Ultrasound presentation of abdominal non-Hodgkin lymphomas in pediatric patients.

INTRODUCTION: Burkitt's lymphoma accounts for approximately 25% of lymphomas diagnosed in children of developmental age. The tumor is localized mainly in the intestine (usually in the ileocecal region), mesenteric lymph nodes and extraperitoneal space. The clinical symptoms are non-specific and include: abdominal pain, vomiting, gastrointestinal bleeding, and acute abdomen suggesting appendicitis or intestinal intussusception. On ultrasound examination, Burkitt's lymphoma may manifest itself in various ways, depending on the origin of the lesion. AIM: The aim of this paper was to review the ultrasound manifestation of abdominal Burkitt's lymphoma in children. MATERIAL AND METHODS: The analysis included 15 pediatric patients with Burkitt's non-Hodgkin lymphoma in the abdominal cavity. The mean age of the patients was 9.5. Abdominal and gastrointestinal ultrasound examinations were conducted using a Siemens scanner with a convex transducer of 3.5-5 MHz and linear array transducer of L4 - 7.5 MHz. RESULTS: Ultrasound examinations conducted in the group of 15 patients revealed pathological masses localized in the gastric wall in 3 patients (20%), in the ileocecal region in 10 patients (67%) and a disseminated process in 2 patients (13%). In 12 patients with a diagnosed Burkitt's non-Hodgkin lymphoma in an extragastric localization, differences in the morphology of the lesions were observed. CONCLUSIONS: The clinical and ultrasound picture of abdominal Burkitt's lymphoma in children is variable. A careful ultrasound assessment of all abdominal organs conducted with the use of convex and linear probes increases the chances of establishing an adequate diagnosis.

Differential ex vivo activity of bortezomib in newly diagnosed paediatric acute lymphoblastic and myeloblastic leukaemia.

The proteasome inhibitor, bortezomib, is known to be effective in the therapy of various neoplasms. The objective of this study was the analysis of the ex vivo activity of bortezomib in paediatric acute lymphoblastic leukaemia (ALL), in comparison to paediatric acute myeloid leukaemia (AML). A total of 159 patients entered the study, including 106 ALL (including 86 precursor-B-cell ALL, and 20 T-cell ALL) and 53 AML children. The ex vivo sensitivity to bortezomib and 16 other drugs was studied by MTT assay. Paediatric AML samples were more resistant than paediatric ALL samples to most of the tested drugs, except for cytarabine and thioguanine. With respect to immunophenotype, ex vivo drug resistance in T-cell ALL (T-ALL) was higher for most of the drugs. No differences in drug resistance between T-ALL and common/pre-B-cell-ALL were found for daunorubicin, mitoxantrone and 6-thioguanine. Bortezomib was the only compound which was more active in T-ALL than in common/pre-B-ALL paediatric samples. In conclusion, bortezomib had good ex vivo activity in paediatric T-ALL samples.

Comparison of clofarabine activity in childhood and adult acute leukemia: individual tumor response study.

BACKGROUND: Clofarabine is a second-generation nucleoside analogue. The aim of the study was the analysis of ex vivo activity of clofarabine and 14 other anticancer drugs in pediatric and adult acute lymphoblastic (ALL) and myeloid (AML) leukemia. PATIENTS AND METHODS: The ex vivo drug resistance profile was analyzed in 282 patients, including 201 children with ALL de novo, 24 children with relapsed ALL, 25 children with AML de novo and 32 adults with AML. Cellular ex vivo drug resistance was tested by means of the MTT assay. RESULTS: Clofarabine had comparable ex vivo activity against lymphoblasts and myeloblasts, both on initial diagnosis and at relapse, both in children and in adults. Its activity in acute myeloid leukemia was independent of patient age. No significant differences in drug resistance to clofarabine between pediatric age-based subgroups of ALL were detected, while it was observed for most of other drugs. An activity of clofarabine in relapsed pediatric ALL patients was as good as in newly-diagnosed ones. CONCLUSION: In comparison to childhood acute lymphoblastic leukemia, lack of differences in ex vivo activity gives rationale for use of clofarabine in refractory and relapsed pediatric and adult patients with acute myeloid leukemia.

Prognostic impact of combined fludarabine, treosulfan and mitoxantrone resistance profile in childhood acute myeloid leukemia.

BACKGROUND: The role of cellular drug resistance in childhood acute myeloid leukemia (AML) has not yet been established. The aim of the study was the analysis of the clinical value of ex vivo drug resistance in pediatric AML. PATIENTS AND METHODS: A cohort of 90 children with de novo AML were assayed for drug resistance profile by the 3-4,5-dimethylthiazol-2-yl-2,5-difenyl tetrazolium bromide (MTT) assay and prognostic model of in vitro drug sensitivity was analyzed. RESULTS: Children who relapsed during follow-up showed higher in vitro resistance of leukemic blasts to most of the drugs tested, except for cytarabine, cladribine, vincristine, mercaptopurine and thioguanine. A combined in vitro drug resistance profile to fludarabine, treosulfan and mitoxantrone (FTM score) was defined and it had an independent prognostic significance for disease free survival in pediatric AML. CONCLUSION: The combined fludarabine, treosulfan and mitoxantrone resistance profile to possibly may be used for better stratification of children with AML or indicate the necessity for additional therapy.

[Results of immunosupressive therapy in children with severe aplastic anaemia. Report of the Polish Paediatric Haematology Group]. / Wyniki leczenia ciezkiej postaci anemii aplastycznej u dzieci. Raport Polskiej pediatrycznej grupy do spraw nienowotworowych chorób ukladu krwiotwórczego.

INTRODUCTION: Bone marrow transplantation from HLA identical family donors is the treatment of choice for children with severe aplastic anaemia (SAA). When there is no donor available, combined immunosuppressive therapy is given. AIM: evaluation of results of immunosupressive therapy in children with severe aplastic anaemia. MATERIAL AND METHODS: SAA was diagnosed in 105 children (42 girls, 73 boys), aged 2-18 years, in the eleven haematological centres in Poland, between 1993-2007. All patients received the Severe Aplastic Anaemia Working Party of the EBMT protocol which included: antilymphocyte globulin or antithymocyte globulin, cyclosporin A, prednisolone. Granulocyto- or granulocytomacrophagic-cell stimulation factor was additionally administered during deep neutropenia. Haematological response was evaluated on day 84 or 112 and 180 of the therapy. RESULTS: complete remission occurred in 53 patients (51.5%), partial remission in 27 (24.7%), no response was obtained in 25 children (23.8%) on day 180, of the therapy. Period of observation was from 12 months to 12.5 years. During this time relapse occurred in 10 patients (9.5%). We observed 22 deaths: 8 early, during the first 3 months of IS and 14 after the first 3 months of immunosuppresive therapy (IS). At present 70 children (66.6%) are in first remission with lasts from 12 months to 12.5 years. The survival at 12.5-years is 78.6%. During the 12.5 years of follow-up we had two cases with a late clonal complication (PNH and MDS). Transformation to acute nonlymphoblastic leukaemia was observed in two of our patients. CONCLUSIONS: 1. Immunosuppresive therapy (IS) in children with SAA, without bone marrow family donors, is more effective after introduction of combined IS (12.5 years survival in this study was 80% for children with very severe aplastic anaemia (v SAA). 2. In our studies among the children followed up after IS therapy, there were: 1 case of periodic nocturnal haemoglobinuria (PNH), 1 case of myelodysplastic syndrome (MDS) and 2 cases of myeloid leukaemia (probability of incidence was 3.8%).

Predictive value of multidrug resistance proteins and cellular drug resistance in childhood relapsed acute lymphoblastic leukemia.

PURPOSE: Cellular resistance in childhood acute leukemias might be related to profile and function of multidrug resistance proteins and apoptosis regulating proteins. The aims of the study were: (1) analysis of expression of MRP1, PGP1, LRP, BCL-2 and p53 proteins; (2) correlation with ex vivo drug resistance, and (3) analysis of their prognostic impact on clinical outcome in childhood acute lymphoblastic (ALL) and acute myeloid (AML) leukemia. METHODS: Total number of 787 children diagnosed for initial ALL (n = 527), relapsed ALL (n = 104), initial AML (n = 133) and relapsed AML (n = 23) were included into the study. Mean follow-up period was 3.5 years. Drug resistance for up to 30 anticancer agents was performed by the MTT assay. Expression of all proteins was tested by flow cytometry. RESULTS: Both initial AML and relapsed ALL samples showed higher drug resistance than initial ALL samples. No significant differences were found in drug resistance between initial and relapsed AML samples. The presence of multidrug resistance and apoptosis proteins had no impact on pDFS in iALL and iAML, however strong trend towards adverse prognostic impact of MRP1, PGP and LRP on pDFS in rALL was observed. The same trend was observed for each of analyzed co-expressions of tested multidrug resistance proteins. CONCLUSIONS: The phenomenon of cellular drug resistance in childhood acute leukemias is multifactorial and plays an important role in response to therapy. Expression of MRP1, PGP and LRP proteins, as well as their co-expression play possible role in childhood relapsed ALL.

[Rheumatological symptoms masking neoplasm in children]. / Objawy reumatologiczne jako przepowiadajace schorzenia nowotworowe--obserwacje wlasne.

UNLABELLED: Fevers, arthritis, myalgia and skin changes are the most typical features of rheumatic diseases, although one should remember that the same symptoms could mask neoplasm. This study shows that some patients with rheumatological symptoms treated in the Department of Lung Diseases and Children Rheumatology, Medical University of Lublin were finally diagnosed with neoplasm. In focus is the initial phase of the patients' illnesses. MATERIAL AND METHODS: We analyzed retrospectively the case histories of all patients admitted to the department between 1997 and 2005 (1560 hospitalizations). An oncological disease was diagnosed in 9 cases: leukemia in 4 children (acute lymphoblastic leukemia-ALL- in 3 cases, acute non-lymphoblastic leukemia-ANLL- in 1 case), Hodgkin's disease in 1 child, bone tumours in 2 children, liver tumour in 1 child and a tumour of the central nervous system in 1 child. CONCLUSIONS: The cases described should draw the physicians' attention to the fact that in the initial phase an oncological disease may be masked by rheumatological symptoms.

Skin involvement in highly malignant non-Hodgkin lymphomas of childhood and adolescence.

OBJECTIVE: The aim of this study was to demonstrate the clinical spectrum of highly malignant cutaneous non-Hodgkin lymphoma (NHL) in children and to define the outcome among these patients. MATERIAL AND METHODS: A retrospective analysis of children with NHL treated at Polish oncology centers was carried out in order to determine patients with skin involvement. Thirteen subjects with primary and 4 with secondary cutaneous NHL were studied. The diagnosis of NHL was based on histological and immunohistochemical examination of skin biopsy. RESULTS: Nine of 13 cases of primary cutaneous NHL presented as a tumors. Other manifestations were as follows: hard infiltration, edema of subcutaneous tissue, maculopapular lesions, and generalized erythroderma. The mean time between the first cutaneous symptoms and diagnosis of NHL was 5.6 +/- 3.3 months. Secondary cutaneous lesions during the course of NHL were described as maculopapular or nodular eruption. In addition, 2 subjects had generalized ichthyosis. Among patients with primary cutaneous NHL, 11 (84.6%) subjects are still alive without any signs of the disease. Two children (15.4%) died. In patients with secondary skin involvement during the course of NHL only one child is still alive with a residual tumor mass in the mediastinum. The estimated 5-year overall survival for primary cutaneous NHL was significantly better than for individuals with secondary cutaneous NHL (p = 0.02). CONCLUSIONS: Primary cutaneous NHL has a relatively favorable prognosis. On the other hand, cutaneous metastases of extracutaneous NHL seem to be a poor prognostic factor.

[Results of immunosuppressive therapy in children with severe aplastic anaemia. Report by the Polish Paediatric Leukaemia and Lymphoma Study Group]. / Efekty leczenia immunosupresyjnego ciezkiej postaci anemii aplastycznej u dzieci. Raport polskiej pediatrycznej grupy ds. leczenia bialaczek i chloniaków.

INTRODUCTION: Bone marrow transplantation from HLA identical family donors is the treatment of choice for children with severe aplastic anaemia (SAA). When no donor is available, combined immunosuppressive therapy is given. AIM: Evaluation of results of immunosuppressive therapy in children with severe aplastic anaemia. MATERIAL AND METHODS: SAA was diagnosed in 85 children (31 girls, 54 boys) aged 2-17.5 years in the eleven centres of the Polish Paediatric Leukaemia and Lymphoma Study Group (PPLLSG) in Poland between 1993-2003 years. All patients received protocol of the Severe Aplastic Anaemia Working Party of the Europe Bone Marrow Transplant (EBMT): antilymphocyte globulin or antithymocyte globulin, cyclosporin A, prednisolone and granulocyto- or granulocyto-macrophagic-cell stimulation factor was additionally administered during deep neutropenia. Haematological response was evaluated on day 84, 112 or 180 of the therapy. RESULTS: complete remission occurred in 43 patients (50.5%), partial remission in 22 (25.4%), no response was obtained in 20 children (23.7%) in 180 day of the therapy. Period of observation was from 12 months to 10.5 years. During this time relapse occurred in 6 patients (7%). We observed 16 deaths: 7 early during the first 3 months of immunosuppressive therapy (IS) and 9 after the first 3 months of IS. CONCLUSION: the actual survival at 10-years, after immunosuppressive therapy is 81.2% in our group. Transformation to leukaemia or myelodysplastic syndrome (MDS) was not observed in any of our patients. We observed one case with paroxysmal nocturnal haemoglobinuria (PNH).

Diagnosis and staging of children's lymphoma using the technetium-labelled somatostatin analogue, 99mTc-depreotide.

Somatostatin receptor scintigraphy (SRS) is useful in diagnosing tumours with increased expression of somatostatin receptors. Lymphoma cells are known to express somatostatin receptors; however, the application of indium-labelled analogues in children is limited. The aim of this study was to investigate whether the technetium-labelled somatostatin analogue, depreotide, may be useful in diagnosing and staging malignant lymphoma in children. Fifteen children (mean age 13.8 years) with malignant lymphoma were studied (eight with Hodgkin's lymphoma and seven with non-Hodgkin's lymphoma). All children were investigated for verification of staging established by other modalities. Imaging was performed 3-5 h after administration of 300-550 MBq (99m)Tc-depreotide. All patients underwent whole-body scan and single-photon emission tomography of the chest and/or abdomen. Images were assessed visually. In all patients, foci of increased tracer uptake were found. The neck and thorax were the most frequent lesion localisations. Abdominal lesions were found in four patients, and bone lesions in three. In two patients, diffusely increased uptake was observed throughout the skeleton (verified as representing bone marrow involvement). In 11 patients, the number of abnormal sites detected by SRS was greater than that detected by CT. Based on radionuclide examination, three children were upstaged and none were downstaged. It is concluded that (99m)Tc-depreotide shows increased accumulation in pathological sites in malignant lymphoma in children. SRS with (99m)Tc-depreotide provides a single-day imaging method with high sensitivity in lymphoma and with all the advantages of a technetium-labelled compound. Further studies are required on the specificity and the possible value of (99m)Tc-depreotide in the follow-up of these patients.

[Non-Hodgkin lymphomas of the nasopharynx in children--diagnostic and therapeutic difficulties]. / Chloniaki nieziarnicze nosogardla u dzieci--trudnosci diagnostyczne i terapeutyczne.

UNLABELLED: About 7% of all childhood cancers comprise non-Hodgkin's lymphoma (NHL). NHL are heterogenous group of neoplasms deriving from lymphatic system (cell B and T). B-cell NHL characterize by high malignancy, but coincidentally good reaction for treatment. In about 20% primary tumour is localised within head and neck, and nasopharynx lymphomas comprise 10%. This location maintains the biggest diagnostic and therapeutic difficulties because of tumours of this site proliferate in the region of frequent infections postponing a proper diagnosis and the local control after complete treatment is difficult. AIM OF THE STUDY: The authors analyse clinical symptoms before diagnosis, the incidence of nasopharynx lymphomas, histopathological type of neoplasm, clinical stage, results of treatment. MATERIAL AND METHODS: The study includes 97 patients who were treated because of lymphomas between 1993-2002. The character of clinical symptoms and their duration, histopathological type of lymphomas, results of treatment were analysed. RESULTS: The primary nasopharynx location was assessed in 9 patients (9.3%). Sex: 7 boys, 2 girls, age: 2-17 years. The duration which elapsed from initial clinical symptoms to diagnosis was 2-10 weeks. The histopathological assessment in 6 children was Burkitt lymphoma and in 3 children--Burkitt-like lymphoma. Metastases: CNS--1 patient, bone marrow--1 patient, abdomen--1 patient. Treatment was performed according to LMB-89 protocol. RESULTS: First complete remission--7 patients; second complete remission--2 patients. CONCLUSIONS: Lymphomas of nasopharynx cause diagnostic problems because of their early stage pseudo-inflammatory manifestation. Special attention should be paid to perform imaging studies (MRI/CT), which are useful in the reaching the proper diagnosis. The radiologic evaluation of primary lesion is still difficult. In the doubtful cases, the surgery and histopathological examination are necessary.

[Progress in the treatment of non-Hodgkin's lymphoma (NHL) in children. The report of Polish Pediatric Leukaemia/lymphoma Study Group (PPLLSG)]. / Postep w leczeniu nieziarniczych chloniaków zlosliwych (NHL) u dzieci. Raport Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków u Dzieci (PPGLBC).

Treatment results of non-Hodgkin lymphoma (NHL) in children has been shown in this study. From 1979 to 2003 children were registered with the diagnosis of NHL in oncology centers of Polish Pediatric Leukaemia/Lymphoma Study Group, a group of 397 patients with NHL B, 222 pts with NHL T and 54 pts with anaplastic large cell lymphoma (ALCL). The pts with NHL T have been treated according to BFM-90 protocol. The predominant primary site of disease was mediastinum (59.3%). Complete remission (CR) was achieved by 87%. EFS for all NHL T pts was 65% and 56% for pts with extensive tumours and 73% for pts with tumours < 10 cm. Patients with NHL B were treated according to the adopted LMB-89 protocol. The majority were Burkitts type and presented abdominal location (50%). 80% with disseminated disease. CR was achieved by 89% patients, but 94% with LDH < 500 IU/L and 73% with LDH > 500 IU. The median time of follow up was 53 months. EFS was 73% for all patients. The patients with ALCL were treated according to several protocols. Peripheral nodes were the most often primary location (40%), than mediastinum (24%) and abdomen (21%). EFS for all pts was 63%. Despite great progress in the therapy of NHL in children during 20 years of observation, the results are not satisfactory in disseminated stages. It is necessary to look for new prognostic markers which make it possible to improve classification of patients. Major surgery in advanced stages is not recommended since it delays chemotherapy and fails to improve overall survival. Early detection of neoplasm is one of the most important efforts to improve therapy success.

[Efficacy of idarubicin in the treatment of childhood acute non-lymphoblastic leukemia: report of Polish Pediatric Leukemia/Lymphoma Study Group]. / Zastosowanie idarubicyny w leczeniu ostrej bialaczki nielimfoblastycznej u dzieci--Raport Polskiej Grupy Pediatrycznej ds Bialaczek i Chloniaków.

UNLABELLED: Results of treatment of childhood ANLL remained unsatisfactory for a long time, and introduction of a new drug seemed justified as the EFS achieved in this disease between 1993-97 was 42%. In 1998 a new protocol containing idarubicine in dose 12 mg/m2 (each dose regardless of treatment phase) was introduced. Between 1998 and 2001, 137 children with ANLL were referred to nine participating centers of PPLLSG. Thirty nine were uneligible, so 98 were evaluated. Among them 56 were qualified to standard risk group (SRG) and 35 to high risk group (HRG). In 7 children the risk group was not established due to early death. Remission rate was 79% in the whole group and 98% and 63% in SRG and HRG, respectively. The actuarial 3-year overall survival (OS), 3-year event-free survival (EFS) and 3-year event-free interval (EFI) are respectively: In the whole group 61%, 54% and 67%; in SRG 81%, 70% and 71%; in HRG 40%, 40%, and 53%. CONCLUSIONS: Due to introduction if idarubicine significant improvement of the results was achieved in SRG (better OS, EFS and EFI). Better new treatment methods are required in HRG.

Urinary excretion of N-acetyl-beta-D-glucosaminidase and alpha1-microglobulin in children with proliferative blood diseases.

The purpose of the study was to estimate the urinary excretion of NAG and alpha-1M among children who suffer from proliferative blood diseases. The group of the examined children included those who went through a viral hepatitis (VH) and who are or were treated by means of cytostatic drugs. The study comprised 73 children aged from 4 to 18 (average 11.7+/-3.5. There were 70 children with the diagnosis of leukemia and 3 with the diagnosis of non-Hodgkin lymphoma. The examined group was divided according to the stage of treatment of a basic disease. Group I--22 children who are treated currently or whose treatment has been completed recently. Group II--51 children whose treatment was completed over two years ago. In group II there were 4 subgroups distinguished depending on positive antigenemia HBs and the presence of HCV antibodies. There were no clinical or biochemical features of damage of renal function observed among any of the children. The testing group consisted of 70 healthy children who were selected regarding age and sex. The urinary excretion of NAG and alpha-1M was estimated in the second morning portion of urine and it was presented as NAG/creatinine and alpha-1M/creatinine ratio. The results of the research underwent the statistical analysis by means of a t-Student test. It was stated that the urinary excretion of NAG and alpha-1M was higher among children who currently are or were treated by means of cytostatics drugs. It was also stated that the urinary excretion of NAG was higher among the children who went through viral hepatitis C in comparison with HBs antigen carriers. Similarly, the urinary excretion of alpha-1M was higher among children with positive markers of viral hepatitis B and C markers in comparison with a group of HBs antigen carriers.

In vitro activity of glufosfamide in childhood acute leukemia.

Glufosfamide is a new agent for cancer chemotherapy. The objective of the study was the comparison of the in vitro drug resistance profile of glufosfamide with other oxazaphosphorines in 106 samples of childhood acute leukemia by means of the MTT assay. The following drugs were tested: glufosfamide, 4-HOO-ifosfamide, 4-HOO-cyclophosphamide, mafosfamide cyclohexylamine salt, prednisolone, vincristine, L-asparaginase, daunorubicin and cytarabine. In the group of initial Acute Lymphoblastic Leukemia (ALL) samples, equivalent cytotoxicity values for glufosfamide, 4-HOO-ifosfamide, 4-HOO-cyclophosphamide and mafosfamide were 5.95, 9.92, 4.60 and 3.90 microg/ml, respectively. In comparison to initial ALL samples, the relative resistance for glufosfamide and 4-HOO-ifosfamide in relapsed ALL samples were 1.9 (p=0.049) and 1.3 (ns), and in initial Acute Myeloblastic Leukemia (AML) samples, respectively, 31 (p<0.001) and 5 (p=0.001). All oxazaphosphorines showed highly significant cross-resistance. In conclusion, in vitro activity of glufosfamide is comparable to ifosfamide. Glufosfamide shows high activity against lymphoblasts both on diagnosis and on relapse, however it cannot circumvent resistance to other oxazaphosphorines.

Ex vivo drug resistance profile in childhood acute myelogenous leukemia: no drug is more effective in comparison to acute lymphoblastic leukemia.

Therapy results in childhood acute myelogenous leukemia (AML) differ from those of acute lymphoblastic leukemia (ALL). Cellular drug resistance might be one of the reasons of therapy failure in AML. The aim of the study was the analysis of ex vivo drug resistance profile in childhood initial and relapsed AML in comparison to initial ALL. Fifty-three AML samples were tested for chemosensitivity and results were compared with those of 106 initial ALL samples. Ex vivo drug resistance was tested by means of the MTT assay. Up to 29 cytotoxic drugs were tested for each patient. When compared to de nova ALL samples, myeloblasts from initial AML samples were significantly more resistant to most tested drugs, except cytarabine, mercaptopurine and thioguanine. Relapsed AML samples, in relation to initial AML samples, showed comparable sensitivity to cytarabine, idarubicin, fludarabine and cladribine. Patients, who have died due to refractory or relapsing disease, were already on first diagnosis 2-fold more resistant to cytarabine, 6.4-fold more resistant to cisplatin and 3-fold more resistant to carboplatin, when compared to those who stay in remission. Resistance to prednisolone was observed in 85% initial and all relapsed AML samples, in comparison to 33% of ALL samples. Resistance to cytarabine occurred in 2.1% of ALL and 12% of AML cases while a patient with Down syndrome presented the most sensitive drug resistance profile. In conclusion this study shows that no drug was found which, on average, was more effective in AML than in ALL samples. The sensitivity of myeloblasts to platinum derivatives might have prognostic value.