Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Individuals with Early Alzheimer's Disease: Amyloid Imaging Positron Emission Tomography and Safety Results from a Phase 2 Study.

BACKGROUND: ACC-001 is an investigational therapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer's disease. OBJECTIVES: To evaluate safety, immunogenicity, impact on brain amyloid, and other exploratory endpoints in participants receiving ACC-001. DESIGN: Randomized, phase 2, interventional study. TRIAL REGISTRATION: Clinicaltrials.gov ID NCT01227564. PARTICIPANTS: Individuals with early Alzheimer's disease (Mini-Mental State Examination scores ≥25, a global Clinical Dementia Rating of 0.5, and evidence of elevated baseline brain amyloid burden). INTERVENTION: Participants were randomized to ACC-001 3 µg or 10 µg with QS-21 adjuvant (50 µg), or placebo. MEASUREMENTS: The primary endpoint was change in brain amyloid burden by 18F-florbetapir positron emission tomography in composite cortical standard uptake value ratio. RESULTS: A total of 63 participants were randomized and 51 completed the study. At week 104, no significant differences were observed in 18F-florbetapir positron emission tomography composite cortical standard uptake value ratio between either ACC-001 dose compared with placebo. In both ACC-001 + QS-21 treatment groups, following the initial immunization, the anti-amyloid-beta geometric mean titers increased after each subsequent vaccination and then declined, with less apparent decline after the later compared with earlier immunizations. The majority of treatment-emergent adverse events in the ACC-001 + QS-21 groups were injection site reactions, which occurred at a greater rate in active treatment groups than in the placebo group. No amyloid-related imaging abnormalities of edema or effusion were reported. CONCLUSION: No statistically significant differences were observed between groups in the change from baseline brain amyloid burden despite apparently robust systemically measured anti-amyloid-beta antibody response at both dose levels. Insufficient antibody titers, poor quality immune response, short duration of treatment, or small sample size may have resulted in these findings. The safety and tolerability profile was acceptable.

Immunoregulatory factors controlling terminal differentiation of malignant B-lymphocytes.

B-lymphocytes of patients with chronic lymphocytic leukemia differentiate in vitro towards plasma cells upon activation with Pokeweed mitogen (PWM) and Cowan. The level of response is much lower than that of normal cells and so is the helper T-cell function. However, concanavalin A-activated suppressor T-cell function of Ig synthesis is normal. Malignant B-cells have a normal capacity to stimulate Ig synthesis in the mixed lymphocyte cultures, but they respond poorly to an allogeneic stimulus. Thymosin (TFX) causes a marked enhancement of PWM-driven differentiation of malignant B-cells.

[Autoimmune thrombocytopenia in pregnant women: diagnosis, treatment and prevention of complications in children]. / Autoimmunologiczna maloplytkowosc u kobiet w ciazy: rozpoznawanie, leczenie, zapobieganie powiklaniom u dzieci.

9 pregnancies (in 6 women) complicated by autoimmune thrombocytopenia were studied. Corticosteroids and/or azathioprine and/or intravenous immunoglobulins (IgG i.v.) were administered to 5 women during pregnancy. 1 complete remission (CR) was achieved after 3 mo. of treatment by corticosteroids and azathioprine. In peripartum period the treatment was administered in 7 cases (corticosteroids, IgG i.v., platelet transfusion). There were no haemorrhagic complications during peripartum period (8 vaginal delivery, 1 cesarean section). In 3 of 5 examined cases IgG antiplatelet antibody was detected. Study group was to small to define the correlation between level of antiplatelet antibodies and neonatal thrombocytopenia. 10 infants were born. 4 infants (including siblings) were found to have normal platelet counts immediately after delivery. They mothers were treated by IgG i.v. in 2 cases and 1 women in CR at the time of delivery. 4 infants were thrombocytopenic but required no treatment. Duration time of thrombocytopenia was 1 to 4 weeks. In these cases mothers were treated only by corticosteroids or had no therapy.

[A trial of treatment with thymus factor (TFX) for chronic autoimmune hemolytic anemias]. / Próba leczenia wyciagiem grasicy (TFX) przewleklych postaci niedokrwistosci autoimmunohemolitycznych.

30 days treatment TFX was performed in 8 cases AIHA (autoimmune hemolytic anemia) with presence of warm antibodies refractory after routine treatment (glucocorticosteroids, azathioprine, splenectomy): After TFX treatment in 2 cases autoantibodies were not detectable, in 5 cases reaction DAT (direct antiglobulin test) was decreased. Eluate antibody level and serum antibody level were decreased, too. Decreasing amount of red cells autoantibodies was confirmed by enzyme-linked antiglobulin test (ELAT) in 2 cases. Autoantibody level measured by semiquantitative and quantitative methods did not increase in any other case. Adverse effects of TFX treatment were not observed.

[Long-term observation of patients with autoimmune hemolytic anemia]. / Wieloletnia obserwacja chorych z niedokrwistosciami autoimmunohemolitycznymi.

Forty-nine cases of idiopathic and secondary autoimmune hemolytic anaemia (AIHA) were observed. Infections developed in 64% of them before the diagnosis of the idiopathic form had been established. In 83% of the patients warm antibodies were found, and in half these cases complement activation was observed on the blood cells. In 16% of cases autoantibodies to other tissues were present as well. Higher grade of anaemia and more severe course of the disease were observed in secondary AIHA. The survival time of patients with malignant lymphoma and haemolysis developing during the proliferation phase was twice as long as in cases with simultaneously diagnosed lymphoma and haemolysis. Idiopathic AIHA was more frequent chronic and mild. During over 2 years of follow-up haemolysis regressed in 44% of cases (in idiopathic AIHA in 65% and in secondary AIHA in 19%). The followed-up group comprised 36 patients. No immediate favourable effect of splenectomy was noted. In 43% of cases infections were a complication of pharmacological treatment and (or) splenectomy. Alloimmunization against blood cells was noted in 16% of cases.

[Clinical analysis of 15 cases of T-cell malignant lymphoma in adults]. / Analiza kliniczna 15 przypadków chloniaka zlosliwego t--komórkowego u osób doroslych.

In the years 1981-1987 T-cell lymphoma was diagnosed in 7 women and 8 men (2.2% of all hospitalized cases of malignant lymphomas). Chronic lymphatic and prolymphocytic leukaemias and T-zone lymphomas prevailed. In most cases systemic symptoms and lymphadenopathy were characteristic features. In 6 cases cutaneous changes coexisted having the appearance of desquamative erythema, in 2 cases cutaneous changes preceded by 10 years the generalization of the process. In 10 cases other organs were involved. Absolute lymphocyte count ranged from value below normal to values above normal range. In 8 cases hypergammaglobulinaemia was present. The results of treatment were bad. Early drug-induced myelosuppression was observed. Nine patients died. In the group of lymphoblastic lymphoma and Pinkus lymphoma all 5 patients died.

[Analysis of pregnancy, labor, child development and disease course in women with Hodgkin's disease]. / Analiza ciaz, porodów, urodzonych dzieci i przebiegu choroby u kobiet chorych na ziarnice zlosliwa.

Twenty pregnancies were observed in 16 women with Hodgkin's disease. During 3 pregnancies cytostatic treatment was given. In 6 cases the disease was diagnosed in pregnancy and the treatment was started after labour. Eleven pregnancies were diagnosed during remission, after a mean period of 4 years (range: 6 months to 8 years) from the completion of treatment. All pregnancies had a normal course and labours were not complicated. In 2 cases of successive pregnancies disease recurrence developed. in 1 case the active disease was exacerbated. Twenty healthy babies were born, in one low birth weight was noted. The development of all children in a period of 6 years, on average, was normal.

[Treatment of low-malignancy lymphomas by spleen irradiation]. / Leczenie chloniaków o malej zlosliwosci napromienianiem sledziony.

The spleen was irradiated in 8 patients with chronic lymphatic leukaemia using RTG radiation in doses of 225 to 800 cGy for one treatment course. The follow-up after radiotherapy lasted 12.5 months on average. In 7 cases a considerable reduction was observed in the size of the spleen, and in 6 cases the absolute leucocyte and lymphocyte counts decreased by a mean of 46% and 50% respectively. In patients in late phase of the disease the improvement was short-lasting; 5 patients died (2 from infectious complications). In patients in early phase remissions of 30 months were obtained with normalization of the proportions or T and B cells During the radiotherapy a significant rise was observed in the per cent of granulocytes and a fall of albumin level. Increased gamma-globulin and uric acid levels and decreased hemoglobin level and erythrocyte count were not significant. Variable changes were noted in the platelet count. No bleeding tendency was noted. Spleen irradiation may be used in the treatment of non-Hodgkin lymphoma associated with malignant proliferation prevailing in the spleen, that is in chronic prolymphocytic leukaemia and hairy-cell leukaemia Favourable effects of spleen irradiation were observed in chronic lymphatic leukaemia and this induced us to use this method in our eight cases.

[Results of the treatment of patients with advanced Hodgkin's disease by the ABDiC and/or BVCPP protocols]. / Wyniki leczenia programami ABDiC i/lub BVCPP chorych w zaawansowanym okresie ziarnicy zlosliwej.

In 22 patients with phase IV of Hodgkin's disease refractory to treatment by the programmes MOPP and/or CVPP, and ABCD and/or BACOP, and in patients with recurrences after this treatment the ABDIC and/or BVCPP programmes were applied. In 5 cases this treatment was associated with radiotherapy. Complete remission lasting 30 months was achieved in one case. In 9 cases only clinical improvement was noted. Twelve patients failed to respond to this treatment. Ten patients died. The mean survival time of all patients from the beginning of treatment by ABDIC and BVCPP programmes to the end of the observation was 14 months, and the time from the diagnosis to the end of the observation was 69 months. The results of this treatment are not satisfactory.

The use of vinca alkaloids in preparation for splenectomy of corticosteroid refractory chronic immune thrombocytopenic purpura patients.

Administration of vinca alkaloids (VA) to chronic corticosteroid refractory immune thrombocytopenia (ITP) patients results in a temporary increase of platelet count. The aim of the study was to evaluate the efficacy of vinca alkaloids in preparing adult corticosteroid refractory chronic ITP patients for splenectomy as well as to compare the costs of this method with costs of applying intravenous immunoglobulins. The study included 12 chronic ITP patients refractory to corticosteroids applied for 3-144 months. The patients were prepared for splenectomy with average 3.0 (from 1 to 4) 2-h intravenous infusions of vinca alkaloids at 7 day intervals. In eight patients, vincristin was used in a total dose of 6 mg (2 mg per infusion), in two patients, vinblastin was used in total dose of 30 mg (10 mg per infusion), and in two patients, vincristin and vinblastin infusions were administered alternatively. In nine of the 12 treated patients (75%) the platelet count increased to > or = 80 x 10(9)/l, which allowed safe splenectomy. Three patients unreactive to VA treatment were prepared for splenectomy with intravenous gammaglobulin infusions. Splenectomy was performed in 12 patients, in eight with laparoscopic method, in four with classic method. No complications during surgical intervention were observed. In none of the VA treated patients was myelosupression or liver or/and kidney dysfunction observed. Splenectomy resulted in normalization of platelet count in all patients after operation and in six of nine patients followed up for 10 months (on the average). Matching of VA costs with treatment efficacy and comparison with similar costs for intravenous immunoglobulin treatment revealed many fold lower costs of the former method.

Observations on behavior of platelet adhesiveness at the late stage of burn disease.

Results of investigations on platelet adhesiveness in burned patients after the stage of shock were presented. In all cases studied (17 patients) the values of platelet adhesiveness were lower than in healthy subjects. Further investigations are required to explain this finding.