Managing chronic conditions care across primary care and hospital systems: lessons from an Australian Hospital Avoidance Risk Program using the Flinders Chronic Condition Management Program.

Objective The study aimed to determine the impact of the Flinders Chronic Condition Management Program for chronic condition self-management care planning and how to improve its use with Bendigo Health's Hospital Admission Risk Program (HARP). Methods A retrospective analysis of hospital admission data collected by Bendigo Health from July 2012 to September 2013 was undertaken. Length of stay during admission and total contacts post-discharge by hospital staff for 253 patients with 644 admissions were considered as outcome variables. For statistical modelling we used the generalised linear model. Results The combination of the HARP and Flinders Program was able to achieve significant reductions in hospital admissions and non-significant reduction in emergency department presentations and length of stay. The generalised linear model predicted that vulnerable patient groups such as those with heart disease (P=0.037) and complex needs (P<0.001) received more post-discharge contacts by HARP staff than those suffering from diabetes, renal conditions and psychosocial needs when they lived alone. Similarly, respiratory (P<0.001), heart disease (P=0.015) and complex needs (P=0.050) patients had more contacts, with an increased number of episodes than those suffering from diabetes, renal conditions and psychosocial needs. Conclusion The Flinders Program appeared to have significant positive impacts on HARP patients that could be more effective if high-risk groups, such as respiratory patients with no carers and respiratory and heart disease patients aged 0-65, had received more targeted care. What is known about the topic? Chronic conditions are common causes of premature death and disability in Australia. Besides mental and physical impacts at the individual level, chronic conditions are strongly linked to high costs and health service utilisation. Hospital avoidance programs such as HARP can better manage chronic conditions through a greater focus on coordination and integration of care across primary care and hospital systems. In support of HARP, self-management interventions such as the Flinders Program aim to help individuals better manage their medical treatment and cope with the impact of the condition on their physical and mental wellbeing and thus reduce health services utilisation. What does this paper add? This paper sheds light on which patients might be more or less likely to benefit from the combination of the HARP and Flinders Program, with regard to their impact on reductions in hospital admissions, emergency department presentations and length of stay. This study also sheds light on how the Flinders Program could be better targeted towards and implemented among high-need and high-cost patients to lessen chronic disease burden on Australia's health system. What are the implications for practitioners? Programs targeting vulnerable populations and applying evidence-based chronic condition management and self-management support achieve significant reductions in potentially avoidable hospitalisation and emergency department presentation rates, though sex, type of chronic condition and living situation appear to matter. Benefits might also accrue from the combination of contextual factors (such as the Flinders Program, supportive service management, clinical champions in the team) that work synergistically.

TRAIL conjugated to nanoparticles exhibits increased anti-tumor activities in glioma cells and glioma stem cells in vitro and in vivo.

Glioblastomas (GBM) are characterized by resistance to chemotherapy and radiotherapy, and therefore, alternative therapeutic approaches are needed. TRAIL induces apoptosis in cancer but not in normal cells and is considered to be a promising anti-tumor agent. However, its short in vivo half-life and lack of efficient administration modes are serious impediments to its therapeutic efficacy. Nanoparticles (NP) have been used as effective delivery tools for various anticancer drugs. TRAIL was conjugated to magnetic ferric oxide NP by binding the TRAIL primary amino groups to activated double bonds on the surface of the NP. The effect of NP-TRAIL was examined on the apoptosis of glioma cells and self-renewal of glioma stem cells (GSCs). In addition, the ability of the NP-TRAIL to track U251 cell-derived glioma xenografts and to affect cell apoptosis, tumor volume, and survival among xenografted rats was also examined. Conjugation of TRAIL to NP increased its apoptotic activity against different human glioma cells and GSCs, as compared with free recombinant TRAIL. Combined treatment with NP-TRAIL and γ-radiation or bortezomib sensitized TRAIL-resistant GSCs to NP-TRAIL. Using rhodamine-labeled NP and U251 glioma cell-derived xenografts, we demonstrated that the NP-TRAIL were found in the tumor site and induced a significant increase in glioma cell apoptosis, a decrease in tumor volume, and increased animal survival. In summary, conjugation of TRAIL to NP increased its apoptotic activity both in vitro and in vivo. Therefore, NP-TRAIL represents a targeted anticancer agent with more efficient action for the treatment of GBM and the eradication of GSCs.

Antitumor treatment using interleukin- 12-secreting marrow stromal cells in an invasive glioma model.

OBJECTIVE: Marrow stromal cells (MSCs) have the potential to migrate toward sites of injury or disease in the central nervous system. Encouraging results have been obtained by using MSCs to deliver therapeutic molecules. However, most brain tumor animal models--unlike in actual human disease states--use cells with limited invasion properties. In the present study, C57/B16 mice were implanted with the highly invasive Ast11.9-2 glioma cell line to investigate the potential therapeutic effects of interleukin-12 (IL-12)-secreting MSCs. METHODS: MSCs were infected with adenovirus encoding murine IL-12 (AdIL12). The infection conditions were optimized by determination of cytotoxicity and IL-12 secretion after AdIL12 infection in vitro. After implanting Ast11.9-2 tumor into mouse brain, we conducted a survival experiment to compare 4 distinct treatment groups by injecting culture medium control (sham), MSCs alone, MSCs infected with control virus (MSC-adenovirus encoding green fluorescent protein), and MSCs infected with IL-12-expressing virus (MSC-AdIL12) in the peritumoral region of the brain. Tumor tissues were analyzed by hematoxylin and eosin staining. IL-12 expression was analyzed by immunohistochemistry staining. Y chromosome fluorescent in situ hybridization was used to detect injected MSCs. Cell populations of CD57 (natural killer cells), CD3 (total T cells), and 7-AAD (dead cells) in whole brain tissue were analyzed by fluorescence-activated cell sorting at days 4 and 7 after therapeutic treatment. RESULTS: Serum IL-12 increased significantly at days 4 and 7 after MSC-AdIL12 implantation. IL-12-expressing cells were detected by immunohistochemistry staining and Y chromosome-positive staining cells were found in the tumor area, confirming successful IL-12 delivery. MSC-AdIL12 treatment yielded increased natural killer cell infiltration in brain tissue at day 4, leading to an expected increase in nonspecific cell death, while total T-cell counts remained unchanged. MSC-IL-12 treatment extended animal survival but did not result in a statistically significant difference in comparison to other groups. Because all animals ultimately died of the brain tumors, MSC-AdIL12 treatment did not completely arrest the invasive growth pattern of these lesions. CONCLUSION: The results indicate that MSCs may serve as useful delivery vehicles for IL-12 and other antineoplastic agents in brain tumor therapy.

Polynuclear platinum anticancer drugs are more potent than cisplatin and induce cell cycle arrest in glioma.

We have evaluated the efficacy of the multinuclear platinum chemotherapeutics BBR3464, BBR3571, and BBR3610 against glioma cells in culture and animal models and investigated their mechanism of action at the cellular level. In a clonogenic assay, BBR3610, the most potent compound, had an IC90 dose (achieving 90% colony formation inhibition) that was 250 times lower than that of cisplatin for both LNZ308 and LN443 glioma cells. In subcutaneous xenografts of U87MG glioma cells, BBR3610 approximately doubled the time it took for a tumor to reach a predetermined size and significantly extended survival when these cells were implanted intracranially. Analysis of apoptosis and cell cycle distribution showed that BBR compounds induced G2/M arrest in the absence of cell death, while cisplatin predominantly induced apoptosis. Interestingly, the BBR compounds and cisplatin both induced extracellular signal-regulated kinase 1/2 phosphorylation, and inhibition of this pathway at the level of MEK antagonized the induction of G2/M arrest or apoptosis, respectively. Analysis of Chk1 and Chk2 status did not show any differential effects of the drugs, and it is thus unlikely to underlie the difference in response. Similarly, the drugs did not differentially modulate survivin levels, and knockdown of survivin did not convert the response to BBR3610 to apoptosis. Together, these findings support continued development of BBR3610 for clinical use against glioma and provide a framework for future investigation of mechanism of action.

Related to testes-specific, vespid, and pathogenesis protein-1 (RTVP-1) is overexpressed in gliomas and regulates the growth, survival, and invasion of glioma cells.

In this study, we examined the expression and functions of related to testes-specific, vespid, and pathogenesis protein 1 (RTVP-1) in glioma cells. RTVP-1 was expressed in high levels in glioblastomas, whereas its expression in low-grade astrocytomas and normal brains was very low. Transfection of glioma cells with small interfering RNAs targeting RTVP-1 decreased cell proliferation in all the cell lines examined and induced cell apoptosis in some of them. Overexpression of RTVP-1 increased astrocyte and glioma cell proliferation and the anchorage-independent growth of the cells. In addition, overexpression of RTVP-1 rendered glioma cells more resistant to the apoptotic effect of tumor necrosis factor-related apoptosis-inducing ligand and serum deprivation. To delineate the molecular mechanisms involved in the survival effects of RTVP-1, we examined the expression and phosphorylation of various apoptosis-related proteins. We found that overexpression of RTVP-1 decreased the phosphorylation of c-Jun-NH2-kinase and increased the expression of Bcl2 and that the protective effect of RTVP-1 was partially mediated by Bcl2. Finally, we found that RTVP-1 regulated the invasion of glioma cells as was evident by their enhanced migration through Matrigel and by their increased invasion in a spheroid confrontation assay. The increased invasive potential of the RTVP-1 overexpressors was also shown by the increased activity of matrix metalloproteinase 2 in these cells. Our results suggest that the expression of RTVP-1 is correlated with the degree of malignancy of astrocytic tumors and that RTVP-1 is involved in the regulation of the growth, survival, and invasion of glioma cells. Collectively, these findings suggest that RTVP-1 is a potential therapeutic target in gliomas.

Requirement of an integrated immune response for successful neuroattenuated HSV-1 therapy in an intracranial metastatic melanoma model.

Neuroattenuated herpes simplex virus ICP34.5 mutants slow progression of preformed tumors and lead to complete regression of some tumors. Although this was previously thought to be due to viral lysis of infected tumor cells, it is now understood that there is an immune component to tumor destruction. We have previously shown that no difference in survival is seen in lymphocyte-depleted mice after viral or mock therapy of syngeneic intracranial melanomas. We have also demonstrated the presence of a wide spectrum of immune cells following viral therapy, including larger percentages of CD4+ T cells and macrophages. In this paper, the contribution of the immune system to tumor destruction has been further delineated. Viral therapy of intracranial melanoma induces a tumor-specific cytotoxic and proliferative T cell response. However, there is no increase following viral therapy in either serum tumor antibody levels or viral-neutralizing antibodies. Thus specific T cell responses appear to mediate viral-elicited prolongation in survival. These data suggest that designing new viruses capable of augmenting T cell responses may induce stronger tumor destruction upon viral therapy.

Herpes simplex virus latency-associated transcript gene function.

A major area of interest in the study of herpes simplex virus type 1 (HSV-1) involves the persistence of the virus within a latent state in neuronal cells of infected humans. The latency-associated transcripts (LATs) are believed to play a key role during HSV-1 latency. This review will discuss the most recent findings on the involvement of the LAT region with apoptotic pathways and how this relates to other potential functions of the LATs.

Regions of the herpes simplex virus type 1 latency-associated transcript that protect cells from apoptosis in vitro and protect neuronal cells in vivo.

Recent studies have suggested that the latency-associated transcript (LAT) region of herpes simplex virus type 1 (HSV-1) is effective at blocking virus-induced apoptosis both in vitro and in the trigeminal ganglia of acutely infected rabbits (Inman et al., J. Virol. 75:3636-3646, 2001; Perng et al., Science 287:1500-1503, 2000). By transfecting cells with a construct expressing the Pst-Mlu segment of the LAT, encompassing the LAT exon 1, the stable 2.0-kb intron, and 5' part of exon 2, we confirmed that this region was able to diminish the onset of programmed cell death initiated by anti-Fas and camptothecin treatment. In addition, caspase 8-induced apoptosis was specifically inhibited in cells expressing the Pst-Mlu LAT fragment. To further delineate the minimal region of LAT that is necessary for this antiapoptotic function, LAT mutants were used in our cotransfection assays. In HeLa cells, the plasmids lacking exon sequences were the least effective at blocking apoptosis. However, similar to previous work (Inman et al., op. cit.), our data also indicated that the 5' end of the stable 2.0-kb LAT intron appeared to contribute to the promotion of cell survival. Furthermore, cells productively infected with the 17N/H LAT mutant virus, a virus deleted in the LAT promoter, exon 1, and about half of the intron, exhibited a greater degree of DNA fragmentation than cells infected with wild-type HSV-1. These data support the finding that the exon 1 and 2.0-kb intron region of the LAT transcription unit display an antiapoptotic function both in transfected cells and in the context of the virus infection in vitro. In trigeminal ganglia of mice acutely infected with the wild-type virus, 17, and 17DeltaSty, a virus lacking most of exon 1, apoptosis was not detected in cells that were positive for virus particles. However, dual staining was observed in cells from mice infected with 17N/H virus, indicating that the LAT antiapoptotic function demonstrated in cells transfected by LAT-expressing constructs may also play a role in protecting cells from virus-induced apoptosis during acute viral infection in vivo.