Acute cytomegalovirus infection modulates the intestinal microbiota and targets intestinal epithelial cells.

Primary and recurrent cytomegalovirus (CMV) infections frequently cause CMV colitis in immunocompromised as well as inflammatory bowel disease (IBD) patients. Additionally, colitis occasionally occurs upon primary CMV infection in patients who are apparently immunocompetent. In both cases, the underlying pathophysiologic mechanisms are largely elusive - in part due to the lack of adequate access to specimens. We employed the mouse cytomegalovirus (MCMV) model to assess the association between CMV and colitis. During acute primary MCMV infection of immunocompetent mice, the gut microbial composition was affected as manifested by an altered ratio of the Firmicutes to Bacteroidetes phyla. Interestingly, these microbial changes coincided with high-titer MCMV replication in the colon, crypt hyperplasia, increased colonic pro-inflammatory cytokine levels, and a transient increase in the expression of the antimicrobial protein Regenerating islet-derived protein 3 gamma (Reg3γ). Further analyses revealed that murine and human intestinal epithelial cell lines, as well as primary intestinal crypt cells and organoids represent direct targets of CMV infection causing increased cell death. Accordingly, in vivo MCMV infection disrupted the intestinal epithelial barrier and increased apoptosis of intestinal epithelial cells. In summary, our data show that CMV transiently induces colitis in immunocompetent hosts by altering the intestinal homeostasis.

Evaluation of Dose-Staged Gamma Knife Radiosurgical Treatment Method for High-Risk Brain Metastases.

OBJECTIVES: The study aim was to evaluate the utility of 2-fraction, dose-staged Gamma Knife radiosurgery (GKRS) in patients with large, high-risk brain metastases (BMs). METHODS: A total of 63 large BMs in eloquent areas in 61 patients were treated with GKRS in 2 reduced doses. Treatment planning was conducted on the 50% isodose line and included the whole tumor volume as seen on T1 contrast-enhanced and T2-weighted magnetic resonance imaging sections. The median margin and central dose were 12 Gy and 24 Gy, respectively, for both fractions. Patients were assessed using the Graded Prognostic Assessment, Recursive Partitioning Analysis, and Score Index for Radiosurgery. RESULTS: Thirty-two patients (53%) had been diagnosed with multiple BMs, and extracranial metastases were present in a majority of patients before GKRS treatment. Significant decreases in tumor volume were observed between the first and second treatment stages. At 3-month follow-up, a majority of patients presented with stable or decreased lesion volumes. The remaining patients showed intralesional hemorrhaging or increasing edema that was managed conservatively. Three patients were diagnosed with tumor progression at the last follow-up and received microsurgical treatment. The median time to radiologic progression was 7 months. The median survival time after initial BM diagnosis was 6 months. Survival times were significantly longer than 3 of 4 calculated prognostic survival estimates. CONCLUSION: The new 2-fraction, dose-staged GKRS concept seems to be a well-tolerated and effective treatment option for large BMs. This method may be indicated in elderly patients or patients with surgical contraindications with large or high-risk brain metastases.

Flattening filter free beams in SBRT and IMRT: dosimetric assessment of peripheral doses.

PURPOSE: Recently, there has been a growing interest in operating medical linear accelerators without a flattening filter. Due to reduced scatter, leaf transmission and radiation head leakage a reduction of out-of-field dose is expected for flattening filter free beams. The aim of the present study was to determine the impact of unflattened beams on peripheral dose for advanced treatment techniques with a large number of MUs. MATERIAL AND METHODS: An Elekta Precise linac was modified to provide 6 and 10 MV photon beams without a flattening filter. Basic beam data were collected and implemented into the TPS Oncentra Masterplan (Nucletron). Leakage radiation, which predominantly contributes to peripheral dose at larger distances from the field edge, was measured using a Farmer type ionisation chamber. SBRT (lung) and IMRT (prostate, head&neck) treatment plans were generated for 6 and 10 MV for both flattened and unflattened beams. All treatment plans were delivered to the relevant anatomic region of an anthropomorphic phantom which was extended by a solid water slab phantom. Dosimetric measurements were performed with TLD-700 rods, radiochromic films and a Farmer type ionisation chamber. The detectors were placed within the slab phantom and positioned along the isocentric longitudinal axis. RESULTS: Using unflattened beams results in a reduction of treatment head leakage by 52% for 6 and 65% for 10 MV. Thus, peripheral doses were in general smaller for treatment plans calculated with unflattened beams. At about 20 cm distance from the field edge the dose was on average reduced by 23 and 31% for the 6 and 10 MV SBRT plans. For the IMRT plans (10 MV) the average reduction was 16% for the prostate and 18% for the head&neck case, respectively. For all examined cases, the relative deviation between peripheral doses of flattened and unflattened beams was found to increase with increasing distance from the field. CONCLUSIONS: Removing the flattening filter lead to reduced peripheral doses for advanced treatment techniques. The relative difference between peripheral doses of flattened and unflattened beams was more pronounced when the nominal beam energy was increased. Patients may benefit by decreased exposure of normal tissue to scattered dose outside the field.