Polilactofate microspheres for Paclitaxel delivery to central nervous system malignancies.

PURPOSE: The purpose of this study was to demonstrate that surgically implanted, controlled-release, biodegradable polilactofate microspheres (Paclimer) can be used safely to bypass the blood-brain barrier and deliver paclitaxel to malignant brain tumors. EXPERIMENTAL DESIGN: The rate of paclitaxel release from Paclimer microspheres submerged in PBS was measured in vitro by high-performance liquid chromatography. In vivo studies of Paclimer were performed as intracranial implants in Fischer 344 rats in the presence or absence of 9L gliosarcoma. Mantel-Cox statistics were used to assess the efficacy of Paclimer at extending survival of tumor-bearing animals compared with control implants. Paclimer implants tagged with [(3)H]paclitaxel were used to measure biodistribution of paclitaxel from the Paclimer implant. RESULTS: Paclimer released paclitaxel at a constant rate for up to 3 months in vitro. In vivo, Paclimer implants placed intracranially in rats released active drug for up to 30 days after implantation and doubled the median survival of rats bearing established 9L gliosarcomas (median survival of paclitaxel-treated animals = 35 days; median survival of control-treated animal = 16 days; P < 0.0001). Active drug was distributed throughout the rat brain based on liquid scintillation counting and TLC. Rats implanted with Paclimer demonstrated no overt signs of neurotoxicity and exhibited local cytopathological changes consistent with exposure to an antimicrotubule agent. CONCLUSIONS: Paclimer extends survival in a rodent model of glioma with minimal morbidity and optimal pharmacokinetics.     

Tissue-conserving surgery for prognosis,treatment, and function preservation

Objectives: To describe an approach based on initial tissue-conserving surgery used to obtain histologically determined prognostic information that has therapeutic implications and the potential to enhance preservation of function. Study Design: Analysis of a group of patients with head and neck cancer treated initially with tissue-conserving surgery based on Mohs' histographic sectioning and selected neck dissection to derive histologically determined prognostic information with therapeutic implications and preservation in function. Methods: This study is primarily based on an analysis of patients from January 1, 1989, through June 4, 1996 assigned to a protocol evaluating resection of oral cavity squamous cell cancer with margin control using Mohs' histographic technique and/or a group of patients with neck assessment of N0 on clinical examination who are undergoing supraomohyoid neck dissections. Results: Thirty-three primary tumor resections were performed using the Mohs' technique, and 54% required two or more Mohs' sections before clear histologic margins were obtained following resection based on clinically determined negative margins. There were 44 patients who underwent unilateral or bilateral supraomohyoid neck dissections, and 33% had occult, histologically positive nodes. When compared with the disease of the neck specimens, a preoperative computed tomography scan had a sensitivity of 25%, a specificity of 77%, and an accuracy of 63%. Conclusions: This report describes the effectiveness of Mohs' histographic sectioning and selective neck dissection as a means of determining prognostic information that can be used to develop a focused and cost-effective treatment program that, along with contemporary reconstructive techniques, provides a potential enhancement of function preservation. Laryngoscope, 108:1599–1604, 1998     

Detection of p21WAF1/Cip1 in brain metastases

The p21^WAF1/Cip1 (p21) protein, a negative regulator of G₁ checkpoint control, was overexpressed in the majority of human gliomas. To investigate whether p21 expression in brain metastases from various systemic origins is similar to that in gliomas and whether p21 expression is regulated differently in brain metastases and in corresponding primary tumors, we used immunohistochemical staining to examine the expression of p21 in paraffin-embedded sections prepared from primary colon and breast carcinomas and from metastatic brain tumors that originated from colon, breast, lung, and kidney cancers and from melanoma. Our results showed that 56% (28 of 50) of the brain metastases samples have more than 1% p21-positive staining cells compared with 87% of primary gliomas reported previously. Among the samples analyzed, p21 expression in brain metastases from breast carcinomas was much higher than in primary breast carcinomas. In contrast, p21 expression in brain metastases from colon carcinomas was less than primary colon carcinomas. The results from this pilot study suggest that p21 expression is regulated differently in metastatic and primary tumors.     

Ross River virus and its vectors in Sorell Municipal Area, south-eastern Tasmania, January to March 2002.

In 2002, Tasmania reported the largest number of Ross River virus (RRV) infections ever recorded for the state. Of the 117 cases, 37 lived in, or had visited, the Sorell Municipal Area, east of Hobart. In early 2002, a combination of spring tides and high summer rainfall produced extensive salt marsh habitat in the Sorell region, resulting in unseasonably high densities of the mosquito Ochlerotatus camptorhynchus, recognised vector of RRV. Four isolates of RRV were identified from collections of adult mosquitoes. All four isolates were from Oc. camptorhynchus, collected near the Carlton River. This is the furthest south that RRV has been identified in Australia and the first identification from south-east Tasmania. The virus carriage rate in the mosquito vector populations were very high, with successive weekly minimum infection rates of 17.1, 3.0 and 11.1 per 1,000 Oc. camptorhynchus at Carlton River from mid-February to early March. The first isolation of RRV from mosquitoes coincided with the onset dates of the first human cases of RRV infection.     

Exposure to polybrominated diphenyl ethers (PBDEs): changes in thyroid, vitamin A, glutathione homeostasis, and oxidative stress in American kestrels (Falco sparverius).

Polybrominated diphenyl ethers (PBDEs), a class of additive flame retardants, are temporally increasing in wildlife tissues and capable of disrupting normal endocrine function. We determined whether in ovo and post-hatch exposure of captive American kestrels (Falco sparverius) to environmentally relevant PBDEs alter thyroid, retinol, and oxidative stress measures. Control eggs were injected with safflower oil and subsequent nestlings fed the same vehicle; dosed eggs received PBDE congeners (BDE-47, -99, -100, -153), which mainly comprise the Penta-BDE commercial mixture, dissolved in safflower oil at concentrations (1500 ng/g total [Sigma] PBDEs) approximating those in Great Lakes gull eggs. Nestlings hatching from dosed eggs were orally exposed for 29 days to variable SigmaPBDE concentrations that are similar to levels reported in tissues of Great Lakes trout (100 ng/g). Treatment kestrels had lower plasma thyroxine (T(4)), plasma retinol, and hepatic retinol and retinyl palmitate concentrations, but unaltered triiodothyronine (T(3)) concentrations and thyroid glandular structure. BDE-47, -100, and -99 were negatively associated with plasma T(4), plasma retinol (BDE-100, -99) and hepatic retinol (BDE-47). Despite an antioxidant-rich diet, PBDE exposure induced hepatic oxidative stress, particularly in females, with an increased hepatic GSSG:GSH ratio, a marginal increase in lipid peroxidation, and increased oxidized glutathione. Positive associations were found between concentrations of BDE-183 and thiols and, in males, between BDE-99 and reduced GSH, but a negative association occurred between BDE-99 and TBARS. Subsequently, concentrations of PBDE congeners in wild birds may alter thyroid hormone and vitamin A concentrations, glutathione metabolism and oxidative stress.     

Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31.

PURPOSE: Trastuzumab is effective in treating human epidermal growth factor receptor 2 (HER2) -positive breast cancer, but it increases frequency of cardiac dysfunction (CD) when used with or after anthracyclines. PATIENTS AND METHODS: National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel plus 52 weeks of trastuzumab beginning concurrently with paclitaxel in patients with node-positive, HER2-positive breast cancer. Initiation of trastuzumab required normal post-AC left ventricular ejection fraction (LVEF) on multiple-gated acquisition scan. If symptoms suggestive of congestive heart failure (CHF) developed, source documents were blindly reviewed by an independent panel of cardiologists to determine whether criteria were met for a cardiac event (CE), which was defined as New York Heart Association class III or IV CHF or possible/probable cardiac death. Frequencies of CEs were compared between arms. RESULTS: Among patients with normal post-AC LVEF who began post-AC treatment, five of 814 control patients subsequently had confirmed CEs (four CHFs and one cardiac death) compared with 31 of 850 trastuzumab-treated patients (31 CHFs and no cardiac deaths). The difference in cumulative incidence at 3 years was 3.3% (4.1% for trastuzumab-treated patients minus 0.8% for control patients; 95% CI, 1.7% to 4.9%). Twenty-seven of the 31 patients in the trastuzumab arm have been followed for > or = 6 months after diagnosis of a CE; 26 were asymptomatic at last assessment, and 18 remained on cardiac medication. CHFs were more frequent in older patients and patients with marginal post-AC LVEF. Fourteen percent of patients discontinued trastuzumab because of asymptomatic decreases in LVEF; 4% discontinued trastuzumab because of symptomatic cardiotoxicity. CONCLUSION: Administering trastuzumab with paclitaxel after AC increases incidence of CHF and lesser CD. Potential cardiotoxicity should be carefully considered when discussing benefits and risks of this therapy.     

Evidence-based practice: Quality indicator analysis of antecedent exercise in autism spectrum disorders

The purpose of the research was to conduct a quality indicator analysis of studies exploring the effects of antecedent exercise on self-stimulatory behaviors of individuals with autism spectrum disorders (ASD). Educational Resources Information Center (ERIC), Google Scholar, SPORTDiscus, PsychINFO, and PubMed/MedLine databases from 1980 to October 2010 and reference lists of included articles were searched. Twelve research studies employing group experimental (Gersten et al., 2005) or single-subject designs (Horner et al., 2005) met inclusion criteria. Each study was assessed for the presence and clarity of quality indicators. Group experimental and single-subject designs met 48% and 82% of quality indicators, respectively. This suggests that the effects of antecedent exercise on self-stimulatory behaviors of individuals with ASD is incomplete and claims of exercise being an evidence-based practice are premature. Several indicators were difficult to interpret or lacking clear definitions. Recommendations for clarifying and applying the quality indicators are offered.     

Gene Therapy Strategies to Exploit TRIM Derived Restriction Factors against HIV-1

Restriction factors are a collection of antiviral proteins that form an important aspect of the innate immune system. Their constitutive expression allows immediate response to viral infection, ahead of other innate or adaptive immune responses. We review the molecular mechanism of restriction for four categories of restriction factors; TRIM5, tetherin, APOBEC3G and SAMHD1 and go on to consider how the TRIM5 and TRIMCyp proteins in particular, show promise for exploitation using gene therapy strategies. Such approaches could form an important alternative to current anti-HIV-1 drug regimens, especially if combined with strategies to eradicate HIV reservoirs. Autologous CD4⁺ T cells or their haematopoietic stem cell precursors engineered to express TRIMCyp restriction factors, and provided in a single therapeutic intervention could then be used to restore functional immunity with a pool of cells protected against HIV. We consider the challenges ahead and consider how early clinical phase testing may best be achieved.