Long-term Clinical Outcomes and Safety Profile of SBRT for Centrally Located NSCLC.

PURPOSE: Previous studies suggest that stereotactic body radiation therapy (SBRT) is associated with higher toxicity rates for central lung tumors relative to peripheral tumors when using 3 fraction SBRT. The initial results from Radiation Therapy Oncology Group study 0813 suggest a safe toxicity profile of SBRT administered in 5 fractions for central non-small cell lung cancer (NSCLC). We reviewed our institutional data to evaluate the safety and efficacy of SBRT for central NSCLC. METHODS AND MATERIALS: We reviewed our prospectively collected SBRT database for patients with central NSCLC who received SBRT between 2008 and 2014. The most frequent dose and fractionations were 50 Gy in 5 fractions (59%) and 48 Gy in 4 fraction (30%). Local control (LC), regional control, metastasis-free survival, and overall survival were calculated using Kaplan-Meier estimates. The National Cancer Institute Common Terminal Criteria for Adverse Events were used for toxicity grading. RESULTS: A total of 110 central lung tumors in 103 patients were included. The median age was 74 years (range, 40-95 years), and the median follow-up time of living patients was 50 months. The mean tumor size was 20 mm (range, 5-70 mm). The 5 year rate of LC, regional control, and distant control was 89%, 77%, and 82%, respectively. The median and 5-year overall survival were 3.5 years and 35%, respectively. No treatment variables were associated with tumor control or other clinical outcomes. A single patient experienced grade 3 radiation pneumonitis (0.97%). The rate of late toxicity grade ≥3 was 9.7% (grade 3, 7.7%; grade 4, 0.97%; grade 5, 0.97%) and included pneumonitis (3.9%), bronchial necrosis (2.9%), myocardial dysfunction (1.9%), and worsening heart failure (0.97%). CONCLUSIONS: SBRT for central NSCLC provides high rates of LC. Despite excellent LC, patients remain at risk for regional and distant failure. The rate of grade 3 pneumonitis was consistent with that of prior reports. We observed low rates of grade 4-5 toxicity potentially attributable to SBRT. Our results contribute to the growing body of data in support of the safety of SBRT for central NSCLC.

Gamma Knife Stereotactic Radiosurgery for the Treatment of Primary and Metastatic Ocular Malignancies.

BACKGROUND: Gamma knife radiosurgery (GKR) can be used for precise targeting of malignant lesions of the CNS when brachytherapy is not an appropriate option. OBJECTIVES: This study reports treatment technique, efficacy, and radiation-induced adverse effects in patients with primary and metastatic ocular lesions treated with Leksell GKR. METHODS: A retrospective, single-institution review was conducted of 28 patients with primary or metastatic ocular disease, treated from 2000 to 2014. The dose to margin was 17-27 Gy (maximum dose 28-54 Gy). Primary outcomes included overall survival (OS), local control, progression-free survival (PFS), and enucleation. RESULTS: The median age at diagnosis was 70 years, and the median follow-up was 26.4 months. Of the 28 patients, 11 (39%) had metastatic ocular disease, and 17 (61%) were diagnosed with primary ocular melanoma (stage T2a-T4e). The average maximum dose and dose to margin were 41 and 21 Gy, respectively. The mean dose to the optic nerve was 12.6 Gy. The 5-year OS was 46% (95% CI: 23.6-68.4%) for the entire cohort; the 5-year PFS for M0 patients who presented with primary ocular melanoma lesions was 90% (95% CI: 71-100%). Only 1 patient required enucleation after radiation treatment. CONCLUSION: GKR is an effective option, with acceptable levels of toxicity, in the treatment of primary and metastatic ocular lesions.

Utility of 18F-FDG PET for Predicting Histopathologic Response in Esophageal Carcinoma following Chemoradiation.

INTRODUCTION: For patients with esophageal cancer undergoing neoadjuvant chemoradiation (CRT) followed by surgical resection, complete histopathologic response (pCR) is associated with favorable overall survival (OS). The aim of this study was to evaluate the correlation between 18F-fluorodeoxyglucose positron emission tomography (FDG PET) response to neoadjuvant CRT and pCR. METHODS: Maximum standardized uptake values and standardized uptake ratios (SURs) were measured before and after CRT. SUR was normalized to liver uptake and mediastinal blood pool uptake. FDG PET complete response was defined as metabolic activity normalization to hepatic and blood pool activity. The correlation between FDG PET parameters and pCR was examined through logistic regression analyses. RESULTS: In total, 193 patients were monitored for a median of 3.6 years after initiation of CRT. Most tumors were adenocarcinoma (85%) and stage T3 (75%). Complete FDG PET response and pCR occurred in 27% and 34% of patients, respectively. Histologic findings, chemotherapy type, tumor stage, and radiation dose were not significantly associated with complete radiographic response. The rates of pCR in patients with and without radiographic complete response were 42% and 31% (p = 0.17), respectively. No predictive correlation was found between pCR and change in maximum standardized uptake value (p = 0.25), in SUR normalized to blood pool uptake (p = 0.20), or in SUR normalized to liver uptake (p = 0.15). The 5-year OS rate was 46% for patients with a complete FDG PET response versus 44% without a complete response (p = 0.78). The 5-year OS rate of patients who achieved pCR was 49% versus 43% for patients with residual tumor (p = 0.04). CONCLUSION: For patients with esophageal cancer who received neoadjuvant chemoradiation, pretreatment and posttreatment FDG PET parameters did not correlate with pCR or OS.

Immune Responses to rAAV6: The Influence of Canine Parvovirus Vaccination and Neonatal Administration of Viral Vector.

Recombinant adeno-associated viral (rAAV) vectors promote long-term gene transfer in many animal species. Significant effort has focused on the evaluation of rAAV delivery and the immune response in both murine and canine models of neuromuscular disease. However, canines provided for research purposes are routinely vaccinated against canine parvovirus (CPV). rAAV and CPV possess significant homology and are both parvoviruses. Thus, any immune response generated to CPV vaccination has the potential to cross-react with rAAV vectors. In this study, we investigated the immune response to rAAV6 delivery in a cohort of CPV-vaccinated canines and evaluated multiple vaccination regimens in a mouse model of CPV-vaccination. We show that CPV-vaccination stimulates production of neutralizing antibodies with minimal cross-reactivity to rAAV6. In addition, no significant differences were observed in the magnitude of the rAAV6-directed immune response between CPV-vaccinated animals and controls. Moreover, CPV-vaccination did not inhibit rAAV6-mediated transduction. We also evaluated the immune response to early rAAV6-vaccination in neonatal mice. The influence of maternal hormones and cytokines leads to a relatively permissive state in the neonate. We hypothesized that immaturity of the immune system would permit induction of tolerance to rAAV6 when delivered during the neonatal period. Mice were vaccinated with rAAV6 at 1 or 5 days of age, and subsequently challenged with rAAV6 exposure during adulthood via two sequential IM injections, 1 month apart. All vaccinated animals generated a significant neutralizing antibody response to rAAV6-vaccination that was enhanced following IM injection in adulthood. Taken together, these data demonstrate that the immune response raised against rAAV6 is distinct from that which is elicited by the standard parvoviral vaccines and is sufficient to prevent stable tolerization in neonatal mice.

Expression of the dystrophin isoform Dp116 preserves functional muscle mass and extends lifespan without preventing dystrophy in severely dystrophic mice.

Dp116 is a non-muscle isoform of dystrophin that assembles the dystrophin-glycoprotein complex (DGC), but lacks actin-binding domains. To examine the functional role of the DGC, we expressed the Dp116 transgene in mice lacking both dystrophin and utrophin (mdx:utrn(-/-)). Unexpectedly, expression of Dp116 prevented the most severe aspects of the mdx:utrn(-/-) phenotype. Dp116:mdx:utrn(-/-) transgenic mice had dramatic improvements in growth, mobility and lifespan compared with controls. This was associated with increased muscle mass and force generating capacity of limb muscles, although myofiber size and specific force were unchanged. Conversely, Dp116 had no effect on dystrophic injury as determined by muscle histopathology and serum creatine kinase levels. Dp116 also failed to restore normal fiber-type distribution or the post-synaptic architecture of the neuromuscular junction. These data demonstrate that the DGC is critical for growth and maintenance of muscle mass, a function that is independent of the ability to prevent dystrophic pathophysiology. Likewise, this is the first demonstration in skeletal muscle of a positive functional role for a dystrophin protein that lacks actin-binding domains. We conclude that both mechanical and non-mechanical functions of dystrophin are important for its role in skeletal muscle.

Therapy for neuromuscular disorders.

Research into therapeutic approaches for both recessive and dominant neuromuscular disorders has made great progress over the past few years. In the field of gene therapy, antisense-mediated exon skipping is being applied to bypass deleterious mutations in the dystrophin gene and restore dystrophin expression in animal models of muscular dystrophy. Approaches for the dominant genetic muscle diseases have turned toward elimination of the mutant gene product with anti-sense oligonucleotide therapy and RNA interference techniques. Refinements of adeno-associated viral vectors and strategies for their delivery are also leading towards future clinical trials. The discovery of new, multipotent cell lineages, some of which possess the ability to successfully engraft muscle following vascular delivery, presents exciting prospects for the field of stem cell therapy. These discoveries represent steady progress towards the development of effective therapies for a wide range of neuromuscular disorders.

Antisense oligonucleotide against GTPase Rab5b inhibits metabotropic agonist DHPG-induced neuroprotection.

(S)-3,5-dihydroxyphenylglycine (DHPG), a group I metabotropic glutamate receptor (mGluR1 and 5) agonist reduced NMDA-mediated membrane currents, NMDA-induced cell death and up-regulated Rab5b, a small GTPase involved in endocytosis [M. Blaabjerg, A. Baskys, J. Zimmer and M. P. Vawter, Changes in hippocampal gene expression after neuroprotective activation of group I metabotropic glutamate receptors, Molec. Brain Res. 117 (2003) 196-205; M. Blaabjerg, L. Fang, J. Zimmer and A. Baskys, Neuroprotection against NMDA excitotoxicity by group I metabotropic glutamate receptors is associated with reduction of NMDA stimulated currents, Experimental Neurol. 183 (2003) 573-580.]. To examine the role of Rab5b on DHPG-mediated neuroprotection in organotypic hippocampal cultures, we developed antisense oligonucleotide targeted to suppress Rab5b translation. Treatment of cultures with the antisense (24 h) but not scrambled sequence oligonucleotide suppressed DHPG-induced increase in Rab5b expression and significantly disrupted DHPG-induced protection against NMDA toxicity in a concentration-dependent manner (0.01-10 nM). Antisense but not scrambled oligonucleotide treatment reduced NMDA toxicity (to 74.4+/-5.9% of control) and this effect could be blocked by protein kinase C inhibitor staurosporine (0.2 microM) or with the protease inhibitor leupeptin (100 microM). Application of osmotic shock followed by K(+) depletion to disrupt endocytosis abolished the protective effect of DHPG. These data suggest that neuroprotection by DHPG against NMDA-mediated injury may involve facilitation of NMDA receptor endocytosis likely stimulated by DHPG-induced increase in Rab5b synthesis.