Combined zidovudine and interferon-alpha treatment in patients with AIDS-associated Kaposi's sarcoma

The effectiveness of addition of interferon-alpha (IFN-alpha) to zidovudine in patients with AIDS-associated Kaposi's sarcoma was assessed in a non-randomized, phase II clinical trial. Twenty-one patients were treated with oral zidovudine (600 mg daily) and IFN-alpha was increased to 18 MU daily for another 4 weeks. Only one of the 20 evaluable patients achieved a partial response at 8 weeks, that lasted for 3 months. Despite IFN-alpha dose escalation in six patients, no further responses were seen. While myelotoxicity was mild, fatigue was the dose-limiting side-effect that prevented dose escalation in seven eligible patients. The combined treatment did not result in a decrease in HIV-Ag. In summary, our results indicate that the addition of IFN-alpha to zidovudine in patients with AIDS-associated Kaposi's sarcoma is not an efficacious treatment.     

Hepatitis B and C genotyping: methodologies and implications for patient management

Abstract   The spontaneous tendency of the hepatitis B virus (HBV) and hepatitis C virus (HCV) to mutate has led in both cases to the emergence of distinct viral genotypes with uneven geographic distributions. Numerous studies point to differential impacts of these genotypes on the course of chronic liver disease and response to treatment with currently approved drugs. HCV genotype plays a pivotal role in determining an individual's response to treatment. Evidence is also accumulating that HBV genotypes influence HBeAg seroconversion rates, the natural history and severity of chronic HBV liver disease, and the development of antiviral drug-resistance and precore/core promoter mutational patterns—all of which have an impact on disease prognosis and patient management. An overview of HBV and HCV genotypes, diagnostic methodologies for their determination, and the clinical relevance of genotypes for patient management is presented.     

Quality of life and cost-effectiveness of interferon-alpha in malignant melanoma: results from randomised trial

A definitive conclusion regarding the value of low-dose extended duration adjuvant interferon-alpha therapy in the treatment of malignant melanoma is only possible once data on health-related quality of life (HRQoL) and costs have been considered. This trial randomised 674 patients to interferon alpha-2a (3 megaunits three times per week for 2 years or until recurrence) or placebo. Health-related quality of life (QoL) was to be assessed up to 60 months using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. Data for the economic analysis, including cost information and the EQ-5D were also collected. Patients in the observation (OBS) group had significantly better mean follow-up quality of on five dimensions of the EORTC QLQ-C30 functional scales: role functioning (P = 0.033), emotional functioning (P = 0.003), cognitive functioning (P = 0.001), social functioning (P = 0.003) and global health status (P = 0.001). Patients in the OBS group had significantly better mean follow-up symptom scores on seven dimensions of the EORTC QLQ-C30 V1 symptom scales. Economic data showed that costs were 3066 pounds higher in the interferon group and produces an incremental cost per quality-adjusted life year of 41,432 pounds at 5 years. The results show that interferon has significant effects on QoL and symptomatology and is unlikely to be cost-effective in this patient group in the UK.     

慢性乙型肝炎患者干扰素治疗后外周血树突状细胞的变化

目的:动态观察慢性乙型肝炎患者复合α干扰素(consensus interferon,C IFN)治疗过程中DC细胞亚群的变化。方法:采用流式细胞分析技术检测23例慢性乙型肝炎患者C IFN治疗过程中外周血树突状细胞(den-dritic cell,DCs)亚群百分比及数量,同时检测乙型肝炎病毒血清学标志和血清HBVDNA,以及肝功、肾功、血常规。结果:经C IFN治疗后,患者的应答率为43.5%。慢性乙型肝炎患者外周血MDC及PDC的百分比和绝对数显著减少(P<0.05),且有效组和无效组的MDC及PDC的百分比和绝对数在同一时间点无明显差别。动态观察C IFN治疗过程中血清HBVDNA载量与MDC、PDC绝对数的关系,未发现明确的相关性(P>0.05)。结论:慢性乙型肝炎患者经CIFN治疗后,部分患者可以获得持续性病毒学及生化学应答,外周血MDC及PDC的百分比和绝对数明显下降。     

Antiproliferative effects of 5-fluorouracil and interferon-alpha in combination on a hepatocellular carcinoma cell line in vitro and in vivo

Background and Aim: We investigated the antiproliferative effects of interferon‐alpha (IFN‐α) and 5‐fluorouracil (5‐FU) in combination on a hepatocellular carcinoma (HCC) cell line. Method: In the in vitro study, IFN‐α and/or 5‐FU was added to the culture of the poorly differentiated‐type HCC cell line, HAK‐1B, and their antiproliferative effects and additional or synergic effects in combination treatment were examined. In the in vivo study, HAK‐1B cells were transplanted into nude mice and the changes in tumor volume and weight, apoptosis, BrdU and cyclin A positive cells, and artery‐like blood vessels were investigated. Expressions of angiogenesis factors and IFN‐α receptor (IFNAR‐2) were examined in the developed tumors. Results: In vitro growth of HAK‐1B cells was suppressed dose‐dependently to 5‐FU, but the addition of IFN‐α did not induce additional or synergic effects. In vivo growth in terms of tumor diameter and weight was suppressed at most in the IFN‐α + 5‐FU (combination) group, that is, the tumor volume became 29.3% and the tumor weight became 54.7% of the control. In the combination group, numbers of BrdU‐positive S‐phase cells and cyclin A positive cells increased together with the increase in apoptotic cells, but there was no significant relation between the tumor shrinkage effects and angiogenesis factors or artery‐like blood vessels. In the combination group, INFAR‐2 decreased significantly in comparison to the other groups. Conclusion: The synergic growth‐suppression effects in the current in vivo study using the combination treatment are attributable to the enhanced induction of S‐phase arrest and of apoptosis.     

TRAIL-mediated killing of acute lymphoblastic leukemia by plasmacytoid dendritic cell-activated natural killer cells

Acute lymphoblastic leukemia (ALL) still frequently recurs after hematopoietic stem cell transplantation (HSCT), underscoring the need to improve the graft-versus-leukemia (GvL) effect. Natural killer (NK) cells reconstitute in the first months following HSCT when leukemia burden is at its lowest, but ALL cells have been shown to be resistant to NK cell-mediated killing. We show here that this resistance is overcome by NK cell stimulation with TLR-9-activated plasmacytoid dendritic cells (pDCs). NK cell priming with activated pDCs resulted in TRAIL and CD69 up-regulation on NK cells and IFN-γ production. NK cell activation was dependent on IFN-α produced by pDCs, but was not reproduced by IFN-α alone. ALL killing was further enhanced by inhibition of KIR engagement. We showed that ALL lysis was mainly mediated by TRAIL engagement, while the release of cytolytic granules was involved when ALL expressed NK cell activating receptor ligands. Finally, adoptive transfers of activated-pDCs in ALL-bearing humanized mice delayed the leukemia onset and cure 30% of mice. Our data therefore demonstrate that TLR-9 activated pDCs are a powerful tool to overcome ALL resistance to NK cell-mediated killing and to reinforce the GvL effect of HSCT. These results open new therapeutic avenues to prevent relapse in children with ALL.     

Characterization of anti-interferon-alpha antibodies appearing during recombinant interferon-alpha 2a treatment.

Patients with malignant midgut carcinoid tumours received recombinant interferon-alpha 2a (rIFN-alpha 2a) or rIFN-alpha 2a and chemotherapy (streptozocin and doxorubicin) for 6 months, and then rIFN-alpha 2a alone. Antibodies, mainly of IgG type, binding to rIFN-alpha 2a developed in nine of 22 patients (41%), as determined by immunoassay. In seven patients, antibodies also neutralized the biologic (anti-viral) activity of rIFN-alpha 2a. Anti-IFN-alpha 2a antibodies were equally frequent in both sexes and treatment groups, but were not observed in those patients (n = 8) that had previously received other types of IFN. Antibodies appeared after a median of 6 months of rIFN-alpha 2a treatment and had a median duration of 6 months. The anti-IFN-alpha 2a antibody titres declined with time with no obvious relation to change of therapy, also during continued IFN-alpha 2a treatment. High titres of neutralizing antibodies appeared to impair anti-tumoural effects in individual potential responders. Anti-IFN-alpha 2a antibodies further examined in six patients bound to native IFN-alpha subtypes present in both allogenic and autologous leucocyte IFN-alpha. Such autoantibodies neutralized the biologic activity of autologous IFN-alpha in two patients, and in a third were partially neutralizing.     

Anterior cingulate activation and error processing during interferon-alpha treatment.

BACKGROUND: There has been increasing interest in the role of immunologic processes, notably cytokines, in the development of behavioral alterations, especially in medically ill patients. Interferon (IFN)-alpha is notorious for causing behavioral symptoms, including depression, fatigue, and cognitive dysfunction, and has been used to investigate the effects of cytokines on the brain. METHODS: In the present study we assessed the effects of low-dose IFN-alpha on brain activity, using functional magnetic resonance imaging during a task of visuospatial attention in patients infected with hepatitis C virus (HCV). RESULTS: Despite endorsing symptoms of impaired concentration and fatigue, IFN-alpha-treated patients (n = 10) exhibited task performance and activation of parietal and occipital brain regions similar to that seen in HCV-infected control subjects (n = 11). Interestingly, however, in contrast to control subjects, IFN-alpha-treated patients exhibited significant activation in the dorsal part of the anterior cingulate cortex (ACC), which highly correlated with the number of task-related errors. No such correlation was found in control subjects. CONCLUSIONS: Consistent with the role of the ACC in conflict monitoring, ACC activation during IFN-alpha administration suggests that cytokines might increase processing conflict or reduce the threshold for conflict detection, thereby signaling the need to exert greater mental effort to maintain performance. Such alterations in ACC activity might in turn contribute to cytokine-induced behavioral changes.     

Matrigel-embedded 3D culture of Huh-7 cells as a hepatocyte-like polarized system to study hepatitis C virus cycle

Hepatocytes are highly polarized cells where intercellular junctions, including tight junctions (TJs), determine the polarity. Recently, the TJ-associated proteins claudin-1 and occludin have been implicated in hepatitis C virus (HCV) entry and spread. Nevertheless, cell line-based experimental systems that exhibit hepatocyte-like polarity and permit robust infection and virion production are not currently available. Thus, we sought to determine whether cell line-based, Matrigel-embedded cultures could be used to study hepatitis C virus (HCV) infection and virion production in a context of hepatocyte-like polarized cells. In contrast to standard bidimensional cultures, Matrigel-cultured Huh-7 cells adopted hepatocyte polarization features forming a continuous network of functional proto-bile canaliculi structures. These 3D cultures supported HCV infection by JFH-1 virus and produced infective viral particles which shifted towards lower densities with higher associated specific infectivity. In conclusion, our findings describe a novel use of Matrigel to study the entire HCV cycle in a more relevant context.     

A Case of Hypereosinophilic Syndrome Presenting With Multiorgan Infarctions Associated With Disseminated Intravascular Coagulation

Thromboembolism is one of the most critical complications of hypereosinophilic syndrome (HES). We report here a case of multi-organ infarctions related to HES. A 23-year-old woman was referred to our hospital with hemoptysis. Not only pulmonary, but also renal and splenic infarctions were detected on computed tomography images. Blood tests showed profound peripheral eosinophilia. She was diagnosed with HES with disseminated intravascular coagulation (DIC). We initiated infusion of corticosteroids, which effectively suppressed peripheral eosinophilia. However, consumptive coagulopathy did not improve and intracerebral hemorrhage related to thrombosis then developed. Addition of interferon-alpha resulted in the correction of the DIC associated with HES.