[Staging of non-Hodgkin's lymphoma--recommendations of the Czech Lymphoma Study Group]. / Urcování rozsahu onemocnení u non-Hodgkinových lymfomu--doporucení Kooperativní lymfomové skupiny.

BACKGROUNDS: The Ann Arbor system is typically used for the staging of Non-Hodgkin's lymphomas. This classification was nevertheless originally developed in the 1970s for Hodgkin's lymphoma, a disease usually confined to the lymph nodes with less frequent dissemination to extralymphatic organs/tissues and extremely rare primary extranodal involvement. Non-Hodgkin's lymphomas, however, are more often associated with extralymphatic involvement and primary extranodal lymphomas are relatively common (approximately 1/3 of cases). Therefore, the value of the Ann Arbor staging system appears to be limited in these cases. An analysis of data from centres participating within the Czech Lymphoma Study Group showed that staging of Non-Hodgkin's lymphomas with extranodal involvement is not uniform. DESIGN: At the end of 2009, a draft for a Non-Hodgkin's lymphomas staging system was put forward for use by the lymphoma register of the Czech Lymphoma Study Group with special regard paid to the involvement of extralymphatic organs/tissues. This draft was further refined following comments from members of the Czech Lymphoma Study Group committee and the final form was accepted at the meeting of the Czech Lymphoma Study Group committee in January 2010. RESULTS: A consensus was reached at the meeting of the Czech Lymphoma Study Group committee regarding the staging of various combinations of nodal and extranodal involvement. For the purpose of suitable staging and appropriate treatment intensity, extranodal organs were divided into "major"--liver, lungs, bones, mesothelium (pleura, peritoneum, pericardium) and soft tissues. All other organs were defined as "minor". CONCLUSION: The Ann Arbor staging system is suitable for the staging of Non-Hodgkin's lymphomas with lymph node/lymphatic tissue involvement. As regards the extralymphatic spread of the disease or primary extranodal lymphomas, this classification should rather be adapted to practical needs. The validity of the updated classification system will be assessed in both prospective and retrospective Czech Lymphoma Study Group studies.

Complex analysis of cyclin D1 expression in mantle cell lymphoma: two cyclin D1-negative cases detected.

BACKGROUND AND AIM: The cytogenetic and diagnostic hallmark of mantle cell lymphoma (MCL) is translocation t(11;14)(q13;q32), resulting in overexpression of cyclin D1. Cyclin D1 expression was analysed in 32 cases of MCL. METHODS: The t(11;14) translocation was detected by fluorescence in situ hybridisation, level of cyclin D1 mRNA by competitive RT-PCR, and level of cyclin D1 and D2 proteins by immunohistochemistry and/or immunoblotting. RESULTS: In 30 cases, the presence of translocation t(11;14), a high level of cyclin D1 mRNA, and a high level of the cyclin D1 protein were confirmed. Two cyclin D1-negative cases overexpressing cyclin D2 were detected by immunoblotting. CONCLUSIONS: There are rare cyclin D1-negative cases of MCL overexpressing cyclin D2. Anti-cyclin D1 antibodies with low specificity can bind both cyclin D1 and cyclin D2, thus providing false cyclin D1-positive signals in immunohistochemical analysis.

[Chronic fatigue syndrome in cancer patients. Diagnostic and treatment options]. / Unavový syndrom u onkologického pacienta: moznosti diagnostiky a lécby.

Fatigue is the most frequent symptom accompanying a cancer disease and its treatment according to the visual analogue scale. Fatigue is reported by as many as 100% of patients in the course of cancer treatment and still by 40 to 70% of patients one year after the treatment has finished. This symptom has become known under the designation of "cancer-related fatigue" in the English language literature on the subject. The knowledge of the causes and mechanisms of fatigue is relatively limited. Based on practical guidelines, an algorithm has been used to detect, evaluate and influence by treatment the syndrome of fatigue caused by a cancer disease. Research in the field has been focused on both pharmacological and non-pharmacological approach. The highest efficiency in the treatment of fatigue syndrome has been recorded for the treatment of anaemia with erythropoietin, while aerobic exercise programmes have proven to be most efficient among the behavioural measures. In spite of a dramatically growing interest in the above problem in the past decade, a number of issues continue unresolved with respect to chronic fatigue syndrome related to a cancer disease or to its treatment. Based on their own experience and on the relevant literature, the authors deal with issues of chronic fatigue syndrome and the options for its diagnosing and treatment in patients undergoing cancer treatment.

[Practical aspects and clinical value of t(14;18) monitoring in peripheral blood of the follicular lymphoma patients]. / Praktické aspekty a reálný klinický význam sledování t(14;18) v periferní krvi pacientu s folikuláirním lymfomem.

BACKGROUND: Evaluation of practical value of monitoring t(14:18) in peripheral blood in follicular lymphoma. METHODS AND RESULTS: t(14;18) was tested in 115 follicular lymphoma patients by methods: FISH, nested and multiplex PCR of blood, bone marrow and lymph node specimens. We tested the patients with rearrangement MBR quantitatively by real-time PCR. Testing intervals of t(14;18) in peripheral blood were 1 month during treatment, 2-3 months during the first year after the end of treatment, then every 4 to 6 months. Patients were clinically examined in the same intervals and regular restaging was done by CT/PET. Each patient was evaluatee separately. Total detection of t(14;18) was 97% regardless tissue and methods of detection, FISH was superior to PCR (95% vs. 72%). The higher number of copies were observed in lymph nodes in comparison to bone marrow (p = 0.036) and peripheral blood (p = 0.016); 46/115 (40%) patients were positive for MBR, we followed up behaviour of t(14;18) in peripheral blood in 33 of them in long intervals (>6 months, med. 33 months). Molecular and clinical courses correlated in 20/33 (61%) patients, 7/33 (21%) clinically relapsed in lasting molecular remission. We found very short interval to clinical relaps in 7 cases of molecular relapses (0-5 months, median 3 months). We could not define "threshold quantity" of clinically important molecular relaps. Lasting molecular remission was associated with clinical in about 60% cases; lasting molecular activity corresponded with clinical relaps in 86% patients. CONCLUSIONS: t(14;18) is highly associated with follicular lymphoma. In practice, monitoring of t(14;18) is feasible only in part of patients. Even if there is some correlation of clinical and molecular course, monitoring of t(14;18) in blood bears only limited prognostic value for the concrete patient. The treatment of patient can not be accomplished on the basis of these results only.

[Comparison of plasmatic levels of B-natriuretic peptide with echocardiographic indicators of left ventricle function after doxorubicin therapy]. / Srovnání plazmatických hladin B-natriuretického peptidu s echokardiografickými ukazateli funkce levé komory srdecní po lécbe doxorubicinem.

THE STUDY OBJECTIVE: The aim of the study was to find out the relationship between plasmatic levels of brain natriuretic peptide (BNP) and echocardiographic indicators of left ventricle (LV) function in patients who were in a long-term remission after the therapy of hematological malignity and examined in order to diagnose the late cardiotoxicity of doxorubicin. METHODS AND PATIENT SAMPLE: We enrolled 55 patients (31 men/24 women) aged 43 +/- 16 (median 41; 21-79) who were treated for historically diagnosed malignant lymphoma. At the time of examination, all patients were in a long-term remission and, at the same time, they completed their initial therapy 6.2 +/- 1.5 (median 5; 5-10) years ago. Patients were examined via resting echocardiography before and after the therapy and during the follow-up examination. We determined the left ventricle ejection fraction (LV EF), parameters of diastolic function and the Doppler parameters of systolic and diastolic function (MPI-Tei index). During the follow-up examination, we measured plasmatic levels of BNP (standard levels were between 0 and 29 pmol/1). RESULTS: Follow-up examination showed that EF of five patients (9 %) decreased below 50% and three patients had symptoms of heart failure. Although EF of another eleven patients (20%) was in the physiological range, it decreased by more than 10% as compared with their pre-treatment EF values. Seventeen patients (30 %) showed higher MPI > 0.55 and twenty patients (36%) demonstrated diastolic dysfunction (impaired relaxation). BNP > 29 pmol/l was observed only in patients with EF < 50% and heart failure symptoms. BNP values significantly correlated only with endsystolic (r = 0.82; p < 0.0001) and enddiastolic (r = 0.72; p < 0.0001) volume of LV. On the other hand, BNP of 11.4 pmol/l showed negative predictive value for the following parameters: 80% for decrease of EF by more than 10%; 72% for detection of MPI > 0.55; and 70% for detection of relaxation disorder, i.e. the diagnostics of subclinical cardiotoxicity. CONCLUSIONS: The present study highlights the practical importance of measuring BNP levels when diagnosing the late changes of LV functions after doxorubicin chemotherapy. Standard cut-off BNP (29 pmol/1) used in diagnostics of heart failures identifies patients with pathological EF and heart failure symptoms. Cut-off BNP of 11.4 pmol/l has sufficient negative predictive value to exclude subclinical damage to the myocardium.

[Late cardiotoxicity in patients with malignant lymphoma treated with doxorubicin chemotherapy]. / Pozdní kardiotoxicita u nemocných lécených pro maligní lymfomy chemoterapií s doxorubicinem.

AIM OF THE STUDY: Chronic cardiotoxicity of doxorubicin occurs at least one year after the chemotherapy is finished. As such, it is a serious late complication in patients with malignant lymphomas. The aim of the study was to identify the incidence of late clinical and subclinical doxorubicin cardiotoxicity and cardiopulmonary performance of patients being in remission for five and more years from the initial therapy. GROUP OF PATIENTS: We worked with 96 patients (47 men and 49 women) aged 43 +/- 15 (median 41, 23-79) years. Average period of monitoring was 6.2 +/- 1.5 (median 6.5-10) years. On the basis of therapy protocol, the patients were administered a maximum doxorubicin cumulative dose (CD DOX) of 377 +/- 147 (median 300, 50-880) mg/m2. Additional treatment after initial conventional therapy was performed in 32 patients (33%) due to high risk, progression or relapse of tumour. EXAMINATION METHODS: Patients were examined by resting echocardiography before and after initial therapy, and during follow-up examination after 5 years. Also, dynamic stress echocardiography and spiroergometry were performed during follow-up examination. Left ventricle ejection fraction (LVEF) decrease below 50 %, progressive decrease of LVEF > 10 % as compared with initial value, and decreased peak oxygen intake pVO2 < 20 ml/kg/min were considered as pathological. We also evaluated systolic function and index of myocardial performance (Tei-index). RESULTS: Clinical cardiotoxicity was observed in 4 % of patients, subclinical in 31% of patients. Diastolic dysfunction was found in 38 % of patients; pathological values of Tei-index were noted in 31% of patients. Value of stress increment of LVEF was 13 +/- 4 % (median 12; 5-25). Decreased pVO2 was observed in 15 % of patients. Cardiovascular disease and age > 60 years represent a higher risk of left ventricular dysfunction. Additional treatment after initial therapy represents a higher risk only if diastolic dysfunction is found (OR = 2.37, p < 0.05). Multi-dimensional regression analysis proved the relationship between pathological EF, CD DOX > or = 300 mg/m2, age > 60 years and cardiovascular disease (for CD DOX p < 0.05; age p < 0.01; concomitant cardiovascular disease p < 0.01, with r = 0.57 and p < 0.02 values for the overall model). CONCLUSIONS: The above-mentioned findings should positively influence the approach of oncologists and haematologists to long-term cardiological monitoring (at least with the help of resting echocardiography) in adult patients treated with antracyclines during initial chemotherapy.

Evaluation of acute and early cardiotoxicity in survivors of Hodgkin's disease treated with ABVD or BEACOPP regimens.

The study was conducted to compare the presence of cardiotoxicity after the treatment of Hodgkin's disease with the standard ABVD or BEACOPP protocol. We examined 29 patients treated by means of the ABVD regimen and 34 treated with the BEACOPP regimen. Using rest echocardiography we assessed the left ventricular function before and after the therapy. One year after the completion of therapy, a control examination was performed with a battery of tests; the rest and dynamic stress echocardiography and cardiopulmonary tests were carried out to assess cardiopulmonary performance. A similar significant deterioration of ejection fraction and diastolic function was apparent after the treatment in both sub-groups with a further progression at the one-year control. Only one patient from the BEACOPP sub-group showed a pathological drop of EF <50%. The most affected parameters of left ventricular function (LV) were Doppler indices. We found a significant relationship of the parameters of LV function compared with age, the cumulative dose of doxorubicin and the cumulative dose of radiotherapy. Multivariate analysis demonstrated that diastolic dysfunction correlated with advanced age and the cumulative dose of doxorubicin, and decreased cardiopulmonary performance with advanced age, radiotherapy, and female gender. Both parameters were significantly influenced by the presence of hypertension. The used regimens demonstrated similar subclinical cardiotoxicity, thus the most aggressive regimen, BEACOPP, is not accompanied by a higher rate of cardiac impairment. The clinical value of such subclinical cardiotoxicity will be estimated in a further prospective follow-up.

[Effect of high-dose chemotherapy with subsequent transplantation of blood-forming cells on left ventricle function in patients with malignant lymphomas treated with doxorubicin in primary chemotherapy]. / Vliv vysokodávkované chemoterapie s následnou transplantací krvetvorných bunek na funkci levé komory srdecní u nemocných s maligními lymfomy lécenými doxorubicinem v primární chemoterapii.

PURPOSE OF STUDY: The authors examined whether high-dose chemotherapy with hematogenic tissue transplantation might negatively affect function of left ventricle (LV) in oncology patients with malignant lymphomas initially treated with conventional chemotherapy consisting of doxorubicin (DOX) in contrast to patients treated without the transplantation in medium-term follow up. PATIENTS AND METHODOLOGY: The follow up group included 77 patients (39 women/38 men) at the age of 36 +/- 15 (median 30, 16-67 years). All 77 patients were treated with initial chemotherapy with DOX, 22 out of that group later received high-dose chemotherapy with hematogenic tissue transplantation (HTT). 16 (73 %) patients of this subgroup underwent autologous transplantation and 5 (23 %) allogeneic transplantation. One female patient (4 %) underwent both autologous and allogeneic transplantation. The follow up period after completion of initial chemotherapy was 5-10 years (median 6 years). The patients were examined with rest echocardiography before start, after chemotherapy, and during follow-up examination. Spiroergometric test (SET) was only performed at the follow-up examination. RESULTS: Both subgroups showed significant decrease of ejection fraction (EF) after chemotherapy, with further decrease in the control examination period, without mutual difference. While the HTT (HTT+) group showed no EF drop below 50 %, in the non-HTT (HTT-) group EF dropped in two (4 %) patients after chemotherapy and in four (8%) patients at the control examination. Progressing decrease of EF > 10 % was reported with 25 % of the HTT- patients (p < 0.05), but with just 13 % of the HTT+ patients (non-significant). The diastolic insufficiency (DF) was present identically in both groups with 36 % of the patients, which represents a statistically significant increase in comparison to the pre-chemotherapy condition. SET did not show any differences in burden toleration and circulation indicators between the two groups. The drop of pVO2 < 20 ml/kg/min occurred with 22 patients of both groups. Linear regression data analysis revealed existence of a significant relationship between EF change, some diastolic function indicators, pVO2 and cumulative dose of DOX (p < 0.05). The current age significantly and negatively correlated with pVO2 (p < 0.001) and DF indicators (p < 0.001). The follow up period inversely correlates with the changes of EF (p < 0.05) and pVO2 (p < 0.05), not correlating with diastolic function indicators. Multi-variant analysis did not confirm any higher risk of administration of high-dose chemotherapy with HTT for significant drop of EF or its drop down to the pathological zone below 50 % (OR = 0.46; non-significant), for discovery of reduced cardio-pulmonary performance (pVO2 < 20 ml/kg/min) (OR = 0.35; non-significant) or for development of diastolic dysfunction (OR = 1.0; non-significant). CONCLUSIONS: Treatment with high-dose chemotherapy with HTT application within medium-term follow up does not result in any significant systolic or diastolic malfunction of myocardium and deterioration of cardiopulmonary performance in comparison to patients not undergoing this therapy. Treatment with cardiotoxic doxorubicin administered in the context of basic conventional chemotherapy is most likely to be responsible for occurrence of the pathological effects across the followed up group. Length of monitoring is a significant factor correlating with changed ejection fraction. This finding justifies the need for long-term prospective monitoring of ejection fraction of the left ventricle in adult patients treated with cardiotoxic chemotherapy.

Cardiac function and cardiopulmonary performance in patients after treatment for non-Hodgkin's lymphoma.

Authors conducted a one-year prospective study to determine whether CHOP regimen (cyclophosphamide, doxorubicin, vincristin, and prednisone), used in the treatment of aggressive non-Hodgkin s lymphoma, is associated with the presence of an early impairment of cardiac function. Forty seven patients were prospectively examined (27 male and 20 female) aged 49+/-14 years who were treated with CHOP regimen. Rest echocardiography was performed at baseline and one-year control. Cardiopulmonary exercise test was carried out at one-year control examination. The ejection fraction (EF), parameters of diastolic function, myocardial performance index (MPI), and pVO2 were used as parameters of cardiopulmonary performance. The cumulative dose (CD) of doxorubicin was 277+/-56 (300 mg/m(2)) was given. The baseline EF 64+/-5% (64%) decreased to 58+/-7% (57%) at the one-year control (p<0.0001). 23% of patients exhibited a drop in EF >10% during the follow-up. 43% revealed a pathologically increased value of MPI >0.55, and 47% impaired diastolic function compared to the baseline values, respectively. 21% of patients exhibited a decrease of pVO(2) < 20 ml/kg/min, and 17% pVO(2) < 80% of the reference value, respectively. None of the patients developed signs of heart failure. The Doppler parameters of both diastolic and global LV function were the most affected measures and significantly influenced the cardiopulmonary performance. Multivariate analysis showed that CD > or =300 mg/m(2) (OR=8.08; p<0.05) and the presence of risk factors (OR=9.48; p<0.008) are the best predictors of cardiotoxicity. The results show that subclinical cardiac impairment was frequent in patients receiving the CHOP regimen with safe cumulative doses of doxorubicin. The value of described changes for the development of heart failure has to be assessed during the prospective follow-up.

Echocardiographic evaluation of early and chronic cardiotoxicity in adult patients treated for Hodgkin's disease with ABVD regimen.

The prospective study was conducted to determine whether standard regimen ABVD used in the treatment of Hodgkin's disease is accompanied by the presence of early and chronic myocardial impairment. The study comprised 52 patients (30 male and 22 female) aged 34+/-15 years (range 18-71; median 30) with Hodgkin's disease and the control group with 40 healthy volunteers (21 male and 19 female) aged 40+/-8 years (range 20-70; median 38). The maximal administered cumulative dose (CD) of doxorubicin was 297+/-50 mg/m2 (range 150-450; median 300). Radiotherapy of the mediastinum was delivered to 27 (52%) patients with a mean dose 41+/-4 Gy (range 30-46; median 42). Echocardiography was performed at baseline and before each course of chemotherapy. The control examination was done at one month after the treatment and after one year. The stress echocardiography was performed at one-year control. Significant change of ejection fraction (EF) during the treatment was observed only in 10 (18%) patients (7 male/3 female) aged 29+/-13 years (range 18-56; median 22). The mean toxic CD of doxorubicin was 170+/-33 mg/m2 (range 100-200; median 175) and the mean time of the onset EF decline was 13.3+/-3 weeks (range 8-16; median 14). These changes were asymptomatic, and all patients completed the treatment successfully. Four patients (8%) demonstrated significant asymptomatic decline of EF after the chemotherapy. When compared the value of EF after one-year examination, a stable significant decline of EF in the sub-group with early toxicity was found. Despite a difference in the rest EF, the exercise increment of EF did not reveal any significant difference among tested groups and the contractile reserve of the left ventricle in patients was not impaired. The present data shows that the treatment of Hodgkin's disease with the standard ABVD regimen is accompanied with mild early and chronic asymptomatic changes of the left ventricular function. These changes were not reversible during one-year follow-up.

[Evaluation of the clinical effectivity and toxicity of the FDN regimen (fludarabin, mitoxantron, dexamethason) in patients with follicular lymphoma]. / Hodnocení klinické ucinnosti a toxicity rezimu FND (fludarabin, mitoxantron, dexamethason) u pacientu s folikulárním lymfomem.

BACKGROUND: One of the perspective therapeutic possibilities in follicular lymphomas (FL) is the fludarabine-based regimen FND (fludarabine, mitoxantron, dexamethason). However serious signs of myelotoxicity and significant immunosuppression with appearance of the opportunistic infections were described after the fludarabine treatment. METHODS AND RESULTS: Follicular lymphoma patients with advanced disease grade I-II were treated with FND (6-8 cycles). The immunotoxicity was evaluated by measuring of immunoglobuline levels (IgA, IgG, IgM) and that of lymphocytes subpopulations (CD3+, CD4+, CD8+, CD20+, CD56+) in peripheral blood. The myelotoxicity was evaluated by cultures of progenitor cells (CFC and LTC-IC). Totally 34 patients (median age 55.5 years) were evaluated, the overall response was 72% (CR 61%, PR 11%, progression 28%). 73% patients of 11 after 6-8 FND show persisting CR (27% relapsed) with median follow-up about 15 months. The dominating toxicity was myelotoxicity. The leucopenia grade III-IV occurred in about 30% cycles. Because of toxicity it was necessary to reduce doses of FND in 10% cycles and this treatment had to be finished ahead of schedule in 29% patients. The significant immunotoxicity was found only in the decrease of whole lymphocyte population (p < 0.05) and of IgG level (p < 0.05). The decrease of lymphocyte subpopulations did not reach any statistical significance. The long-term myelotoxicity caused the decrease of LTC-IC that had a clinical correlation with the very difficult mobilization of PBSC. CONCLUSIONS: FND is efficient in treatment of follicular lymphoma. However myelotoxicity seems to be limiting. Myelotoxicity doesn't allow administering scheduled dose of FND in substantial amount of patients, long-term myelotoxicity complicates PBSC-mobilization. Lymphotoxicity is apparent, but seems not to be clinically important.

[Dexrazoxane in patients with B-lymphomas or acute leukemias in the 2nd complete remission enables further therapy with cardiotoxic anthracyclines over recommended cumulative doses]. / Dexrazoxan u nemocných s B-lymfomy nebo akutními leukémiemi ve 2. kompletní remisi umoznuje dalsí lécbu kardiotoxickými antracykliny nad doporucené kumulativní dávky.

UNLABELLED: Daunorubicin (DNR) and doxorubicin (DOX) have significant antitumor activity in acute myeloid leukemias (AML) and non-Hodgkin's lymphomas (NHL) but their use is limited by their life-threatening cumulative dose related cardiotoxicity. It is generally recommended not to administer DOX or DNR to patients in doses greater than 500 mg/sqm or 700 mg/sqm, respectively. the aim of the study was to follow up cardiotoxicity and efficacy of DNR or DOX above these limits in the 2nd complete remission (CR) patients pretreated with anthracyclines when they were given 30 minutes after cardioprotective agent dexrazoxane (DRZ) in the ratio 1:10 of DZR. RESULTS: Two patients (54 and 53 years old) with mantle cell or diffuse large cell B-NHL, stage IV, who had relapsed after 6-8 cycles of classical CHOP therapy, reached their 2nd CR after 2-3 cycles of IDEA therapy (ifosfamide 1000 mg/sqm/day x 4, dexamethasone 30 mg/sqm/day x 4, etoposide 75 mg/sqm/day x 4, DOX 30 mg/sqm/day on days 1 and 3). Then they received further 3 cycles IDEA with DRZ 300 mg/sqm before every dose of DOX. After cumulative doses of DOX 600 mg/sqm and 700 mg/sqm these patients survived 12 months in their 2nd CR without significant signs of cardiotoxicity, even after their successful autologous peripheral stem cells transplantation. Their left ventricular ejection fraction (LVEF) remained above 60%. Six patients with AML in their 2nd CR were treated with consolidation cycles consisting of 10 high doses of cytosine arabinoside (2000 mg/sqm/12 hr) plus 2 doses of DNR 45 mg/sqm on the day 4 and 5. Two patients received cumulative doses corresponding to 1300 mg/sqm and 1000 mg/sqm of DNR, the other received DNR doses 550-850 mg/sqm. No signs of significant cardiotoxicity were observed in all 6 patients and their LVEF remained over 50%. One of two patients, transplanted with HLA-identical sibling bone marrow in her 2nd complete remission (CR), is still 8 years in her 2nd CR. Dexrazoxane enables to administer anthracyclines in doses over the recommended cumulative ones in pretreated patients with B-NHL or AML in their 2nd CR with the follow-up of their LVEF.

Ifosfamide- and etoposide-based chemotherapy as salvage and mobilizing regimens for poor prognosis lymphoma.

Treatment of early relapsing or resistant non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) remains problematic. High-dose chemotherapy followed by autologous peripheral blood stem cell (PBSC) transplantation improves the prognosis for patients in response following standard dose regimens. We adopted the strategy of using salvage chemotherapy to debulk disease and simultaneously mobilize stem cells. We used regimens based on ifosfamide and etoposide because these drugs are not usually used as the front-line treatment. Twenty-seven patients with NHL received MINE chemotherapy (mesna and ifosfamide 1330 mg/m2 and etoposide 65 mg/m2 i.v. days 1-3, and mitoxantrone 8 mg/m2 i.v. day 1). The same schedule, but higher doses were used for PBSC stimulation (mesna, ifosfamide 1700 mg/m2, etoposide 175 mg/m2, mitoxantrone 10 mg/m2). Forty-six patients with HD received VIM chemotherapy (mesna, ifosfamide 1200 mg/m2 i.v. days 1-5, etoposide 90 mg/m2 i.v. days 1, 3, and 5, methotrexate 30 mg/m2 i.v. days 1 and 5). After both VIM and high dose MINE, chemotherapy for mobilization was followed by G-CSF administered at a dose 5-16 micrograms/kg/day depending on the clinicians judgement of the patient's pretreatment. Complete response after VIM and MINE were 39% and 38%, respectively; partial response (PR) rates were 17% and 29%, and stable disease (SD) 25% and 4%, respectively. In both groups, patients with relapsing disease had better responses than did those with primary progressive disease. Both regimens exhibited excellent mobilizing capacity. We performed 213 aphereses with a median 3 per patient starting on either day 13 as a median for VIM, or on day 12 as a median for MINE. In the majority of patients, the collection started in the time interval median +/- 1 day (n = 62, 85%). The median yields were 10.6 x 10(6) CD34+ cells/kg and 53.1 x 10(4) CFU-GM/kg for VIM, and 13.3 x 10(6) CD34+ cells/kg and 54.5 x 10(4) CFU-GM/kg for MINE. We collected at least 2.5 x 10(6) CD34+ cells/kg in all but six patients (8%), and the harvested amount of CD34+ cells was less than 1.0 x 10(6)/kg in only two patients (3%). The toxicity of VIM and MINE was minimal and chemotherapy-induced trombocytopenia did not occur with PBSC collection.

[Cardiotoxicity of antineoplastic therapy]. / Kardiotoxicita protinádorové lécby.

Cardiotoxicity is a serious complication of anti-tumorous treatment. Cytostatics can cause a number of undesirable side-effects such as arrhythmias, angina pectoris, acute myocardial infarction, sudden death, cardiac failure. The probably most serious cardiotoxicity is chronic cardiac failure after treatment with anthracyclines. Interest in the diagnosis, monitoring and treatment of cardiotoxicity revealed new findings of cardiac complications after various cytostatics, high-dosage chemotherapy and transplantation of haematopoietic cells. Prospective paediatric studies provided evidence of the serious character of late cardiotoxicity of anthracyclines. The authors review the most frequent cardiac complications of anti-tumorous treatment. They emphasize in particular the toxicity of anthracyclines and its possible prevention.

Radiotherapy of early stages Hodgkin's disease. 10 years experience of the Masaryk Memorial Cancer Institute.

Radiotherapy and chemotherapy, alone or in combination, are curative treatment methods in early stages of Hodgkin's disease (HD). The choice of treatment depends on the stage of the disease, histological type and localization of the tumor, as well as on other prognostic factors. A retrospective study was conducted including 145 patients with clinical Stages I and II of HD according to Ann Arbor classification, all treated in the Masaryk Memorial Cancer Institute in Brno during the years 1985 through 1994. 80 patients were males (55%) and 65 patients females (45%). The age of the patients ranged from 11 to 77 years, with an average of 34.8 years. 41 patients were diagnosed with Stage IA tumor, 1 patient with Stage IB, 75 patients with Stage IIA and 28 with Stage IIB disease. The histological types of the disease were lymphocyte predominant in 23 patients, nodular sclerosis in 49 patients, mixed cellularity in 65 cases and lymphocyte depletion in 8 cases. 91 patients were treated with radiotherapy alone. In this group 14 patients relapsed within the radiation field (15%) and 25 outside the radiation field (28%). 39 patients were treated with combination of radiotherapy and chemotherapy. In this group relapse occurred within the radiation field in 3 patients (8%) and outside the radiation field in 7 patients (18%). 15 patients were given chemotherapy alone, 7 patients from this group experienced a relapse. The five-year survival was 81% in patients with Stages IA and IIA disease, 65% in Stages IB and IIB disease. The five-year survival in the patients who relapsed was 56%. Radiotherapy remains the curative method of choice in highly selected group of patients with early stages of Hodgkin's disease. The results of radiotherapy alone are unsatisfactory in unselected clinical Stage I--II patients because of the presence of patients with adverse prognostic factors, particularly B symptomatology, mixed cellularity/lymphocyte depletion histology, higher age. These patients are candidates for combined treatment. Modern equipment and meticulous treatment are conditions crucial for the outcome of curative radiotherapy in patients with Hodgkin's disease. Combination chemotherapy is very effective in the treatment of relapse following the primary radiotherapy.

[Effect of high-dose chemotherapy in patients with relapsing or resistant Hodgkin's disease]. / Efekt vysokodávkované chemoterapie u nemocných s relabující nebo rezistentní Hodgkinovou chorobou.

The authors evaluated a group of 48 patients with relapsing or resistant Hodgkin's disease. The patients were treated by life-saving chemotherapy followed by large doses of chemotherapy and autologous transplantation of haematopoietic cells. For life-saving chemotherapy they used most frequently a combination of VIM in 40 patients and combinations of DHAP, MINE, MiniDexaBEAM. In 11 patients they changed the regime of life-saving chemotherapy because of a poor response. After completed life-saving chemotherapy 18 (37.5%) patients were in CR, 27 (56.2%) in PR and in 3 (6.3%) the disease progressed. For large dose chemotherapy the authors used BEAM in 32 patients, CBV in 2, Busulfan with Cyclophosphamide in 13 patients and Busulfan with Melfalan in one patient. After completion of large dose chemotherapy and subsequent autologous transplantation of bone marrow 31 (64.6%) patients were in CR, 8 (16.7%) in PR and the disease progressed in 9 (18.7%). In August 1999 a total of 44.9% patients in CR survive, the median period of follow up after autologous transplantation was 23 months. Life-saving chemotherapy with subsequent large dose chemotherapy led in the investigated group to induction of CR in 64.6% patients which is the basic prerequisite of long-term survival.

[Damage of left ventricular function after treatment with doxorubicin in patients with malignant lymphomas]. / Poskození funkce levé komory srdecní po lécbe doxorubicinem u nemocných s maligními lymfomy.

The authors evaluated using clinical and echocardiographic examination the effect of chemotherapy involving bolus administration of doxorubicin on the heart muscle in 90 patients with non-Hodgkin lymphoma and with Hodgkin lymphoma. In 18% of patients they found an asymptomatic decrease of the left ventricular ejection fraction during chemotherapy, chronic cardiotoxicity was recorded in 5% patients, in 2% of the patients one year after termination of chemotherapy a clinically latent myocardial infarction was found. The diastolic function was impaired (impaired relaxation) in 44% patients after terminated chemotherapy and in 50% after one year. Echocardiographic examination provided evidence that the impaired systolic and diastolic function persists even after one year following termination of chemotherapy. High-dose chemotherapy with administration of peripheral stem cells did not lead to marked deterioration of left ventricular function as compared with patients who did not undergo this treatment. The main clinical complications--death, cardiotoxicity, relapse of the malignant disease, cardiovascular complications--were present in the course of a 18.5-month follow up after establishment of the diagnosis in 32% of the patients.

[Kinetics of hematopoiesis after high-dose chemotherapy and autologous peripheral stem cell transplantation]. / Kinetika obnovy krvetvorby po vysokodávkované chemoterapii a autologní transplantaci periferních kmenových bunek.

BACKGROUND: Autologous peripheral blood stem cell transplantation (APBSCT) is gradually replacing autologous bone marrow transplantation in many clinical settings. The key question is how to evaluate the quality of grafts. We analyzed the relationship between hematopoietic reconstitution and characteristics of patients and grafts. METHODS AND RESULTS: Data from 95 APBSCTs were analyzed. Peripheral stem cells were obtained after mobilization using anti-neoplastic chemotherapy followed by Neupogen (G-CSF). After high dose chemotherapy and APBSCT, patients received Leucomax (GM-CSF). Patients were reinfused with a median of 6.1 x 10(6) (range 0.83-29.3) CD34+ cells/kg, and 25.1 x 10(4) (range 1.0-167.0) CFU-GM/kg of body weight. The median time to engraftment was 12 days (both for granulocytes 1 x 10(9)/l and platelets 50 x 10(9)/l). We found a significant correlation between the number of CD34+ cells and CFU-GM reinfused and also between their respective graft sizes and time to leukocytes, platelets, and granulocytes recovery. We did not find a significant correlation between the number of mononuclear cells reinfused and any analyzed parameter (time to engraftment, age, diagnosis, number of previous chemotherapies, type of mobilization or high-dose regimen). However, administration of preparative high-dose chemotherapy consisted of busulphan and cyclophosphamide was associated with the risk of a transient secondary graft failure. CONCLUSIONS: We conclude that the content of progenitors in PBSC grafts and time to booth leukocyte and platelet recovery are best estimated by the number of CD34+ cells (not less than 1 x 10(6)/kg) and CFU-GM (not less than 1 x 10(4)/kg). The number of mononuclear cells in an autologous PBSC graft is not suitable and useful for prediction of engraftment rate. There is probably no additional benefit of reinfusion of more than 8-10 x 10(6) CD34+ cells/kg and/or 50 x 10(4) CFU-GM/kg, because hematopoietic recovery is not more rapid.

[Warning signs preceding the development of septic shock in patients with neutropenia treated for hematologic malignancies]. / Varovné príznaky predcházející rozvoj septického soku u neutropenických nemocných lécených pro hematologické malignity.

BACKGROUND: In patients with haematological malignities infectious complications take a very rapid course, and in particular during the period of neutropenia, they are not necessarily manifested by a clear symptomatology. Frequently they may be manifested only by an elevated temperature and general deterioration of the condition. The onset of shock then can be rapid and surprising. The objective of the work was to identify clinical and laboratory signs warning against the possible development of septic shock. METHODS AND RESULTS: The investigation comprised a total of 38 patients hospitalised due to infectious complications at the intensive care unit because of general deterioration of the condition. 18 developed septic shock (group S), the remaining 20 (group N) achieved during hospitalisation at the ICU a stabilised condition. In both groups the laboratory values and clinical condition were followed up for 2-3 days prior to deterioration of the condition. Risk factors for development of septic shock in the group of investigated patients were: unusual weakness, heart rate above 95/min. beyond the temperature peak, hypoalbuminaemia, mucositis, hypokalaemia, presence of a central venous catheter and administration of parenteral nutrition.

Ifosfamide and etoposide-based chemotherapy as salvage and mobilizing regimens for poor prognosis lymphoma.

We treated 40 patients with poor prognosis lymphomas. Patients with non-Hodgkin's lymphoma (NHL, n = 14) received MINE chemotherapy (mesna, ifosfamide 1330 mg/m2 and etoposide 65 mg/m2 by i.v. infusions on days 1-3, mitoxantrone 8 mg/m2 i.v. on day 1), and those with Hodgkin's disease (HD, n = 26) received VIM chemotherapy (mesna, ifosfamide 1200 mg/m2 by i.v. infusion on days 1-5, etoposide 90 mg/m2 by i.v. infusion on days 1, 3 and 5, and methotrexate 30 mg/m2 i.v. on days 1 and 5). Chemotherapy was followed by G-CSF (10 or 16 microg/kg in two divided doses daily) to mobilize PBSC. We performed 134 aphereses (median three leukaphereses per patient) starting on either day 13 (median; VIM) or day 12 (median; MINE). The median yield was 9.9x10(6) CD34+ cells/kg and 53.2x10(4) CFU-GM/kg for VIM, and 13.5x10(6) CD34+ cells/kg and 53.4x10(4) CFU-GM/kg for MINE. Except for predictable myelosuppression, no serious toxicity was seen. Response rate using MINE was 63% (18% CR, 45% PR) and using VIM 50% (17% CR, 33% PR). We conclude that VIM and MINE are effective and well-tolerated salvage regimens in patients with lymphomas and, followed by G-CSF, they also exhibit good capacity to mobilize stem cells in a predictable time interval.