Microglia contributes to remyelination in cerebral but not spinal cord ischemia.

Inflammation after injury of the central nervous system (CNS) is increasingly viewed as a therapeutic target. However, comparative studies in different CNS compartments are sparse. To date only few studies based on immunohistochemical data and all referring to mechanical injury have directly compared inflammation in different CNS compartments. These studies revealed that inflammation is more pronounced in spinal cord than in brain. Therefore, it is unclear whether concepts and treatments established in the cerebral cortex can be transferred to spinal cord lesions and vice versa or whether immunological treatments must be adapted to different CNS compartments. By use of transcriptomic and flow cytometry analysis of equally sized photothrombotically induced lesions in the cerebral cortex and the spinal cord, we could document an overall comparable inflammatory reaction and repair activity in brain and spinal cord between day 1 and day 7 after ischemia. However, remyelination was increased after cerebral versus spinal cord ischemia which is in line with increased remyelination in gray matter in previous analyses and was accompanied by microglia dominated inflammation opposed to monocytes/macrophages dominated inflammation after spinal cord ischemia. Interestingly remyelination could be reduced by microglia and not hematogenous macrophage depletion. Our results show that despite different cellular composition of the postischemic infiltrate the inflammatory response in cerebral cortex and spinal cord are comparable between day 1 and day 7. A striking difference was higher remyelination capacity in the cerebral cortex, which seems to be supported by microglia dominance.

Comparing Local and Systemic Control between Partial- and Whole-Breast Radiotherapy in Low-Risk Breast Cancer-A Meta-Analysis of Randomized Trials.

PURPOSE/OBJECTIVE: The standard treatment for localized low-risk breast cancer is breast-conserving surgery, followed by adjuvant radiotherapy and appropriate systemic therapy. As the majority of local recurrences occur at the site of the primary tumor, numerous trials have investigated partial-breast irradiation (PBI) instead of whole-breast treatment (WBI) using a multitude of irradiation techniques and fractionation regimens. This meta-analysis addresses the impact on disease-specific endpoints, such as local and regional control, as well as disease-free survival of PBI compared to that of WBI in published randomized trials. MATERIAL AND METHODS: We conducted a systematic literature review and searched for randomized trials comparing WBI and PBI in early-stage breast cancer with publication dates after 2009. The meta-analysis was based on the published event rates and the effect sizes for available oncological endpoints of at least two trials reporting on them. We evaluated in-breast tumor recurrences (IBTR), local recurrences at the primary site and elsewhere in the ipsilateral breast, regional recurrences (RR), distant metastasis-free interval (DMFI), disease-free survival (DFS), contralateral breast cancer (CBC), and second primary cancer (SPC). Furthermore, we aimed to assess the impact of different PBI techniques and subgroups on IBTR. We performed all statistical analyses using the inverse variance heterogeneity model to pool effect sizes. RESULTS: For the intended meta-analysis, we identified 13 trials (overall 15,561 patients) randomizing between PBI and WBI. IBTR was significantly higher after PBI (OR = 1.66; CI-95%: 1.07-2.58; p = 0.024) with an absolute difference of 1.35%. We detected significant heterogeneity in the analysis of the PBI technique with intraoperative radiotherapy resulting in higher local relapse rates (OR = 3.67; CI-95%: 2.28-5.90; p < 0.001). Other PBI techniques did not show differences to WBI in IBTR. Both strategies were equally effective at the primary tumor site, but PBI resulted in statistically more IBTRs elsewhere in the ipsilateral breast. IBTRs after WBI were more likely to be located at the primary tumor bed, whereas they appeared equally distributed within the breast after PBI. RR was also more frequent after PBI (OR = 1.75; CI-95%: 1.07-2.88; p < 0.001), yet we did not detect any differences in DMFI (OR = 1.08; CI-95%: 0.89-1.30; p = 0.475). DFS was significantly longer in patients treated with WBI (OR = 1.14; CI-95%: 1.02-1.27; p = 0.003). CBC and SPC were not different in the test groups (OR = 0.81; CI-95%: 0.65-1.01; p = 0.067 and OR = 1.09; CI-95%: 0.85-1.40; p = 0.481, respectively). CONCLUSION: Limiting the target volume to partial-breast radiotherapy appears to be appropriate when selecting patients with a low risk for local and regional recurrences and using a suitable technique.

No Difference in Overall Survival and Non-Breast Cancer Deaths after Partial Breast Radiotherapy Compared to Whole Breast Radiotherapy-A Meta-Analysis of Randomized Trials.

PURPOSE/OBJECTIVE: Adjuvant radiotherapy after breast conserving surgery is the standard approach in early stage breast cancer. However, the extent of breast tissue that has to be targeted with radiation has not been determined yet. Traditionally, the whole breast was covered by two opposing tangential beams. Several randomized trials have tested partial breast irradiation (PBI) compared to whole breast irradiation (WBI) using different radiation techniques. There is evidence from randomized trials that PBI might result in lower mortality rates compared to WBI. We aimed to reassess this question using current data from randomized trials. MATERIAL/METHODS: We performed a systematic literature review searching for randomized trials comparing WBI and PBI in early stage breast cancer with publication dates after 2009. The meta-analysis was performed using the published event rates and the effect sizes for overall survival (OS), breast cancer-specific survival (BCSS), and non-breast cancer death (NBCD) as investigated endpoints. Analysis of subgroups using different radiation techniques was intended. We used hazard ratios (HR) and risk differences (RD) to estimate pooled effect sizes. Statistical analysis was performed using the inverse variance heterogeneity model. RESULTS: We identified eleven studies randomizing between PBI and WBI. We did not find significant differences in OS (n = 14,070; HR = 1.02; CI-95%: 0.89-1.16; p = 0.810, and n = 15,203; RD = -0.001; CI-95%: -0.008-0.006; p = 0.785) and BCSS (n = 15,203; RD = 0.001; CI-95%: -0.002-0.005; p = 0.463). PBI also did not result in a significant decrease of NBCD (n = 15,203; RD = -0.003; CI-95%: -0.010-0.003; p = 0.349). A subgroup analysis by radiation technique also did not point to any detectable differences. CONCLUSION: In contrast to a previous assessment of mortality, we could not find a detrimental effect of WBI on OS or NBCD. A longer follow-up might be necessary to fully assess the long-term mortality effects of PBI compared to WBI.

Recent advances in radiotherapy of breast cancer.

Radiation therapy is an integral part of the multidisciplinary management of breast cancer. Regional lymph node irradiation in younger trials seems to provide superior target coverage as well as a reduction in long-term toxicity resulting in a small benefit in the overall survival rate. For partial breast irradiation there are now two large trials available which support the role of partial breast irradiation in low risk breast cancer patients. Multiple randomized trials have established that a sequentially applied dose to the tumor bed improves local control with the cost of worse cosmetic results.

Performance evaluation and first clinical experience with the Varian RGSC module for breath detection of 15 lung cancer patients.

The University Hospital of Düsseldorf, Germany (UKD) recently installed the Respiratory Gating for Scanners module (RGSC) (Varian Medical Systems, Palo Alto, USA). The aim of this article is to report on the commissioning and clinical implementation of the RGSC system. The steps encompassed the validation of the manufacturer's specifications including functionality tests using a commercial and in-house developed breathing phantom, to establish calibration procedures, and clinical workflow analysis involving breath acquisition and patient data evaluation. In this context also the RGSC signal without motion was performed to assess the calibration procedure. Reproducibility test were conducted as well with breathing phantoms. Fifteen clinical breath curves were examined in order to assess the impact of treatment related uncertainties such as noises of the CT, patient positioning, movement of the CT table, unintended patient motion. Finally, different binning approaches were assessed and the effect on the CT reconstructions and methodic advantages were investigated. All technical specifications of the manufacturer were confirmed. A baseline drift of 1.83mm of the measured breath curve occurred during longitudinal movement of the CT table. This drift is smaller if the direction of table motion coincides precisely with the level of calibration. If the calibration is carried out on extensions for patient positioning we measured a baseline drift up to 6mm. It was found that especially for a combination of a ceiling mounted IR-camera and amplitude based 4D-CT reconstructions, precise calibration is prerequisite. The evaluations of patient breath curves and corresponding CT reconstructions revealed patient specific aspects and variations, respectively. Consequently patient selection criteria need to be established in parallel with the technical implementation and validation phase of respiratory gating.

Rho inhibition by lovastatin affects apoptosis and DSB repair of primary human lung cells in vitro and lung tissue in vivo following fractionated irradiation.

Thoracic radiotherapy causes damage of normal lung tissue, which limits the cumulative radiation dose and, hence, confines the anticancer efficacy of radiotherapy and impacts the quality of life of tumor patients. Ras-homologous (Rho) small GTPases regulate multiple stress responses and cell death. Therefore, we investigated whether pharmacological targeting of Rho signaling by the HMG-CoA-reductase inhibitor lovastatin influences ionizing radiation (IR)-induced toxicity in primary human lung fibroblasts, lung epithelial and lung microvascular endothelial cells in vitro and subchronic mouse lung tissue damage following hypo-fractionated irradiation (4x4 Gy). The statin improved the repair of radiation-induced DNA double-strand breaks (DSBs) in all cell types and, moreover, protected lung endothelial cells from IR-induced caspase-dependent apoptosis, likely involving p53-regulated mechanisms. Under the in vivo situation, treatment with lovastatin or the Rac1-specific small molecule inhibitor EHT1864 attenuated the IR-induced increase in breathing frequency and reduced the percentage of γH2AX and 53BP1-positive cells. This indicates that inhibition of Rac1 signaling lowers IR-induced residual DNA damage by promoting DNA repair. Moreover, lovastatin and EHT1864 protected lung tissue from IR-triggered apoptosis and mitigated the IR-stimulated increase in regenerative proliferation. Our data document beneficial anti-apoptotic and genoprotective effects of pharmacological targeting of Rho signaling following hypo-fractionated irradiation of lung cells in vitro and in vivo. Rac1-targeting drugs might be particular useful for supportive care in radiation oncology and, moreover, applicable to improve the anticancer efficacy of radiotherapy by widening the therapeutic window of thoracic radiation exposure.

Determination of the ion recombination correction factor for intraoperative electron beams.

The ion recombination correction factor (ks) is determined for the Advanced Markus chamber exposed to electron beams produced by a dedicated intraoperative radiation therapy (IORT) accelerator at medium dose-per-pulse values. The authors evaluate five different methods. Three of them are known as Boag's modified expressions, which are based on the two-voltage-analysis method and include the free-electron component. In the fourth method the IAEA TRS-398 protocol is applied, which uses the same two-voltage-analysis method but ignores the free-electron component, and finally the fifth approach is known as the Jaffé plot. ks values were obtained in the range of 4 mGy/pulse to 42 mGy/pulse and were compared with ks values determined by means of radiochromic films, which are independent of the dose rate. It was found that ks values that resulted from the three Boag's modified expressions and the TRS-398 protocol deviated by on average 1.5% and 1.4%, respectively, from the reference ks values based on film dosimetry. These results are within the estimated relative uncertainty of ±3%. On the other hand, the absolute deviation of each method depends on the dose-per-pulse value at which the method is investigated. In conclusion, in the medium dose-per-pulse range all Boag's modified expressions could be used for ks determination. Above a dose-per-pulse value of 35 mGy/pulse, the TRS-398 approach should be avoided. At 27 mGy/pulse and a maximum operation voltage of 300 V the ks value resulting from the Jaffé plot showed a 0.3% deviation from the reference value. More investigation on the Jaffé plot is necessary at higher dose-per-pulse values.

Macrophages prevent hemorrhagic infarct transformation in murine stroke models.

OBJECTIVE: Inflammation is increasingly viewed as a new therapeutic target in subacute stages of brain infarction. However, apart from causing secondary damage, inflammation could equally promote beneficial lesion remodeling and repair. Distinct subpopulations of monocytes/macrophages (MOs/MPs) may critically determine the outcome of lesion-associated inflammation. METHODS: We addressed the role of bone marrow-derived MOs/MPs in 2 different mouse models of ischemic stroke using a combined cell-specific depletion, chemokine receptor knockout, bone marrow chimeric, and pharmacological approach. RESULTS: Starting within 24 hours of stroke onset, immature Ly6c(hi) monocytes infiltrated into the infarct border zone and differentiated into mature Ly6c(lo) phagocytes within the lesion compartment. MO/MP infiltration was CCR2-dependent, whereas we did not obtain evidence for additional recruitment via CX3CR1. Depletion of circulating MOs/MPs or selective targeting of CCR2 in bone marrow-derived cells caused delayed clinical deterioration and hemorrhagic conversion of the infarctions. Bleeding frequently occurred around thin-walled, dilated neovessels in the infarct border zone and was accompanied by decreased expression of transforming growth factor (TGF)-ß1 and collagen-4, along with diminished activation of Smad2. Injection of TGF-ß1 into the lesion border zone greatly reduced infarct bleeding in MO/MP-depleted mice. INTERPRETATION: Bone marrow-derived MOs/MPs recruited via CCR2 and acting via TGF-ß1 are essential for maintaining integrity of the neurovascular unit following brain ischemia. Future therapies should be aimed at enhancing physiological repair functions of CCR2(+) MOs/MPs rather than blocking their hematogenous recruitment.

Proton therapy of uveal melanomas: intercomparison of MRI-based and conventional treatment planning.

BACKGROUND AND PURPOSE: Proton therapy for uveal melanoma provides high-conformal dose application to the target volume and, thus, an optimal saving of the organs at risk nearby. Treatment planning is done with the model-based treatment-planning system EYEPLAN. Tumor reconstruction is based only on a fundus composite, which often leads to an overestimation of the clinical target volume (CTV). The purpose was to exploit MRI on trial in a proton therapy-planning system by using the novel image-based treatment-planning system OCTOPUS. PATIENTS AND METHODS: Ten patients with uveal melanomas received both a high-resolution planning CT and MRI of the eye. MR examinations were made with an eye coil. EYEPLAN requires eye geometry data for modeling, and tantalum marker clips for submillimeter positioning and additional information from ultrasound and 3-D imaging. By contrast, OCTOPUS provides the full integration of 3-D imaging (e. g., CT, MRI). CTVs were delineated in each slice. For all patients, CTVs (EYEPLAN vs. OCTOPUS) were compared intraindividually. RESULTS: OCTOPUS planning led to a mean reduction of the target volume by a factor of 1.7 (T1-weighted [T1w]) and 2.2 (T2w) without compromising safety. The corresponding field size could be scaled down on average by a factor of 1.2 (T1w) and 1.4 (T2w), respectively. CONCLUSION: Compared with the conventional EYEPLAN, MRI-based treatment planning of ocular tumors with OCTOPUS could be a powerful tool for reducing the CTV and, consequently, the treatment volume and the field size. This might be translated into a better patient compliance during treatment and a decreased late toxicity.