Jarosław Peregud-Pogorzelski

Thiopurine S-methyltransferase (TPMT) polymorphisms in children with acute lymphoblastic leukemia, and the need for reduction or cessation of 6-mercaptopurine doses during maintenance therapy: The Polish multicenter analysis†

6‐Mercaptopurine (6‐MP) is used for the treatment of pediatric acute lymphoblastic leukemia (ALL). Mutations in the TPMT gene may influence the efficacy and safety of 6‐MP treatment. This multicenter study investigated the association between TPMT genotype, 6‐MP dose adjustments, and the incidence of adverse effects in patients.

Thymic carcinoma in children: A report from the Polish pediatric rare tumors study

Invasive thymomas and thymic carcinomas are rare tumors jointly accounting between 0.2% and 1.5% of malignancies in adults. They are usually at an advanced stage when diagnosed and have both high recurrence and poor survival rates. In this report, the aim is to explore our experience in the treatment of thymic carcinomas in Polish children.

First-line immunosuppressive treatment in children with aplastic anemia: rabbit antithymocyte globulin.

Immunosuppressive therapy is the treatment of choice in children with acquired severe aplastic anemia (AA) and no HLA-matched family donor. The paper presents results of a multicenter study of 63 children with AA treated with rabbit antithymocyte globulin (r-ATG) and cyclosporine A as the first line treatment in the years 1996-2012. Therapeutic effects were evaluated at Days 112, 180, and 360. At Day 112, remission was achieved in 28 out of the 63 patients (44.4 %), complete remission in 10 patients (15.9 %), and partial remission in 18 (28.5 %). At Day 180, 31 patients (49.2 %) were in remission including 15 cases in complete (23.8 %), and 16 cases in partial remission (25.4 %). One year after therapy onset, 34 patients (64.9 %) were in remission including 24 patients (38.0 %) in complete and 10 (15.9 %) in partial remission. Relapse occurred in 4 patients, from 8 months up to 2 years and 2 months after remission. One child, 5 years after remission, was diagnosed with paroxysmal nocturnal hemoglobinuria. The estimated 10-year overall survival rate and 10-year event-free survival rate were 67 % and 57 %, respectively.

Highly effective unconventional management of aspergillosis of the left maxillary sinus in an 11-year-old girl with rhabdomyosarcoma embryonale of the frontal sinus.

Invasive fungal infections are common causes of death in children treated for malignancies, and therefore present an important and growing clinical problem. Fungal invasion usually affects immunocompromised patients, but increased incidences are also associated with intensification of antineoplastic therapy and increased numbers of organ and bone marrow transplantations. Fungal infections in parameningeal and cerebral locations carry high risks of treatment failure. We describe the case of an 11-year-old female patient with rhabdomyosarcoma embryonale of the frontal sinuses with metastases to the neck lymph nodes, treated according to the CWS 2002 protocol for high-risk patients. Left maxillary sinus aspergillosis was diagnosed during chemotherapy following radiotherapy, and 56 days after surgical excision of the tumour. No effect was achieved by use of amphotericin B. Further treatment included intravenous voriconazole at 6 mg per kg body weight every 12 h for 2 weeks, followed by oral voriconazole at 4 mg per kg body weight twice daily for 6 months. Simultaneous excision of necrotic tissues from the nasal cavity, ethmoid bone, maxillary sinus and frontal recess was performed. The sinus was kept open for 3 weeks to allow voriconazole lavage every 12 h for 3 weeks. This unconventional treatment resulted in eradication of sinus aspergillosis and allowed intensive chemotherapy to be continued with no recurrence of aspergillosis.

Evidence for the efficacy of immunotherapy in children with high-risk neuroblastoma.

Neuroblastoma is the most common extra-cranial malignancy of childhood, with the highest incidence in children younger than 4 years. The prognosis depends on many factors, such as age at diagnosis, stage of disease and molecular genetic subtype. More than 50% of children who present with the disease are deemed to have high-risk neuroblastoma. The standard therapy for children with high-risk neuroblastoma consists of intensive chemotherapy, surgery, radiotherapy, myeloablative consolidation with autologous haematopoietic stem cell rescue followed by the treatment of minimal residual disease with 13-cis-retinoic acid. Unfortunately, more than half of the patients relapse regardless of the treatment intensity. Combined therapy with monoclonal antibodies (anti-GD2), intravenous interleukin-2 (Il-2), intravenous granulocyte-macrophage colony-stimulating factor (GM-CSF) and oral 13-cis-retinoic acid have been proved to be effective in some randomised trials. A better understanding of the underlying immunological processes in therapy with anti-GD2 antibodies will allow its success to be evaluated more accurately and direct future endeavours. Nevertheless, the long-term benefit of this treatment approach needs to be established.

Bone marrow of multiorgan donors underutilized: implications for improvement of accessibility of hematopoietic cells for transplantations.

Background. The demand for human hematopoietic stem and progenitor cells (HSPCs) for transplantation is increasing. Thus, effective alternative sources of HSPCs are required. Consequently, we sought to expand the accessibility of hematopoietic cells for clinical purposes by the investigation of hematopoietic reconstitution after transplantation of human HSPCs harvested from the bone marrow (BM) of heparinized deceased organ donors (HDODs). Methods. For multipart research comparison, human BM HDODs-, healthy donor-derived, umbilical cord blood nuclear cells, or CD34+ cells were transplanted into sublethally irradiated NOD/SCID mice. Twenty-eight days after transplantation nuclear cells were isolated from the murine BM, spleen, and peripheral blood and were used to quantitatively detect human CD45 antigen by quantitative real-time reverse transcriptase–polymerase chain reaction and flow cytometry. The clonogenic growth of human colony-forming units was also investigated. Results. We found that umbilical cord blood-derived HSPCs showed the greatest transplantation potential in our in vivo model. Interestingly, the transplantation potential of HSPCs collected from the BM of HDODs was of the same quality as cells obtained from healthy BM donors. Conclusion. Based on these results, we conclude that HDODs are a strongly underappreciated source of HSPCs that are ready to use for clinical purposes.

Safety and Feasibility of Lin- Cells Administration to ALS Patients: A Novel View on Humoral Factors and miRNA Profiles

Therapeutic options for amyotrophic lateral sclerosis (ALS) are still limited. Great hopes, however, are placed in growth factors that show neuroprotective abilities (e.g., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF)) and in the immune modulating features, in particular, the anti-inflammatory effects. In our study we aimed to investigate whether a bone marrow-derived lineage-negative (Lin-) cells population, after autologous application into cerebrospinal fluid (CSF), is able to produce noticeable concentrations of trophic factors and inflammatory-related proteins and thus influence the clinical course of ALS. To our knowledge, the evaluation of Lin- cells transplantation for ALS treatment has not been previously reported. Early hematopoietic Lin- cells were isolated from twelve ALS patients’ bone marrow, and later, the suspension of cells was administered into the subarachnoid space by lumbar puncture. Concentrations of selected proteins in the CSF and plasma were quantified by multiplex fluorescent bead-based immunoassays at different timepoints post-transplantation. We also chose microRNAs (miRNAs) related to muscle biology (miRNA-1, miRNA-133a, and miRNA-206) and angiogenesis and inflammation (miRNA-155 and miRNA-378) and tested, for the first time, their expression profiles in the CSF and plasma of ALS patients after Lin- cells transplantation. The injection of bone marrow cells resulted in decreased concentration of selected inflammatory proteins (C3) after Lin- cells injection, particularly in patients who had a better clinical outcome. Moreover, several analyzed miRNAs have changed expression levels in the CSF and plasma of ALS patients subsequent to Lin- cells administration. Interestingly, the expression of miR-206 increased in ALS patients, while miR-378 decreased both in the CSF and plasma one month after the cells’ injection. We propose that autologous lineage-negative early hematopoietic cells injected intrathecally may be a safe and feasible source of material for transplantations to the central nervous system (CNS) environment aimed at anti-inflammatory support provision for ALS adjuvant treatment strategies. Further research is needed to evaluate whether the observed effects could significantly influence the ALS progression.

Rola radioterapii w leczeniu zlokalizowanej postaci nowotworów tkanek miękkich u dzieci

Wstep i cele Miesaki tkanek miekkich, mimo ze stanowią heterogenną grupe nowotworow zlośliwych, ze wzgledu na wspolne cechy biologiczne, kliniczne i wrazliwośc na stosowane cytostatyki podlegają zblizonej strategii leczenia. W 11 ośrodkach onkohematologicznych w Polsce, w ramach Polskiej Pediatrycznej Grypy Guzow Litych (PPGGL) od lat prowadzone jest leczenia zgodne z miedzynarodowym protokolem CWS. Pacjenci i metody Analizą objeto 52 pacjentow w III stopniu zaawansowania choroby, zarejestrowanych i leczonych przez PPGGL, wg protokolu CWS-96 w latach 1997–2003. Wyniki W calej analizowanej grupie chorych stwierdzono 30% wznow miejscowych, natomiast w wyselekcjonowanej grupie pacjentow z RMS stwierdzono 24% wznow miejscowych. Stwierdzono zjawisko zwiekszenia liczby wznow miejscowych u chorych, u ktorych rozpoczeto napromienianie po 20 tygodniu od rozpoczecia leczenia. Roznica ta najwyraźniej wystąpila u dzieci z rozpoznaniem RMS zarodkowego (44% vs 12,5%, p = 0,047). Wznowa miejscowa wystąpila najcześciej u pacjentow z rozpoznaniem histopatologicznym pozakostnej postaci miesaka Ewinga (PNET/EES) – 8 wznow na 13 chorych (61%). Wnioski Opoźnienie napromieniania wplywa na zwiekszenie liczby wznow miejscowych, szczegolnie u pacjentow z rozpoznaniem RMS embryonale. Wysoki odsetek niepowodzen leczenia pacjentow z rozpoznaniem pozakostnej postaci miesaka Ewinga sugeruje rozwazenie u tych chorych modyfikacji stosowanego w protokole CWS96 sposobu terapii.

Ocena wielkości i funkcji nerek u dzieci z ostrą białaczką limfoblastyczną (OBL) po zakończeniu leczenia

Wstep Nerki są organem szczegolnie narazonym na upośledzenie ich funkcji oraz wystepowanie powiklan w czasie leczenia i po zakonczonym leczeniu ostrej bialaczki limfoblastycznej (OBL), ktore w sposob istotny mogą wplywac na komfort i dlugośc zycia pacjentow. Cel pracy Celem pracy byla ocena wielkości i funkcji nerek u dzieci, oraz określenie czynnikow mających wplyw na wystepowanie nieprawidlowości w ich funkcjonowaniu po zakonczonym leczeniu OBL za pomocą wybranych badan klinicznych, biochemicznych i obrazowych. Material i metody Badaniami objeto grupe 48 dzieci, w tym 29 (60%) chlopcow i 19 (40%) dziewczynek, w wieku 79–275 miesiecy (średnia 159 miesiecy; SD 49 miesiecy), u ktorych w latach 1989–2001 ustalono rozpoznanie OBL. Wyniki i wnioski Wykazano, ze stosowany program chemioterapii i czas obserwacji dluzszy niz 5 lat po zakonczenia leczenia w sposob istotny wplywaly na obnizenie wartości GFR, wystepowanie blizn w nerkach oraz zmniejszenie objetości i dlugości nerek. Dlatego konieczne wydaje sie objecie okresową opieką nefrologiczną pacjentow po zakonczeniu leczenia OBL.