[Immunohistochemical prognostic factors of primary refractory Hodgkin's lymphoma].

In order to identify immunohistochemical markers associated with primary refractory Hodgkin's lymphoma, 20 patients with primary refractory form at stage IIAB in complete remission underwent histological examination and immunohistochemical determination of Bcl-6, Bcl-2, c-kit (CD117), CD15, CD30, P-53, Ki-67. In the group with primary refractory Hodgkin's lymphoma at stage IIAB Bcl-6 expression was found in 2 patients (10%), Bcl-2 in 14 patients (70%), c-kit (CD117) in 16 patients (80%), CD15 in 9 patients (45%). The expression of CD30 and P-53 was observed in all patients in this group (100%). The expression of Ki-67 ranged from 20% to 100%, 80-100% in 16 patients (80%). As a result, multivariate analysis revealed no immunohistochemical markers of primary refractory Hodgkin's lymphoma. In univariate and multivariate analyzes in a group of primary refractory Hodgkin's lymphoma a high level P-53 expression (80-100%) was significantly associated with decreased overall survival. A 5-year overall survival in patients with Hodgkin's lymphoma with the expression level of P-53 < 80% was 78%, with the expression level of P-53 80-100%-22%. A 5-year overall survival of Hodgkin's lymphoma primary patients in complete remission significantly exceeded the rates of patients with primary refractory Hodgkin's lymphoma--100% vs. 52%.

[Effectiveness and toxicity of MOPP, ABVD, BEACOPP chemotherapy in first-diagnosed Hodgkin lymphoma with a poor prognosis].

In a retrospective study during the primary mode MOPP to primary patients LH II/IVAB stages with a poor prognosis rate of CR, 5--and 10-year DFS, OS was 69%, 71% and 68%, 74% and 64%, ABVD--76%, 78%, 83% and 68%, BEACOPP-baseline--73%, 97%, 85% and 82%, respectively. When the program ran BEACOPP-baseline it was revealed higher rates of DFS compared with ABVD and MOPP. Higher OS rates were observed in the primary patients treated with BEACOPP-baseline compared with MOPP (p = 0.04). In terms of DFS and OS MOPP regimen did not differ from ABVD. Program ABVD and BEACOPP-baseline had no differences in terms of OS. The frequency of primary refractory forms of LH did not depend on the conducted regimens of PCT. Significantly less recurrences occurred during the regimen of BEACOPP-baseline compared to MOPP and ABVD. BEACOPP-baseline was accompanied by a more pronounced reversible hematologic toxicity. Against the background of the program BEACOPP-baseline, neutropenia of III-IV degree was detected in 32%, ABVD--16%, MOPP--13%.

[Combined effect of gemcitabine and lomustine in mice with intracranial transplanted lymphosarcoma LIO-1].

SHR mice with intracranial transplanted lymphosarcoma LIO-1 received a single intraperitoneal gemcitabine injection in maximal tolerated dose of 25 mg/kg or single maximal tolerated oral dose of lomustine, 50 mg/kg. Compared to control group gemcitabine injection increased the mice lifespan 1.4-fold (p < 0,01) and oral lomustine 1.6-fold (p < 0,01). The median lifespan of the mice receiving both gemcitabine and lomustine in maximal dose underwent a significant 3.3-fold increase (p < 0,01) compared to controls (2.4-fold compared to gemcitabine and 2.1-fold compared to lomustine group). Combined therapy didn't cause an increase of toxicity.

[Relapse in Hodgkin lymphoma].

The retrospective study revealed the 15% relapse rate in patients with stage II-IV unfavorable prognosis Hodgkin lymphoma, 5-year OS in relapsed patients was 84%. Karnofsky score less than 80 (p=0,0001), more than 1 extranodal lesion (p=0,0004), extensive (equal to stage III-IV) involvement on relapse (p=0,001), b-symptoms on relapse (p=0,023), more than 5 lymph nodal lesions (p=0,027), albumin level less than 40 g per liter (p=0,037), detection of new nodal lesions (p=0,041) were shown by discriminative analysis as the therapy effect predictors in patients with Hodgkin lymphoma relapse. In patients with second-line therapy failure the actuarial survival rate was lower by 55% in comparison to patients with chemosensitive relapses (40% and 95%). The secondary therapy resistance was shown to be an unfavorable prognosis predictive factor (p=0,0001). The multifactorial overall survival analysis revealed the following adverse prognostic factors: failure of second-line treatment (p=0,0001), first early relapse (p=0,01), albumin level on relapse less than 40 g per liter (p=0,02), use of standard chemotherapy instead of irradiation (p=0,02). The relapse patients with 1 or less risk factors had 95% 5-year OS, the patients with 3 or more adverse risk factors had 70% OS (p=0,0002). The lowest 10-year OS was observed in patients with 2 or more adverse risk factors, 48% and 28% accordingly. Adverse risk factors must be considered while choosing the optimal treatment strategy aimed at better survival rate.

[Primary refractory and relapsed Hodgkin lymphoma with unfavorable prognosis].

In this retrospective clinical study 100 patients with primary unfavorable prognosis stage II Hodgkin lymphoma (HL) (n = 50) or stage IV HL (n = 50). The ABVD chemotherapy allowed to achieve remission in 90% of cases with 5-year relapse-free survival (RFS) and overall survival (OS) of 64% and 92%, the basic BEACOPP regimen lead to the same 90% remission rate with 74% DFS and 94% OS. These results for ABVD and basic BEACOPP regimens are characterized by similar statistic values (p = 1.0; p = 0.6; p = 0.9), although the use basic BEACOPP lead to statically valid decrease of grade III-IV toxicity (p = 0.005). The occurrence of primary refractory HL was slightly higher in basic BEACOPP group (18% versus 10% in ABVD group), although this difference had no statistical value (p = 0.3) and was probably due to higher number of patients with > 1 extranodal localizations. The occurrence of primary refractory HL correlated to disease stage: 6% in stage II and 22% in stage IV (p = 0.04). HL relapse frequency in ABVD and BEACOPP groups was similar (12% and 8%), there was no statistically valid difference (p = 0.5). In ABVD and basic BEACOPP recipients with stage II/IV HL the primary refractory disease rate was 15%, relapse rate was 10%. Five-year OS in primary refractory and relapsed patients was lower, than in general patient population (64% and 70% compared to 80%), although the difference had no statistical significance (p = 0.6, p = 0.7).

[Primary-refractory forms of Hodgkin's lymphoma].

Retrospective analysis defined risk factors of primary-refractory course of Hodgkin's lymphoma as well as adverse prognostic factors, efficacy of I and II therapy lines in patients with primary-refractory forms of Hodgkin's lymphoma. By means of discriminant analysis risk factors were as follows: massive tumor lesion, chemotherapy as compared to chemoradiotherapy in the I line, intoxication symptoms, IPS > or = 3, LDH level more than 1,5xULN, late beginning of specialized treatment (over 12 months from initial symptoms of disease), damage of 5 and more areas of lymph nodes, age more than 45 years, increase of ESR higher than 30 mm/h in Stage B and 50 MM/H in Stage A, Stage IV of disease, leukocyte rate higher than 15 x 10(9)/l, presence of more than one extranodal lesion. As a result there were revealed 4 prognostic factors unfavorably influencing on survival rates in primary-refractory forms of Hodgkin's lymphoma with originally Stages II/IV with poor prognosis. The worst 5-year survival rates were found in the presence of 3 and 4 adverse prognostic factors. These circumstances should be taken into consideration choosing optimal treatment and predicting of success of the proposed treatment.

[Investigation of gemcitabine plus lomustine treatment in mice with transplantable lymphosarcoma LIO-1].

Efficiency of gemcitabine plus lomustine treatment of transplantable lymphosarcoma LIO-1 in mice was significantly higher than that of monotherapy. According to the area under the kinetic curve for tumor growth, antitumor action, for single maximum tolerable dose of gemcitabine 25 mg/kg body, rose 4.6 times (p < or = 0.001), for lomustine 50 mg/kg body,--2.9 times (p < or = 0.01). The combination involved moderately increased toxicity. Lethality rate for gemcitabine+lomustine, 50 mg/kg body each, was as low as one and a half times as compared with gemcitabine therapy alone, 50 mg/kg body, (30 and 20%, respectively). The antitumor action of the combination (50 mg/kg body), was 32 times that of gemcitabine 50 mg/kg body (p < or = 0.001) and lomustine 50 mg/kg body--30 times (p < or = 0.001).

[Synergism of antitumor activity of gemcitabine and dioxadet in mice with ascitic Ehrlich's tumor].

Antitumor activity of a new cytostatic drug combination of gemcitabine and dioxadet have been studied in 86 female SHR mice transplanted with 5 x 10(6) of ascitic Ehrlich's tumor cells each. All mice received a single injection of gemcitabine, dioxadet on combination 48 hams after tumor cells introduction. In first series, experimental animals received maximal tolerable dose of gemcitabine (25 mg/kg) and one half of dioxadet maximal tolerable dose (2.5 mg/kg). In the second series of experiments, the animals received 5 mg/kg of dioxadet along with the same gemcitabine dose. Effect of drugs was compared using the time to ascites detection, body weight increase, and survival time. Gemcitabine and dioxadet administered separately and in combination inhibited the growth of ascitic Ehrlich's tumor in the mice. In both series of experiments antineoplastic activity of gemcitabine and dioxadet combination was significantly higher in comparison to the control groups receiving these drugs separately. The highest antineoplastic activity of the gemcitabine and dioxadet combination was observed when the maximal tolerable doses of both drugs was applied. However, the tumor cells growth was also significantly inhibited in mice receiving half of dioxadet dose. Synergism of antitumor activity of gemcitabine and dioxadet was not accompanied by appreciable increase in toxicity.

[Antitumor activity of dioxadet compared with cisplatin on ascitic ovarian tumor in rats].

Antitumor activity of dioxadet in comparison with cisplatin was studied on the model of ascitic ovarian tumor in 32 female Wistar rats. Ascitic ovarian tumor was transplanted intraperitoneally 0.5 ml per rat dissolved by saline in ratio 1 to 4. Dioxadet (1.5 mg/kg b.w.) and cisplatin (4.0 mg/kg b.w.) were administered intraperitoneally at their single maximal tolerable doses 48 hours after tumor cells transplantation. For drug activity estimation time to ascites detection and survival time values were used. In control group without no treatment the time till ascites occurrence and median life span were 5.4 +/- 0.25 and 7.5 days, correspondingly. In comparison with the control group dioxadet increased the average time of ascites occurrence and median of life span by 30% and 113% (p < 0.05), cisplatin increased these parameters by 28% and 147% (p < 0.05). Hence, antitumor activity of dioxadet is comparable with cisplatin activity for intraperitoneal therapy of the ascitic ovarian tumor.

[Can extended induction chemoradiotherapy be effective in the combined treatment of stage IIIB Hodgkin's disease ?].

The paper evaluates the results of chemoradiaton (2-4 cycles of preliminary treatment to suppress intoxication symptoms plus total, or subtotal exposure of the lymph nodes to tumor-killing doses in cases of intact iliac inguinal nodes) in 89 patients with Hodgkin's disease stage IIIB. The data are evaluated vis-à-vis regression in exposed foci as intoxication symptoms receded. Overall survival was significantly lower (p = 0.044) when tumor regression was well below 75%. Similar trends were reported with regard to relapse-free survival. It is concluded that, with our regimen, combined treatment will not be effective unless 75% or more regression of tumor is assured.

[Clinical features and combined treatment of the central nervous system in Hodgkin's disease].

Spinal cord compression was diagnosed in 33 patients with Hodgkin's disease. Specific involvement of the brain was identified in 17 cases of dissemination relapse. Timely use of cytostatic and/or radiotherapy resulted in sustained and complete recovery of the spinal cord. The results in cases of sustained spinal disorders were worse. Tumor-induced specific changes in the brain and spinal cord compression had worse prognosis and median of survival from time of tumor detection was approx. 12 months. In patients with spinal cord compression or cerebral involvement and with concomitant neurologic symptoms, sustained response after chemotherapy with derivatives of nitrosourea (nitrosomethylurea, lomustine and carmustine) (CCNU-OPP, NVPP/NOPP, DVCPP) was (59%) and (64%), respectively. Adequate polychemotherapy with nitrosourea and radiotherapy derivatives and surgery, if required, can improve the efficacy of treatment of Hodgkin's disease patients with spinal cord compression.

[Dicarbamin--an effective protector of myelodepression in combined treatment for Hodgkin's disease].

Clinical trials were carried out of the protective action of dicarbamin in 33 patients with Hodgkin's disease (13 males and 20 females, average age--31 years). They received standard chemotherapy ABVD (doxorubicin--25 mg/m2, bleomycin--10 mg/m2, vinblastine--6 mg/m2, dacarbazine--375 mg/m2, intravenously, on days 1 and 15 of each cycle, every 4 weeks. Patients suffering neutropenia after the first injection of the cytostatic drugs were given dicarbamin 100 mg/day on day 5 before a second administration. Treatment with dicarbamin continued for 15 days. Its protective effect was reported in 27 patients (81.8%). Leukocyte and granulocyte count before dicarbamin was 3.74 +/- 0.25 x 10(9)/l and 1.42 +/- 0.17 x 10(9)/l, respectively. On completion of the polychemotherapeutic cycle, the indices rose to 5.0 +/- 0.28 x 10(9)/13 and 2.49 +/- 0.25 x 10(9)/l, respectively. The beneficial effect of dicarbamin was also demonstrated by a quick recovery of leukocyte levels than in controls (p > 0.5). After the next cycle of polychemotherapy (ABVD) plus dicarbamin was given for Hodgkin's disease and grade III-IV leuko- and granulocytopenia, leukocyte and granulocyte concentrations returned back to normal which indicated the protective action of dicarbamin.

[Is irradiation of intact ileoinguinal lymph nodes necessary in radiochemotherapy for stage-III Hodgkin's disease?].

Data are presented on radiochemotherapy (1-4 cycles of combined therapy+total (TI) or subtotal (STI) irradiation of lymph nodes) given to 120 patients, with stage III Hodgkin's disease, whose ileoinguinal lymph nodes were intact. Analysis of overall survival of patients with stage III Hodgkin's disease showed that 87% of STI patients survived for 10-years as compared with 73% in TI (p=0.07). What is most important is that 10-year relapse-free survival in STI patients (92%) was significantly higher than that in TI (75%) (p=0.01).

[Clinical evaluation of combined treatment of stage III(B) Hodgkin's disease].

Patients with stage III Hodgkin's disease (110) received 2-3 courses of combination chemotherapy followed by total or subtotal irradiation, or exposure of primarily involved lymph nodes. The study did not include patients with persistent symptoms of intoxication. Overall 5- and 10-year survival rates were 78 and 68%, recurrence-free--75 and 74% respectively.

[Use of Venofer in management of anemia in cancer patients].

Therapy of anemia raises hemoglobin (Hb) level which in turn improves quality of life. Venofer was tested in 20 anemic (grade 1) patients with various malignancies. The drug was administered in 3 courses, i/v, 200 mg at a 4-5 week interval during chemotherapy. Hb levels rose or remained unchanged in 75%; they fell mostly in cases of tumor progression. There was no correlation between Hb concentration and chemotherapy regimen--with or without platinum. Venofer treatment was followed by improvement in quality of life or by stabilization only in 73.3%. Quality of life improved by 9,3% (FACT-An) after an 1g/dl increase in Hb level. Venofer treatment prevented further anemia.