Re-irradiation for recurrent glioblastoma multiforme: a critical comparison of different concepts.

PURPOSE: Purpose of this study was to investigate outcome and toxicity of re-irradiation for recurrent primary glioblastoma (rGBM). We evaluated a group of patients with rGBM and identical primary treatment comprising adjuvant radiotherapy (30â€¯× 2 Gy) with concurrent temozolomide (TMZ). METHODS: In this retrospective study of 46 patients, all received adjuvant or definitive normofractionated radiotherapy to a pretreated area, some with concurrent chemotherapy. Impact of different clinical, histological, or epidemiological factors on survival and radiation toxicity was reviewed. RESULTS: Of 46 patients, 40 completed the intended therapy. Overall survival (OS) was 20 months (range 6-72 months). Overall survival and progression-free survival after re-irradiation (OS2 and PFS2) were 9.5 and 3.4 months (range 2-40 and 0.7-44 months). Simultaneous systemic therapy improved PFS2 and OS2 (4.3 vs. 2.0, p < 0.001 and 12 vs. 4 months, p = 0.13, respectively). Therapy with TMZ or bevacizumab improved PFS2 vs. nitrosureas (6.6 vs. 2.9, p = 0.03 and 5.1 vs. 2.9 months, p = 0.035, respectively). TMZ also improved PFS2 and OS2 vs. all other systemic therapies (6.6 vs. 4, p < 0.001 and 17 vs. 10 months, p = 0.1). In a subgroup analysis for patients with methylation of the MGMT promoter, doses of >36 Gy as well as TMZ vs. no systemic therapy improved PFS2 (p = 0.045 and p = 0.03, respectively). 27.5% of all patients had no acute toxicity. Three patients with acute and four patients with late grade 3 toxicities were reported. CONCLUSION: Normofractionated radiotherapy is a feasible option for rGBM with a good toxicity profile. Simultaneously applied systemic therapy was associated with improved outcome. For MGMT promoter-methylated histology, higher radiation doses improved survival.

Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy.

Frameshift mutations in the DMD gene, encoding dystrophin, cause Duchenne muscular dystrophy (DMD), leading to terminal muscle and heart failure in patients. Somatic gene editing by sequence-specific nucleases offers new options for restoring the DMD reading frame, resulting in expression of a shortened but largely functional dystrophin protein. Here, we validated this approach in a pig model of DMD lacking exon 52 of DMD (DMDΔ52), as well as in a corresponding patient-derived induced pluripotent stem cell model. In DMDΔ52 pigs1, intramuscular injection of adeno-associated viral vectors of serotype 9 carrying an intein-split Cas9 (ref. 2) and a pair of guide RNAs targeting sequences flanking exon 51 (AAV9-Cas9-gE51) induced expression of a shortened dystrophin (DMDΔ51-52) and improved skeletal muscle function. Moreover, systemic application of AAV9-Cas9-gE51 led to widespread dystrophin expression in muscle, including diaphragm and heart, prolonging survival and reducing arrhythmogenic vulnerability. Similarly, in induced pluripotent stem cell-derived myoblasts and cardiomyocytes of a patient lacking DMDΔ52, AAV6-Cas9-g51-mediated excision of exon 51 restored dystrophin expression and amelioreate skeletal myotube formation as well as abnormal cardiomyocyte Ca2+ handling and arrhythmogenic susceptibility. The ability of Cas9-mediated exon excision to improve DMD pathology in these translational models paves the way for new treatment approaches in patients with this devastating disease.

Worth a local treatment? - Analysis of modern radiotherapy concepts for oligometastatic prostate cancer.

BACKGROUND: Prostate cancer (PCA) is the most-prevalent non-skin cancer in men worldwide. Nevertheless, the treatment of oligometastatic, especially lymph-node (ln) recurrent, PCA remains elusive. The aim of our study was to provide insights in radiotherapy (RT)-treatment of recurrent PCA exhibiting ln- or osseous (oss)-oligometastases. METHODS: Between April 2012 and April 2017, 27 oligometastatic PCA patients (19 ln and 8 single oss) were treated with RT at our institution. RESULTS: The metastasis-free survival (MFS) was 24.8 m (22.0-36.0 m) and 25.4 m (23.9-28.1 m) for the ln- and oss-subgroup resulting in 1-year MFS of 75.4 and 100% and 2-year MFS of 58.7 and 83.3% for ln- and oss-metastatic patients, respectively. Of notice, none of the recurrences for ln-patients was in the RT-field, constituting a local control of 100%. Within the ln-group, pre-RT median-PSA was 2.6 ng/ml, median post-RT PSA was 0.3 ng/ml, which was significant (p = 0.003). Median biochemical-free survival (bfS) was 12.2 m. PCA that was initially confined to the prostate had a better bfS (p < 0.001) and MFS (p = 0.013). The oss-group had a median PSA of 4.9 ng/ml pre-treatment which dropped to a median value of 0.14 ng/ml (p = 0.004). Toxicities were moderate, with only 1 case of III° toxicity. There were no deaths in the ln-group, thus overall survial was 100% here. CONCLUSION: Our study points out the feasibility of RT as a treatment option in recurrent PCA and demonstrates an excellent local control with a low-toxicity profile.

A preclinical Talbot-Lau prototype for x-ray dark-field imaging of human-sized objects.

PURPOSE: Talbot-Lau x-ray interferometry provides information about the scattering and refractive properties of an object - in addition to the object's attenuation features. Until recently, this method was ineligible for imaging human-sized objects as it is challenging to adapt Talbot-Lau interferometers (TLIs) to the relevant x-ray energy ranges. In this work, we present a preclinical Talbot-Lau prototype capable of imaging human-sized objects with proper image quality at clinically acceptable dose levels. METHODS: The TLI is designed to match a setup of clinical relevance as closely as possible. The system provides a scan range of 120 × 30 cm2 by using a scanning beam geometry. Its ultimate load is 100 kg. High aspect ratios and fine grid periods of the gratings ensure a reasonable setup length and clinically relevant image quality. The system is installed in a university hospital and is, therefore, exposed to the external influences of a clinical environment. To demonstrate the system's capabilities, a full-body scan of a euthanized pig was performed. In addition, freshly excised porcine lungs with an extrinsically provoked pneumothorax were mounted into a human thorax phantom and examined with the prototype. RESULTS: Both examination sequences resulted in clinically relevant image quality - even in the case of a skin entrance air kerma of only 0.3 mGy which is in the range of human thoracic imaging. The presented case of a pneumothorax and a reader study showed that the prototype's dark-field images provide added value for pulmonary diagnosis. CONCLUSION: We demonstrated that a dedicated design of a Talbot-Lau interferometer can be applied to medical imaging by constructing a preclinical Talbot-Lau prototype. We experienced that the system is feasible for imaging human-sized objects and the phase-stepping approach is suitable for clinical practice. Hence, we conclude that Talbot-Lau x-ray imaging has potential for clinical use and enhances the diagnostic power of medical x-ray imaging.

LEA29Y expression in transgenic neonatal porcine islet-like cluster promotes long-lasting xenograft survival in humanized mice without immunosuppressive therapy.

Genetically engineered pigs are a promising source for islet cell transplantation in type 1 diabetes, but the strong human anti-pig immune response prevents its successful clinical application. Here we studied the efficacy of neonatal porcine islet-like cell clusters (NPICCs) overexpressing LEA29Y, a high-affinity variant of the T cell co-stimulation inhibitor CTLA-4Ig, to engraft and restore normoglycemia after transplantation into streptozotocin-diabetic NOD-SCID IL2rγ-/- (NSG) mice stably reconstituted with a human immune system. Transplantation of INSLEA29Y expressing NPICCs resulted in development of normal glucose tolerance (70.4%) and long-term maintenance of normoglycemia without administration of immunosuppressive drugs. All animals transplanted with wild-type NPICCs remained diabetic. Immunohistological examinations revealed a strong peri- and intragraft infiltration of wild-type NPICCs with human CD45+ immune cells consisting of predominantly CD4+ and CD8+ lymphocytes and some CD68+ macrophages and FoxP3+ regulatory T cells. Significantly less infiltrating lymphocytes and only few macrophages were observed in animals transplanted with INSLEA29Y transgenic NPICCs. This is the first study providing evidence that beta cell-specific LEA29Y expression is effective for NPICC engraftment in the presence of a humanized immune system and it has a long-lasting protective effect on inhibition of human anti-pig xenoimmunity. Our findings may have important implications for the development of a low-toxic protocol for porcine islet transplantation in patients with type 1 diabetes.

Frequently co-occurring pesticides and volatile organic compounds in public supply and monitoring wells, southern New Jersey, USA.

One or more pesticides were detected with one or more volatile organic compounds (VOCs) in more than 95% of samples collected from 30 public supply and 95 monitoring wells screened in the unconsolidated surficial aquifer system of southern New Jersey, USA. Overall, more than 140,000 and more than 3,000 unique combinations of pesticides with VOCs were detected in two or more samples from the supply and monitoring wells, respectively. More than 400 of these combinations were detected in 20% or more of the samples from the supply wells, whereas only 17 were detected in 20% or more of the samples from the monitoring wells. Although many constituent combinations detected in water from the supply and monitoring wells are similar, differences in constituent combinations also were found and can be attributed, in part, to differences in the characteristics of these two well types. The monitoring wells sampled during this study yield water that typically was recharged beneath a single land-use setting during a recent, discrete time interval and that flowed along relatively short paths to the wells. Public supply wells, in contrast, yield large volumes of water and typically have contributing areas that are orders of magnitude larger than those of the monitoring wells. These large contributing areas generally encompass multiple land uses; moreover, because flow paths that originate in these areas vary in length, these wells typically yield water that was recharged over a large temporal interval. Water withdrawn from public supply wells, therefore, contains a mixture of waters of different ages that were recharged beneath various land-use settings. Because public supply wells intercept water flowing along longer paths with longer residence times and integrate waters from a larger source area than those associated with monitoring wells, they are more likely to yield water that contains constituents that were used in greater quantities in the past, that were introduced from point sources, and/or that are derived from the degradation of parent compounds along extended flow paths.

Preterm infants with high polyunsaturated fatty acid and plasmalogen content in tracheal aspirates develop bronchopulmonary dysplasia less often.

OBJECTIVE: Oxygen toxicity causes chronic bronchopulmonary dysplasia (BPD) in extremely preterm infants. Polyunsaturated fatty acids (PUFA) and plasmalogens are the two main substrates for lipid peroxidation in the pulmonary surfactant. In the present study, we tested whether low concentrations of both were associated with development of BPD and whether both were further reduced during mechanical ventilation with oxygen. DESIGN: Prospective, noninterventional, descriptive study. SETTING: Level III neonatal intensive care unit in a university hospital. PATIENTS: In 25 extremely low birth weight infants with respiratory distress syndrome, tracheal aspirates were collected immediately after birth and in the following 4 days. As control, tracheal and pharyngeal aspirates were collected from healthy infants immediately after birth. The amount of PUFA and dimethylacetals (DMA, representing plasmalogens) was determined gas-chromatographically. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The relative percentages of PUFA and DMA on all fatty acids in non-BPD infants (PUFA% 26+/-8.9, DMA% 3.5+/-1.2) were higher compared with infants who developed BPD (PUFA% 14.5+/-3.8, DMA% 1.8+/-0.9). In term healthy infants, DMA% and PUFA% were in the same range as in the BPD group. The higher levels found for non-BPD infants decreased after day 1 to values equal to the BPD group and remained low. CONCLUSIONS: The results suggest that initially higher levels of PUFA and plasmalogens in the tracheal effluent are associated with a reduced risk of developing BPD and are reduced during the first day of ventilation.