The impact of additional cytogenetic abnormalities at diagnosis and during therapy with tyrosine kinase inhibitors in Chronic Myeloid Leukaemia.

BACKGROUND: Chronic Myeloid Leukemia's (CML) treatment was optimized since the development of tyrosine kinase inhibitors (TKI) and an increased overall survival during TKI was noticed. During the TKI era, protocols for assessing response and resistance to treatment were developed. Additional chromosomal abnormalities (ACAs) are strongly associated with disease progression but their prognostic impact and influence on treatment response are yet to be defined. The aim of this study was to analyze the impact of ACAs on time to achieve complete cytogenetic response (CCyR), treatment and overall survival. MATERIALS AND METHODS: Since 2005 until 2013, the data from the Hematology and Bone Marrow Transplantation Department of Fundeni Clinical Institute was collected. In this observational retrospective single centre study, 28 CML patients with ACAs at diagnosis and during TKI treatment were included. RESULTS: From ACAs at diagnosis group, the most frequent major route ACAs were trisomy 8, trisomy 19 and second Philadelphia (Ph) chromosome and the most frequent minor route ACAs were monosomies and structural abnormalities (inversions and translocations). From the ACAs during the TKI group, the most frequent major route cytogenetic abnormalities in Ph positive and negative cells were trisomy 8, trisomy 19 and second Ph chromosome and the most frequent minor route cytogenetic abnormalities in Ph positive and negative cells were marker chromosomes and structural abnormalities (inversions, translocations and dicentric chromosomes). CONCLUSIONS: In both groups, the time to CCyR was longer and long-term results were inferior in comparison with standard patients but the differences were not significant and in accordance to published data. The 12 months follow-up after the study's end showed that 26 patients were alive and in long-term CCyR and 2 deaths were reported. ABBREVIATIONS: CML = Chronic Myeloid Leukemia, BCR-ABL1 = Break Cluster Region - Abelson gene, TKI = tyrosine kinase inhibitor treatment, ACAs = additional cytogenetic abnormalities, CCyR = complete cytogenetic response, PCyR = partial cytogenetic response, mCyR = minor cytogenetic response, MMR = major molecular response, HSCT = hematopoietic stem cell transplant, HLA = human leukocyte antigens, CP = chronic phase, AP = accelerated phase, BP = blast phase, OS = overall survival, CBA = chromosome banding analysis, +8 = trisomy 8, i(17q) = isochromosome (17q), +Ph = second Philadelphia chromosome, -7 = monosomy 7, -17 = monosomy 17, +17 = trisomy 17, -21 = monosomy 21, +21 = trisomy 21, -Y = loss of Y chromosome, ELN = European LeukemiaNet, IMA600 = Imatinib 600 mg daily, IMA400 = Imatinib 400 mg daily, NILO600 = Nilotinib 600 mg daily, DASA100 = Dasatinib 100mg daily, DASA140 = Dasatinib 140 mg daily.

Current therapy in children and adolescents with von Willebrand disease.

The article represents a review of recent data about the therapy of von Willebrand disease in children and adolescents (hereditary as well as acquired forms of the disease). The treatment of bleeding events in these patients, the indications in different subtypes, and the future lines of research are mentioned.

Actual biological diagnosis of acute myeloblastic leukemia in children.

Acute myeloblastic leukemia accounts for approximately 20% of acute leukemias in children. The days the microscope represented the main tool in the diagnosis and classification of Acute Myeloblastic Leukemia seem to be very far. This review summarizes the current diagnosis of this malignancy, where the morphological, cytochemical, immunophenotyping, cytogenetic and molecular characterization represents the basement of a risk group related therapy.

Up to date concepts about Von Willebrand disease and the diagnose of this hemostatic disorder.

The authors review the current data in literature regarding the recent knowledge about hemostase, coagulation and clinical and laboratory diagnostic algorithms of hemostatic disorders. They also present the pathological classification of bleeding disorders - the basis to clinical approach of these diseases.

Medullary allotransplant in acute myeloblastic leukemia in a child.

Although acute myeloblastic leukemia (AML) is more resistant to chemotherapy than acute lymphoblastic leukemia (ALL), significant progresses have been achieved over the last 20 years with an improvement in the long-term survival up to 50-60%. This may be attributed to the intensification of chemotherapy, including the increased use of stem-cell transplantation (HSCT) in well-defined subgroups. Allo-HSCT represents an extremely effective alternative in pediatric AML treatment panel, but its efficiency is limited both by the toxic effects and by the difficulty of finding a matched HLA donor.

Fludarabine, low-dose cyclophosphamide and rabbit antithymocyte globulin allowed stable engraftment after allogeneic peripheral blood stem cell transplantation for poly-transfused dyskeratosis congenita patient: case report.

BACKGROUND: Dyskeratosis congenita (DC) is characterized by the clinical triad of reticular skin pigmentation, oral leukoplakia, and nail dystrophy associated with bone marrow failure (BMF) and an high risk to develop cancer and pulmonary complications. The only curative treatment for patients with DC and BMF is stem cell transplantation. Due to the rarity of the disease, the best transplant procedure is not yet known. The use of myeloablative procedures has been associated with high mortality. In the last 2 decades, encouraging results have been obtained with nonmyeloablative procedures. Heavily transfused patients have an additional risk of graft failure. CASE REPORT: Herein we have reported a 4-year-old boy with DC and severe BMF at the time of transplantation, who had been transfused with nonleucodepleted blood products for 18 months. He experienced a favorable outcome after nonmyeloablative transplant conditioning using low-dose cyclophosphamide (40 mg/kg), fludarabine (180 mg/kg), and rabbit antithymocyte globulin (10 mg/kg). The patient received a peripheral stem cell graft containing 7.52 × 10(6) CD34/kg from an HLA identical sister. Graft versus host disease (GVHD) prophylaxis consisted of a short-term combination of cyclosporine and methotrexate. RESULTS: We observed rapid neutrophil engraftment on day +21 and for platelets on day +40. No early or late complications were recorded during 15 months follow-up. The patient developed only grade I skin GVHD. On day +30, chimerism assay showed 100% donor cells. CONCLUSION: Long-term follow-up is essential to establish the efficacy and safety of this procedure.

Post-transplant lymphoproliferative disorders after solid organ transplantation in children.

Post-transplant lymphoproliferative disease (PTLD) is a well recognized complication of solid organ transplantation (SOT) or bone marrow transplantation (BMT) associated with therapeutic immunosuppression (IS), first reported in 1968. Risk factors, therapy, and outcomes differ between PTLD observed following BMT and SOT. PTLD is a potentially fatal complication in the clinical course of transplant recipients, representing the most common malignancy after SOT in children and the second in the adult setting. This review presents the predisposing risk factors to the development of PTLD, along with clinical aspects, diagnostic work-up and therapeutic options in order to obtain a durable and complete remission with minimal toxicity. The extreme diversity of clinical presentations, sometimes with rapidly aggressive evolution, together with the heterogeneity of imagistic and histological findings, have proven the importance of the high degree of clinical suspicion. The early recognition and the prompt adequate treatment may improve the outcome.

Cytokine gene polymorphisms support diagnostic monitoring of Romanian multiple myeloma patients.

INTRODUCTION: Cytokines and their receptor genes are very polymorphic. SNPs in the promotor region of the gene may influence the rate of cytokine secretion and may affect the biological activity of the encoded cytokine. A number of cytokines and cytokine receptors have been directly linked to the development of human cancers. The aim of our study was to determine the cytokine gene polymorphism in Romanian multiple myeloma patients. MATERIAL AND METHODS: Cytokine genotyping was performed in 80 patients and 100 healthy blood donors using molecular biology methods (SSP-Invitrogen, USA). RESULTS: Analyzing each polymorphic site, there was an increased frequency of the following genotypes in patients compared to control group: Interleukin-1beta (IL-1ß) pos.+3962 TT, IL-12 pos.-1188 CC, gamma-Interferon (γ-IFN) pos.+874 AA, Transforming Growth Factor- beta1 (TGF- ß1) codon10 TT, IL-2 pos.-330 TG and pos.+166 TT, Interleukin-4Receptor alpha (IL-4Rα) pos.-33 TC, IL-10 pos.-1082 GG and pos.-592 CC, IL-6 pos.-174 GG. It should be noted that almost one third of multiple myeloma patients had IL-6 pos.-174 GG genotype and 62% IL-10 GCC haplotype. These identified haplotypes are high interleukins producer, and this fact was confirmed by serum IL-6 and IL-10 levels performed by ELISA and enhanced chemiluminiscence methods. CONCLUSION: These markers could be successfully used, together with other specific clinical and biological parameters, as reliable individualized prognostic factors in multiple myeloma patients.

Laparoscopic subtotal splenectomy in hereditary spherocytosis : to preserve the upper or the lower pole of the spleen?

BACKGROUND: Clinical manifestations of hereditary spherocytosis can be controlled by splenectomy. The use of this procedure has been restricted due to concerns regarding exposure of patients to a lifelong risk of overwhelming infections. Subtotal splenectomy, which removes 85-90% of the enlarged spleen, is a logical alternative. In the first cases performed by laparoscopy we have chosen to preserve the upper pole. However, this technique showed some disadvantages, especially concerning the correct intraoperative evaluation of the splenic remnant volume. Therefore, we developed a new variant of the procedure by preserving the lower pole of the spleen. METHODS: Based on the authors' experience in laparoscopy (176 laparoscopic splenectomies), 10 laparoscopic subtotal splenectomies were performed in patients with hereditary microspherocytosis, preserving either the upper or the lower splenic pole. RESULTS: Patient age ranged between 5 and 35 years. The mean volume of the remnant spleen was 41.4 cm3. There were no complications, and no transfusions were needed. Follow-up for 1-30 months was available. CONCLUSIONS: Subtotal splenectomy appears to control hemolysis while maintaining splenic function. The laparoscopic approach is safe and effective and should be considered the procedure of choice in hereditary microspherocytosis. Laparoscopic subtotal splenectomy presents an advantage over open subtotal splenectomy, resulting in decreased blood loss, shorter hospital stay, no conversions, fewer operative and postoperative complications, and excellent remission rates. On the basis of our experience, the preservation of the lower pole of the spleen seems to be a first-line option for the optimal evaluation of the residual splenic mass.

Total body irradiation prior to bone marrow transplantation--the experience of the Institute of Oncology Prof. Dr. Al. Trestioreanu Bucharest.

PURPOSE: To present the technique of total body irradiation (TBI), applied for the first time in Romania, at the Institute of Oncology Bucharest, as part of stem cell transplantation for hematological malignancies. PATIENTS AND METHODS: The total dose administered was 12 Gy at the reference point, 2 Gy/fraction, one fraction per day, 6 consecutive days, with a total dose of 8 - 11.4 Gy delivered to the lung, using Mevatron Primus linear accelerator (6 MV & 15 MV, 200-300 cGy/min in isocenter), in vivo dosimetry detectors and equipment for the reference dosimetry, personalized blocks for lung shielding sustained by polymethylmethaacrylate (PPMA) plate, Simulix HP simulator, and computer tomographic (CT) scans. Techniques used were: a) two parallel opposed anteroposterior / posteroanterior (AP/PA) fields with the patient in prone and supine position; b) two parallel opposed lateral fields with the patient placed on a lateral table, at 320 cm from the source. The percentage depth dose, tissue maximum ratio (TMR), off axis ratio (OAR) and the reference dose rate were measured for every patient's geometrical characteristics, with an uncertainty of +/- 2.2% and were used to calculate monitor units and to evaluate the dose in organs at risk (lungs, gonads, eyes etc). RESULTS: 5 patients (3 with the AP/PA technique and 2 with the lateral technique) were irradiated. All patients completed their irradiation in good clinical condition. The acute side effects were minimal (WHO grade 1: nausea/ vomiting--all patients; diarrhea--1 patient; headache--2 patients; photophobia and diplopia--1 patient; head and neck skin erythema--all patients). Because of the short follow-up period no safe evaluation of late side effects can be done. However, during this period one patient developed a non-aggressive form of chronic liver graft vs. host disease (GVHD) and one patient died due to acute GVHD. CONCLUSION: TBI as part of stem cell transplantation for hematological malignancies was successfully realized at our Institute, with favorable clinical results. This technique is easy to carry out and reproducible.

[Laparoscopic subtotal splenectomy in the treatment of hereditary spherocytosis]. / Splenectomia subtotala laparoscopica în tratamentul microsferocitozei ereditare.

Clinical manifestations of hereditary spherocytosis, the most common red blood cell membrane disorder, can be controlled by splenectomy. However, concerns regarding exposure of patients to a life long risk for overwhelming infections have restricted its use, especially în children. Subtotal splenectomy, as long as 80% to 90% of the enlarged spleen is removed, is a logical alternative. Subtotal splenectomy was effective în decreasing the hemolytic rate, while maintaining the phagocytic and immune function of the spleen. This surgical procedure should be considered în transfusion-dependent infants and children whit hereditary spherocytosis and în older patients whit erythrocyte membrane defects. Based on our experience în laparoscopy (120 laparoscopic splenectomies) and open subtotal splenectomy (5 cases) we performed 2 laparoscopic subtotal splenectomies in patients with hereditary microspherocytosis with good short term results. We have had no problem with blood loss and no transfusions were needed. The procedure can be performed safely and easily with all the traditional advantages of a minimally invasive approach. In order to evaluate the long term clinical benefit a minimal follow-up of 5 years is needed.

[Neonatal convulsions: the current concepts and classification]. / Convulsiile neonatale: conceptii actuale si clasificare.

The authors presented a new classification of the neonatal convulsions, based on prolonged EEG registrations related to concomitant clinical or videorecording of fits. They focussed on the atypical neonatal convulsions and on the differential diagnosis between epileptic and nonepileptic seizures. Finally, they discussed the therapeutical consequences of these new conceptions about the conclusions in the neonate.

[The characteristics of the anti-infectious defenses in newborn infants]. / Particularitati ale apararii antiinfectioase la nou-nascut.

The authors reviewed the up to date conceptions concerning the temporary alterations of the host defense mechanisms in the neonatal period (natural barriers, macrophages, complement system, cell-mediated and humoral immunity). They try to establish correlations between this temporary alterations and the high infectious risk and the severity of most of the infections in the newborn. A special attention is paid to the peculiar situation of the premature, and also to the modifications needed in the therapeutic schedules for serious neonatal infections.

[Pathogenetic mechanisms in neonatal infections]. / Mecanisme patogenice în infectiile neonatale.

The authors reviewed the pathogenetic mechanisms of ante-, intra- and postnatal infections of the newborn. They also discussed the results of the antenatal infections on embryo and foetus, and the clinical variants of intra- and postnatal infections. The attention is focused on the relationship between pathogenetic mechanisms and the relevant clinical and paraclinical alterations for the diagnosis of the most frequent encountered infections of the newborn.

[Antiviral chemotherapy in pediatrics--its present and prospects]. / Chimioterapia antivirala în pediatrie--prezent si perspective.

Authors discuss the general aspects of viral infections and the principles of antiviral chemotherapy. First section deals with the stages, the types of viral infections and the basic principles for action of antiviral drugs. Authors review also the up-to-date situation of antiviral therapy in pediatrics, the problem of resistant strains and formulate the expected progress in the field of antiviral chemotherapy.

[The diagnostic algorithm in neonatal infections]. / Algoritmul diagnostic în infectiile neonatele.

Authors review the principles of diagnosis in neonatal bacterial infections (local and systemic), in congenital, peri- and postnatal viral infections and also in Candida spp. and other mycotic infections of the neonatal period. They try to delineate the clinical and epidemiological criteria of suspicion and modalities of confirmation of the neonatal infections by specific paraclinical methods. Attention is focused on modern diagnostic methods (such as immunofluorescent techniques, counterimmunoelectrophoresis and so on), which are important for the early etiological diagnosis and for thr rapid initiation of specific therapy. Authors made a practical diagnostic algorithm for the most frequent encountered neonatal infections. They also focused on the recent changes in the etiology of neonatal infections and their therapeutic significance.