Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma.

BACKGROUND: Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma. METHODS: We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. RESULTS: At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P=0.04). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.73 [95% CI, 0.45 to 1.18]; P=0.20) [corrected]. All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity. CONCLUSIONS: A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin's lymphoma, with a 4.9 percentage-point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490 ; EudraCT number, 2011-005450-60 .).

Prognostic value of end-of-induction PET response after first-line immunochemotherapy for follicular lymphoma (GALLIUM): secondary analysis of a randomised, phase 3 trial.

BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study. METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968. FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, p<0·0001). According to Lugano 2014 criteria, 2·5-year progression-free survival in complete metabolic responders was 87·4% (95% CI 83·7-90·2) and in non-complete metabolic responders was 54·9% (40·5-67·3; HR 0·2, 95% CI 0·1-0·3, p<0·0001). INTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed. FUNDING: F Hoffmann-La Roche.

[Novel oral anticancer drugs: a review of adverse drug reactions, interactions and patient adherence]. / Az újabb orális tumorellenes készítmények mellékhatásprofiljának, interakcióinak és az adherencia problémáinak áttekintése.

Each aspect of oncological care is widely affected by the spread of oral anticancer agents, which raises several questions in terms of safe medication use and patient adherence. Over the past decade targeted therapies have appeared in clinical practice and revolutionized the pharmacological treatment of malignancies. Regular patient - doctor visits and proper patient education is crucial in order to comply with the therapy previously agreed upon with the oncologist, to increase patient adherence, to detect and to treat adverse effects in early stages. Since the information on the new medicines in Hungarian language is sparse it is the intention of the authors to give an overview of the basic knowledge, patient safety issues, adverse effects and interactions. Official drug information summaries and data on pharmacokinetics, interactions and adverse effects from the literature are reviewed as the basis for this overview.

Immunochemotherapy and Maintenance With Obinutuzumab or Rituximab in Patients With Previously Untreated Marginal Zone Lymphoma in the Randomized GALLIUM Trial.

The aim of this study was to explore the efficacy and safety of obinutuzumab (G)- versus rituximab (R)-chemotherapy in a subgroup of patients with previously untreated marginal zone lymphoma (MZL) in the phase III GALLIUM trial (NCT01332968). Patients had stage III/IV (or stage II with bulky disease), splenic, nodal, or extranodal MZL requiring treatment. Patients were randomized 1:1 to receive G- or R-chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone; cyclophosphamide, vincristine, and prednisone; or bendamustine, allocated at patient level). Patients with complete/partial response at the end of induction (EOI) received G/R maintenance. Investigator-assessed progression-free survival (PFS), other time-to-event endpoints, response, and safety were assessed. Overall, 195 patients with MZL were included in this analysis: G-chemotherapy (n = 99), R-chemotherapy (n = 96). Median observation time: 59.3 months. No meaningful difference was observed between arms for PFS (4-y PFS rates: G-chemotherapy, 72.6%; R-chemotherapy, 64.1%), other time-to-event endpoints, or EOI response rates (by computed tomography [CT; G-chemotherapy, 81.8%; R-chemotherapy, 81.3%] and positron emission tomography CT [G-chemotherapy, 79.2%; R-chemotherapy, 87.5%]). All patients experienced ≥1 adverse event (AE). G-chemotherapy was associated with a higher incidence of grade 3-5 (86.1% versus 77.4%), grade 5 (14.9% versus 9.7%), and serious (66.3% versus 51.6%) AEs versus R-chemotherapy. Both arms had a higher incidence of grade 3-5 and serious AEs than patients with follicular lymphoma (GALLIUM), with G-chemotherapy being less tolerable than R-chemotherapy. Based on the observed tolerability of G-chemotherapy versus R-chemotherapy, and the comparable efficacy of G-chemotherapy and R-chemotherapy in this analysis, G-chemotherapy cannot be recommended as first-line treatment for MZL.

Adolescent hodgkin lymphoma: are treatment results more favorable with pediatric than with adult regimens?

BACKGROUND: The aim of our work was to compare the treatment modalities and the survival rates in adolescents (14 to 21 y) with Hodgkin lymphoma (HL) treated with adult (A) or with pediatric (P) regimens. PROCEDURE: From January 1990 to December 2004, 134 (A) and 111 (P) adolescents with HL were treated. Male:female ratio was 1:1.48 (A) and 1:1.36 (P), the mean-age 18.6 (A) and 15.8 years (P), respectively. RESULTS: The patients were treated either with doxorubicin, bleomycin, vinblastine and dacarbazine (A) or with OPPA/OEPA ± COPP regimens (P). About 82% (A) and 89% (P) of the patients received radiotherapy. Relapse rates were 13% (A) and 14% (P). Fourteen patients died in group (A) and 9 in group (P). There were no significant differences in the overall survival and event-free survival rates at 5 and 10 years between the 2 patient's groups. For children under age of 18 years old overall survival was 92.8 ± 3% at 5 and 89.6 ± 3% at 10 years in group (P) and 89.4 ± 4% at 5 years and 83.1 ± 6% at 10 years (P=0.2822) in group (A). For children under the age of 18 years event-free survival was 82.4 ± 4% at 5 and 10 years in group (P) and 69.6 ± 7% at 5 years and 59.1 ± 8% at 10 years (P=0.0192) in group (A). CONCLUSION: In case of the patients younger than 18 years, the survival rates are more favorable by using pediatric regimens, so these patients might have a benefit if they are treated in pediatric institutes.

[Diabetes and cancer risk: oncologic considerations]. / Diabetes és rákkockázat az onkológus szemszögébol.

Type 2 diabetes mellitus and malignant tumors are frequent diseases worldwide. The incidence of these two diseases is growing continuously and causes serious health care problem. Population based epidemiologic studies show that the coexistence of type 2 diabetes and malignant tumors is more frequent than expected by the age-corrected incidence and prevalence of each disease. Epidemiologic studies and meta-analyses show that type 2 diabetes increases the risk and tumor specific mortality of certain cancers. The overlapping risk factors of the diseases suggest a relationship between type 2 diabetes and malignant tumors, with a significant role of obesity as a major risk factor. In the pathophysiology of type 2 diabetes there are several biological processes, which may explain the higher cancer risk in type 2 diabetes. In vitro experiments, and in vivo animal studies show that the mitotic effect of hyperinsulinemia plays an important role in the relationship of cancer and type 2 diabetes mellitus. Recent studies show that the different treatment modalities, antidiabetic drugs and their combinations used for the treatment of type 2 diabetes can modify cancer risk. The majority of the data show that metformin therapy decreases, while insulin secretagog drugs slightly increase the risk of certain types of cancers in type 2 diabetes. Metformin can decrease cell proliferation and induce apoptosis in certain cancer cell lines. Endogenous and exogenous (therapy induced) hyperinsulinemia may be mitogenic and may increase the risk of cancer in type 2 diabetes. Human studies showed that the analogue insulin glargin increases the risk of certain cancers. As a result of conceptual weaknesses in study design, data collection, and statistical methods the results of these studies are questionable. According to present knowledge, obtaining and maintaining optimal metabolic target values with the appropriate choice of treatment modality is the aim of treatment in type 2 diabetes. Presently, study results showing elevated mitogenic potential with some antidiabetic treatment modalities are not taken into account, when considering the choice of antidiabetic treatment in type 2 diabetic patients. In the care of patients with increased cancer risk, oncologic considerations should be taken into account. Well designed, prospective, clinical studies would be necessary to demonstrate the possible correlation between treatment modalities of type 2 diabetes and change of cancer risk in type 2 diabetes mellitus.

[Standard CHOP immuno-chemotherapy for primary mediastinal lymphomas]. / A primer mediastinalis lymphomák standard R-CHOP immun-kemoterápiás kezelése.

INTRODUCTION: Primary mediastinal lymphoma (PMBCL) is an aggressive diffuse large B-cell lymphoma entity. It is a rare disease with specific clinical symptoms. The tumor is predominantly localized in the mediastinum but grows rapidly and infiltrates the surrounding tissues and organs. Two thirds of the patients are young females. Previous studies showed that third generation treatments are more effective than former standard cyclophosphamide-doxorubicin-vincristine-prednisolone (CHOP) regimens. AIM: Authors' goal was to assess whether adding the anti-CD20 monoclonal antibody, rituximab to the standard CHOP regimen improves the efficacy of the treatment compared to their previous results with CHOP and third generation chemotherapy regimens. METHODS: Between October, 2002 and December, 2004 they have started the rituximab-CHOP (R-CHOP) treatment of 20 newly diagnosed, previously untreated PMBCL patients. Results were compared to the data of 24 patients receiving CHOP (n = 9) or procarbazin-prednisolone-doxorubicin-cyclophosphamide-etoposide-cytosin-arabinoside-bleomycin-vincristin-methotrexate (ProMACE-CytaBOM) (n = 15) treatment in the past. RESULTS: During an average follow-up of 64.6 months, the 5-year overall survival (OS) rate was significantly higher in the R-CHOP group compared to the CHOP treatment (79.4% vs. 33.3%; p = 0.026). However, due to the low number of cases, significant statistical difference could not be demonstrated in the 5-year event-free survival (EFS: 70.0% vs. 33.3%; p>0.05), disease-free survival (DFS: 70.0% vs. 33.3%; p>0.05) and relapse-free survival rate (RFS: 93.0% vs. 100%; p> 0.05), despite of the remarkable numeric difference. When comparing the 5-year survival rates of R-CHOP and ProMACE-CytaBOM treatments, the results were very similar without any significant statistical difference between the two types of treatment (OS: 79.4% vs. 80%; EFS: 70.0% vs. 60.0%; DFS: 70.0% vs. 60.0%; RFS: 93.0% vs. 82.0%; p> 0.05 in all cases). With adding rituximab to CHOP treatment, which was previously considered an insufficient treatment on its own, authors have obtained as good results in treating PMBCL as with third generation regimens. Patients have received the R-CHOP treatments without major side effects and mainly as out-patients. CONCLUSIONS: Standard R-CHOP treatment could therefore replace the more toxic third generation regimens in PMBCL as well. The data are comparable with those reported in the international literature.

[Introduction of a clinical protocol for extravasation at the National Institute of Oncology, Budapest, Hungary]. / Extravazációs protokoll bevezetése az Országos Onkológiai Intézetben.

Extravasation of cytostatics occurs when an infusion containing a cytotoxic drug leaks into the surrounding perivascular and subcutaneous tissues. Incidence of cytostatic extravasation is found to be 0.1-6% according to the literature. Depending on the severity of complications, pain, loss of function in the extremities, or in extreme cases tissue necrosis necessitating an amputation may develop, drawing consequences like delay or interruption of the chemotherapy. Extent of complications is greatly influenced by the type of medication administered, general condition of the patient, and professional preparedness of staff providing the oncological health service. The protocol recently implemented in the National Institute of Oncology is a short, compact guidance for physicians and nurses providing oncological care, so by quick and adequate management of extravasation cases, severe complications could be prevented. More complex practical guidelines including algorithms could be created as a result of a wider collaboration, with the help of which oncological health professionals could easily cope with this rare problem. The authors describe in their review the implementation of the use of dry warm and cold packs, dymethylsulfoxide and hyaluronidase and their function within the algorithm of extravasation treatment.

[Results of immuno-chemotherapeutic treatment of patients with diffuse large B-cell lymphoma]. / Diffúz nagy B-sejtes lymphomák immunokemoterápiás kezelésével elért eredményeink.

Treatment with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) has been considered as the standard therapy for diffuse large B-cell lymphoma (DLBCL) for more than 20 years. CHOP treatment in combination with targeted immunotherapy, rituximab (R-CHOP), resulted in significant improvements in the treatment of this group of patients. In this study, efficacy of R-CHOP and R-CHOP-like treatments was analysed. Results were compared to the data of historical patients only receiving CHOP treatment or CHOP-like treatment. Between September 2002 and April 2005, 140 newly diagnosed, untreated DLBCL patients started to receive R-CHOP treatment in a single centre. The eligibility criteria included advanced stage (clinical stages III-IV), or large tumour size (>7 cm) and/or symptom B or extranodal manifestation in the case of clinical stages I-II. The results were compared to the data of 130 patients only receiving CHOP treatment in the past. In the patients receiving R-CHOP, the therapeutic outcomes were superior for all parameters. During an average follow-up period of 44 or 52 months, the overall remission rate was 73.6% in the R-CHOP group in comparison with 47.7% in the CHOP group. The 5-year overall survival was 68.6% vs. 41.0% (RR: 0.4293, CI: 0.2963-0.6221; p < 0.0001), the event-free survival was 59.8% vs. 33.5% (RR: 0.5038, CI: 0.3606-0.7038; p < 0.0001) and the progression-free survival was 64.4% vs. 37.6% (RR: 0.4915, CI: 0.3442-0.7019; p < 0.0001). Since prognostic parameters were more favourable in the R-CHOP group, patient groups were also compared using the International Prognostic Index score. Again, significant differences were revealed by the subgroup analyses. The 5-year overall survival was 74.4% vs. 47.9% (RR: 0.4475, CI: 0.2418-0.8285; p = 0.0084) and 52.0% vs. 28.8% (RR: 0.4989, CI: 0.3098-0.8035; p = 0.003) in the group with good prognosis and in the group with poor prognosis, respectively. In the group with very good prognosis, the statistical difference between the two groups in terms of the 5-year survival parameters remained undetectable as a result of the already very high therapeutic effect and low case number (OS and EFS: CHOP: 100% and 62.5% vs. R-CHOP: 90.9% and 87.0%; p = 0.3873 and p = 0.1702). Combining the standard CHOP treatment with rituximab resulted in a significant improvement of the therapeutic outcomes irrespective of the prognostic grouping. The data are comparable with those reported in the international literature.

[Prognostic value of FDG-PET in Hodgkin lymphoma for posttreatment evaluation. Long-term follow-up results]. / Az FDG-PET prognosztikai értéke Hodgkin-lymphomás betegek követésében - hosszú távú eredményeink.

UNLABELLED: In the past few decades Hodgkin lymphoma (HL) has become a highly curable malignant disease, as a result of using modern polychemotherapy and irradiation. Differentiation of active tumor from fibrosis or necrosis within residual radiographic masses represents a problem of interpretation. AIMS: The aim of this retrospective study is to assess the value of FDG-PET for prediction of remission or relapse in HL. PATIENTS AND METHODS: Data of 128 patients, who had residual masses on CT after completion of their planned treatment, have been analyzed. FDG-PET was performed between January 1995 and February 2005. RESULTS: The median duration of the follow-up from PET was 75.5 months (range: 20-180 months). 89 (70%) patients had negative and 39 (30%) patients had positive FDG-PET results. The numbers of true-positive, true-negative, false-positive and false-negative subjects were 29, 83, 10 and 6, respectively. Sensitivity of post-treatment FDG-PET was 83%, specificity 93%, positive predictive value 74%, negative predictive value 93%, and accuracy 88%. The difference between the event free survival of PET positive and negative cases is highly significant (p = 0.0000), according to the Mantel-Cox test. CONCLUSION: Our results, in accordance with literature, clearly indicate that patients with negative FDG-PET results are unlikely to progress or relapse during a long follow-up. However, false positive uptake is a problem. We have investigated the effect of age, histological subtype, clinical stage and the type of treatment on the accuracy, but on the basis of these facts we could not find any significant difference. However, the date of the investigation influenced the results: before 2000 the number of false results was significantly higher than after that time, which shows the importance of investigators' experience.

Comprehensive analysis of how experimental parameters affect H2S measurements by the monobromobimane method.

A rapidly increasing number of studies report on widespread biological functions for endogenous hydrogen sulfide. However, the use of multiple, chemically distinct analytical methods to measure free hydrogen sulfide levels in biological samples accumulate data that are not in agreement with each other. In this work a widely appreciated technique, the monobromobimane method, was thoroughly investigated with the overall aims i) to demonstrate how results obtained by different versions of the method should be interpreted and ii) to provide an easy protocol for the community in order to obtain reliable and comparable results. We demonstrate that none of the previously published versions of the method measure free sulfide concentrations in blood serum or plasma samples due to significant interferences with the biomolecule-bound sulfide pool. On the other hand, we stress the biological relevance of these measurements in cases in which they are carefully conducted. To aid future studies, we extensively investigated the entire procedure from sample withdrawal through handling and storing of injection-ready samples until the detection protocol in order to pinpoint all parameters that can affect the final readouts. Based on our rigorous analytical investigations a set of recommendations were compiled that are necessary to ensure reliable, reproducible and comparable results in the field and a detailed standardized protocol is provided.

[Hodgkin's lymphoma in adolescents: where to treat it--in an adult or pediatric institution?]. / Hodgkin-lymphoma adolescens korban. Hol érdemes kezelni: felnôtt- vagy gyermekintézményben?

UNLABELLED: Adolescent patients with Hodgkin's lymphoma (HL) are treated either in pediatric, or in adult oncological wards. AIM: The aim of our work was to compare the treatment modalities and the survival rates in adolescents with HL treated in adult (A) or pediatric (P) institutes. METHODS: From January 1990 to December 2004, 138 patients (14-21 years) with HL were treated in two adult institutes (A) and 107 in the 10 centres of the Hungarian Pediatric Oncology Network (P). RESULTS: Male:female ratio was 1:1.15 (A) and 1:1.38 (P). The mean age was 18.6 (A) and 15.7 (P) years. There was no difference between the distribution of the stages in the two patient groups. The distribution of histological subtypes (A and P): nodular sclerosing 47% and 59%, mixed cellularity 45% and 25%, lymphocyte rich 1.5% and 10%, lymphocyte depleted 4% and 1%, nodular lymphocyte predominant 1.5% and 3% and unknown 1% and 2%. The majority of the patients were treated with ABVD (A) and OPPA/OEPA +/- COPP (P). One hundred and fifteen (A) and 97 (P) adolescents received irradiation therapy. 80% (A) and 91% (A) of the patients got radiotherapy. In group A 14%, in group P 13% of the patients had relapse. In group A 16 patients died and in group P 7. There was no significant difference in the overall survival (OS) rates at 5 and 10 years in the two patient groups. The event-free survival (EFS) was 76.5 +/- 4% and 72.5 +/- 4% at 5 and 10 years in group A, and 85.3 +/- 4% at both times in group P ( p = 0.0452). CONCLUSION: Survival rates in HL are quite high, 80-90% of the patients can be cured. Event-free survival was higher in pediatric than in adult institutes. In case of patients younger than 18 years, the survival rates were much better in pediatric institutes, so these patients should be treated in pediatric institutes or with protocols used by the pediatricians.

Efficacy and Tolerability of a 2-Year Rituximab Maintenance Therapy in Patients with Advanced Follicular Lymphoma after Induction of Response with Rituximab-Containing First Line-Regimens (HUSOM Study).

Follicular lymphoma is a lymphoid malignancy commonly showing slow progression which makes the treatment of the disease challenging. Rituximab monotherapy and rituximab added to standard chemotherapy has been proven to increase survival among patients with advanced stage of the disease. However, the benefit of a rituximab maintenance therapy after induction was still unclear at the time of the initiation of this study. HUSOM was a phase III open-label, single-arm, multi-centre study aimed to assess the efficacy and the safety of the 12 cycles of rituximab (375 mg/m2 every 8 weeks) maintenance therapy in patients had already presented partial or complete response to R-CVP or R-CHOP. Efficacy endpoints such as event-free survival and overall survival were estimated. Adverse events were recorded during the entire course of the study. A total number of 124 patients were enrolled by 15 Hungarian study sites. Out of these, 86 patients received 12 cycles of rituximab and 69 patients completed the 3-year follow-up phase as well. The probabilities of the event free survival and progression at 4.3 years were estimated to be 70.3% and 74.4%, respectively. The overall and the disease free survival at 4 years were estimated to be 90.7% and 87.9%, respectively. A total number of 85 adverse events were reported during the study out of which 5 AEs were considered to be related to the administration of rituximab. Analyses of the efficacy variables have revealed comparable results to those reported by controlled clinical trials (EORTC 20981, PRIMA) conducted in parallel with the HUSOM study.

Detection and quantification of MBR/JH2 t(14;18) BCL-2 gene rearrangement in follicular lymphoma using a combined real-time polymerase chain reaction assay.

We report our experience with a new real-time polymerase chain reaction (PCR) assay applicable for simultaneous quantification and characterization of MBR/JH translocation in follicular lymphomas. This technique, which combines amplification with the FRET probe with SYBR Green I melting curve analysis, allows efficient detection of tumor cells in bone marrow or peripheral blood and their comparison with the original neoplastic clone.

[Complex diagnosis of follicular lymphomas]. / Follicularis lymphomák komplex diagnosztikája.

INTRODUCTION: In the Western world the second most common type of non-Hodgkin's lymphomas is follicular lymphoma (FL) comprising 30-35% of all cases. According to the data of the National Cancer Registry and our institute, this ratio is lower in Hungary and is about 15-20%, but the occurrence shows an increasing tendency. AIMS: Our aim was to survey and revise FLs that had been diagnosed at the National Institute of Oncology between 1990-1995. We studied the diagnostic relevance of histology, immunohistochemistry and the detection of immunoglobulin heavy chain (IgH) and bcl-2 gene rearrangements. MATERIALS AND METHODS: We surveyed 53 cases that were previously diagnosed as follicular or centrocytic, centroblastic lymphoma. Following histological re-examination, immunohistochemistry (CD20, CD3, bcl-2, CD10, bcl-6, CD5, p53, cyclin D1 and Ki-67) was performed on each case. We also studied the IgH and bcl-2 (major breakpoint region=MBR) gene rearrangement on paraffin embedded samples with conventional PCR methods. The classification was made according to the new WHO classification. RESULTS: After the revision of the 53 cases we found 37 follicular, 11 diffuse large B-cell, 1 mantle cell and 1 marginal zone lymphomas, 1 nodular lymphocyte predominant Hodgkin's lymphoma and 2 follicular hyperplasias. The grade of the FLs correlated with the expression of different antigens. CD10, bcl-2 expression and the proliferation index with Ki-67 showed good correlation with the grade of FLs. We could detect bcl-2 gene rearrangement in 55% of the FLs. CONCLUSION: Considering the diagnostic relevance of the different methods we can conclude that histology alone is not sufficient to make a correct diagnosis. Ninety percent of our cases were solvable with the help of immunohistochemistry and in 10% of the cases the diagnosis was partly based on the molecular pathological results.

Endothelins: a possible mechanism of cytostatics-induced cardiomyopathy.

Endothelium responds to physical and chemical stimuli by synthesis and release of a variety of vasoactive and signal molecules. Cardiac performance is regulated by cardiac endothelial cells in a paracrine manner, analogous to vascular endothelial control of vascular tone. Endothelin-1 (ET-1), one of the most potent vasoconstrictor peptides, which is synthetized and released by endothelial cells. The role of ET-1 in some special pathological state is still unclear. Authors have investigated the effect of anthracyclines (maximal dose: 450 mg/bodysurface m2) on left ventricular systolic and diastolic function and on the level of plasma ET-1, in 31 (13 male, aged 19-70 years, mean: 38.9) patients suffered from Hodgkin (24) and Non-Hodgkin (7) lymphomas. They have also studied the association between plasma ET-1 concentration and echocardiographic parameters. Serum ET-1 was measured by ELISA method. Left ventricular function analyzed by echocardiography: ejection fraction (EF), time velocity integral (VTI), E and A waves, E/A ratio, deceleration time (DT), Doppler index were assessed. Statistical analysis was made by the Wilcoxon rank test. ET-1 plasma level decreased significantly after therapy (5.6 +/- 3.5 vs. 3.1 +/- 0.9 pg/ml, P < 0.0006). EF (56.4 +/- 5.0% vs. 48.7 +/- 5.1%, P < 0.0001) decreased, and DT (168.1 +/- 36.8 ms vs. 206.5 +/- 58.8 ms, P < 0.0073) increased significantly after administration of anthracycline, showing that both systolic and diastolic left ventricular performance was deteriorated. There was no difference in other echocardiographic parameters before and after therapy. In conclusion, decrease of serum ET-1 concentration might be a result of anthracyclin's direct cytotoxic effect and the decreasing level of ET-1 may play a role in the reduction of the EF. More studies are needed to evaluate the presence and severity of endothelial damage, and long-term follow-up may reveal the importance of low ET-1 level and may show the time is needed for the restoration of the ET-1 concentration to the basic level after cessation of cytostatic therapy.

Endothelin-1 and cardiac function in anthracycline-treated patients: a 1-year follow-up.

Anthracyclines are widely used chemotherapeutic agents in the treatment of lymphomas known to induce cardiomyopathy in more than 20% of patients. There is increasing experimental evidence that cardiac endothelial cells regulate cardiac performance and that endothelin-1 (ET-1) is a central substance in this regulatory mechanism. Twenty (seven male, aged 20-68 years) patients with Hodgkin's or non-Hodgkin's lymphoma treated with anthracycline were followed-up for 1 year. At baseline, after cessation of anthracycline treatment and at 1 year, the plasma ET-1 level was measured by enzyme-linked immunosorbent assay and cardiac function was estimated by echocardiographic measurement of the ejection fraction, the E/A ratio and the deceleration time. The ET-1 level decreased significantly after therapy (5.47 +/- 3.34 pg/mL versus 3.44 +/- 0.69 pg/mL, P < 0.02), and remained significant at 1 year (3.43 +/- 0.57 pg/mL, P < 0.008). The ejection fraction (57.80 +/- 4.73% versus 48.05 +/- 5.65%, P < 0.0001) and the E/A ratio (1.35 +/- 0.40 versus 1.15 +/- 0.40, P < 0.01) decreased, and the deceleration time (177.00 +/- 44.96 ms versus 209.50 +/- 66.25 ms, P < 0.04) increased significantly after therapy, showing that both systolic and diastolic left ventricular performance were deteriorated. Compared with the baseline, the same significant changes were found at 1 year (ejection fraction, 50.65 +/- 8.87%, P < 0.0007; E/A ratio, 1.10 +/- 0.34, P < 0.003; deceleration time, 223.25 +/- 46.85 ms, P < 0.002). The decrease of the ET-1 concentration might be a result of anthracyclines' direct cytotoxic effect and the decreasing level of ET-1 may play a role in the ejection fraction reduction. The results of 1-year follow-up suggest that, although anthracycline toxicity occurs shortly after treatment, the undesirable effect remains.

[Radiotherapy of MALT-lymphoma of the stomach]. / A gyomor MALT-lymphomák sugárkezelése.

INTRODUCTION: The stomach is the most common extranodal site of the low-grade MALT lymphoma. This lymphoma usually appears in elderly patients, with typically indolent signs. At the time of the diagnosis, the lymphoma is usually localized in the stomach and/or the adjacent lymph nodes. The choice in these cases is local treatment, which in the past involved only a surgical approach (total/partial gastrectomy), whereas more recently radiotherapy is preferred. PURPOSE: The radiation fields cover the whole stomach and the paragastric lymph nodes. The radiation doses range from 30 to 40 Gy, given in 1.5 Gy fractions 5 days a week. An adequate dose distribution to the target volume can be achieved by 3D treatment planning and conformal irradiation. METHODS: At our institute, 5 patients were treated with this method, the intention was curative in 3 cases, and palliative in 2 cases. The median dose in the 4 cases completed as initially planned was 33.6 Gy, delivered at 1.5 Gy per fraction. The adjacent critical organs do not exceed the tolerance doses by this method. RESULTS: In these 4 cases, complete regression was achieved, as determined by endoscopy and biopsy. In the fifth, locally advanced case, irradiation had to be terminated because of gastric bleeding. During irradiation, no other severe acute side-effects were detected. CONCLUSION: The literature and our preliminary results confirm that radiation therapy for early, localized MALT lymphoma of the stomach, or in disseminated cases, can be not only effective and safe, but offers the significant advantages of low treatment-related morbidity and preservation of the gastric function.

[The role of PET scan in the investigation of the lymphatic spreading of Hodgkin's disease]. / A PET szerepe a Hodgkin-kór nyirokterjedésének vizsgálatában.

The authors investigated the role of PET, as a non-invasive diagnostic method, in the analysis of lymphatic spreading of Hodgkin's disease (HD). Whole-body FDG scans were carried out in 71 patients along with [11C]-methionine examinations, if necessitated by inconclusive FDG results. Based on these findings involvement-frequencies were calculated for each lymphatic region. The three most frequently involved lymphatic regions were the mediastinum (83.1%), the left cervical and left supraclavicular regions (78.9%) and the right cervical and right supraclavicular regions (76.1%). These data support the hypothesis that HD originates from the cervical or supraclavicular regions and reaches the distant sites by basically retrograde spreading in a non-random manner. The appropriate values of site involvement-rate were compared with those obtained by other authors based on pathologic staging and a good correlation was found. The high level of correspondence between these involvement-frequencies supported the general validity (i.e. valid for both treated and untreated cases) of the principles governing lymphatic spreading of HD.

[Treatment of primary mediastinal large B-cell lymphomas]. / Primer mediasztinalis nagy B-sejtes lymphomák kezelése.

INTRODUCTION: Primary mediastinal large B-cell non-Hodgkin's lymphoma is a relatively rare disease with specific clinical symptoms. This tumour originates from a subset of B-cells of the thymus and at the time of the diagnosis the disease is predominantly localised in the mediastinum. The tumor grows rapidly and frequently involves other thoracic structures. The majority of the patients are young females. There are no histologic features that reliably distinguish these tumors from other diffuse large B-cell lymphomas. This is the only lymphoma subtype which can only be defined by the combination of clinical and pathologic features. Analysis with DNA microarrays verified that primary mediastinal and diffuse large B-cell lymphomas are different diseases. AIMS: Comparing the effectiveness of two types of anthracycline-based standard chemotherapy regimens and the evaluation of the prognostic markers which are applied in large B-cell lymphomas. METHODS: 27 patients with primary mediastinal lymphoma were treated by the authors with anthracycline-based polychemotherapy with complementary radiotherapy from January 1995 to December 2002. RESULTS: Complete remission was obtained in 15 patients (56%) and no relapse was observed in this group. 9 additional patients (33%) achieved partial remission, while in 3 cases (11%) the treatment was ineffective. The patients who failed to achieve complete remission were subsequently treated with more intensive chemotherapy. Afterwards, those patients who were chemosensitive, underwent high-dose chemotherapy with autologous peripheral blood stem-cell transplantation. The chemoresistant patients received palliative chemotherapy. The 5-year overall survival rate of the 27 patients was 62.11%. CONCLUSION: The authors found that the procarbazine, prednisolone, adriamycin, cyclophosphamide, etoposide, cytosine-arabinoside, bleomycin, vincristine, methotrexate treatment was more effective than the cyclophosphamide, adriamycin, vincristine, prednisolone combination. The expected 5-year overall survival rates were 83.57% vs. 33.33%, respectively. This difference was significant (p = 0.017). No prognostic value of age adjusted international prognostic index, LDH- and b2-microglobulin levels were found. The results with the new standard of combined immuno-chemotherapy (rituximab--cyclophosphamide, adriamycin, vincristine, prednisolone) seem to be hopeful and more effective than earlier treatments.