[First Hungarian report of Geotrichum capitatum/Saprochaete capitata infection in an immunocompromised child]. / Geotrichum capitatum/Saprochaete capitata fertozés elso hazai esete egy immunszupprimált gyermekben.

Patients with leukemia may occasionally suffer from rare opportunistic fungal infections with poor prognosis. Fungal infection caused by Geotrichum captitatum has not yet been described in Hungary. With this case report, we would like to draw attention to the fungal infection caused by G. capitatum. The 1.5-year-old girl with acute myeloid leukemia was treated for relapse diagnosed +120 days after a sibling donor bone marrow transplantation. High-grade, fluctuating fever began 11 days after the start of chemotherapy which did not decrease despite combined treatment with broad-spectrum antibiotics and antifungals (posaconasole). Due to worsening respiratory symptoms, a chest CT-scan was performed, raising suspicion of an invasive fungal infection. Blood culture confirmed G. capitatum infection. Initial empiric treatment with liposomal amphotericin B was combined with voriconazole based on international experience. However, we did not observe any improvement, and a few days later the patient passed away due to progression of the underlying disease. G. capitatum (presently known as Saprochaete capitata) is an ubiquitous yeast that can cause an infection with a poor prognosis, mainly in patients with leukemia. Its symptoms primarily appear in the skin and respiratory tract. The accurate identification of this pathogen is essential because the standard diagnostic tests do not give a specific reaction. Based on the limited international experience, the combination of amphotericin B and voriconazole can play a fundamental role in the treatment, however, even with adequate therapy 50% of the cases are fatal. By describing the first Hungarian case caused by G. capitatum, we draw attention to the importance of this rare, opportunistic fungal species with a poor prognosis that develops in immunosuppressed patients. Orv Hetil. 2023; 164(26): 1034-1038.

PersonALL: a genetic scoring guide for personalized risk assessment in pediatric B-cell precursor acute lymphoblastic leukemia.

BACKGROUND: Recurrent genetic lesions provide basis for risk assessment in pediatric acute lymphoblastic leukemia (ALL). However, current prognostic classifiers rely on a limited number of predefined sets of alterations. METHODS: Disease-relevant copy number aberrations (CNAs) were screened genome-wide in 260 children with B-cell precursor ALL. Results were integrated with cytogenetic data to improve risk assessment. RESULTS: CNAs were detected in 93.8% (n = 244) of the patients. First, cytogenetic profiles were combined with IKZF1 status (IKZF1normal, IKZF1del and IKZF1plus) and three prognostic subgroups were distinguished with significantly different 5-year event-free survival (EFS) rates, IKAROS-low (n = 215): 86.3%, IKAROS-medium (n = 27): 57.4% and IKAROS-high (n = 18): 37.5%. Second, contribution of genetic aberrations to the clinical outcome was assessed and an aberration-specific score was assigned to each prognostically relevant alteration. By aggregating the scores of aberrations emerging in individual patients, personalized cumulative values were calculated and used for defining four prognostic subgroups with distinct clinical outcomes. Two favorable subgroups included 60% of patients (n = 157) with a 5-year EFS of 96.3% (excellent risk, n = 105) and 87.2% (good risk, n = 52), respectively; while 40% of patients (n = 103) showed high (n = 74) or ultra-poor (n = 29) risk profile (5-year EFS: 67.4% and 39.0%, respectively). CONCLUSIONS: PersonALL, our conceptually novel prognostic classifier considers all combinations of co-segregating genetic alterations, providing a highly personalized patient stratification.

Next-Generation Sequencing-Based Genomic Profiling of Children with Acute Myeloid Leukemia.

Pediatric acute myeloid leukemia (AML) represents a major cause of childhood leukemic mortality, with only a limited number of studies investigating the molecular landscape of the disease. Here, we present an integrative analysis of cytogenetic and molecular profiles of 75 patients with pediatric AML from a multicentric, real-world patient cohort treated according to AML Berlin-Frankfurt-Münster protocols. Targeted next-generation sequencing of 54 genes revealed 17 genes that were recurrently mutated in >5% of patients. Considerable differences were observed in the mutational profiles compared with previous studies, as BCORL1, CUX1, KDM6A, PHF6, and STAG2 mutations were detected at a higher frequency than previously reported, whereas KIT, NRAS, and KRAS were less frequently mutated. Our study identified novel recurrent mutations at diagnosis in the BCORL1 gene in 9% of the patients. Tumor suppressor gene (PHF6, TP53, and WT1) mutations were found to be associated with induction failure and shorter event-free survival, suggesting important roles of these alterations in resistance to therapy and disease progression. Comparison of the mutational landscape at diagnosis and relapse revealed an enrichment of mutations in tumor suppressor genes (16.2% versus 44.4%) and transcription factors (35.1% versus 55.6%) at relapse. Our findings shed further light on the heterogeneity of pediatric AML and identify previously unappreciated alterations that may lead to improved molecular characterization and risk stratification of pediatric AML.

Full Body Surface Coverage with Water-Equivalent Bolus as Novel Technique for Total Body Irradiation before Hematopoietic Stem Cell Transplantation in Pediatric Acute Lymphoid Leukemia.

BACKGROUND: Total body irradiation (TBI) 2 × 2 Gy for 3 consecutive days followed by chemotherapy for conditioning pediatric patients with acute lymphoid leukemia (ALL) before bone marrow transplantation is superior to chemo-conditioning alone. The globally used anterior-posterior/posterior-anterior (AP/PA) technique is the most referable method, but volumetric modulated arc therapy (VMAT) with modern linear accelerators is more precise in terms of ensuring better dose distribution, especially for skin, and higher protection of organs at risk, resulting in less side effects. METHOD: For TBI, a modern VMAT technique was used. Whole-body immobilization in the supine position was performed using a vacuum mattress with a full body coverage, with a water-equivalent bolus of 1 cm thickness. The design goal was to achieve dose inhomogeneity of less than ±10%. RESULTS: From 2020 to 2022, we performed TBI for five pediatric patients with ALL, with full body bolus and VMAT, who later received hematopoietic stem cell transplantation. No acute complications related to TBI were observed during the treatment period with a median follow-up of 1.27 (0.43-2.11) years. CONCLUSION: Using full body water-equivalent bolus with VMAT for TBI provides a safe method for children with a better organ sparing in the short term follow-up.

A Novel Method for the Evaluation of Bone Marrow Samples from Patients with Pediatric B-Cell Acute Lymphoblastic Leukemia-Multidimensional Flow Cytometry.

Multicolor flow cytometry (FC) evaluation has a key role in the diagnosis and prognostic stratification of ALL. Our aim was to create new analyzing protocols using multidimensional dot-plots. Seventy-two pediatric patients with ALL were included in this single-center study. Data of a normal BM sample and three BM samples of patients with BCP-ALL were merged, then all B cell populations of the four samples were presented in a single radar dot-plot, and those parameters and locations were selected in which the normal and pathological cell populations differed from each other the most. The integrated profile of immunophenotype resulted in a simple, rapid, and accurate method. There were no significant differences between the percentages of lymphoblasts in the detection of minimal residual disease (MRD) by multidimensional or conventional FC method (p = 0.903 at Day 15 and p = 0.155 at Day 33). Furthermore, we found associations between the position and the number of clusters of blast cells in the radar plots and cytogenetic properties (p = 0.002 and p < 0.0001 by the position and p = 0.02 by the number of subclones). FC analysis based on multidimensional dot-plots is not only a rapid, easy-to-use method, but can also provide additional information to screen cases which require detailed genetic examination.

Recent Advances in the Management of Pediatric Acute Myeloid Leukemia-Report of the Hungarian Pediatric Oncology-Hematology Group.

Outcome measures of pediatric acute myeloid leukemia (AML) improved considerably between 1990 and 2011 in Hungary. Since 2012, efforts of the Hungarian Pediatric Oncology-Hematology Group (HPOG) included the reduction in the number of treatment centers, contemporary diagnostic procedures, vigorous supportation, enhanced access to hematopoietic stem cell transplantation (HSCT), and to targeted therapies. The major aim of our study was to evaluate AML treatment results of HPOG between 2012 and 2019 with 92 new patients registered (52 males, 40 females, mean age 7.28 years). Two periods were distinguished: 2012-2015 and 2016-2019 (55 and 37 patients, respectively). During these periods, 2 y OS increased from 63.6% to 71.4% (p = 0.057), and the 2 y EFS increased significantly from 56.4% to 68.9% (p = 0.02). HSCT was performed in 37 patients (5 patients received a second HSCT). We demonstrate advances in the diagnosis and treatment of acute promyelocytic leukemia (APL) in two cases. Early diagnosis and follow-up were achieved by multidimensional flow cytometry and advanced molecular methods. Both patients were successfully treated with all-trans retinoic acid and arsenic-trioxide, in addition to chemotherapy. In order to meet international standards of pediatric AML management, HPOG will further centralize treatment centers and diagnostic facilities and join efforts with international study groups.

Late mortality in survivors of childhood cancer in Hungary.

The Hungarian Pediatric Oncology Network provides centralized treatment and population-based registration for cases of childhood cancer since 1973. We collected and analized data on late mortality, secondary malignancies and cardiac diseases in survivors (> 5 years) of childhood cancer to evaluate long-term risks. We extracted all solid tumour cases (3,650 followed up for 5-39.3 years, diagnosis: 1973-2008) from the database of the Hungarian Childhood Cancer Registry and checked against the Population Registry. Among the 301 patients who died after 5 years (8.2%) the most common causes of death were progression of primary cancer (52.5%), secondary malignancies (16%) and cardiovascular diseases (8%). Late mortality rates (SMR, total: 35,006 pyrs) showed highly elevated risk of death (SMR: 10.7 95% CI 9-12.4) for the second 5 years of follow up and moderately elevated risk for 10-year survivors (SMR: 3.5 95% CI 3-4.1). Marked differences were detected in the pattern of causes of death between diagnostic groups of primary cancer; with highest risks beyond 10 years for CNS tumours, Hodgkin disease, osteosarcoma and advanced stage neuroblastoma. The longstanding mortality risk for 5-year survivors underlines the need for tailored long-term follow-up and monitoring of late consequences according to the context of different primary diseases of childhood cancer.

Children and Adults with Refractory Acute Graft-versus-Host Disease Respond to Treatment with the Mesenchymal Stromal Cell Preparation "MSC-FFM"-Outcome Report of 92 Patients.

(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced. (2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored. (3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%. (4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.

Central and peripheral airway nitric oxide in patients with stable and exacerbated chronic obstructive pulmonary disease.

Nitrative stress pathways are involved in airway inflammation characterizing chronic obstructive pulmonary disease (COPD). Extended nitric oxide (NO) analysis allows the partitioned measurement of nitrative stress in the conducting bronchi and peripheral airways/alveolar spaces. However, pulmonary NO production at these two sites has not been systemically studied in stable and exacerbated COPD. Twenty-eight patients with stable COPD, 34 patients during an exacerbation, and 15 smoking controls were recruited. Exhaled NO was measured at constant flow rates of 50 ml s-1 (for FENO50) and 100-150-200-250 ml s-1 (for the extended NO analysis). Clinical variables, including lung function, white blood cell count, C-reactive protein concentration, blood gas values and symptom score (COPD assessment test) were collected. The measurements were repeated in 26 patients with an exacerbation during convalescence. The exhaled NO parameters were analysed with non-parametric tests. The alveolar NO (CANO) was higher in stable COPD (median (interquartile range), 4.24 (2.35-6.09) ppb, p < 0.01) and in patients with an exacerbation (3.83 (2.31-6.62) ppb, p < 0.05) than in the controls (2.05 (1.77-2.80) ppb), but no difference was found between the stable and exacerbated disease (p > 0.05). The CANO correlated with the blood eosinophil percentage in all COPD patients (r = 0.29, p = 0.02). The total flux of bronchial NO (JawNO) increased in an exacerbation (exacerbated: 1.01 (0.45-2.44) nl s-1 versus stable: 0.47 (0.16-0.81) nl s-1, p < 0.01; exacerbated versus control: 0.38 (0.27-0.80) nl s-1, p < 0.05), and it was reduced in convalescence after therapy (0.50 (0.31-0.96) nl s-1, p = 0.01). Neither CANO and JawNO or their change were related to the clinical variables or the length of hospital stay in COPD. JawNO correlated with FENO50 during exacerbation (r = 0.80, p < 0.001). Extended NO analysis is a feasible method to monitor nitrative stress at different anatomical sites within the airways in stable and exacerbated COPD patients. Our results suggest that nitrative stress is constantly elevated in the small airways in COPD and increases in the conducting airways during an exacerbation.

Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM).

The inability to generate mesenchymal stromal cells (MSCs) of consistent potency likely is responsible for inconsistent clinical outcomes of patients with aGvHD receiving MSC products. We developed a novel MSC manufacturing protocol characterized by high in vitro potency and near-identity of individual doses, referred to as "MSC-Frankfurt am Main (MSC-FFM)". Herein, we report outcomes of the 69 patients who have received MSC-FFM. These were 51 children and 18 adults with refractory aGvHD grade II (4%), III (36%) or IV (59%). Patients were refractory either to frontline therapy (steroids) (29%) or to steroids and 1-5 additional lines of immunosuppressants (71%) were given infusions in four weekly intervals. The day 28 overall response rate was 83%; at the last follow-up, 61% and 25% of patients were in complete or partial remission. The median follow-up was 8.1 months. Six-month estimate for cumulative incidence of non-relapse mortality was 27% (range, 16-38); leukemia relapse mortality was 2% (range, 0-5). This was associated with a superior six-month overall survival (OS) probability rate of 71% (range, 61-83), compared to the outcome of patients not treated with MSC-FFM. This novel product was effective in children and adults, suggesting that MSC-FFM represents a promising therapy for steroid refractory aGvHD.

[Necrotizing otitis externa in a 5-month-old infant]. / Otitis externa necrotica öt hónapos csecsemon.

This report presents the case of a healed 5-month-old infant with necrotising (malignant) bilateral otitis externa from acute mastoiditis on the right side and sepsis caused by Pseudomonas aeruginosa infection. Despite of immediately performed mastoidectomy, targeted antibiotics and intensive local treatment, two third of both external auditory canal's epithelium had shown subcutaneous concentric necrosis and ejection which have been removed with repeated necretomies. After the remission of inflammatory symptoms, successful bilateral auditory canal reconstructions were performed. The observed right peripheral facial paresis at the beginning of disease remained stationary. The patient healed with residual symptoms after 2 months of treatment. Neither immune deficiency, nor diabetes could have been proven.

[Successfully treated neck abscess secondary to peritonsillar abscess]. / Peritonsillaris abscessus szövodményeként kialakult nyaki tályog gyógyult esete.

The complications of peritonsillar abscess are potentially life-threatening conditions. The acute tonsillar infections frequently extend in the peritonsillar tissues from which the rare form of neck and mediastinal abscess can develop. The authors review the case of 17 years old boy, at whom the infection spread from peritonsillar space to the neck space. Complications of the peritonsillar abscess today are potentially life-threatening conditions. The wide incision performed at appropriate time resulted in complete healing and prevented the progress into the mediastinal space. The authors have not met similar case neither in their administrative area, nor in the Hungarian literature, however the number of reports in English is abundant.

[Rare case of congenital transsphenoidal meningoencephalocele causing respiratory problems]. / Légzési panaszokat okozó veleszületett transspheniodalis meningoencephalokele ritka esete.

INTRODUCTION: Congenital meningoencephalocele is a rare and severe malformation. AIMS: The authors describe the case of congenital, basal transsphenoidal meningoencephalocele associated with other neurological malformations, which projected between the margins of palatoschisis producing respiratory problems at neonatal age. METHOD: Presented with detailed photo-documentation. RESULTS: Cranial meningoencephalocele reconstruction with an approach of bifrontal craniotomy was performed. The base of skull was closed multilaminarly with auto-graft gained from parietal bone and Lyodura. The closure of nasopharyngeal sac was performed in second sitting. Postoperatively the progression of hydrocephalus was so extensive, that implantation of ventriculo-peritoneal shunt was unavoidable. Later on closure of tracheotomy performed for continued air passage support was done. The authors report the course of disease and the surgeries performed. CONCLUSIONS: Auto-graft from skull bone for closure of large basal-cranial defect proved to be ideal. Prognosis depends on other malformations. Successful treatment needs co-operation of different specialties.