Alterations of Nutritional Status in Children and Adolescents with Acute Lymphoblastic Leukemia.

Malnutrition is often observed in pediatric cancer patients and has been recognized as a risk factor for relapse and survival. Maintaining an appropriate nutritional status during anticancer treatment has, therefore, been more and more frequently perceived as an additional requirement for optimal therapy outcomes. The aim of our study was to establish alterations of nutritional status in 26 children and adolescents treated for acute lymphoblastic leukemia (ALL) at the Children's Hospital in Zagreb, Croatia, between 2016 and 2021, by using anthropometric measures and serum albumin levels. The majority of patients (53.8% female, median 4 years, 52.2% intermediate-risk leukemia group) had normal weight at the beginning of chemotherapy. The percentage of overweight/obese patients increased from 4.2% at diagnosis to 37.5% at the end of intensive therapy. Apart from a significant increase in body weight (BW) and body mass index (BMI) for age, a notable decline in body height/body length (BH/BL) for age in the observed period was recorded, especially in high-risk leukemia patients. The alterations in serum albumin values were not significant, nor was their correlation with BMI. Dietary consultation was offered to all patients, while children with a decline in BMI and BH/BL received additional nutritional support.

Bacteriuria in Paediatric Oncology Patients: Clinical Features, Distribution and Antimicrobial Susceptibility of Bacterial Pathogens at University Hospital Centre Zagreb, Croatia over a 4-Year Period.

Bacteriuria in paediatric oncology patients have not been well studied. This retrospective study analysed clinical features, distribution and antimicrobial susceptibility of bacterial pathogens cultured from urine in paediatric oncology patients over a 4-year period (2019-2022). A total of 143 episodes of bacteriuria were documented in 74 patients. Neutropenia was present in 17.5% (25/143), symptoms in 25.9% (37/143) and urinary catheter in 7.0% (10/143) episodes. Symptomatic bacteriuria episodes were statistically significantly more frequent in patients with neutropenia (p = 0.0232). The most common bacterial pathogens were Escherichia coli (n = 49; 32.2%), Klebsiella spp. (n = 34; 22.4%), Pseudomonas aeruginosa (n = 22; 14.5%) and Enterococcus spp. (n = 21; 13.8%). Extended-spectrum ß-lactamases-producing (ESBL) Enterobacterales were found in 11 episodes (11/143; 7.7%) with the highest proportion among Klebsiella pneumoniae isolates (n = 7/34; 20.6%). No carbapenem-resistant Enterobacterales, multidrug-resistant P. aeruginosa or vancomycin-resistant Enterococcus spp. were found. The most important novelties are demonstrating P. aeruginosa as one of the prominent bacteriuria pathogens in this patient population, presence of ESBL isolates and carbapenem-resistant P. aeruginosa later during hospitalization highlights the need for appropriate antimicrobial treatment. However, because of the small number of symptomatic patients, further studies are needed to clarify the importance of including urine culture in the diagnostic process in patients with febrile neutropenia.

Bloodstream Infections in Pediatric Oncology Patients: Bacterial Pathogen Distribution and Antimicrobial Susceptibility at the University Hospital Centre Zagreb, Croatia-A 5-Year Analysis.

The epidemiology of bacterial pathogens causing bloodstream infections (BSIs) in pediatric hematology/oncology patients is changing and resistance to antimicrobial agents is globally spread. We retrospectively assessed demographic, clinical, and microbiologic data of BSIs during a 5-year period at a pediatric hematology/oncology unit from January 1, 2017, to December 31, 2021, at the University Hospital Centre Zagreb, Zagreb, Croatia. In 66 pediatric patients with malignancies, 93 BSI episodes were registered and 97 bacterial isolates were cultured. The Gram-positive versus Gram-negative ratio was 67 (69.1%) versus 30 (30.9%). Coagulase-negative staphylococci (48; 49.6%) were the most frequent isolates, followed by Enterobacterales (17; 17.5%) and Staphylococcus aureus (6; 6.2%). Multidrug resistance isolates included extended spectrum ß-lactamase producers (n=3). Resistance rates to piperacillin/tazobactam, cefepime, and meropenem in Gram-negative isolates were 15.4%, 14.3%, and 0.0%, respectively. Gram-positive bacteria are the most common cause of BSI in our patients. Resistance rates to piperacillin/tazobactam and cefepime in Gram-negative isolates make meropenem a better choice for empirical antimicrobial treatment. As national and hospital data may differ, the surveillance of pathogen distribution and antimicrobial susceptibility in pediatric hematology/oncology wards is necessary to adjust empirical treatment accordingly.

Management of Childhood Iron Deficiency Anemia in a Developed Country-A Multi-Center Experience from Croatia.

Iron deficiency anemia (IDA) continues to be a global public health concern, mostly in the developing countries. However, precise epidemiological data on childhood IDA in Croatia are lacking. In order to establish its frequency, underlying etiologies, the rationale for tertiary care visits, diagnostic practices, and current treatment regimens of IDA, medical records of children referred to pediatric hematologists for iron deficiency in a five-year period at tertiary institutions (Zagreb, Rijeka, Split, Osijek) throughout Croatia were retrospectively analyzed. Eight hundred and sixty-four children, predominately of preschool age, were referred mainly by the primary care pediatricians, who, in general, performed basic diagnostics but failed to initiate oral iron therapy in half of the patients. Approximately one-third of patients were symptomatic, with inadequate nutrition prevailing as underlying etiology. Dextriferron was the preferred iron formulation among hematologists, with a median dose of 5 mg/kg, with acceptable compliance rates (63.5-93.2%). Hospital admission rates varied among the centers (9.4-35%), and so did transfusion policies (6.4-22.9%). The greatest difference was observed in the frequency of parenteral iron administration (0.3-21.5%). In conclusion, the burden of childhood IDA, even in a high-income country, remains substantial, necessitating consistent implementation of national guidelines and additional education of primary health care providers.

Retroperitoneal Paraganglioma Treated With Tumor Resection and Replacement of the Inferior Vena Cava.

Retroperitoneal paragangliomas are tumors of neuroectodermal origin rarely appearing in the pediatric population. We report a case of a large paraganglioma infiltrating the right kidney and inferior vena cava in a 16-year-old boy who initially presented with a right-sided varicocele. Right retroperitoneal paraganglioma was embolized preoperatively, followed by total tumor excision, right nephrectomy, inferior vena cava resection, and reconstruction using a prosthetic vascular graft. Retroperitoneal tumors requiring surgery can successfully be treated by radical resection and replacement of the inferior vena cava in experienced centers.

Evaluation of a multimodal pain therapy approach with relapse prophylaxis for back pain (MMS-RFP study): a study protocol for a cluster randomised controlled trial.

INTRODUCTION: The need for an interdisciplinary multimodal approach to the treatment of back pain has already been demonstrated by various studies. However, when considering the periods of incapacity to work in the longitudinal course after the multimodal pain therapy (MPT), limits in terms of its sustainable effect become clear. Patients who receive MPT subsequently return to standard outpatient care, which is associated with a risk of relapse. A 12-month relapse prophylaxis (RP) programme, intended to follow a 4-week MPT, was developed to help patients make the transition to health-conscious and physically active behaviour in everyday life and to identify and prevent impending relapses at an early stage. The evaluation, based on a cluster randomised controlled trial, seeks to provide information on the benefits of early and intensive RP as part of MPT, examine whether it is cost effective, reduces the days of incapacity to work and increases functional capacity, as well as to examine other parameters. METHODS AND ANALYSIS: The study population comprises members of a regional statutory health insurance fund in Germany, who are ≤62 years old, gainfully employed and have been incapacitated for work for at least 21 days due to a diagnosis of back pain. Over a recruitment period of 24 months, a maximum of 368 individuals can potentially be included in the MPT. The intervention group (IG) and control group (CG) will both receive MPT, after randomisation IG will receive RP and CG will receive no further therapy or support as part of the trial. The evaluation is carried out on the following levels: structural, process and results quality. Cost effectiveness is also assessed by means of a health economic evaluation. In addition to the collection of qualitative and quantitative primary data, claims data from the regional health insurance fund are also included in the analysis. ETHICS AND DISSEMINATION: This study has received approval by the ethics committee of the Hannover Medical School (reference number: 8548_BO_S_2019). The study results will be disseminated in national and international journals and conference presentations. TRIAL REGISTRATION NUMBER: DRKS00017654.

The cost of the circadian desynchrony on the Leydig cell function.

The increased frequency of different lifestyles that disrupts circadian rhythms, together with a trend in the accretion of male idiopathic infertility, imposes the necessity to understand the contribution of circadian rhythms disruption to fertility regulation. In this study, the effects of circadian desynchrony (CD) on the steroidogenic capacity of adult Leydig cells were studied. Adult rats were housed under a disturbing light regime (2 days of constant light, 2 days of continual dark, and 3 days of 12:12 h light:dark schedule) designed to mimic shiftwork in humans. CD was characterized by changed and decreased rhythmic locomotor activity and reduced blood testosterone. In the Leydig cells changed transcription of the clock genes (Bmal1, Clock, Cry1 and Reverba/b increased while Per1/2 reversed phase) was detected. This was followed by reduced transcription of genes (Star, Cyp11a1, and Hsd3b1/2) primarily involved in mitosteroidogenesis. In parallel, mitochondrial membrane potential (Δψi) and ATP production declined losing their characteristic oscillatory pattern. Also, the main markers of mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam, Cytc), fusion (Mfn2), and mitophagy (Pink1 and Tfeb) were disturbed. Collectively, CD targets mitochondria in Leydig cells by reducing mitosteroidogenesis, mitoenergetics, and disturbing mitochondrial dynamics. These changes contribute to testosterone decline compromising androgen-dependent functions, including reproduction.

Immunohistochemical expression of cyclin-dependent kinase inhibitors p16 and p57 in rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a highly malignant cancer and is the most common soft tissue sarcoma in children and adolescents, but it is rare in adults (<1% of all adult malignancies). Altered expression and molecular abnormalities of cell-cycle-regulatory proteins are one of the most prominent features in RMS. Therefore, we evaluated the expression of cyclin-dependent kinase inhibitors p57 and p16, as well as p16 methylation status, along with clinicopathological characteristics and overall survival (OS) in RMS patients. This analysis was conducted on 23 pediatric and 44 adult patients. There was a male predominance in both groups and extremities were the most frequent tumor site. In adults, alveolar and pleomorphic types were almost equally represented. The majority of pediatric tumors were low grade, whereas, in adults, only one patient had a low-grade tumor. Seven pediatric (30.43%) and eight adult (18.18%) patients had a low p16 expression. The analysis of methylation status of the p16 promoter showed the presence of methylated allele only in one sample with pleomorphic histology. Six (26.1%) pediatric and 15 (34.1%) adult patients had low p57 expression, while in 17 (73.9%) pediatric and 29 (65.9%) adult patients it was assessed as high. Ninetyone percent of the pediatric patients and 32.6% of adults were alive at the end of the observational period. In adults, significant associations were found between OS and age (P = 0.020), gender (P = 0.027), tumor size (P < 0.001), lymph node status (P < 0.001), presence of metastases (P = 0.015), and p57 expression (P = 0.039). Stratification by histological type showed the correlation of low p57 expression (P = 0.030) and worse OS of patients with alveolar RMS. Univariate analysis identified age > 50 yrs. (HR 2.447), tumors > 5 cm (HR 21.31), involvement of regional lymph nodes (HR 3.96), the presence of metastases (HR 2.53), and low p57 expression (HR 2.11) as predictors of lower OS. Tumor size, regional lymph nodes involvement, and metastases were the independent predictors after multivariate analysis, while p57 did not predict OS in an independent way. In summary, although p57 was not confirmed to be an independent predictor of OS, our results indicate that its low expression may be the marker of aggressive phenotype and poor prognosis in adult RMS patients. Also, our findings suggest that epigenetic inactivation of p16 is not important in the pathogenesis of rhabdomyosarcoma.

Low cardiac output syndrome requiring extracorporeal membrane oxygenation following pericardiocentesis in an adolescent with Hodgkin Lymphoma: a case report.

We present a case of a 16-year-old male with large pericardial effusion due to Hodgkin Lymphoma (HL). Shortly after drainage of pericardial effusion he developed a low cardiac output syndrome which had to be treated with extracorporeal membrane oxygenation (ECMO). This 9-day ECMO support helped the patient to recover his cardiac function, and thereafter a remission of his primary disease was successfully achieved with chemotherapy. It is a matter of discussion whether a large pericardial effusion with moderate symptoms in patients with HL should be evacuated or just observed since the effusion should ameliorate with chemotherapy. But based upon our experience in this case of hemodynamic instability due to a large effusion requiring evacuation, we propose that pericardiocentesis procedure should be performed with caution at a slow drainage rate of 0.5-1 ml/kg/hour with a maximum rate of 50 ml/hour, to help avoid the low cardiac output syndrome in patients with similar disease conditions.

Synthesis, characterization, DFT calculation and biological activity of square-planar Ni(II) complexes with tridentate PNO ligands and monodentate pseudohalides. Part II.

Three square-planar complexes of Ni(II) with condensation derivative of 2-(diphenylphosphino)benzaldehyde and 4-phenylsemicarbazide and monodentate pseudohalides have been synthesized and characterized on the basis of the results of X-ray, NMR and IR spectroscopy and elemental analysis. Investigated complexes exhibited moderate antibacterial and cytotoxic activity. The most pronounced cytotoxic activity (in the range of cisplatin) to HeLa cell line was observed for ligand and all the complexes. Azido complex and ligand induced concentration dependent cell cycle arrest in the S phase, as well as decrease of percentage of cells in G1 phase, without significant increase of apoptotic fraction of cells. The interaction of the azido complex and ligand with CT-DNA results in changes in UV-Vis spectra typical for non-covalent bonding. The observed intrinsic binding constant of azido complex-CT-DNA and ligand-CT-DNA were 3.22 × 10(5) M(-1) and 2.79 × 10(5) M(-1). The results of DNA cleavage experiments showed that azido complex nicked supercoiled plasmid DNA.

[Diffuse infantile hepatic hemangioendothelioma: a case report]. / Difuzni infantilni hepatalni hemangioendoteliom: prikaz bolesnika.

Infantile hepatic hemangioendothelioma (IHHE) is the most common benign hepatic tumor in children (12% of hepatic tumors), that usually responds well to therapy and has low mortality rates. In extremely rare cases of diffuse tumors resistant to therapy, size and blood flow can lead to cardiorespiratory failure and death. A 3-month-old male infant presented with respiratory infections and an abdominal mass, with frequent broncho-obstructive attacks. The CT, MRI and DSA exams showed typical morphology of hemangiendothelioma that was proven on histopathological biopsy. The tumor was resistant to standard medical therapy, and its volume led to cardiopulmonary arrest and death at 13 months of age. In rare cases of diffuse therapy-resistant IHHE a liver transplantation should be considered as an earlier treatment.

[Treatment of langerhans cell histiocytosis in children]. / Lijecenje histiocitoze langerhansovih stanica u djece.

Langerhans' cell histiocytosis (LCH) is a disease characterised by pathologic accumulation and proliferation of histiocytes, cells from the monocyte-macrophage system, in various tissues and organs. In this retrospective study we analyzed patients charts treated in the Department of pediatric hematology and oncology at the University Hospital Zagreb with the diagnosis of LCH. Twenty-two children were diagnosed between January 1st 1996 and December 31st 2010, and all were treated with chemotherapy. 19 patients survived (86%) and the remaining 3 (14%), all under the age of 2 with multisystem disease, died. At the time of diagnosis 12 children (55%) presented with single-system disease, the most common were bone lesions in 8 children (36%). All children were treated according to protocols LCH-I and LCH -III. Eight children had mild complications of treatment and the disease itself. Diabetes insipidus remains in 4 children.

Synthesis and in vitro anticancer activity of octahedral platinum(IV) complexes with cyclohexyl-functionalized ethylenediamine-N,N'-diacetate-type ligands.

The present study describes the synthesis and anticancer activity of novel octahedral Pt(IV) complexes with cyclohexyl functionalized ethylenediamine-N,N'-diacetate-type ligands. Molecular mechanics calculations and density functional theory analysis revealed that s-cis is the preferred geometry of these Pt(IV) complexes with tetradentate-coordinated (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate. The viability of cancer cell lines (U251 human glioma, C6 rat glioma, L929 mouse fibrosarcoma, and B16 human melanoma) was assessed by measuring mitochondrial dehydrogenase activity and lactate dehydrogenase release. Cell-cycle distribution, oxidative stress, caspase activation, and induction of autophagy were analyzed by flow cytometry using appropriate fluorescent reporter dyes. The cytotoxic activity of novel Pt(IV) complexes against various cancer cell lines (IC(50) range: 1.9-8.7 microM) was higher than that of cisplatin (IC(50) range: 10.9-67.0 microM) and proceeded through completely different mechanisms. Cisplatin induced caspase-dependent apoptosis associated with the cytoprotective autophagic response. In contrast, the new Pt(IV) complexes caused rapid, caspase-independent, oxidative stress-mediated non-apoptotic cell death characterized by massive cytoplasmic vacuolization, cell membrane damage, and the absence of protective autophagy.

Changes of the corpus callosum in children who suffered perinatal injury of the periventricular crossroads of pathways.

There is a high incidence of periventricular leukomalacia, caused by hypoxia-ischemia, in preterm infants. These lesions damage the periventricular crossroads of commissural, projection and associative pathways, which are in a close topographical relationship with the lateral ventricles. We explored to what extent abnormalities of echogenicity of the periventricular crossroads correlate with changes in size of the corpus callosum. Our study included nine infants (gestation from 26-41 weeks; birth weight between 938-4450 grams) with perinatal brain injury. Periventricular areas, which topographically correspond to the frontal, main and occipital crossroad, were readily visualized by cranial ultrasound scans, performed during the first two weeks after birth. Corpus callosum mediosagittal area measurements were performed using magnetic resonance images, acquired between the first and sixth postnatal month (postmenstrual age 40-49 weeks). We found a statistically significant correlation between the increased echogenicity in the crossroad areas and the decrease of the corpus callosum midsagittal area (p < 0.05). This supports the hypothesis that callosal fibers can be damaged, during growth through the periventricular crossroads of pathways.

[Use of flow cytometry in the diagnosis of gestational trophoblastic disease]. / Primjena protocne citometrije u dijagnostici gestacijske trofoblasticne bolesti.

INTRODUCTION: Histopathologic analysis of aborted tissue in molar pregnancy is frequently complicated by scarcity of tissue as well as by the fact that ultrasound and biochemistry permit the clinical diagnosis of gestational trophoblastic disease at the very beginning of pregnancy, when all classical morphologic features have not yet developed. Flow cytometry is today a widely used method that can help the pathologist reach a correct diagnosis, having implications for the patient. AIM: To show the role of flow cytometry in addition to classical histopathologic methods in the early diagnosis of gestational trophoblastic disease, i. e. molar pregnancy. PATIENTS AND METHODS: A total of 103 consecutively received placental tissue samples from spontaneous/medically induced abortions were histopathologically examined and submitted to flow cytometry analysis. RESULTS: The patient mean age was 31 (range 19-50) years, and mean gestational age was 10 (range 5-19) weeks. Residual placental tissue with or without degenerative changes was found in 51.5% of the samples; in 8.7% embryonal/fetal tissues were identified as well. The histopathologic diagnosis of partial hydatiform mole was made in 34% and of complete hydatiform mole in 5.8% of cases. The difference in mean age of women according to histopathologic findings or placental ploidy was not significant. Flow cytometry revealed 42.7% of diploid samples, 58.3% of aneuploid samples and 1% of tetraploid samples. Of 53 samples showing normal morphology or degenerative hydropic changes, 60.4% were diploid and 39.6% aneuploid; of 9 samples containing fetal tissues 44.4% were diploid and 55.5% aneuploid (NS). A significant difference (p < 0.01) was found between the placental tissue ploidy with histopathologic diagnosis of residual placental tissue, and with histopathologic diagnosis of partial hydatiform mole (p < 0.001); when fetal tissues were present the difference was not significant CONCLUSION: This study confirmed the partial hydatiform mole to be a common but clinically underdiagnosed condition. Except for the knowledge whether the abortion was caused by cytogenetic factors, flow cytometry helps the pathologist reach an accurate diagnosis and has a place in daily practice.