Anaphylaxis in Turkish children: a multi-centre, retrospective, case study.

BACKGROUND: Anaphylaxis is a serious and potentially lethal systemic reaction affecting more than one organ or system. OBJECTIVE: We aimed to describe the demographic characteristics, clinical features, causes, settings, and administered therapy in Turkish children. METHODS: This retrospective, case note study included all children referred to the outpatient clinics of the Pediatric Allergy Departments of the participating study centres from 1 July 1999 to 30 June 2009 for investigation of anaphylaxis or who were seen by us at the moment of the reaction during the same period and who met the clinical criteria of anaphylaxis. RESULTS: Two hundred and twenty-four cases of anaphylaxis were reported in 137 children (88 boys, P = 0.0001). The mean ± SD age at the referral was 7.7 ± 4.2 years (range: 4 months-17 years). Ninety-eight episodes (43.8%) occurred at home. The symptoms were cutaneous in 222 (99.1%) episodes, respiratory in 217 (96.9%), neuro-psychiatric in 118 (52.7%), cardiovascular in 92 (41.1%), and gastrointestinal in 88 (39.3%). Biphasic reaction was reported in seven episodes (3.1%, 95% CI: 1.5-6.3). Death occurred in one case (0.4%, 95% CI: 0.08-2.4). Treatment was available in 158 episodes (70.5%). Of them, 148 (93.7%) received antihistamines, 132 (83.5%) corticosteroids, 51 (32.3%) epinephrine, and 17 (10.8%) beta-2-mimetics. The causative agents were foods in 86 (38.4%) episodes, hymenoptera venom in 84 (37.5%), drugs and medications in 47 (21.0%), and latex in 5 (2.2%). In two episodes (0.9%), the causative agent was unidentified. Allergy to the trigger was known prior to anaphylaxis in 116 (51.8%) episodes. An epinephrine auto-injector had been prescribed for 70 children (51.1%). CONCLUSIONS AND CLINICAL RELEVANCE: Anaphylaxis was seen significantly more in boys. Most of the reactions occurred at home. Foods were the most frequent cause. Epinephrine, the first-line treatment of anaphylaxis, was administered in only a third of the children.

Paediatricians’ perspectives on the use of pneumococcal vaccine in healthy and asthmatic children

Background: Pneumococcal polysaccharide vaccines were developed in recent decades to reduce the burden of pneumococcal diseases. Little is known about paediatricians’ perspectives on the use of pneumococcal vaccine. Objective: We aimed to examine physicians’ self-reported beliefs and attitudes about the pneumococcal vaccine and their daily clinical practice concerning immunisation against pneumococci in healthy and asthmatic children before the introduction of a nationwide vaccination program. Methods: A questionnaire survey was applied to the paediatricians attending a national paediatrics congress in 2008. Results: Of the 265 paediatricians, 167 responded to the questionnaire. Most (74.5%) believed that antimicrobial resistance could be reduced with the use of the vaccine. 88.5% of the paediatricians declared the pneumococcal vaccine to be a safe vaccine and agreed that the polysaccharide conjugate vaccine-7 should be added to the national vaccination programme. Nearly half of the paediatricians believed that asthmatic children vaccinated with pneumococci had fewer and less severe asthma attacks. 40.0% of the responders stated that the pneumococcal vaccine should be reserved for severe asthmatic children. As the duration of experience increases, the number of patients evaluated per week decreases, and the physicians working in the outpatient clinics tend to vaccinate all children. Conclusion: Despite the paediatricians’ belief in the necessity and importance of the pneumococcal vaccine, none of the examined factors influenced their clinical practice. As the asthma guidelines become clearer regarding the effect of pneumococcal diseases in asthmatics, the perspective of paediatricians may evolve towards greater immunisation

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Paediatricians' perspectives on the use of pneumococcal vaccine in healthy and asthmatic children.

BACKGROUND: Pneumococcal polysaccharide vaccines were developed in recent decades to reduce the burden of pneumococcal diseases. Little is known about paediatricians' perspectives on the use of pneumococcal vaccine. OBJECTIVE: We aimed to examine physicians' self-reported beliefs and attitudes about the pneumococcal vaccine and their daily clinical practice concerning immunisation against pneumococci in healthy and asthmatic children before the introduction of a nationwide vaccination program. METHODS: A questionnaire survey was applied to the paediatricians attending a national paediatrics congress in 2008. RESULTS: Of the 265 paediatricians, 167 responded to the questionnaire. Most (74.5%) believed that antimicrobial resistance could be reduced with the use of the vaccine. 88.5% of the paediatricians declared the pneumococcal vaccine to be a safe vaccine and agreed that the polysaccharide conjugate vaccine-7 should be added to the national vaccination programme. Nearly half of the paediatricians believed that asthmatic children vaccinated with pneumococci had fewer and less severe asthma attacks. 40.0% of the responders stated that the pneumococcal vaccine should be reserved for severe asthmatic children. As the duration of experience increases, the number of patients evaluated per week decreases, and the physicians working in the outpatient clinics tend to vaccinate all children. CONCLUSION: Despite the paediatricians' belief in the necessity and importance of the pneumococcal vaccine, none of the examined factors influenced their clinical practice. As the asthma guidelines become clearer regarding the effect of pneumococcal diseases in asthmatics, the perspective of paediatricians may evolve towards greater immunisation.

Pattern of pediatric poisoning in the east Karadeniz region between 2002 and 2006: increased suicide poisoning.

In the present study, 386 patients with the diagnosis of poisoning admitted to the Pediatric Emergency Unit of Farabi Hospital of Medical Faculty of Karadeniz Technical University between January 2002 and December 2006 were retrospectively evaluated with respect to gender, age, cause of poisoning, type of substance used, route of exposure, reason for the intake, signs and symptoms, time of referral to the hospital, hospitalization period, and prognosis. The age group of most poisoning cases was <5 years of age and constituted 51% (n = 197) of all cases. The main toxic agent was drugs (70.2%), followed by foods (8.8%), rodenticides (7%), insecticides/pesticides (4.9%), and carbon monoxide (4.7%). In childhood poisonings, accidental drug poisoning was frequent in toddlers, whereas suicidal poisoning was frequent in adolescents. The suicidal poisoning rate was 23.8% among all poisoning patients, and 98.9% of these patients were adolescents. The suicidal poisoning rates for males and females were 30% and 70%, respectively. An increase in suicidal and inhalation poisonings was observed when compared with previous studies that have been conducted in the same region. The results of the present study suggest that poisonings still represents an important health problem that could be prevented by safe drug storage at home, as well as parental education on adolescence issues, particularly those regarding females.

Prevalence of immunoglobulin E-mediated food allergy in 6-9-year-old urban schoolchildren in the eastern Black Sea region of Turkey.

BACKGROUND: The prevalence of adverse reactions to food in childhood in Turkey is not known. OBJECTIVE: We aimed to investigate the prevalence and characteristics of IgE-mediated food allergies (FAs) in 6-9-year-old urban schoolchildren. METHODS: This cross-sectional study recruited 3500 of the randomly selected 6-9-year-old urban schoolchildren from the eastern Black Sea region of Turkey during 2006. Following a self-administered questionnaire completed by the parents and the child, consenting children were invited for skin prick tests (SPTs) and oral food challenges. Children with suspected IgE-mediated FA were skin prick tested with a predefined panel of food allergens (milk, hen's egg, soy, wheat, peanut, fish, and hazelnut), aeroallergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat, dog, Alternaria, grass pollen mix, weed pollen mix, and tree pollen mix), and food allergens reported in the questionnaire. All children with a positive SPT to any food were invited for a double-blind, placebo-controlled food challenge (DBPCFC). The prevalence of IgE-mediated FA was established using DBPCFCs. RESULTS: The response rate to the questionnaire was 78.2% (2739/3500). The estimated prevalence of parental-reported IgE-mediated FA was 5.7% (156/2739) [95% confidence interval (CI), 4.83-6.57%]. The rate of sensitization to the food allergens was 33.1% (48/145) in the parental-reported group. The confirmed prevalence of IgE-mediated FA by means of DBPCFC in 6-9-year-old urban schoolchildren living in the eastern Black Sea region of Turkey was 0.80% (22/2739) (95% CI, 0.47-1.13%). The most common allergenic foods were beef (31.8%), cow's milk (18.1%), cocoa (18.1%), hen's egg (13.6%), and kiwi (13.6%). CONCLUSIONS: The rate of reported IgE-mediated FA was significantly higher than clinically confirmed FA by means of DBPCFC (odds ratio, 7.46; 95% CI, 4.67-12.01; P<0.0001). The order of allergenic foods was different and somewhat unique to the eastern Black Sea region of Turkey when compared with western countries.

A multicenter survey of childhood asthma in Turkey. II: Utilization of asthma drugs, control levels and their determinants.

Many surveys worldwide have consistently demonstrated a low level of asthma control and under-utilization of preventive asthma drugs. However, these studies have been frequently criticized for using population-based samples, which include many patients with no or irregular follow-ups. Our aim, in this study, was to define the extent of asthma drug utilization, control levels, and their determinants among children with asthma attending to pediatric asthma centers in Turkey. Asthmatic children (age range: 6-18 yr) with at least 1-yr follow-up seen at 12 asthma outpatient clinics during a 1-month period with scheduled or unscheduled visits were included and were surveyed with a questionnaire-guided interview. Files from the previous year were evaluated retrospectively to document control levels and their determinants. From 618 children allocated, most were mild asthmatics (85.6%). Almost 30% and 15% of children reported current use of emergency service and hospitalization, respectively; and 51.4% and 53.1% of children with persistent and intermittent disease, respectively, were on daily preventive therapy, including inhaled corticosteroids. Disease severity [odds ratio: 12.6 (95% confidence intervals: 5.3-29.8)], hospitalization within the last year [3.4 (1.4-8.2)], no use of inhaled steroids [2.9 (1.1- 7.3)], and female gender [2.3 (1.1-5.4)] were major predictors of poor asthma control as defined by their physicians. In this national pediatric asthma study, we found a low level of disease control and discrepancies between preventive drug usage and disease severity, which shows that the expectations of guidelines have not been met even in facilitated centers, thus indicating the need to revise the severity-based approach of asthma guidelines. Efforts to implement the control-based approach of new guidelines (Global Initiative for Asthma 2006) would be worthwhile.

Food-dependent exercise-induced anaphylaxis to lentil and anaphylaxis to chickpea in a 17-year-old boy.

We report the case of a 17-year-old boy who experienced 4 episodes of exercise-induced anaphylactic reaction after ingestion of lentil and 2 episodes of anaphylaxis following ingestion of chickpea. His medical history revealed that he had allergic rhinitis with positive results after skin prick tests (SPT) with mites. His SPTs and specific immunoglobulin E antibody testing with lentil and chickpea were positive. Oral challenge with chickpea was not performed due to patient refusal. Treadmill exercise challenge tests in the fasting state and 1 hour after a meal not containing lentil were negative. However, an exercise challenge test 1 hour after intake of lentil soup resulted in pruritus of the hands, forearms, shoulders, and back, urticarial lesions on the face and shoulders, mild angioedema of the lips, and mild hoarseness and cough. To our knowledge, this is the first case of food-dependent exercise-induced anaphylaxis due to lentil.

In vitro evaluation of bendamustine induced apoptosis in B-chronic lymphocytic leukemia.

Bendamustine is a novel cytostatic agent, with activity in non-Hodgkin's lymphomas including B-chronic lymphocytic leukemia (B-CLL). The knowledge about its mode of action, however, is still limited. Here, we investigated the in vitro ability of bendamustine to induce apoptosis on freshly isolated peripheral lymphocytes in B-CLL and analyze the potential underlying mechanisms of action for inducing apoptosis. In CLL cells taken from 37 previously treated and untreated CLL patients, we investigated the influence of bendamustine alone, and in combination with fludarabine, on the induction of apoptosis and changes of Bcl-2 and Bax expression on mRNA and protein level using the RNase protection assay or flow cytometry, respectively. Apoptotic cells were determined with flow cytometry using the fluorescent DNA-binding agent 7-ADD. Using bendamustine alone in concentrations from 1 microg/ml to 50 microg/ml, a dose- and time-dependent manner of cytotoxicity from 30.4% to 94.8% after 48 h could be observed. The LD50 for untreated and pretreated CLL cells was 7.3 or 4.4 microg/ml, respectively. The median apoptotic rate was similar in both groups. The combination of bendamustine with fludarabine led to a highly synergistic effect in inducing apoptosis, which was 150% higher than expected for bendamustine plus fludarabine. The level of the initial Bcl-2 and Bax protein and the m-RNA expression remained unchanged during the incubation with bendamustine. In conclusion, this study demonstrates for the first time the in vitro efficacy of bendamustine in inducing apoptosis in B-CLL cells alone and in combination with fludarabine.

Reduced-dose cladribine (2-CdA) plus mitoxantrone is effective in the treatment of mantle-cell and low-grade non-Hodgkin's lymphoma.

Cladribine (2-chlorodeoxyadenosine) (2-CdA) has been shown to be effective in mantle-cell (MCL) and low-grade lymphomas (lgNHL). The aim of this multicentre study was to evaluate the rate and duration of remissions and to examine the toxicity of the combination of reduced-dose 2-CdA and mitoxantrone (CdM) in MCL and lgNHL as first-line therapy or for patients in their relapse. A total of 285 courses, median of five courses per patient, were administered to 62 evaluable patients (42 previously untreated, 20 relapsed) with 5 mg/m(2) 2-CdA per day given as an intermittent 2-h infusion over 3 consecutive days combined with 8 mg/m(2) mitoxantrone on days 1 and 2 for the untreated patients or 12 mg/m(2) mitoxantrone on day 1 for patients in their first relapse for a maximum of six cycles every four weeks. 32 follicular, 18 MCL, 9 lymphoplasmacytoid, 2 marginal zone and 1 unclassified low-grade B-cell lymphoma were involved in the study. 56 of the 62 patients responded to CdM resulting in an overall response rate of 90% (95% confidence interval (CI), 80-96%) with a complete remission (CR) rate of 44% (95% CI, 31-57%) and a median duration of remission of 25 months (range 6-42+). The overall survival rate at 48 months was 80%. For 42 previously untreated patients, the overall response rate was 88% (95% CI, 74-96%) with a CR rate of 38% (95% CI, 24-54%), whereas the response rate for the group of 20 previously treated patients was similar with a 95% overall response (95% CI, 75-100%) and a CR rate of 55% (95% CI, 32-77%). In MCL, CdM showed a high activity, achieving a response rate of 100% (95% CI, 81-100%) with a CR rate of 44% and a median duration of remission of 24 months (range 6-35+). Myelosuppression was the major toxicity with 23% grade 3 granulocytopenia and 50% grade 4. Thrombocytopenia was less commonly observed, with only 8% grades 3 and 4. These results demonstrate that the combination of reduced-dose 2-CdA and mitoxantrone is a highly active regimen in the treatment of low-grade lymphomas, and in particular of MCL.

The coexpression of the apoptosis-related genes bcl-2 and wt1 in predicting survival in adult acute myeloid leukemia.

The Wilms tumor gene wt1 and the protooncogene bcl-2 are upregulated in acute myeloid leukemia (AML) and are known to regulate or to inhibit the onset of apoptosis. Since wt1 has been shown to regulate the expression of bcl-2, we investigated the association of the expression of these genes and their prognostic relevance in AML. Leukemic blasts from the bone marrow of 152 patients with newly diagnosed AML were analyzed for bcl-2 and wt1 mRNA expression using RT-PCR and quantitative PCR. Therapy outcome was correlated with the level of bcl-2 and wt1 transcripts. Bcl-2-specific mRNA was detectable in 127/152 (84%) patients and wt1 mRNA in 113/152 (74%) patients with AML. In monocytic subtypes the frequency of bcl-2 and wt1 transcripts was significantly lower. The expression of bcl-2 mRNA was correlated significantly with that of wt1 mRNA (P < 0.0001). In AML patients <60 years, high expression of bcl-2 and wt1 was associated with a reduced rate of continuing complete remission (CCR, P = 0.002 and P = 0.005, respectively) and increased death rate (P = 0.0002 and P = 0.04, respectively) in contrast to patients >60 years, where the expression of bcl-2 or wt1 had no prognostic impact. Based on the coexpression of bcl-2 and wt1, we established a prognostic model defining three risk groups with significant differences in CCR rate (P = 0.01), overall survival (P < 0.04) and disease-free survival (P < 0.03). Thus, bcl-2 and wt1 mRNA expression are associated with response and long-term outcome in AMLs. The coexpression of these genes allows determination of prognostic groups with high predictive value for overall and disease-free survival.

Rhenium 188-labeled anti-CD66 (a, b, c, e) monoclonal antibody to intensify the conditioning regimen prior to stem cell transplantation for patients with high-risk acute myeloid leukemia or myelodysplastic syndrome: results of a phase I-II study.

The conditioning regimen prior to stem cell transplantation in 36 patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) was intensified by treating patients with a rhenium 188-labeled anti-CD66 monoclonal antibody. Dosimetry was performed prior to therapy, and a favorable dosimetry was observed in all cases. Radioimmunotherapy with the labeled antibody provided a mean of 15.3 Gy of additional radiation to the marrow; the kidney was the normal organ receiving the highest dose of supplemental radiation (mean 7.4 Gy). Radioimmunotherapy was followed by standard full-dose conditioning with total body irradiation (12 Gy) or busulfan and high-dose cyclophosphamide with or without thiotepa. Patients subsequently received a T-cell-depleted allogeneic graft from a HLA-identical family donor (n = 15) or an alternative donor (n = 17). In 4 patients without an allogeneic donor, an unmanipulated autologous graft was used. Infusion-related toxicity due to the labeled antibody was minimal, and no increase in treatment-related mortality due to the radioimmunoconjugate was observed. Day +30 and day +100 mortalities were 3% and 6%, respectively, and after a median follow-up of 18 months treatment-related mortality was 22%. Late renal toxicity was observed in 17% of patients. The relapse rate of 15 patients undergoing transplantation in first CR (complete remission) or second CR was 20%; 21 patients not in remission at the time of transplantation had a 30% relapse rate. (Blood. 2001;98:565-572)

Interleukin 4 therapy for patients with chronic lymphocytic leukaemia: a phase I/II study.

Interleukin 4 (IL-4) is a pleiotropic type II cytokine which has been shown to have a direct killing effect on lymphoma and B-cell chronic lymphocytic leukaemia (B-CLL) cells in vitro. The clinical effects and toxicity of IL-4 treatment in patients with B-CLL were evaluated. Fourteen patients with B-CLL who were in partial remission after chemotherapy received one, two or three 8-week cycles of escalating doses (2, 4 or 6 microg/kg/d s.c.) of IL-4 for 3 d/week. Clinical response was analysed after each treatment cycle and toxicity was monitored continuously. Ten patients (71%) had progressive disease (PD) during IL-4 treatment. This was mainly attributable to an increase (two- to fourfold) of the blood lymphocyte count during IL-4 therapy. After cessation of IL-4 treatment, the lymphocytosis decreased spontaneously in 8 out of 12 evaluable patients. Splenomegaly remained unchanged in 7/7 patients, whereas enlarged lymph nodes were reduced by > 50% in 1/13 patients and by 25-50% in 4/13 patients. None of the patients achieved an objective tumour regression (complete or partial remission). A temporary increase (16-60%) of the platelet count was observed during IL-4 treatment. The platelet count decreased in 8/11 patients after the end of IL-4 therapy. World Health Organization (WHO) grade I/II fever, arthralgia and fatigue was observed in one-third of the patients and was more commonly seen with the highest dose (6 microg/kg/d). One patient developed pulmonary oedema and WHO grade III neutropenia was recorded in three patients. IL-4 was well tolerated by most patients in an outpatient setting. The anti-tumour activity observed in previous in vitro studies was not verified by the present in vivo trial which showed that IL-4 may instead increase the number of CLL cells in blood, indicating that IL-4 may have induced a stimulatory or antiapoptotic effect on the CLL cells in blood. These results may have important implications for the development of immunotherapy of CLL. In addition, the potential platelet-stimulatory effect of IL-4 warrants further studies.

CD34+ selected cells in mismatched stem cell transplantation: a single centre experience of haploidentical peripheral blood stem cell transplantation.

Over the past 3 years we have performed 10 haploidentical peripheral blood stem cell transplants in patients with incurable haematological malignancies and no prospect of a matched unrelated donor within an adequate time period. Conditioning consisted of ATG, TBI, thiotepa, cyclophosphamide and additional radioimmunotherapy in five patients. All patients received G-CSF mobilized peripheral blood stem cell grafts. GVHD prophylaxis consisted of T cell depletion by CD34+ selection; no post-transplant immunosuppression was given in nine patients. Stable engraftment was achieved in nine patients; one case of acute graft rejection was observed. Seven patients developed grade I acute GVHD, and six patients have developed chronic GVHD. Infections were the most significant clinical problem post transplant. Two patients have suffered a relapse of their disease and two further patients have died of transplant-related complications. After a median follow-up of 13 months (range 5-37 months) six patients are surviving in remission. We conclude that haploidentical PBSCT is a reasonable alternative to a MUD transplant.

High expression of bcl-2 mRNA as a determinant of poor prognosis in acute myeloid leukemia.

BACKGROUND: The bcl-2 oncoprotein is suggested to be directly involved in the emergence of drug resistance by disrupting or delaying the apoptotic program and promoting tumor survival. PATIENTS AND METHODS: In order to define the clinical relevance of the bcl-2 mRNA expression in acute myeloid leukemia (AML) and its correlation to therapy outcome and prognosis, we analyzed 219 AML bone marrow (BM) samples, including 119 patients with de novo AML at presentation, 37 with AML following myelodysplastic syndrome (MDS), as well as 42 BM samples of AML in relapse and 21 in complete remission (CR) using RT-PCR. For performing quantitative measurements of bcl-2 mRNA, we developed a quantitative RT-PCR. RESULTS: Bcl-2 mRNA was detectable in 133 of 156 (84%) patients at diagnosis and 40 of 42 (95%) at relapse. AML patients with high bcl-2 mRNA expression achieved lower CR rates than those with no or low expression. Concerning the long-term outcome, the overall (OS) and disease-free survival (DFS) was significantly worse in AML patients with high expression levels of bcl-2 mRNA. The three-year OS for all newly diagnosed AML patients was 49% and 10% (P = 0.028), respectively, and 71% and 15% (P = 0.0004) for patients < 60 years. Comparable significant differences were observed for the DFS. In AML following MDS and patients > 60 years, the bcl-2 expression was not associated with remission rate or survival. CONCLUSIONS: The expression of bcl-2 mRNA may serve as a prognostic factor predicting remission outcome and long-term prognosis in AML.

High levels of Wilms' tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome.

The tumor suppressor gene wt1 (Wilms' tumor gene) encodes for a zinc finger DNA-binding protein with predominantly transcription repressing properties. Because wt1 has been shown to be expressed in the vast majority of patients with acute myeloid leukemias (AML), we investigated the relevance of wt-1 mRNA expression regarding prognosis and possible prediction of relapse during follow-up. Totally bone marrow-derived blasts of 139 AML patients (129 newly diagnosed AML patients, 22 AML patients again in first relapse, and 10 AML patients analyzed primarily in first relapse) were studied for wt1 mRNA expression. Seventy-seven patients were analyzed for wt1 mRNA expression during follow-up. wt1-specific reverse transcription-polymerase chain reaction (RT-PCR) was performed and the amplification product was visually classified as not, weakly, moderately, or strongly amplified, as described previously. PCR products were quantitated by competitive PCR using a shortened homologous wt1 construct standard in representative cases. The expression of wt1 transcripts was correlated to age, French-American-British (FAB) subtype, phenotype, karyotype, and long-term survival. wt1 mRNA was detectable in 124 of 161 (77%) samples at diagnosis and in first relapse. wt1 expression was independent from age, antecedent myelodysplastic syndrome or FAB subtype, with the exception of a significant difference in M5 leukemias showing wt1 transcripts in only 40% (P = .0025). There was no correlation between the level of wt1 mRNA and response to treatment or the prognostic groups defined by the karyotype. Concerning long-term survival, patients with high levels of wt1 had a significantly worse overall survival (OS) than those with not detectable or low levels. The 3-year OS for all newly diagnosed AMLs was 13% and 38% (P = .038), respectively, and 12% and 43% (P = .014) for de novo AMLs. The difference was more distinct in patients less than 60 years of age. During follow-up, all patients achieving complete remission became wt1 negative. Reoccurrence of wt1 transcripts predicted relapse. The data indicate that high expression of wt1 mRNA is associated with a worse long-term prognosis.

Establishment and characterization of a new, factor-independent acute myeloid leukemia line designated Ei501.

We established a factor-independent acute myeloid leukemia cell line, designated Ei501. The line has been growing in RPMI 1640 media for 18 months and can be maintained without addition of growth factors. Ei501 is positive for myeloperoxidase and negative for esterase and PAS. Cytogenetic analysis revealed the FAB M3 associated t(15;17) translocation and a translocation of the chromosomes 7 and 8: 46 XX, -7, +t(7;8)(q32;q13), t(15;17)(q22;q12). This karyotype was confirmed by fluorescence in situ hybridization. Ei501 cells express AML-associated surface markers such as CD13, CD33 and CD38. Although 42% of the patient's blast cells were CD34-positive, the line lacks surface expression of CD34. Furthermore the line has a number of characteristics which are detectable in blasts from AML patients, such as surface adhesion molecules, cytokines such as TGF-beta, cytokine receptors such as the IL-2 receptor beta and gamma chains or the IL-4 receptor and the genes for the transcription factor wt-1 (Wilms' tumor gene) and for the proto-oncogene bcl-2, both shown to be present in the majority of patients with AML. Additionally the line can be used as target in cytotoxicity assays using IL-2 activated cytotoxic lymphocytes as effector cells. In conclusion, besides a rare karyotype the Ei501 cell line has several features common in AML, and may therefore be used as a model to study pathogenetic mechanisms in acute myeloid leukemia.

Peripheral T-cell lymphomas respond well to vincristine, adriamycin, cyclophosphamide, prednisone and etoposide (VACPE) and have a similar outcome as high-grade B-cell lymphomas.

Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of T-cell malignancies including subentities with favourable (large cell anaplastic) or unfavourable (pleomorphic) prognosis. The clinical outcome of PTCL has been controversially discussed, but a worse prognosis than high-grade B-cell Non-Hodgkin's lymphomas (NHL) has been postulated by most authors. In this report we summarize the results of a prospective comparative study investigating the therapy outcome of 27 patients (pts) with PTCL and 55 pts. with high grade B-cell NHL and give an overview of therapy studies in PTCL. The histological subtypes were 14 pleomorphic, 8 large-cell anaplastic (Ki-1+), 2 angioimmunoblastic (AILD) and 3 other PTCL. In three patients the PTCL was associated with non-tropical sprue (11%). Nineteen patients presented with an advanced stage of disease (stage III and IV, 70%), 17 (63%) pts. had B-symptoms. The patients were treated with vincristine 2 mg d1, adriamycin 25 mg/m2 d1-3, cyclophosphamide 800 mg/m2 d1, prednisone 60 mg/m2 d1-7 and etoposide 120 mg/m2 d1-3 (VACPE). In 77% of pts. with PTCL and 84% of patients with high-grade B-cell NHL a complete remission (CR) was achieved. 75% of the complete responders with PTCL and 70% with B-NHL are still in ongoing CR. The subgroup of large-cell anaplastic attained a CR in 88%. The median observation time is 44 months (1(+)-77+). The probability of 1-, 3- and 5-year overall and disease-free survival for the T-cell group were 76%, 54%, 48% and 76%, 62%, 62%, respectively according to Kaplan-Meier. There was no significant difference regarding the remission rate, the overall-, event-free or disease-free survival compared to high-grade B-cell lymphomas. In conclusion, the VACPE regimen is an effective and feasible regimen in the management of PTCL achieving complete remissions in a large proportion of patients.

Recombinant human granulocyte-macrophage colony-stimulating factor after combined chemotherapy in high-grade non-Hodgkin's lymphoma--a randomised pilot study.

High-grade non-Hodgkin's lymphomas (NHL) can potentially be cured with combination chemotherapy, although the optimum schedules still have to be defined. Clinical trials with intensive chemotherapy are predominantly limited by myelosuppression. Here, haematopoetic growth factors open up the possibility of reducing chemotherapy-associated toxicities. In this randomised pilot study, we investigated the effects of a recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) following combined chemotherapy with vincristine, doxorubicin, cyclophosphamide, prednisone and etoposide (VACPE). A total of 35 patients with high-grade NHLs were randomised to receive either rhGM-CSF or placebo during the first two chemotherapy cycles and rhGM-CSF for all following cycles. rhGM-CSF was administered at a dosage of 5 micrograms/kg for 10 days or until neutrophils were > 1/nl following chemotherapy. The analyses revealed a significant reduction of neutropenia and duration of neutropenia in the rhGM-CSF group. Adverse events were rare and generally mild apart from one anaphylactoid reaction. No effects of rhGM-CSF were observed concerning the platelet nadir or duration of thrombocytopenia. The benefit of rhGM-CSF for response induction and survival via rhGM-CSF-supported dose intensification remains to be determined.

Vincristine, doxorubicin, cyclophosphamide, prednisone and etoposide (VACPE) in high-grade non-Hodgkin's lymphoma--a multicenter phase II study.

BACKGROUND: Patients with high-grade non-Hodgkin's lymphoma (NHL) can potentially be cured by intensive chemotherapy. However, many patients still die of their disease, which underscores the need to define patient groups with different long-term prognoses and for more effective and possibly risk-adapted treatment approaches. PATIENTS AND METHODS: In this phase II study we investigated the feasibility and efficacy of a polychemotherapy consisting of 2 mg vincristine (V) on day 1, 25 mg/m2 doxorubicin (A) days 1-3, 800 mg cyclophosphamide (C) day 1, 60 mg/m2 prednisone (P) days 1-7 and 120 mg/m2 etoposide (E) days 1-3. This cycle (VACPE) was repeated on day 22 for up to 5 cycles in stages I-III and 6 cycles in stage IV, respectively, followed by consolidating radiotherapy in 38/73 patients. A total of 75 patients with high-grade NHLs according to the Kiel classification were eligible, and 73 patients are evaluable for response. The predominant histological subtypes were centroblastic, pleomorphic T-cell and large-cell anaplastic lymphomas, 60% of the patients presented with stage III/IV, 55% with a poor performance status (ECOG > or = 2), 53% with B symptoms and 60% with a LDH level >200 U/l. RESULTS: 57/73 patients achieved CR (78%), and the overall response rate (CR-PR) was 95%. The median observation time is 40 months (10+-74+). The 1-, 3- and 5-year overall survivals for the entire VACPE group were 79%, 64% and 61%, respectively. Forty-one patients are in ongoing CR with a continuous complete remission rate (CCR) of 67%. Fourteen of the 16 patients who relapsed (88%) did so within the first 24 months. The predicted 1-, 3- and 5-year DFS for those patients who achieved CR is 83%, 67% and 67%, respectively. The early mortality was 3/73 (4.1%). In patients with reduced performance status the overall survival (OS) (ECOG > or = 2) was significantly reduced, with a predicted 1-, 3- and 5-year survival of 62%, 49% and 49% versus 100%, 84% and 77% in patients with favorable performance status, respectively (p = 0.001). The predicted overall survival in stages III/IV is worse than in early stages with a 1-, 3- and 5-year probability of 73%, 52% and 52% versus 90%, 86% and 78%, respectively (p = 0.02). Comparison of patient groups with cumulative risk factors shows a significant decrease in overall survival. Especially in patients with 0-2 risk factors versus those presenting with >2 risk factors, there is a significantly better 3- and 5-year survival (p = 0.002). In contrast to overall survival, there were no differences between the listed risk groups concerning the disease-free survival of complete responders. CONCLUSION: In conclusion, the VACPE regime is feasible and effective in high-grade NHLs and may also be administered on an outpatient basis. Despite encouraging data, however, a prospective randomized trial is warranted to define a possible superiority to standard CHOP. However, this regimen may be the basis for further randomized and risk adapted innovative approaches for high-grade NHLs.