JCOG0911 INTEGRA study: a randomized screening phase II trial of interferonβ plus temozolomide in comparison with temozolomide alone for newly diagnosed glioblastoma

Purpose

This study explored the superiority of temozolomide (TMZ)?+?interferonβ (IFNβ) to standard TMZ as treatment for newly diagnosed glioblastoma (GBM) via randomized phase II screening design.

Experimental design

Eligibility criteria included histologically proven GBM, with 50% of the tumor located in supratentorial areas, without involvement of the optic, olfactory nerves, and pituitary gland and without multiple lesions and dissemination. Patients in the TMZ?+?radiotherapy (RT) arm received RT (2.0 Gy/fr/day, 30 fr) with TMZ (75 mg/m², daily) followed by TMZ maintenance (100–200 mg/m²/day, days 1–5, every 4 weeks) for 2 years. Patients in the TMZ?+?IFNβ?+?RT arm intravenously received IFNβ (3 MU/body, alternative days during RT and day 1, every 4 weeks during maintenance period) and TMZ?+?RT. The primary endpoint was overall survival (OS). The planned sample size was 120 (one-sided alpha 0.2; power 0.8).

Results

Between Apr 2010 and Jan 2012, 122 patients were randomized. The median OS with TMZ?+?RT and TMZ?+?IFNβ?+?RT was 20.3 and 24.0 months (HR 1.00, 95% CI 0.65–1.55; one-sided log rank P?=?0.51). The median progression-free survival times were 10.1 and 8.5 months (HR 1.25, 95% CI 0.85–1.84). The incidence of neutropenia with the TMZ?+?RT and the TMZ?+?IFNβ?+?RT (grade 3–4, CTCAE version 3.0) was 12.7 versus 20.7% during concomitant period and was 3.6 versus 9.3% during maintenance period. The incidence of lymphopenia was 54.0 versus 63.8% and 34.5 versus 41.9%.

Conclusions

TMZ?+?IFNβ?+?RT is not considered as a candidate for the following phase III trial, and TMZ?+?RT remained to be a most promising treatment. This trial was registered with the UMIN Clinical Trials Registry: UMIN000003466.

     

Extensive and preferential Fas/Fas ligand-dependent death of gammadelta T cells following infection with Listeria monocytogenes

In the spleens of mice infected intraperitoneally with the bacterium Listeria monocytogenes, both alphabeta and gammadelta T cells became rapidly activated, followed by a massive apoptotic death response predominantly within the gammadelta population. The death response involved two major splenic gammadelta T-cell subsets and was Fas/Fas ligand (Fas-L)-dependent. Among T cells isolated from the Listeria-infected spleen, Fas-L was almost exclusively expressed in gammadelta T cells. gammadelta T cells coexpressed Fas and Fas-L, suggesting activation-induced suicide as a mechanism of their death. In vivo treatment with an antibody specific for CD3epsilon induced activation, preferential Fas-L expression and apoptosis of gammadelta T cells, resembling the response pattern in listeriosis, whereas antibodies specific for T-cell receptor-beta (TCR-beta) or TCR-delta did not, suggesting that the complete response seen in listeriosis requires both gammadelta TCR engagement and additional stimuli. L. monocytogenes causes early nonspecific, Fas-independent lymphocyte death in heavily infected tissues. In contrast, the death response described here is selective, Fas-dependent and triggered at low local levels of bacteria, suggesting that it is controlled by interactions with other infection-activated host cells, and perhaps part of a regulatory circuit specifically curtailing gammadelta T cells.     

Sequence variability within the 3′-proximal part of the <Emphasis Type="Italic">Sweet potato mild mottle virus</Emphasis> genome

Summary.  Sweet potato mild mottle virus (SPMMV) is the type member of the genus Ipomovirus (family Potyviridae) and is only known to occur in East Africa. In Uganda, SPMMV is the third most prevalent virus infecting sweet potato. The sequence variability of SPMMV was studied by cloning and sequencing a 1.8-kb fragment representing the 3′-end of the genome of eight SPMMV isolates collected from different districts of Uganda. Sequence comparisons indicated 85.9–99.9% nucleotide sequence identity and 92.8–100% amino acid sequence similarity for the coat protein (CP) encoding region. The nucleotide sequence identity within the 3′-untranslated region (3′ UTR) was 84.7–100%, and the region was variable in length (303–308 nucleotides) due to some deletions within the 5′-proximal part of the 3′ UTR. Phylogenetic analysis of the CP amino acid sequences revealed significant clustering, indicating the existence of distinguishable sequence variants or strains. The low CP amino acid sequence similarity of SPMMV isolates with other characterised viruses of the family Potyviridae and the unusual putative proteolytic cleavage site at the NIb/CP junction further demonstrate SPMMV as a very distinct virus in the family Potyviridae. Received July 9, 2002; accepted October 1, 2002     

Structure and Immunological Specificity of the Streptococcus mutans Group b Cell Wall Antigen

The Streptococcus mutans group b antigen of strain FA1 has been defined as to chemical composition and immunological specificity. The antigen in cold trichloroacetic acid extracts was fractionated on diethylaminoethyl-Sephadex A-25 at pH 8.5. Two forms were isolated: a polysaccharide and a mucoprotein. The two polymers reacted as a single substance in agar gel diffusion against specific adsorbed FA1 rabbit antisera but were separated by gel immunoelectrophoresis. No reaction with any other S. mutans or streptococcal group sera occurred. Galactose composed about one-third and galactosamine about 3% of the total weight of each polymer. Rhamnose was a major component of the polysaccharide (47%) but was present only in traces in the mucoprotein. The protein content of the latter was about 40%. No significant quantities of glycerol, phosphorus, or muramic acid were present in either case. Pepsin and trypsin had no effect on the serological specificity of the mucoprotein. d-Galactose and d-galactosamine were strong inhibitors (70%) of the precipitin reaction, whereas d-glucose, d-glucosamine, and N-acetyl-d-glucosamine inhibited between 25 and 35%. The results indicate that the antigen is a major antigenic component of the cell wall and that the specificity of the antigen resides in binding sites which contain both d-galactose and d-galactosamine. Agglutination of whole cells by specific group b antiserum indicates the antibody receptor sites of the polysaccharide antigen are at the surface of the streptococcal cell. The mucoprotein, but not the polysaccharide, was released from the cell by lysozyme. Lysis did not occur. The immunological specificity and other characteristics of the antigen establishes it as the identifying antigen of S. mutans group b.     

The efficacy and cost‐effectiveness of a family‐based economic empowerment intervention (Suubi + Adherence) on suppression of HIV viral loads among adolescents living with HIV: results from a Cluster Randomized Controlled Trial in southern Uganda

IntroductionEvidence from low‐resource settings indicates that economic insecurity is a major barrier to HIV treatment adherence. Economic empowerment (EE) interventions have the potential to improve adherence outcomes among adolescents living with HIV (ALWHIV) by mitigating the effects of poverty. This study aims to assess the efficacy and cost‐effectiveness of a savings‐led family‐based EE intervention, Suubi + Adherence, aimed at improving antiretroviral therapy (ART) adherence outcomes ALWHIV in Uganda.MethodsAdolescents (mean age 12 years at enrolment; 56% female) receiving ART for HIV at 39 health centres were randomized to Suubi + Adherence intervention (n = 358) or bolstered standard of care (BSOC; n = 344). A difference‐in‐differences analysis was employed to assess the change in the proportion of virally suppressed adolescents (HIV RNA viral load <40 copies/mL) over 24 months. The cost‐effectiveness analysis examined how much the intervention cost to virally suppress one additional adolescent relative to BSOC from the healthcare provider perspective.ResultsAt 24 months, the intervention was associated with an 8.85‐percentage point [95% confidence interval (CI) 0.80 to 16.90 percentage points] increase in the proportion of virally suppressed adolescents between the study arms (p = 0.032). Per‐participant costs were US$177 and US$263 for the BSOC and intervention groups respectively. The incremental cost of virally suppressing one additional adolescent was estimated at US$970 [95% CI, US$508 to 10,725] over two years.ConclusionsOur results support the integration of family‐based EE interventions into adherence‐support strategies as part of routine HIV care in low‐resource settings to address the underlying economic drivers of poor ART adherence among ALWHIV. Moreover, per‐participant costs to achieve viral suppression do not seem prohibitive compared to other community‐based adherence interventions targeted at ALWHIV in low‐resource settings. Further research on combination interventions at the nexus of economic security and HIV treatment and care is needed to inform the development of feasible and scalable HIV policies and programmes.     

A home-based approach to managing multi-drug resistant tuberculosis in Uganda: a case report

ABSTRACT: This case report describes an HIV-positive patient with recurrent tuberculosis in Uganda. After several failed courses of treatment, the patient was diagnosed with multi-drug resistant tuberculosis (MDR-TB). As adequate in-patient facilities were unavailable, we advised the patient to remain at home, and he received treatment at home via his family and a community nurse. The patient had a successful clearance of tuberculosis. This strategy of home-based care represents an important opportunity for treatment of patients in East Africa, where human resource constraints and inadequate hospital facilities exist for complex patients at high risk of infection to others.     

LIVER FAILURE CAUSED BY HEPATIC ANGIODYSPLASIA IN HEREDITARY HEMORRHAGIC TELANGIECTASIA

Hereditary hemorrhagic telangiectasia is a systemic vascular disease with autosomal dominant inheritance that results in telangiectasia, arteriovenous malformations, and hemangiomas. The liver is one of the organs commonly affected in hereditary hemorrhagic telangiectasia, and hepatic lesions consist of angiodysplasia and fibrosis. A patient with hereditary hemorrhagic telangiectasia and significant impairment of synthetic liver function is reported. Dynamic computed tomography revealed marked enlargement of the common hepatic and intrahepatic arteries, heterogeneous parenchymography, and early opacification of the hepatic veins consistent with telangiectasias and arteriovenous shunting. Overall, the liver was predominantly occupied by vascular structures and scarce residual hepatic parenchyma. Other causes of liver dysfunction, such as viral hepatitis and alcohol abuse, were excluded. In general, hepatic fibrovascular dysplasia seen in hereditary hemorrhagic telangiectasia usually results in only mild liver dysfunction; however, this case shows that hepatic involvement may rarely result in hepatic failure.