[Transcatheter treatment of degenerative critical aortic valve stenosis in a patient with severe heart failure and chronic lymphocytic leukemia].

Surgical aortic valve replacement is the standard therapy for severe aortic valve stenosis, however one third of patients are rejected because of high surgical risk. Under medical treatment alone these patients have a very poor prognosis with a high mortality rate. We present a case of 70-year-old male patient with degenerative symptomatic critical aortic stenosis and chronic lymphocytic leukemia. Due to recurrence of leukemia, the patient was denied conventional open heart surgery. Within few months of palliative chemotherapy decompensated aortic stenosis with severe congestive heart failure developed. Such therapeutic alternative as transcatheter aortic valve implantation (TAVI) emerged as a lifesaving procedure for the patient that allowed performing full-dose chemotherapy later. We provide a comprehensive review of current indications and contraindications for TAVI.

[Prognostic significance of immunoglobulin variable region gene mutations in B-CLL patients treated with combination therapy fludarabine plus cyclophosphamide].

AIM: To study prognostic factors in previously untreated patients receiving FC regimen (fludarabine plus cyclophosphamide). MATERIAL AND METHODS: We conducted a retrospective analysis of B-CLL patients observed in Hematology Research Center of Russia (Moscow) and Faculty Therapy Clinic of St. Petersburg State Medical University (St. Petersburg). All patients received FC regimen as a first line treatment (fludarabine 50 mg plus cyclophosphamide 250 mg/m2 for 3 days intravenously, repeated every 28 days). RESULTS: 54 patients were included into the study. The median age was 57.5 yrs (range 40-78 yrs). There were 38 males and 16 females. Before the treatment 22% patients had Binet stage A, 41%--stage B and 37%--stage C. 62% patients had unmutated subtype of B-CLL and 38% mutated subtype. 12 patients (22%) received less than 4 cycles of chemotherapy. In 8 patients (15%) there were significant delays between cycles (more than 2 months). In the whole cohort the median overall survival calculated from the time of treatment initiation was 57.4 months, the median progression free survival--24 months, and the median relapse free survival--27 moths. Mutational status of immunoglobulin variable region genes significantly influenced survival. In patients with unmutated subtype the median progression free survival was 23.6 months, while in patients with mutated subset it was not reached: 75% survival at 22.7 months (p = 0.027). Difference in progression free survival by stages (A versus B+C, A+B versus C) was not significant. CONCLUSION: Our data show that mutational status of immunoglobulin variable region genes remains a significant prognostic factor in patients receiving combined therapy with cyclophosphamide and fludarabine.

[First experience with the modified program NHL-BFM-90 application in adult patients with primary diffuse large B-cell gastric lymphosarcoma with unfavourable prognosis].

AIM: To assess efficacy of a modified program NHL-BFM-90 in adult patients with primary diffuse large B-cell gastric lymphosarcoms (PDLBGL) with unfavourable prognosis. MATERIAL AND METHODS: Modified courses of NHL-BFM-90 were conducted in 5 patients aged 27-67 years from January 2004 to September 2005. Four patients received chemotherapy of the first line, in one patient block therapy followed monotherapy with chlorambucil and a CHOEP course. All the patients were in a severe clinical condition and had several initial factors of unfavourable prognosis: size of the tumor more than 10 cm; stage IE and more advanced; B-symptoms; proliferative activity above 70%. The program NHL-BFM-90 was modified because of the patients' age. Chemotherapy was conducted according to the middle arm of the original program NHL-BFM-90, but methotrexate was introduced in a dose 1 g/m2 for 12 hours, while leukovorin was given 18 hours after the start of methotrexate injection. In two cases the blocks were enhanced with rituximab, 2 patients had doxorubicin in block A, in one case block C was enhanced with methotrexate. A total of 23 modified blocks NHL-BFM-90 were performed: one patient was given 6 blocks, two patients--5, one patient--4 blocks and one patient--3 blocks. RESULTS: Four patients after block 2 and one patient after block 3 of polychemotherapy NHL-BFM-90 achieved remission of the disease of 6 to 22 months duration which still continues. Infectious complications related to hematological toxicity arose more frequently at the latest courses of chemotherapy. CONCLUSION: Treatment according to the modified program NHL-BFM-90 in adult patients with PDLBGL and unfavourable prognosis is highly effective. For a mean follow-up of 10.2 months no recurrences occurred. The number of courses can be reduced to decrease accumulated hematological toxicity and in case of rapid achievement of remission.

[Cytogenetic disorders in chronic B-cell lymphoid leukemia and their relations with clinicobiological features and prognosis of the disease].

AIM: To study a relationship between cytogenetic disorders, clinicobiological characteristics and prognosis in chronic B-cell lymphoid leukemia (B-CLL). MATERIAL AND METHODS: Cytogenetic examination of blood, bone marrow and lymph node cells from 135 patients (90 males and 45 females aged 23-84 years) with chronic B-CLL was made. The patients were followed up from 1 month to 25 years. Before the cytogenetic examination specific therapy was not given. B-CLL was staged by K. Rai, forms--by A.L. Vorobyev and M.D. Brilliant. All the patients have undergone standard cytogenetic examination, FISH with multicolor probe to loci with possible frequent aberrations (del3q14, del11q23, del17p13, trisomia 12), determination of CD38 antigen expression on circulating tumor cells. Mutation status of the genes of immunoglobulins variable region (IgVH) was defined in 61 patients. RESULTS: Del13q14 was detected in 34 cases, del11q23--in 26, trisomia of chromosome 12--in 17 cases, del 17p13--in 8, absence of q-arm of chromosome 13--in 3 cases. 61 patients had no karyotype defects. Three prognostic groups of the patients were identified: favourable prognosis--patients without disorders of karyotype and one chromosomal aberration--del13q14; intermediate prognosis patients with dell1q23 and trisomia of chromosome 12; poor prognosis--patients with del17p13 and complex disorders of karyotype. CONCLUSION. Cytogenetic study help determine prognosis of B-CLL and detect patients in need of early therapy.

[Treatment of adult Berkitt-like lymphoma].

AIM: To compare programs of chemotherapy used in adult Berkitt-like lymphoma (ABLL); to assess efficacy and toxicity of the protocol AblL-M-04. MATERIAL AND METHODS: 31 ABLL patients (23 males, 8 females, mean age 27 years) participated in the study performed in Hematological Research Center in 1995-2004. ABLL stage I, II, III and IV was diagnosed in 3, 5, 8 and 15 patients, respectively. 10 patients had diffuse large B-cell lymphoma. 9 patients received 2 to 6 courses of CHOP, 1 patient--6 courses of Pro-Mace-Cytabom, 11 patients with newly diagnosed ABLL and 5 pretreated with CHOP--NHL-BFM-90. The modified protocol ABLL-M-04 of intensive short-term therapy included 10 patients, 2 of them pretreated. RESULTS: Of 10 patients given CHOP or CHOP-like courses 9 were resistant to therapy, 2 died of rapid progression, 7 were converted to the program therapy. 5 patients on the protocol NHL-BFM-90 died after short-term improvement. None of them achieved remission. Of 10 patients with newly diagnosed ABLL treated according to NHL-BFM-90 protocol, remission was achieved in 4 patients, follow-up median--34 months (2-56). Six patients died: 4 of progression, 2 of chemotherapy complications. BLL-M-04 therapy was made in 9 patients: 7 patients persisted on the first remission, 2 patients died of chemotherapy complications. Overall duration of the treatment was 3-3.5 months. CONCLUSION: The protocol ABLL-M-04 seems to be more effective than a classic NHL-BFM-90, but this must be supported by more cases. CHOP therapy cannot be recommended for patients with ABLL because of poor efficacy (all the CHOP patients died).

[A CHOP-21 course efficacy in therapy of diffuse large B-cell lymphosarcoma].

AIM: To examine efficacy of polychemotherapy (PCT) CHOP-21 in patients with diffuse large B-cell lymphosarcoma (DLBCL). MATERIAL AND METHODS: Fifty-five DLBCL patients received first-line therapy according to CHOP-21 program in 1996-2004. The diagnosis was made by WHO criteria. RESULTS: Initially, 37 patients had lymph node lesions, 18--nonlymphatic lesions. Complete remissions were achieved in 49% (56.7% in nodal lesions, 33.3% in extranodal ones). Overall 5-year survival was 35%, event-free--25%, for patients with nodal lesions--36 and 32%, respectively, extranodal lesions--35 and 22%, respectively. Overall 5-year and event-free survival in patients with local lesions was 85 and 75%, generalized--25 and 20%, respectively. In patients with involvement of the gastrointestinal tract 3-year overall and event-free survival reached 50 and 45%. Event-free survival was not seen in patients with extranodal lesions of other locations in overall 3-year survival 45%. CONCLUSION: PCT program CHOP-21 was effective in DLBCL patients with local nodular lesions except cases with large-size tumors, invasion in the adjacent organs and tissues and isolated gastric lesion.

[Cytogenetics of mantle cell lymphoma]. / Tsitogenetika limfomy iz kletok mantiinoi zony.

AIM: To determine the type and rate of secondary chromosomal aberrations and role in pathogenesis of mantle cell lymphoma (MCL). MATERIAL AND METHODS: Standard cytogenetic examination (SCE) and fluorescent in situ hybridization (FISH) with tests for 11q22/ATM, 13q14, 17p13/p53, 9p21/p16 and chromosome 12 centromere were made in 28 patients. RESULTS: Secondary chromosomal aberrations were detected in 22 patients. Chromosomal abnormalities occurring in more than 2 cases include deletions 6q15-q23 (53% cases); 11q22/ATM (50%); 9p21 (36%, in half the cases deletion 9p21 was biallele); 13q14 (32%); trisomy 3/3q, monosomy 20 and deletions/translocations 1q and 1p (27% and 20%) and deletion 17p13/p53 (18%). Trisomies 12/12q, 6 and 18/18q, monosomies 2 and 16, deletions/translocations 2p and 16p were found in 2 cases each. The FISH technique identified 9 chromosomal anomalies missed at SCE. Deletions 6q15-q23 were seen in patients with privalent lesions of lymph nodes. Deletions 11q, 13q14, 9p21 and 17p13 occur more frequently in transformation and the blastoid variant. Monosomy 20 was found only in patients with large cell transformations. This was the only cytogenetic defect characteristic for transformed cases, in contrast to denovoblastoid ones. Thus, deletions 6q, 11q23, 13q14 and 9p21 are typical for MCL. Deletions 9p21 and 17p13 are more characteristic for large cell variants of the tumor. Deletion 17p13 occurs at the terminal stage of the disease in rapidly growing tumor mass and resistance to chemotherapy. FISH technique is effective in detection of submicroscopic rearrangements especially small deletions. No significant differences were found between transformed and de novo blastoid cases. This shows that the blastoid variant is not a specific biological form, it is rather a less typical manifestation of the disease due to some preclinical cytogenetic disorders. CONCLUSION: Progression and transformation of MCL are related to mutation of proapoptotic genes and genes proteins of which are inhibitors of active complexes of D1 cycline. Specification of these mechanisms requires further investigations in patients with different clinicomorphological forms of the disease at various stages of the disease.

[Factors of an unfavorable prognosis in patients with B-cell chronic lymphoid leukemia: a retrospective analysis of 206 cases]. / Faktory neblagopriiatnogo prognoza u bol'nykh B-kletochnym khronicheskim limfoleikozom: retrospektivnyi analiz 206 sluchaev.

AIM: To assess factors of an unfavourable prognosis in a group of intermediate risk of B-cell chronic lymphoid leukemia (BCCLL). MATERIAL AND METHODS: 206 BCCLL patients (mean age 55.5 years, male/female = 1.66) entered the study conducted by Hematological Research Center in 1992-2000. RESULTS: Nine patients under 35 years of age did not survive 5 years except one female who achieved a complete remission on fludarabin. The type of bone marrow infiltration (diffuse vs interstitial and nodular), the time of lymphocyte count doubling (under or over 12 months) discriminate the patients by prognosis in the group of intermediate risk: medians of overall survival 65 months vs 148 months and 72 vs 133 months, respectively (p < 0.005 for both curves, log-rank criterion). Survival medians in groups with low (< 50% cells) and high (> 50% cells) expression of CD38+ cells in the group of intermediate BCCLL risk comprise 55 and 106 months (p = 0.005). The type of bone marrow infiltration and time of doubling of lymphocyte count overlap: > 70% patients with a diffuse type of bone marrow infiltration have the time of doubling under 12 months and vice versa while expression of CD38 do not overlap with these values. Combination of two signs (type of bone marrow infiltration and CD38 expression or time og lymphocyte count doubling and CD38 expression) allows more precise identification of prognostically unfavourable groups. Medians of survival for combination of the first two signs (two positive against two negative) comprise 51 months vs 169 months (p < 0.0001), for combination of the latter two signs 55 months vs 106 months was not reached (p < 0.001). Although most patients with a tumor form of BCCLL are referred to stage II, the prognosis in this form is much worse than in stage II, survival medians are 44 and 69 months, respectively (p < 0.05). A mutation status of the genes of a variable region of immunoglobulins enable identification of the group of patients with a relatively benign course of BCCLL (survival medians 61 and 289 months, p < 0.0001). CONCLUSION: In patients under 35 years of age BCCLL runs unfavourably and seems to require intensive polychemotherapy. Usage of a combination of the signs (CD38, time of doubling of lymphocyte count and type of bone marrow infiltration) is a simple and reliable method of identification of prognostically different categories of patients in the group of an intermediate BCCLL risk. Prognosis in patients with a tumor form of BCCLL is unfavourable: medians of survival in patients with a tumor form and stage III-IV are comparable. Mutational status of the genes of immunoglobulin variable region may serve a marker of a long-term prognosis.