Limited Treatment Modalities Research Articles

The Investigational Aurora Kinase A Inhibitor MLN8237 Induces Defects in Cell Viability and Cell-Cycle Progression in Malignant Bladder Cancer Cells In Vitro and In Vivo

Despite more than 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluated Aurora kinase A, identified as an upregulated candidate molecule in bladder cancer, as a potential therapeutic target. Gene expression in human bladder cancer samples was evaluated using RNA microarray and quantitative reverse transcriptase PCR. Effects of the Aurora kinase A inhibitor MLN8237 (Millennium) on cell dynamics in malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells were evaluated in vitro and in vivo in a mouse xenograft model. A set of 13 genes involved in the mitotic spindle checkpoint, including Aurora kinases A and B, were upregulated in human urothelial carcinoma compared with normal urothelium. The Aurora kinase A inhibitor MLN8237 induced cell-cycle arrest, aneuploidy, mitotic spindle failure, and apoptosis in the human bladder cancer cell lines T24 and UM-UC-3. MLN8237 also arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model. Finally, in vitro sequential administration of MLN8237 with either paclitaxel or gemcitabine resulted in synergistic cytotoxic effects in T24 cells. Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma and can be exploited with pharmacologic Aurora A inhibition. Given our demonstration of the ability of the Aurora A inhibitor MLN8237 to inhibit growth of bladder cancer in vitro and in vivo, we conclude that Aurora kinase inhibitors warrant further therapeutic investigation in bladder cancer.

Pediatric uveitis: An update

Because of their varied spectrum of clinical presentation and difficulty in management, pediatric uveitis remains a challenge to the ophthalmologist. Variations in clinical presentation, difficulties in eye examination, extended burden of the inflammation over quality of life, limited treatment modalities, risk of amblyopia are the main challenges in the management of pediatric uveitis. Pediatric uveitis is a cause of significant ocular morbidity and severe vision loss is found in 25-33% of such cases. This article summarizes the common causes of uveitis in children with special approach to the evaluation and diagnosis of each clinical entity.

Epicutaneous immunization with protein antigen TNP-Ig alleviates TNBS-induced colitis in mice

BackgroundUlcerative colitis (UC) is a chronic inflammatory autoimmune disease with limited treatment modalities. The animal model of colitis induced by treatment with trinitrobenzene sulfonic acid (TNBS-colitis) is commonly used to test new therapies of this disease. In our previous work we found that epicutaneous (EC) immunization with protein antigen induced a state of profound immunosuppression that inhibited inflammatory response in contact sensitivity, in experimental autoimmune encephalomyelitis (EAE) and in allogeneic skin graft rejection. MethodsTNBS-induced colitis was used as an experimental model. ResultsIn our current work, we showed that EC immunization with TNP-conjugated mouse immunoglobulin (TNP-Ig) prior to induction of TNBS-colitis alleviates disease severity what was determined by the body weight, the length and the weight of the colon, the histological activity index (HAI) and myeloperoxidase activity (MPO). Observed amelioration of the disease in TNP-Ig patched mice was accompanied with decreased production of IFN-γ and IL-17A by splenocytes. Additionally, spleen cells isolated from mice EC immunized with TNP-Ig prior to colitis induction showed increased production of IL-10 suggesting that this cytokine might be involved in inhibiting inflammatory response in the colon. ConclusionThis work shows that EC immunization with protein antigen prior to TNBS-colitis induction ameliorates disease and observed suppression of inflammatory response in the colon might be mediated by IL-10.

Operative treatment of chondral defects in the hip joint: a systematic review

Young patients with cartilage defects in the hip present a complex problem for the treating physician with limited treatment modalities available. Cartilage repair/replacement techniques have shown promising results in other joints, however, the literature regarding the hip joint is limited. The purpose of the current study is to conduct a systematic review of clinical outcomes following various treatments for chondral lesions of the hip and define the techniques for the treatment of these cartilage defects. The full manuscripts of 15 studies were reviewed for this systematic review including case studies, case series, and clinical studies. A variety of techniques have been reported for the treatment of symptomatic chondral lesions in the hip. Microfracture, cartilage repair, autologous chondrocyte implantation, mosaicplasty, and osteochondral allografting have all been used in very limited case series. Although good results have been reported, most studies lack both a control group and a large number of patients. However, the reported results in this article do provide a good foundation for treatments and stimulant for further study in an inherently difficult to treat young patient population with articular cartilage defects in the hip.

Comparison of American and European practices in Primary Immunodeficiency

RATIONALE: Primary immunodeficiency diseases (PIDD) are a rare group of disorders for which limited treatment modalities exist. Data supporting current practices in specific PIDD disease entities are often insufficient. In particular, guidance regarding appropriate frequency and dosage of intravenous immunoglobulin (IVIG) infusions or use of prophylactic antibiotics are limited. We sought to describe use of these interventions within Europe and compare to those in America.

BIOLOGICAL RESTORATION OF CENTRAL NERVOUS SYSTEM ARCHITECTURE AND FUNCTION

STEM CELL THERAPY has emerged as a promising novel therapeutic endeavor for traumatic brain injury, spinal cord injury, stroke, and epilepsy in experimental studies. A few preliminary clinical trials have further supported its safety and early efficacy after transplantation into humans. Although not yet clinically available for central nervous system disorders, stem cell technology is expected to evolve into one of the most powerful tools in the biological management of complex central nervous system disorders, many of which currently have limited treatment modalities. The identification of stem cells, discovery of neurogenesis, and application of stem cells to treat central nervous system disorders represent a dramatic evolution and expansion of the neurosurgeon's capabilities into the neurorestoration and neuroregeneration realms. In Part 3 of a 5-part series on stem cells, we discuss the theory, experimental evidence, and clinical data pertaining to the use of stem cells for the treatment of traumatic, vascular, and epileptic disorders.

Palivizumab in preventing respiratory syncytial virus-related hospitalization in high-risk infants

Respiratory syncytial virus (RSV) causes seasonal epidemics (winter or wet-season) of serious lower respiratory tract infections in young infants with subsequent increased frequency of recurrent wheezing during early childhood. Palivizumab is a humanized monoclonal antibody that provides immunoprophylaxis against RSV when administered monthly over the RSV season. It significantly reduced hospitalizations in high-risk infants including preterm infants with and without bronchopulmonary dysplasia and infants with hemodynamically significant congenital heart disease. Since its license in 1998, approximately 36 methodologically different economic studies have been performed to prove cost–effectiveness of the product. The majority of cost–effectiveness analyses revealed costs of palivizumab exceeding anticipated savings from reduced RSV hospitalizations. A minority of studies performed cost–effectiveness analyses using incremental cost–effectiveness ratios as costs per quality-adjusted life-year gained. The wide variability in the results of economic studies with estimates ranging from cost savings to incremental costs of a high order of magnitude with its use is discussed, in the light of the continuing burden of RSV disease, the limited treatment modalities, and the continuing research for a vaccine.

Konservative Therapie bei Hirnödem – welche Wege führen nach Rom?

In patients with brain edema the pathophysiology of the different forms of edema have to be considered to ensure the prompt, sensible and consistent use of the limited treatment modalities available. Brain edema may be classified into cytotoxic and vasogenic edema, these two types often coexist in one patient. Head elevation, hyperventilation, osmotic therapy and reduction of brain metabolism by sedation or hypothermia should be used closely monitoring ICP and blood pressure. In the future considering the autoregulatory capacity of the individual patient will possibly lead to a more effective action of the treatment modalities described. Further research will open new perspectives how aquaporines are involved in the genesis and mobilisation of brain edema.

Role of pegaptanib sodium in the treatment of neovascular age-related macular degeneration

Age-related macular degeneration (AMD) is responsible for more than half the blind registration in the United Kingdom. Retinal manifestations of AMD can be categorized as either atrophic or neovascular. The hallmark of AMD is the development of choroidal neovascularization (CNV). Until recently, there have been few, limited treatment modalities (eg, photodynamic therapy [PDT]) for this condition and the mainstay of treatment has comprised social and lifestyle support. However, increased understanding of the molecular processes at work in neovascular AMD and CNV in recent years has led to the introduction of new anti-angiogenic agents that target vascular endothelial growth factor (VEGF). These agents either inhibit a selected VEGF isoform (eg, VEGF(165) inhibition by pegaptanib sodium) or inhibit all forms of the VEGF isoform (eg, non-selective VEGF blockade by ranibizumab). The trial data suggest that non-selective inhibition of VEGF offers better treatment outcomes in neovascular AMD. As a result, agents that inhibit all VEGF isoforms are now widely used as first-line therapy for this condition. However, it is known that VEGF plays an important role in maintaining the intergrity of the cardiovascular system and, particularly as the age of patients with AMD places them at an elevated risk of thromboembolic events, long-term post-marketing surveillance data are essential to determining whether non-selective VEGF blockade confers any increased risk. Theoretically, selective VEGF inhibition may reduce any risk associated with pan-VEGF blockade, yet on the basis of initial trials, their use remains more limited at this time. However, clinical practice suggests that initial trials may have under-estimated the efficacy of selective-VEGF inhibition. Observational studies also indicate that better treatment outcomes may be possible by combining VEGF inhibitors sequentially with each other, or with existing therapies (eg, photodynamic therapy [PDT]). The optimum role and indications of anti-VEGF agents will come through careful consideration of the available efficacy and safety data, from the outcomes of long-term follow-up studies, and through assessment of the relative merits of the two approaches to VEGF inhibition in clinical practice. At this time, further head-to-head trials, and economic evaluations, comparing the treatment alternatives are needed.

Epicutaneous (EC) immunization with myelin basic protein (MBP) induces TCRαβ + CD4 + CD8 + double positive suppressor cells that protect from experimental autoimmune encephalomyelitis (EAE)

Multiple sclerosis (MS) is a central nervous system (CNS) chronic inflammatory autoimmune disease with limited treatment modalities. Oral tolerance is one of the experimental methods that protects from autoimmune diseases. However, this method failed to be therapeutic in clinical trials. In our previous work we found that epicutaneous (EC) immunization with protein antigen induced a state of profound immunosuppression that inhibited inflammatory response in contact sensitivity, in experimental autoimmune encephalomyelitis (EAE) and in allogeneic skin graft rejection. In our current work, we precisely determined the phenotype of EC induced T suppressor (Ts) cells that reduce the progress of EAE. Employing TCRδ−/−, CD1d−/− mice, we showed that EC induced Ts cells do not belong either to the population of TCRγδ cells or CD1d restricted NKT cells. Moreover, we noticed that a lack of CD1d−/− restricted NKT lymphocytes resulted in the induction of much stronger suppression of EAE than in wild type mice. This might suggest that NKT cells could interfere with the induction of Ts cells. Using β 2m−/− mice, negative selection and positive selection of EC induced Ts cells, we showed that Ts cells protecting from EAE belong to the population of TCRαβ + CD4 + CD8 + double positive lymphocytes.

Radioisotope Synovectomy for Treating Chronic Synovitis in Inhibitor Patients with Hemophilia.

Hemophilic arthropathy, caused by chronic synovitis is the most common musculoskeletal complication of recurrrent hemarthrosis in hemophilia patients. However, in patients with target joints and chronical synovitis, local directed therapy is more useful than systemic treatment. Radioisotope Synovectomy (RS) consists of destruction of synovial tissue by intra-articular injection of a radioisotope agent. RS has gained acceptance worldwide for 10 years after favourable reports in respect of efficacy and safety. The most frequent and serious complication in hemophilia-A is the development of inhibitors. Due to problems for hemostasis and limited treatment modalities, arthropathy risk is higher in these patients. For last 6 years, we have performed 163 RS procedures in 109 children and young adults in our center. In this report, we present our experience in inhibitor patients (16 cases and 28 joints). All cases were severe hemophilia-A (FVIII<2%). Thirteen patients had high responder (HR)(5–400 BU/ml), three had low responder (LR)(2–5 BU/ml) inhibitor. All patients had target joints and grade-II (n=8) and grade-III (n=20) synovitis. We have used intra-articularly 5 mCi Yttrium 90 for knees (n=16) and 2 mCi Yttrium 90 (n=7) or Rhenium 186 (n=5) for small joints (Schering-CIS, France). The age range was 3–26 years (mean 14.6±6.1yr). We have 4 patients below 10 years. The knees injected 16, elbows 7, ankles 3 and shoulders in 2 joints. Written informed consent was mandatory. For HR patients; recombinant FVIIa (Novoseven) was used (90 mcg/bw / in 2-h interval) in three consecutive doses except one case for 15 joints in 9 patients. Activated PCC (FEIBA) was used (75 IU/bw / in 12 h of interval) in 2 or 3 consecutive doses for 4 patients in 8 joints. High dose FVIII were used for 3 LR patients in 5 joints. Overnight hospitalization was applied. Mean follow-up period after procedure was 2.5 years (range: 6 month-5 year). The efficacy of procedure was evaluated by comparing joint bleedings and signs for synovitis. Seventy-five percent of inhibitor patients had satisfactory results. Pre-procedure joint bleeds were 7.9±3.2 (range: 4–16) for 6 months. After RS, during the first year hemarthroses were significantly decreased as (0.4±1.1). In cases with grade-II synovitis outcome was more better than grade-III synovitis as expected. In two patients, procedure was needed to be repeated due to insufficient effect. After repeated applications, outcome was satisfactory. In other two patients, late recurrence of synovitis was observed after 2 years. One of them, intra-articular injection was repeated and synovitis has improved. No complications have seen. Recently, some suspicions arose due to two children who had had the radioisotope synovectomy using with P32 subsequently developed acute leukemia (ALL) in the USA. However, we have used Y90 and Re186 and no malignancy have reported in the literature and not observed in our study group for 6 years. In conclusion, RS is efficient also in inhibitor patients as far as other patients. RS is cost-effective and easy to perform and hence highly recommended for inhibitor patients. RS seems to be invaluable for treatment of chronic synovitis of inhibitor patients for preventing hemophilic arthropathy.

Neglected Telangiectatic Osteosarcoma of the Clavicle in a Child

We present a case of telengectietic osteosarcoma of the clavicle in a ten-year-old female child. The tumor was neglected for more than six months and no treatment was taken. The case report highlights the neglect of bone tumors in developing countries to a stage where they become untreatable. The malignant nature of the lesion with limited treatment modalities at hand makes the management of these tumors extremely difficult with poor outcome.

Epicutaneously induced TGF-β-dependent tolerance inhibits experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a devastating autoimmune disorder of the central nervous system (CNS) with limited treatment modalities. To evaluate the efficacy of epicutaneous (e.c.) tolerance induction in the prevention of CNS autoimmunity, we utilized an animal model of multiple sclerosis: experimental autoimmune encephalomyelitis (EAE). We show that application of myelin basic protein (MBP) to the skin prior to the induction of EAE by immunization with MBP protected mice from developing disease. In addition, e.c. application of MBP at the first clinical signs of EAE, also resulted in suppression of disease. This therapeutic effect was transferable to naïve recipients with lymph node cells from MBP-treated mice. These regulatory cells were found to be antigen non-specific, as suppression of EAE also occurred when the foreign antigens OVA or TNP were e.c. applied. The mechanistic basis for the tolerance was found to be the production of TGF-β by the antigen induced toleragenic regulatory T cells. These data demonstrate that e.c.-induced regulatory T cells are potent inhibitors of antigen-specific T cell responses, and suggest that e.c. tolerization may have potential effectiveness in the treatment of autoimmune disorders.

In utero development of fetal thirst and appetite: potential for programming.

Thirst and appetite-mediated ingestive behavior develop and are likely programmed in utero, thus preparing for newborn and adult ingestive behavior. Fetal swallowing activity is markedly different from that of the adult, as spontaneous fetal swallowing occurs at a markedly (six-fold) higher rate compared with spontaneous adult drinking activity. This high rate of fetal swallowing is critical for the regulation of amniotic fluid volume and the development of the fetal gastrointestinal tract. Disordered fetal swallowing has been associated with both a decrease (oligohydramnios) and increase (polyhydramnios) in amniotic fluid volume. Both conditions are associated with a significant increase in perinatal morbidity and mortality, and limited treatment modalities are currently available. The mechanisms underlying the high rate of human fetal swallowing are regulated, in part, by tonic activity of central angiotensin II, glutamate N-methyl-D-aspartate receptors, and neuronal nitric oxide synthase. Fetal hypertonicity-mediated dipsogenesis is likely programmed in utero, as offspring of water-restricted ewes demonstrate a programmed syndrome of plasma hypertonicity, with significant hematologic and cardiovascular alterations. Similar to dipsogenic mechanisms, peripheral and central fetal orexic mechanisms also develop in utero, as demonstrated by increased fetal swallowing after both oral sucrose infusion and central injection of neuropeptide Y. The role of leptin in regulating fetal ingestive behavior is interesting because, contrary to actions in adults, leptin does not suppress fetal ingestive behavior. Teleologically, this may be of value during the newborn period, as unopposed appetite stimulatory mechanisms may facilitate rapid fetal and newborn weight gain. An adverse intrauterine environment, with altered fetal orexic factors during the critical developmental period of fetal life, may alter the normal setpoints of appetitive behavior and potentially lead to programming of adulthood hyperphagia and obesity. Further research is needed to delineate the mechanistic relationship between the intrauterine environment and the development of the setpoints of adult appetite and thirst.