoL in both children and parents'(p = 0.02, p = 0.03 respectively). Our findings suggest improved HRQoL and self-esteem in thalassemia patients after HSCT. However, due to the high prevalence of mental disorders in both groups, we would like to emphasize that clinicians should examine not only the physical but also the psychological state of the patients with thalessemia during the their treatment and follow-up period after HSCT.

Patterns and Grading of Gastrointestinal Graft-Versus-Host Disease: A Clinicopathologic Correlation Study.

BACKGROUND: The present study investigated gastrointestinal involvement patterns of acute graft-versus-host disease and assessed the correlation of pathologic severity with clinical grading. METHODS: Pathology reports of gastrointestinal (GI) endoscopic biopsies taken from 164 post-hematopoietic stem cell transplant patients with at least 1 endoscopic gastrointestinal biopsy diagnosed as "consistent with acute graft-versus-host disease" between 2005 and 2019 were retrieved from the automated hospital database. Endoscopic, pathologic and clinical gradings were performed using Freiburg criteria, Lerner and modified Seattle-Glucksberg grading systems, respectively. RESULTS: The majority of the patients (n = 140, 85.4%) were investigated with more than one biopsy from various gastrointestinal sites with a total of 479 biopsies: 44 (9.2%) esophagus, 90 (18.8%) stomach, 91 (19.0%) duodenum, 20 (4.2%) terminal ileum, 32 (6.7%) right colon, 87 (18.2%) left colon and, 115 (23.9%) rectum. Overall, lower gastrointestinal (n = 118/126, 93.6%) and upper gastrointestinal (n = 91/97, 93.8%) involvements were similar (P = .3). While the most severely affected site was duodenum (P = .021) in upper gastrointestinal, pathologic grades were similar in lower gastrointestinal sites, though more severe than upper gastrointestinal (P = .003). Pathologic grading had a low positive correlation with both clinical (r = 0.308, P = .001) and endoscopic grading (coefficient: 0.261, P = .003). CONCLUSION: Considering the similar graft-versus-host disease frequency of upper and lower gastrointestinal tract, distal colon evaluation with rectosigmoidoscopy seems to be a practical approach in patients with suspected gastrointestinal graft-versus-host disease. As it was positively correlated with both endoscopic and clinical grade, pathologic grading should be performed in these patients to assess gastrointestinal involvement patterns.

The Determining Factors for Outcome of Pediatric Intensive Care Admitted Children After Stem Cell Transplantation.

INTRODUCTION: Requiring pediatric intensive care unit (PICU) admission relates to high mortality and morbidity in patients who received hematopoietic stem cell transplantation (HSCT). In this study, we aimed to evaluate the indications for PICU admission, treatments, and the determining risk factors for morbidity and mortality in patients who had allogeneic HSCT from various donors. MATERIALS AND METHODS: In this retrospective study, we enrolled to patients who required the PICU after receiving allogeneic HSCT at our Pediatric Bone Marrow Transplantation Unit between 2005 and 2020. We evaluated to indication to PICU admission, applications, mortality rate, and the determining factors to outcomes. RESULTS: Thirty-three (7%) patients had 47 PICU admissions and 471 patients underwent bone marrow transplantation during 16-year study period. Also, 14 repeated episodes were registered in 9 different patients. The median age of PICU admitted patients was 4 (0.3 to 18) years and 29 (62%) were male. The main reasons for PICU admission were a respiratory failure, sepsis, and neurological event in 20, 8, and 7 patients, respectively. The average length of PICU stay was 14.5 (1 to 80) days, 14 (43%) of patients survived and the mortality rate was 57%. Multiple organ failure ( P =0.001), need for respiratory support ( P =0.007), inotrope agents ( P =0.001), and renal replacement therapy ( P =0.013) were found as significant risk factors for mortality. CONCLUSIONS: Allogeneic HSCT recipients need PICU admission because of its related different life-threatening complications. But there is a good chance of survival with quality PICU care and different advanced organ support methods.

Pediatric Invasive Aspergillosis: a Retrospective Review of 59 Cases.

Invasive aspergillosis (IA) is a major cause of morbidity and mortality. This study aimed to present our 10-year IA experience at a single center. Fifty-nine pediatric patients with IA were included in this study. The male-to-female ratio was 42/17. The median age was 8.75 years. Hematologic malignancy was present in the majority of the patients (40/59, 68%). The mean neutropenia duration was 18.5 days. Cytosine arabinoside was the most common immunosuppressive therapy directed at T cells during IA diagnosis. IA cases were categorized as proven (27%), probable (51%), or possible (22%) according to the 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. The lungs (78%) were the most common site of IA, and nodules were the most frequent radiological findings (75.5%). In 38 patients (64.4%) receiving antifungal prophylaxis, prophylactic agents included fluconazole (30.5%), liposomal amphotericin B (23.7%), posaconazole (8.5%), and voriconazole (1.7%). Initial treatment was most commonly administered as monotherapy (69.5%). The median antifungal treatment duration was 67 days. Eleven deaths (18.6%) were due to aspergillosis. With the increased use of corticosteroids, biological agents, and intensive immunosuppressive chemotherapy, IA will most likely continue to occur frequently in pediatric patients.

Thalassemia-free and graft-versus-host-free survival: outcomes of hematopoietic stem cell transplantation for thalassemia major, Turkish experience.

We report the national data on the outcomes of hematopoietic stem cell transplantation (HSCT) for thalassemia major (TM) patients in Turkey on behalf of the Turkish Pediatric Stem Cell Transplantation Group. We retrospectively enrolled 1469 patients with TM who underwent their first HSCT between 1988 and 2020 in 25 pediatric centers in Turkey. The median follow-up duration and transplant ages were 62 months and 7 years, respectively; 113 patients had chronic graft versus host disease (cGVHD) and the cGVHD rate was 8.3% in surviving patients. Upon the last visit, 30 patients still had cGvHD (2.2%). The 5-year overall survival (OS), thalassemia-free survival (TFS) and thalassemia-GVHD-free survival (TGFS) rates were 92.3%, 82.1%, and 80.8%, respectively. cGVHD incidence was significantly lower in the mixed chimerism (MC) group compared to the complete chimerism (CC) group (p < 0.001). In survival analysis, OS, TFS, and TGFS rates were significantly higher for transplants after 2010. TFS and TGFS rates were better for patients under 7 years and at centers that had performed over 100 thalassemia transplants. Transplants from matched unrelated donors had significantly higher TFS rates. We recommend HSCT before 7 years old in thalassemia patients who have a matched donor for improved outcomes.

Evaluation of the predictors of oral health-related quality of life among 3-5-year-old children with dental trauma

Abstract This study evaluated the influence of socio-demographic, clinical, and parental psychological factors on oral health-related quality of life (OHRQoL) and determined their predictors in preschool-aged children with traumatic dental injury (TDI). The study sample consisted of 324 dyads of children and their parents attending the Clinics of Pediatric Dentistry at Istanbul University. After clinical examination, the Sense of Coherence (SOC), Generalized Self-Efficacy Scale, Early Childhood Oral Health Impact Scale, and Multidimensional Health Locus of Control Scale-MHLC questionnaires were administered to the parents. The statistical analyses included Spearman correlation coefficients, Mann-Whitney U tests, Kruskal-Wallis tests, multiple linear regression, and confirmatory factor analysis. Having mixed TDI, a non-nuclear family, fewer children, and weak parental SOC were important predictors of worse overall OHRQoL and its sections of child and family. Lower internal health locus of control and dental pain due to TDI were predictors of worse overall OHRQoL and child impact, respectively. Consideration of these predictors may help oral health professionals to develop prevention and treatment programs for TDI and oral health literacy programs for families.

Ocular Findings of Pediatric Dry Eye Related to Graft-Versus-Host Disease

Objectives: To evaluate the frequency and findings of dry eye associated with ocular graft-versus-host disease (GVHD) in pediatric hematopoietic stem cell transplantation (HSCT) patients. Materials and Methods: Retrospectively the records of pediatric patients with ocular GVHD were evaluated and ophthalmologic examination findings as well as Schirmer test results, tear film break-up time, and corneal staining grades were recorded. In severe dry eye patients topical cyclosporine-A was prescribed and the results were evaluated. Results: GVHD was detected in 51 (23.4%) of 218 HSCT patients, 4 of whom died during follow-up. Thirty (63.8%) of the remaining 47 patients had chronic ocular GVHD and 4 patients with severe dry eye were treated with topical cyclosporine-A with a median follow-up of 12.1 months. Severe dry eye symptoms and findings significantly improved in 2 patients. However, 1 patient had to stop treatment due to side effects. Conclusion: In children, chronic ocular GVHD is a common finding of GVHD after HSCT. Therefore, these patients should be examined periodically for dry eye.

Tissue Plasminogen Activator Use in Pediatric Patients: A Single Center Experience.

INTRODUCTION: Thrombosis is rare in children and antithrombolytic treatment is controversial. Most commonly used thrombolytic agent is tissue plasminogen activator (t-PA) in pediatrics. In this study, we report our experience in the use of thrombolytic treatment. METHODS: Eighteen patients who had received systemic t-PA between January 2006 and December 2013 were recorded. The response to t-PA was evaluated as complete, partial, and no. The bleeding complication during t-PA administration was graded as minor or major. RESULTS: There were 18 patients (2 mo to 12 y) who received systemic t-PA. Three patients had venous, 14 patients had arterial, and 1 patient had intracardiac thrombosis. Thrombosis was related to cardiac catheterization (61.1%), central venous catheterization (16.7%), cardiac surgery (11.1%), and arrhythmia (5.5%). In 1 patient thrombosis occurred spontaneously (5.5%). Eighteen patients received 25 courses of systemic t-PA (0.15 to 0.3 mg/kg/h). A total of 55.6% of cases had complete, 27.8% had partial, and 16.6% showed no resolution. CONCLUSION: t-PA infusion at doses of median 0.2 mg/kg/h (0.15 to 0.3) seems effective and safe. There is still no consensus on indications and dosing of antithrombolytic treatment in children but in selected patients it decreases long-term complications due to thrombosis.

A Novel PUS1 Mutation in 2 Siblings with MLASA Syndrome: A Review of the Literature.

ABSTRACT: Myopathy, lactic acidosis, and sideroblastic anemia (MLASA) is a rare mitochondrial disorder characterized by MLASA. Variable features of this condition include failure to thrive, and developmental delay or intellectual disability. Additional symptoms consist of cognitive impairment, skeletal and dental abnormalities, delayed motor milestones, cardiomyopathy, dysphagia, and respiratory insufficiency. MLASA has previously been associated with mutations in pseudouridylate synthase 1 (PUS1) and YARS2. PUS1 encodes the nuclear PUS1 enzyme, which is located in both the nucleus and the mitochondria. PUS1 converts uridine into pseudouridine in several cytosolic and mitochondrial transfer RNA positions and increases the efficiency of protein synthesis in both compartments.In the present report, we report on 2 Turkish sisters 4 and 11 of years with an MLASA plus phenotype. Both patients have sideroblastic anemia, lactic acidosis, failure to thrive, developmental delay, and chronic diarrhea; in addition, the older sister has strabismus and skeletal anomalies. The sequencing of the PUS1 gene revealed a novel homozygous p.Glu311* mutation. The phenotype of the older sibling is also unique because of the strabismus and skeletal anomalies, when compared with her sister and other previously reported patients with MLASA. The structural differences in the nuclear versus mitochondrial isoforms of PUS1 and modifier genes may be implicated in the variability of the clinical presentations in MLASA. CONCLUSION: This report adds to the growing number of mutations causing complex clinical manifestations of MLASA including lactic acidosis, sideroblastic anemia, chronic diarrhea, and myopathy.

Nosocomial pneumonia caused by water-born Legionella pneumophila in a pediatric hematopoietic stem cell transplantation recipient for thalassemia major.

BACKGROUND: Nosocomial pneumonia caused by Legionella pneumophila serogroup 2-14 occurred in a 7-year-old patient following allogeneic hematopoietic stem cell transplantation for thalassemia major. CASE: The patient was diagnosed with nosocomial Legionella pneumophila by polymerase chain reaction (PCR) examination of the bronchoalveolar lavage and culturing Legionella pneumophila serogroup 2-14 from the patient`s room faucet water. Legionella pneumophila was eradicated from our hospital`s water distribution system by superheating and chemical eradication methods (hyper-chlorination and hydrogen peroxide). We did not detect any other case after this event. CONCLUSION: Early recognition of contamination of the hospital water system with Legionella proves the importance of prevention in new cases.

Bloodstream infections in pediatric hematology/oncology patients: Six years' experience of a single center in Turkey

Background/aim: Bloodstream infections are the major cause of morbidity, increased cost, prolonged hospitalization, and mortality in pediatric patients. Identifying the predominant microorganisms and antimicrobial susceptibilities in centers helps to select effective empirical antimicrobials which leads to positive clinical outcomes. We aimed to identify the causative microorganisms and their antimicrobial susceptibilities in patients with bloodstream infections. Materials and methods: Data belonging to patients with hematological and/or oncological diseases admitted to our hospital with fever between January 2010 and November 2015 were analyzed. Results: In total, 71 patients who had 111 bloodstream infection episodes were included. Responsible pathogens were detected as follows: 35.1% gram-positive microorganisms, 60.5% gram-negative bacteria, and 4.4% fungi. The most common causative gram-negative pathogen was Escherichia coli and the most commonly isolated gram-positive microorganism was coagulase-negative staphylococci. Conclusion: Gram-negative microorganisms were predominant pathogens in bloodstream infections. Escherichia coli and coagulase-negative staphylococci were the most commonly isolated responsible pathogens. Beta-lactam/lactamase inhibitors were suitable for empirical treatment. However, in critical cases, colistin could have been used for empirical treatment until the culture results were available. Routine glycopeptide use was not required. By identifying the causative microorganisms and their antimicrobial resistance patterns, it will be possible to obtain positive clinical results.

Risks and outcomes of invasive fungal infections in pediatric allogeneic hematopoietic stem cell transplant recipients receiving fluconazole prophylaxis: a multicenter cohort study by the Turkish Pediatric Bone Marrow Transplantation Study Group.

Invasive fungal infections (IFIs) are a major cause of infection-related morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Data from pediatric settings are scarce. To determine the incidence, risk factors and outcomes of IFIs in a 180-day period post-transplantation, 408 pediatric patients who underwent allogeneic HSCT were retrospectively analyzed. The study included only proven and probable IFIs. The cumulative incidences of IFI were 2.7%, 5.0%, and 6.5% at 30, 100, and 180 days post-transplantation, respectively. According to the multivariate analysis, the factors associated with increased IFI risk in the 180-day period post-HSCT were previous HSCT history (hazard ratio [HR], 4.57; 95% confidence interval [CI] 1.42-14.71; P = .011), use of anti-thymocyte globulin (ATG) (HR, 2.94; 95% CI 1.27-6.80; P = .012), grade III-IV acute graft-versus-host-disease (GVHD) (HR, 2.91; 95% CI 1.24-6.80; P = .014) and late or no lymphocyte engraftment (HR, 2.71; 95% CI 1.30-5.62; P = .007). CMV reactivation was marginally associated with an increased risk of IFI development (HR, 1.91; 95% CI 0.97-3.74; P = .063). IFI-related mortality was 1.5%, and case fatality rate was 27.0%.The close monitoring of IFIs in pediatric patients with severe acute GVHD who receive ATG during conditioning is critical to reduce morbidity and mortality after allogeneic HSCT, particularly among those with prior HSCT and no or late lymphocyte engraftment.

Aromatase inhibition by 2-methyl indole hydrazone derivatives evaluated via molecular docking and in vitro activity studies.

A causal association is reported between prolonged exposures to elevated levels of estrogen and breast cancer. Therefore inhibiting aromatase (CYP19A), which catalyses the conversion of androgens to estrogens, is an important approach in prevention and treatment of estrogen receptor positive (ER+) breast cancer. Melatonin, a natural indolic hormone, is reported to prevent free radical induced carcinogenesis and block local estrogen synthesis in breast tissue via aromatase inhibition. However several features of melatonin limit its therapeutic use. In the present study aromatase inhibiting potential of 2-methyl indole hydrazones are investigated, and compared with melatonin, by two in vitro models; a cell-free assay using a fluorescence substrate and a cell-based assay where cell proliferation was determined in ER + human breast cancer cells (MCF-7 BUS) in the absence of estrogen and the presence of testosterone. Aromatase inhibitory effect is also explored by molecular modelling studies. In biological activity assays monochloro substituted indole hydrazones were found to have stronger aromatase inhibitory activity among all tested derivatives and were more active than melatonin. This finding is further confirmed by molecular modelling. These results may be useful in the design and synthesis of novel melatonin analogues with higher inhibitory potency against aromatase.

Is antibiotic lock therapy effective for the implantable longterm catheter-related bloodstream infections in children?

Tural Kara T, Özdemir H, Erat T, Yahsi A, Aysev AD, Taçyildiz N, Ünal E, Ileri T, Ince E, Haskologlu S, Çiftçi E, Ince E. Is antibiotic lock therapy effective for the implantable long-term catheter-related bloodstream infections in children? Turk J Pediatr 2019; 61: 895-904. Catheter-related bloodstream infections (CRBSIs) are an important problem in pediatric patients with central venous catheters. This study aimed to determine the incidence of CRBSIs, responsible pathogens and outcomes of antibiotic lock treatment (ALT) in pediatric patients. Between January 2010 and November 2015 all hospitalized pediatric hematology, oncology and immunology patients diagnosed with CRBSIs were retrospectively analyzed. Seventy-eight CRBSI episodes were detected in 60 pediatric patients. The incidence of CRBSIs was 4.20/1000 catheter days. The most frequently detected pathogen was methicillin-resistant coagulase-negative Staphylococcus. Pseudomonas aeruginosa, Klebsiella spp., and Escherichia coli were other commonly isolated microorganisms. ALT was administered in 42 patients. The success rate of ALT was 81% (34/42). Catheter was removed without ALT in 36 episodes. Common reasons for catheter removal were sepsis and causative microorganisms which had high probability of biofilm formation. CRBSIs are an important cause of morbidity and mortality in pediatric patients. ALT is safe and effective. It is possible to obtain satisfactory results when ALT is used with intravenous systemic antibiotics for CRBSIs, though in some cases catheter removal is necessary. ALT helps to prevent unnecessary catheter removal in pediatric patients.

SLCO1B1 Polymorphisms are Associated With Drug Intolerance in Childhood Leukemia Maintenance Therapy.

BACKGROUND: Therapy discontinuations and toxicities occur because of significant interindividual variations in 6-mercaptopurine (6-MP) and methotrexate (MTX) response during maintenance therapy of childhood acute lymphoblastic leukemia (ALL). 6-MP/MTX intolerance in some of the patients cannot be explained by thiopurine S-methyl transferase (TPMT) gene variants. In this study, we aimed to investigate candidate pharmacogenetic determinants of 6-MP and MTX intolerance in Turkish ALL children. METHODS: In total, 48 children with ALL who had completed or were receiving maintenance therapy according to Children's Oncology Group (COG) protocols were enrolled. Fifteen single-nucleotide polymorphisms in 8 candidate genes that were related to drug toxicity or had a role in the 6-MP/MTX metabolism (TPMT, ITPA, MTHFR, IMPDH2, PACSIN2, SLCO1B1, ABCC4, and PYGL) were genotyped by competitive allele-specific PCR (KASP). Drug doses during maintenance therapy were modified according to the protocol. RESULTS: The median drug dose intensity was 50% (28% to 92%) for 6-MP and 58% (27% to 99%) for MTX in the first year of maintenance therapy, which were lower than that scheduled in all patients. Among the analyzed polymorphisms, variant alleles in SLCO1B1 rs4149056 and rs11045879 were found to be associated with lower 6-MP/MTX tolerance. CONCLUSIONS: SLCO1B1 rs4149056 and rs11045879 polymorphisms may be important genetic markers to individualize 6-MP/MTX doses.

Juvenile Myelomonocytic Leukemia in Turkey: A Retrospective Analysis of Sixty-five Patients.

OBJECTIVE: This study aimed to define the status of juvenile myelomonocytic leukemia (JMML) patients in Turkey in terms of time of diagnosis, clinical characteristics, mutational studies, clinical course, and treatment strategies. MATERIALS AND METHODS: Data including clinical and laboratory characteristics and treatment strategies of JMML patients were collected retrospectively from pediatric hematology-oncology centers in Turkey. RESULTS: Sixty-five children with JMML diagnosed between 2002 and 2016 in 18 institutions throughout Turkey were enrolled in the study. The median age at diagnosis was 17 months (min-max: 2-117 months). Splenomegaly was present in 92% of patients at the time of diagnosis. The median white blood cell, monocyte, and platelet counts were 32.9x109/L, 5.4x109/L, and 58.3x109/L, respectively. Monosomy 7 was present in 18% of patients. JMML mutational analysis was performed in 32 of 65 patients (49%) and PTPN11 was the most common mutation. Hematopoietic stem cell transplantation (HSCT) could only be performed in 28 patients (44%), the majority being after the year 2012. The most frequent reason for not performing HSCT was the inability to find a suitable donor. The median time from diagnosis to HSCT was 9 months (min-max: 2-63 months). The 5-year cumulative survival rate was 33% and median estimated survival time was 30±17.4 months (95% CI: 0-64.1) for all patients. Survival time was significantly better in the HSCT group (log-rank p=0.019). Older age at diagnosis (>2 years), platelet count of less than 40x109/L, and PTPN11 mutation were the factors significantly associated with shorter survival time. CONCLUSION: Although there has recently been improvement in terms of definitive diagnosis and HSCT in JMML patients, the overall results are not satisfactory and it is necessary to put more effort into this issue in Turkey.

Toxicity of Vincristine Combined With Posaconazole in Children With Acute Lymphoblastic Leukemia.

BACKGROUND: Vincristine (VCR) is one of the main drugs of acute lymphoblastic leukemia (ALL) treatment. Azole antifungal medications are used for treatment or prophylaxis of invasive fungal infections in acute leukemia. Coadministration of these drugs increases the risk of VCR toxicity. OBSERVATIONS: We presented a girl with ALL using posaconazole prophylaxis. She developed VCR toxicity that included tubulopathy, high blood pressure, neuropathic pain, difficulty walking, diffuse muscular weakness, constipation, abdominal pain. CONCLUSIONS: There are limited data in children with ALL for posaconazole prophylaxis. We recommend that VCR side effects should be evaluated by careful monitoring of the patients who are on this combination therapy.

The Role of Oxidative Stress Modulators in Breast Cancer.

BACKGROUND: Latest data from International Agency for Cancer Research shows that breast cancer is the leading cancer site in women and is the leading cause of death among female cancers. Induction of reactive oxygen species (ROS) and oxidative stress as a consequence of impaired balance between prooxidants and antioxidants are suggested to be involved in induction and progression of breast cancer. Cancer cells are found to exhibit higher levels of ROS compared to normal cells. However increased antioxidant defence which balances the oxidative status within the cancer cells suggests that high ROS levels may prevent tumorigenesis via various mechanisms. These contradictory roles of ROS and oxidative stress in breast cancer let scientists investigate potential oxidative stress modulators as anticancer strategies. CONCLUSIONS: In the present review we address the mechanisms of ROS production in breast cancer cells, the role of impaired oxidative status as well as the benefits of introducing oxidative stress modulators in therapeutic strategies in breast cancer. This review is focusing more on melatonin which we have been working on during the last decade. Our data, in accordance with the literature, suggest an important role for melatonin in breast cancer prevention and adjuvant therapy.