Safety and effectiveness of long-term interferon gamma therapy in patients with chronic granulomatous disease

In chronic granulomatous disease (CGD), diminished or absent neutrophil NADPH oxidase function leads to recurrent pyogenic infections and granuloma formation. In a recent randomized, placebo-controlled trail, short-term prophylactic use of recombinant human interferon gamma (rIFN-gamma 1b) reduced the risk of serious infection in CGD patients by 67%, The current study evaluated the safety and effectiveness of long-term rIFN-gamma therapy in CGD patients. Patients were treated three times weekly with rIFN-gamma and evaluated semiannually. Serious infections (requiring hospitalization and parenteral antibiotic therapy), adverse clinical events, and measures of growth and development were noted. Thirty patients were evaluated for 12 months. The total average duration of rIFN-gamma therapy was 2.5 years. Three patients developed a total of four serious infections (0.13 infections per patient year). This rate compare favorably with rates of 1.10 and 0.38 infections per patient year found in the placebo and rIFN-gamma groups, respectively, during a previous study. Common adverse events were fever (23%), diarrhea (13%), and flu-like illness (13%). No serious adverse event was attributable to rIFN-gamma therapy and no obvious effects on growth and development were observed. rIFN-gamma is a safe and effective adjunctive therapy for reducing the frequency and severity of serious infections in CGD patients.     

Long-term progression in chronic manganism: ten years of follow-up

We studied the long-term clinical course of five patients with chronic manganese intoxication. The mean scores of the King's College Hospital Rating Scale for Parkinson's disease increased from 15.0 +/- 4.2 in 1987 to 28.3 +/- 6.70 in 1991 and then to 38.1 +/- 12.9 in 1995. The deterioration was most prominent in gait, rigidity, speed of foot tapping, and writing. Tissue concentrations of manganese in blood, urine, scalp hair, and pubic hair returned to normal. Follow-up MRIs did not show paramagnetic high-signal intensity on T1-weighted images. The data indicate that clinical progression in patients with manganese parkinsonism continues even 10 years after cessation of exposure.     

Suppression of cytogenetic clonal evolution with interferon alfa therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia

PURPOSE: To investigate whether cytogenetic clonal evolution can be suppressed with interferon alfa (IFN-alpha) therapy in patients with chronic myelogenous leukemia (CML). PATIENTS AND METHODS: Ninety patients with CML and cytogenetic clonal evolution who received IFN-alpha-based regimens were analyzed. Clonal evolution was defined as the presence of karyotypic abnormalities in addition to the Philadelphia (Ph) chromosome. Patients were evaluated for the suppression of cytogenetic clonal evolution after therapy, the cytogenetic response, and survival. RESULTS: The median age of the population was 39 years (range, 15 to 70 years), median time from diagnosis to clonal evolution 14 months (range, 0 to 145 months), and median percentage of abnormal metaphases 18% (range, 4% to 100%). Fifty six patients (62%) achieved some suppression of cytogenetic clonal evolution; in 41 patients (46%), the suppression was complete. The overall median survival was 51 months, with 43% alive at 5 years. Patients who achieved a complete suppression of cytogenetic clonal evolution had a median survival of 66 months, with 51% alive at 5 years. Characteristics associated with a better response include a lower percentage of abnormal metaphases, time to cytogenetic clonal evolution of 24 months or less, and absence of other features of accelerated disease. A prognostic classification for cytogenetic clonal evolution defined three groups with complete response (CR) rates of 85%, 34%, and 0% (P < .0001) and median survival times of 58, 31, and 30 months, respectively (P=.02). CONCLUSION: Patients with cytogenetic clonal evolution can respond to IFN-alpha therapy, and this response is associated with longer survival. A previously described prognostic model separates patients into subsets with different probabilities of response to IFN-alpha and survival.     

p53 expression in B-cell chronic lymphocytic leukemia: a marker of disease progression and poor prognosis

We have analyzed by immunocytochemistry (ICC) the frequency of p53 protein expression in 181 cases of B-cell chronic lymphocytic leukemia (CLL) followed at a single institution to assess the relationship between p53 and the clinical and morphological features of the disease, as well as the possible involvement of this protein in the pathogenesis of the more aggressive forms of CLL. The overall frequency of p53 protein positivity in CLL was 15% (27 of 181 cases). There were no significant differences in age, sex, absolute lymphocyte count, or lymphocyte doubling time between p53-positive and -negative patients. By contrast, p53-positive patients had a significantly higher percentage of prolymphocytes (P = .002) and a significantly lower percentage of residual CD3-positive T lymphocytes (P = .0001). No correlation was found between the percentage of p53-positive cells and the percentage of cells in cycle assessed by the monoclonal antibody Ki-67. When the percentage of p53 positivity was correlated with the clinical stage of the disease, the proportion of p53-positive cases increased significantly from Binet's stage A (8 of 108; 7.4%), to stage B (12 of 49; 24.4%) and C (7 of 24; 29.2%) (P = .002). p53 positivity correlated also with the phase of the disease, showing a low expression at diagnosis (8 of 112; 7.1%) and a significantly higher expression in patients studied during the course of the disease (7 of 35; 20%) and, to a further extent, with disease progression (12 of 34; 35.3%) (P = .0001). The association of p53 protein expression with mutations in the gene was confirmed by direct sequence of the entire cDNA in 15 of the 17 ICC positive cases tested (88%). A significantly shorter treatment-free interval from diagnosis (P = .003) and a poorer response to therapy (P = .007) was observed in p53-positive compared with p53-negative patients. Overall survival from the time of diagnosis, as well as from the time of p53 protein analysis, was significantly shorter in patients with p53 protein expression (P = .03 and .0001, respectively). Moreover, in multivariate analysis, p53 expression and stage C were independently associated with a short survival. The results of this study indicate that in CLL the expression of the p53 protein, analyzed by a simple and reliable immunocytochemical method, is strongly associated with p53 gene mutations, a morphological variant (CLL with >10% prolymphocytes), advanced clinical stage, progressive disease, poor response to therapy, and short survival.     

The biological therapy of acute and chronic leukemia

With the increasing knowledge of the mechanisms of immune-mediated cytotoxicity, immunotherapeutic strategies are rapidly being incorporated into chemotherapy treatment schemes for acute and chronic leukemias. This includes the use of mAbs, immunotoxins, tumor-specific T cells, and, most recently, vaccines. Much of the new information is derived from bone marrow transplant data, where immune enhancement from IL-2 and donor T-cell infusions are being studied. Trials using humanized mAbs that permit prolonged and repeated dosing will allow better evaluation of the effectiveness of mAb therapy. More sophisticated molecular tests have been developed, allowing the detection of minimal residual disease to a greater degree. It is likely that biological and immunological therapy of leukemia will have its greatest impact here.     

Innovative therapy for chronic myelogenous leukemia

Innovative therapies for chronic myelogenous leukemia (CML) have focused mainly on combining autologous transplantation with another modality of therapy for purging of the graft or treatment of the patient after transplant. Of the three categories of innovative therapies, two are based on studies that demonstrate the bcr/abl gene rearrangement in the pathogenesis of CML, whereas the third is based on the observation that allogeneic disparity is important to maintain remissions in CML. The rationale and data supporting these innovative approaches are reviewed in this article and future strategies are discussed.     

Interferon therapy for chronic myelogenous leukemia

Interferon alpha (IFN alpha) has been used in the treatment of chronic myelogenous leukemia (CML). The initial trial was made in 1983 by Talpaz et al. Their first report suggested that IFN alpha treatment could achieve high hematological remission. The cause of the effect was unclear, but may be mediated through interaction cell surface membrane and inhibitory protein production. IFN alpha was related to some T cell immunity, and could be taken to be Ph1 positive cell inhibition by normal T cell. Although IFN alpha therapy has limited use with get Ph1 negative hematopoiesis, intensive treatment of this kind is needed to minimize Ph1 clone, using various therapy combination with IFN alpha.     

A special fluorescent in situ hybridization technique to study peripheral blood and assess the effectiveness of interferon therapy in chronic myeloid leukemia

Using a highly sensitive fluorescence in situ hybridization method with probes for BCR and ABL1 (D-FISH), we studied 37 paired sets of bone marrow and blood specimens, collected within 24 to 96 hours of each other, from 10 patients before and during treatment for chronic myeloid leukemia (CML). The normal range for 500 interphase nuclei was 相似文献   

Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy

One hundred seventy-four patients with progressive or advanced chronic lymphocytic leukemia (CLL) have received initial therapy with fludarabine as a single agent or fludarabine combined with prednisone. The overall response rate was 78% and the median survival was 63 months. No difference in response rate or survival was noted in the 71 patients receiving fludarabine as a single agent compared with the 103 patients who received prednisone in addition. The median time to progression of responders was 31 months and the overall median survival was 74 months. Patients over the age of 70 years had shorter survivals. Patients with advanced stage disease (Rai III and IV) had a somewhat shorter survival than earlier stage patients. More than half the patients who relapsed after fludarabine therapy responded to salvage treatment, usually with fludarabine-based regimens. Second remissions were more common in patients who had achieved a complete remission on their initial treatment. The CD4 and CD8 T-lymphocyte subpopulations decreased to levels in the range of 150 to 200/microL after the first 3 courses of treatment. Although recovery towards normal levels was slow, the incidence of infections was low in patients in remission (1 episode of infection for every 3.33 patient years at risk) and decreased with time off treatment. There was no association of infections or febrile episodes with the use of corticosteroids or the CD4 count at the end of treatment and a poor correlation with the increase in CD4 counts during remission. Infectious episodes were less common in patients who had a complete response compared with partial responders. Richter's transformation occurred in 9 patients and Hodgkin's disease occurred in 4 patients. Five other patients died from other second malignancies. Fludarabine appears to be an effective initial induction therapy with a reasonable safety profile for patients with CLL.     

Long-term follow-up results of alpha-interferon-based regimens in patients with late chronic phase chronic myelogenous leukemia

The aim of this analysis was to evaluate the efficacy of alpha-interferon (alpha-IFN) regimens in late chronic phase (diagnosis >12 months) chronic myelogenous leukemia (CP-CML). Long-term follow-up results were evaluated in 137 patients with Philadelphia chromosome (Ph)-positive late CP-CML. The alpha-IFN programs were sequential studies with human leukocyte alpha-IFN (seven patients), recombinant alpha-IFN alone (15 patients) or with IFN-gamma (29 patients), hydroxyurea (HU) (19 patients), or low-dose cytarabine (Ara-C) (67 patients). Overall, 57% of the patients achieved complete hematological response (CHR), and 7% obtained partial hematological response. Nineteen patients (15% of the 123 evaluable patients) had a cytogenetic response which was major (Ph-positive <35%) in 10 patients (8%). A trend for better responses was observed with shorter disease duration. The median overall survival from start of therapy was 49 months, with an estimated 5-year survival rate of 41%. Some common pretreatment prognostic factors associated with response did not show statistical associations when applied in late CP-CML; however, characteristics such as smaller spleen size, and lower percentages of peripheral blood and marrow blasts and basophils were associated with better survival experience. When patients were subgrouped according to risk, no significant differences in the incidence of cytogenetic response and in survival outcomes were observed among various risk groups. This study confirms that alpha-IFN-based regimens have a modest activity in late CP-CML, and supports the need to develop investigational strategies aimed at improving patient prognosis in this phase.     

Depression during interferon therapy in chronic hepatitis C patients--a prospective study

The number of patients treated with interferon (IFN) has increased markedly in Japan since 1992, when the Health and Welfare Ministry approved the use of IFN for treating chronic active hepatitis C. It is important to identify and treat depression, which is one of the psychiatric complications of IFN therapy and often leads to discontinuation of the therapy, in patients with chronic hepatitis C. In this study we prospectively investigated the incidence of depression during IFN therapy in patients with chronic active hepatitis C. The psychiatric status of 85 patients (53 men, 32 women; mean age 49.1 years) with chronic active hepatitis C who began receiving IFN at Showa University Hospital was assessed before and 2, 4, 12 and 24 weeks after the start of IFN therapy, using the major depressive episode diagnostic criteria listed in the DSM-III-R and the Hamilton Depression Scale HDS). All of the patients provided informed consent prior to participation in this study. IFN therapy was discontinued in 5 cases (5.9%) because of physical side effects and in 4 cases (4.7%) because of depression. Two, 11, 14, 25 and 16 patients were diagnosed as having major depressive episodes before and 2, 4, 12 and 24 weeks after the start of IFN therapy, respectively. The number of patients who were asymptomatic before the start of IFN therapy but were diagnosed as having a major depressive episode at least once during IFN therapy was 31 (31/83 = 37.3%). The mean HDS scores at 2, 4, 12 and 24 weeks (5.4, 6.0, 8.8 and 6.6) were significantly higher than that before the start of IFN therapy (3.0). The patients whose first diagnosed major depressive episodes occurred more than 4 weeks after the start of IFN therapy tended to be more severely depressed than those in whom it occurred less than 4 weeks after the start of IFN therapy. Compared to the 47 patients who completed 24 weeks of IFN therapy without experiencing depression, the 31 patients who were diagnosed as experiencing major depressive episodes during IFN therapy had significantly higher neuroticism scores determined using the Eysenck Personality Questionnaire, showed a more severely depressed mood and experienced more severe sleep disturbances before the start of IFN therapy. The latter group of patients also tended to have comorbid chronic physical disorders such as hypertension or diabetes mellitus and the histories of mental disorders before the IFN therapy; however these differences were not statistically significant. There were no differences between the two groups in patient age or sex, the severity of hepatitis before the IFN therapy, the type of IFN used in the therapy or the efficacy of IFN in the treatment of the hepatitis C. Our results indicate that the decision as to whether to treat chronic active hepatitis C with IFN should be made carefully and that early intervention and careful monitoring of depression are required during IFN therapy in the treatment of chronic active hepatitis C.     

Factors associated with severity and disease progression in chronic hepatitis C

BACKGROUND/AIMS: Chronic hepatitis C appears to have a highly variable natural course with 20% of patients developing cirrhosis within 20 years, while the majority of them run a relatively mild course. We studied the relationships of epidemiological, biochemical and virological features with histological severity (grade) and liver disease progression (stage). METHODOLOGY: Liver histology, serum HCV RNA level and HCV genotype were determined in a well-defined cohort of 152 consecutive (100 males, 52 females) patients with chronic hepatitis C. RESULTS: Patients with minimal or mild chronic hepatitis were significantly younger than those with moderate or severe chronic hepatitis (mean age: 41.1 vs 49.5 years respectively, p=0.003). On the other hand, patients with no or mild fibrosis compared to those with moderate or severe fibrosis and to those with cirrhosis were significantly more frequently males (73%, 64% and 43%, p=0.01), parenteral drug users (36%, 11% and 11%, p=0.01) and infected with other than 1b genotype (86%, 52% and 33%, p<0.0001), significantly younger (mean age: 37, 48 and 58 years, p<0.0001) and had significantly lower HCV RNA levels (geometric mean: 6.9, 19.2 and 17.5 x 10(5) eq/ml, p=0.007). Multivariate analysis showed that stage was significantly related only to patient age (p<0.0001), HCV genotype (p=0.0025) and HCV RNA level (p=0.044). CONCLUSIONS: In chronic hepatitis C, histological severity seems to be associated only with patient age, while progression of the disease is mainly associated with patient age, HCV genotype and viremia level.     

Predictors of sustained response to alpha interferon therapy in chronic hepatitis C

The short- and long-term creep behaviors of ultra-high-molecular-weight polyethylene (UHMWPE) systems (compression-molded UHMWPE sheets and self-reinforced UHMWPE composites) have been investigated. The short-term (30-120 min) creep experiment was conducted at a load of 1 MPa and a temperature range of 37-62 degrees C. Based on short-term creep data, the long-term creep behavior of UHMWPE systems at 1 MPa and 37 degrees C was predicted using time-temperature superposition and analytical formulas. Compared to actual long-term creep experiments of up to 110 days, the predicted creep values were found to well describe the creep properties of the materials. The creep behaviors of the UHMWPE systems were then evaluated for a creep time of longer than 10 years, and it was found that most creep deformation occurs in the early periods. The shift factors associated with time-temperature superposition were found to increase with increasing temperature, as per the Arrhenius equation. The effects of temperature, materials, and load on the shift factors could be explained by the classical free volume theory.