Bone Turnover Marker for the Evaluation of Skeletal Remodelling in Autosomal Recessive Osteopetrosis after Haematopoietic Stem Cell Transplantation: A Case Report.

Background: Autosomal recessive osteopetrosis (ARO) is a rare genetic disorder of bone metabolism, primarily affecting the remodelling function of osteoclasts. Haematopoietic stem cell transplantation (HSCT) is the first-line treatment for ARO. Traditional tools for the assessment of therapeutic response, such as measuring donor chimerism, do not provide information on bone remodelling. The use of bone turnover markers (BTMs) might be ideal. Here, we report a case of a paediatric ARO patient undergoing successful HSCT. Methods: For the evaluation of donor-derived osteoclast activity and skeletal remodelling throughout the transplantation, the bone resorption marker ß-CTX (ß-C-terminal telopeptide) was used. Results: The low baseline level of ß-CTX markedly increased after transplantation and remained in the elevated range even after 3 months. Donor-derived osteoclast activity reached its new baseline level around the 50th percentile range after 5 months and proved to be stable during the 15-month follow-up time. The apparent increase of the baseline osteoclast activity after HSCT was in consonance with the radiographic improvement of the disease phenotype and the correction of bone metabolic parameters. Despite the successful donor-derived osteoclast recovery, craniosynostosis developed, and reconstructive surgery had to be performed. Conclusions: The use of ß-CTX may be of aid in assessing osteoclast activity throughout the transplantation. Further studies could help to establish the extended BTM profile of ARO patients using the available osteoclast- and osteoblast-specific markers.

Chromosomal breakage tests in the differential diagnosis of Fanconi anemia and aplastic anemia.

BACKGROUND: FA patients are hypersensitive to preconditioning of bone marrow transplantation. OBJECTIVE: Assessment of the power of mitomycin C (MMC) test to assign FA patients. METHODS: We analysed 195 patients with hematological disorders using spontaneous and two types of chromosomal breakage tests (MMC and bleomycin). In case of presumed Ataxia telangiectasia (AT), patients' blood was irradiated in vitro to determine the radiosensitivity of the patients. RESULTS: Seven patients were diagnosed as having FA. The number of spontaneous chromosomal aberrations was significantly higher in FA patients than in aplastic anemia (AA) patients including chromatid breaks, exchanges, total aberrations, aberrant cells. MMC-induced ≥10 break/cell was 83.9 ± 11.4% in FA patients and 1.94 ± 0.41% in AA patients (p < .0001). The difference in bleomycin-induced breaks/cell was also significant: 2.01 ± 0.25 (FA) versus 1.30 ± 0.10 (AA) (p = .019). Seven patients showed increased radiation sensitivity. Both dicentric + ring, and total aberrations were significantly higher at 3 and 6 Gy compared to controls. CONCLUSIONS: MMC and Bleomycin tests together proved to be more informative than MMC test alone for the diagnostic classification of AA patients, while in vitro irradiation tests could help detect radiosensitive-as such, individuals with AT.

Peripheral Bone Relapse of Paediatric TCF3-HLF Positive Acute Lymphoblastic Leukaemia during Haematopoietic Stem Cell Transplantation: A Case Report.

The present case report features a highly uncommon form of a paediatric TCF3-HLF positive acute lymphoblastic leukaemia (ALL) relapse, an extramedullary, peripheral bone manifestation. Following complete remission, during the conditioning for haematopoietic stem cell transplantation (HSCT), our sixteen-year-old male patient complained of fever, pain and swelling of the right forearm. Radiography suggested acute osteomyelitis in the right ulna with subsequent surgical confirmation. Intraoperatively obtained debris culture grew Staphylococcus aureus and Acinetobacter pittii. Measures taken to control the infection were deemed to be successful. However, after the completion of the otherwise uneventful HSCT, a very early medullary relapse was diagnosed. Revising the original surgical samples from the ulna, bone relapse of ALL was immunohistochemically confirmed. Reviewing the previous cases found in the literature, it is advised to consider uncommon forms of ALL relapse when encountering ambiguous cases of osteomyelitis or arthritis during haematological remission.

Case Report: A Child With Hemophilia A Serves as Donor for Hematopoietic Stem Cell Transplantation to Cure His Brother's Severe Aplastic Anemia.

The first-line treatment of severe aplastic anemia is allogeneic hematopoietic stem cell transplantation with a matched sibling donor. However, co-morbidities of the identical donor can make donation difficult. We present a transplantation where in parallel with the patient's conditioning treatment, the preparation of the donor with severe hemophilia A required a special management with perioperative factor VIII substitution. Donation was successful without complications, and 18 months after transplantation, the patient and his donor are well without any long-term sequelae. To our knowledge, this is the first reported succesfull transplantation with hemophilic child serving as a bone marrow donor. The procedure did not mean a significant risk to donor health, so donors with hemophilia should not be excluded from donation.

What Is the Role of HSCT in Philadelphia-Chromosome-Positive and Philadelphia-Chromosome-Like ALL in the Tyrosine Kinase Inhibitor Era?

Previously, the outcome of paediatric Philadelphia-chromosome-positive (Ph+) ALL treated with conventional chemotherapy alone was poor, necessitating the use of haematopoietic stem cell transplantation (HSCT) for the best outcomes. The recent addition of tyrosine kinase inhibitors (TKIs) alongside the chemotherapy regimens for Ph+ ALL has markedly improved outcomes, replacing the need for HSCT for lower risk patients. An additional poor prognosis group of Philadelphia-chromosome-like (Ph-like) ALL has also been identified. This group also can be targeted by TKIs in combination with chemotherapy, but the role of HSCT in this population is not clear. The impact of novel targeted immunotherapies (chimeric antigen receptor T cells and bispecific or drug-conjugated antibodies) has improved the outcome of patients, in combination with chemotherapy, and made the role of HSCT as the optimal curative therapy for Ph+ ALL and Ph-like ALL less clear. The prognosis of patients with Ph+ ALL and persistent minimal residual disease (MRD) at the end of consolidation despite TKI therapy or with additional genetic risk factors remains inferior when HSCT is not used. For such high-risk patients, HSCT using total-body-irradiation-containing conditioning is currently recommended. This review aims to provide an update on the current and future role of HSCT for Ph+ ALL and addresses key questions related to the management of these patients, including the role of HSCT in first complete remission, MRD evaluation and related actions post HSCT, TKI usage post HSCT, and the putative role of HSCT in Ph-like ALL.

Successful nivolumab therapy in an allogeneic stem cell transplant child with post-transplant lymphoproliferative disorder.

Primary CNS PTLD is an extremely rare complication after allogeneic HSCT. At our centre, an 11-year-old patient developed nausea, vomiting, and diplopy on day +82 following HSCT. On brain MRI, multiple white matter lesions were seen. Histology showed a diffuse large B-cell lymphoma with high load of EBV in tissue. Despite stopping immunosuppression, treatment with EBV-specific cytotoxic T cells, systemic rituximab, HD-MTX, and intrathecal chemotherapy, progression was observed. With a combination of HD-MTX and cytarabine, only a partial response could be achieved. Having all conventional modalities not only failed but resulted in significant toxicity, a salvage monotherapy with biweekly nivolumab has been instituted. The starting dose was 1.1 mg/kg, later escalated to 2.2 mg/kg. After 8 months of nivolumab therapy, PET-CT showed complete metabolic remission. Subsequently, the patient has been switched to a maintenance dosage of 1.1 mg/kg. No cytopenias, graft failure, GvHD, or any other alloimmune complications were seen during nivolumab therapy. In conclusion, nivolumab may be considered as an effective and safe option for CNS PTLD therapy when all other modalities have failed.

Pathways to Diagnosis for Teenagers and Young Adults with Cancer in European Nations: A Pilot Study.

PURPOSE: The diagnosis of cancer is often prolonged in teenagers and young adults (TYA). There may be lessons in improving this from international comparisons. However, international studies are complex and so we conducted a pilot study to examine the key barriers to large-scale research in this field. METHODS: We provided translated questionnaires covering key aspects of presentation and clinical management within 60 days of a confirmed cancer diagnosis, to patients 13-29 years of age inclusive, to their primary care physicians and to the cancer specialists managing their cancer. We conducted descriptive analyses of the data and also the process of study implementation. RESULTS: For our pilot, collecting triangulated data was feasible, but varying regulatory requirements and professional willingness to contribute data were key barriers. The time of data collection and the method for collecting symptom reports were important for timely and accurate data synthesis. Patients reported more symptoms than professionals recorded. We observed substantial variation in pathways to cancer diagnosis to explore definitively in future studies. CONCLUSION: Focused research upon the mechanisms underpinning complex cancer pathways, and focusing that research upon specific cancer types within TYA may be the next key areas of study.

Effective BRAF inhibitor vemurafenib therapy in a 2-year-old patient with sequentially diagnosed Langerhans cell histiocytosis and Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare histiocytic disorder, characterized by the xanthomatous infiltration of tissues by CD68-positive and CD1a-/CD100-negative foamy histiocytes. In childhood, ECD is exceptionally rare, and only a dozen cases have been published so far. The cooccurence of Langerhans cell histiocytosis (LCH) and ECD is even rarer. Here, we report a 2-year-old boy, the youngest patient in the literature so far, who was diagnosed with concomitant BRAF mutation-positive LCH and ECD. In his case, conventional LCH treatment proved to be ineffective, but he is the youngest patient who was successfully treated with the BRAF inhibitor vemurafenib.

Factors influencing antimicrobial resistance and outcome of Gram-negative bloodstream infections in children.

OBJECTIVE: The aim of this study was to collect data about pediatric Gram-negative bloodstream infections (BSI) to determine the factors that influence multidrug resistance (MDR), clinical course and outcome of children affected by Gram-negative sepsis. METHODS: In this observational, prospective, multicenter study we collected cases of pediatric Gram-negative BSI during a 2-year period. We analyzed epidemiological, microbiological and clinical factors that associated with acquisition of MDR infections and outcome. RESULTS: One-hundred and thirty-five BSI episodes were analyzed. Median age of children was 0.5 years (IQR 0.1-6.17, range 0-17 years). Predominant bacteria were Enterobacteriaceae (68.3 %), and Pseudomonas spp. (17.9 %). Multidrug resistance was detected in 45/134 cases (33.6 %), with the highest rates in Escherichia coli, Enterobacter and Pseudomonas spp. Acquisition of MDR pathogens was significantly associated with prior cephalosporin treatment, older age, admission to hemato-oncology unit, polymicrobial infections, higher rate of development of septic shock, and multiple organ failures. All-cause mortality was 17.9 %. Presence of septic shock at presentation and parenteral nutrition were associated with higher mortality. Pseudomonas spp., and Enterobacter spp. BSIs had the highest rate of mortality. Inappropriate empiric antibiotic therapy was more frequent in MDR patients, although not significantly associated with poor outcome. CONCLUSION: Rates of multidrug resistance and mortality in children with Gram-negative bloodstream infections remain high in our settings. Empiric broad-spectrum antibiotics and combination therapy could be recommended, especially in children with malignant diseases, patients admitted to the PICU, and for cases with septic shock, who have higher mortality risk.

Advanced pediatric inoperable thymus carcinoma (type C thymoma): case report on a novel therapeutic approach.

Although there has been considerable advancement in treatment techniques but still there are some illnesses that continue to exhibit a rather poor curability, such as thymoma. This report highlights the benefit of octreotide and prednisolone therapy in a 15-year-old girl, who was diagnosed with inoperable thymus carcinoma, with chemotherapy and radiotherapy being the last resort. The detection of type 2 somatostatin receptors on the surface of the tumor justified the introduction of treatment with somatostatin analog and prednisolone. Fortunately, after 6 months of this treatment, the tumor showed partial regression. However, 2 months later, somatostatin receptor negative metastases appeared; therefore, a switch over to imatinib became essential, because the tumor was CD-117 positive. Despite the therapy change, the patient's condition deteriorated owing to tumor progression.

[Imaging of pediatric brain tumors using somatostatin analogue 111Ih-DTPA-D-Phe1-octreotide]. / Gyermekkori agytumorok vizsgálata szomatosztatin-analóg (111In-DTPA-D-Phe1-octreotide) alkalmazásával.

Malignant solid tumors and leukemias are the second most common causes of death in childhood. The most frequent pediatric solid tumors are brain tumors. Brain tumors, especially medulloblastoma should be treated by surgery, irradiation and chemotherapy. However, chemotherapy has only moderate effect. Pediatric brain tumors, especially medulloblastomas, express somatostatin receptors. The aim of this study was the investigation of the expression of somatostatin receptors in pediatric brain tumors for diagnostic and therapeutic purpose. Fifty-six scintigraphic imagings (111In-DTPA-D-Phe1-octreotide) made in 45 children treated with brain tumor at the Unit of Oncology of the 2nd Department of Pediatrics, Semmelweis University. The diagnosis was medulloblastoma in 21 cases (46.7%). MRI scans have been performed parallel with the Octreoscan images. Octreoscan images were positive in 27 of 56 (48.2%) cases. The 27 positive Octreoscan images consisted of 16 medulloblastomas, 4 ependymomas, 4 astrocytomas and 3 glioblastomas. In 37 (66.1%) cases the results of Octreoscans were the same as those of the MRI scans. However, in 19 scans (33.9%) the outcome was different. Octreoscan imaging is not suitable for differential diagnosis in pediatric brain tumors, including medulloblastomas. Isotopes specifically binding to the somatostatin receptors (111In-DTPA-D-Phe1-octreotide) can be applied in medulloblastomas for diagnosis and follow-up treatment. In Octreoscan-positive tumors the Octreoscan images establish the opportunity to somatostatin analogue and/or specifically targeted radiation therapies.