The dose response relationship for the acute gastrointestinal syndrome following total-body irradiation prevents analysis of the full recovery and damage to the gastrointestinal system, since all animals succumb to the subsequent 100% lethal hematopoietic syndrome. A partial-body irradiation model with 5% bone marrow sparing was established to investigate the prolonged effects of high-dose radiation on the gastrointestinal system, as well as the concomitant hematopoietic syndrome and other multi-organ injury including the lung. Herein, cellular and clinical parameters link acute and delayed coincident sequelae to radiation dose and time course post-exposure. Male rhesus Macaca mulatta were exposed to partial-body irradiation with 5% bone marrow (tibiae, ankles, feet) sparing using 6 MV linear accelerator photons at a dose rate of 0.80 Gy min−1 to midline tissue (thorax) doses in the exposure range of 9.0 to 12.5 Gy. Following irradiation, all animals were monitored for multiple organ-specific parameters for 180 d. Animals were administered medical management including administration of intravenous fluids, antiemetics, prophylactic antibiotics, blood transfusions, antidiarrheals, supplemental nutrition, and analgesics. The primary endpoint was survival at 15, 60, or 180 d post-exposure. Secondary endpoints included evaluation of dehydration, diarrhea, hematologic parameters, respiratory distress, histology of small and large intestine, lung radiographs, and mean survival time of decedents. Dose- and time-dependent mortality defined several organ-specific sequelae, with LD50/15 of 11.95 Gy, LD50/60 of 11.01 Gy, and LD50/180 of 9.73 Gy for respective acute gastrointestinal, combined hematopoietic and gastrointestinal, and multi-organ delayed injury to include the lung. This model allows analysis of concomitant multi-organ sequelae, thus providing a link between acute and delayed radiation effects. Specific and multi-organ medical countermeasures can be assessed for efficacy and interaction during the concomitant evolution of acute and delayed key organ-specific subsyndromes.
Several radiation dose- and time-dependent tissue sequelae develop following acute high-dose radiation exposure. One of the recognized delayed effects of such exposures is lung injury, characterized by respiratory failure as a result of pneumonitis that may subsequently develop into lung fibrosis. Since this pulmonary subsyndrome may be associated with high morbidity and mortality, comprehensive treatment following high-dose irradiation will ideally include treatments that mitigate both the acute hematologic and gastrointestinal subsyndromes as well as the delayed pulmonary syndrome. Currently, there are no drugs approved by the Food and Drug Administration to counteract the effects of acute radiation exposure. Moreover, there are no relevant large animal models of radiation-induced lung injury that permit efficacy testing of new generation medical countermeasures in combination with medical management protocols under the FDA animal rule criteria. Herein is described a nonhuman primate model of delayed lung injury resulting from whole thorax lung irradiation. Rhesus macaques were exposed to 6 MV photon radiation over a dose range of 9.0-12.0 Gy and medical management administered according to a standardized treatment protocol. The primary endpoint was all-cause mortality at 180 d. A comparative multiparameter analysis is provided, focusing on the lethal dose response relationship characterized by a lethal dose50/180 of 10.27 Gy [9.88, 10.66] and slope of 1.112 probits per linear dose. Latency, incidence, and severity of lung injury were evaluated through clinical and radiographic parameters including respiratory rate, saturation of peripheral oxygen, corticosteroid requirements, and serial computed tomography. Gross anatomical and histological analyses were performed to assess radiation-induced injury. The model defines the dose response relationship and time course of the delayed pulmonary sequelae and consequent morbidity and mortality. Therefore, it may provide an effective platform for the efficacy testing of candidate medical countermeasures against the delayed pulmonary syndrome.
The objective of this pilot study was to explore whether administration of a catalytic antioxidant, AEOL 10150 (C48H56C15MnN12), could reduce radiation-induced lung injury and improve overall survival when administered after 11.5 Gy of whole thorax lung irradiation in a non-human primate model. Thirteen animals were irradiated with a single exposure of 11.5 Gy, prescribed to midplane, and delivered with 6 MV photons at a dose rate of 0.8 Gy min. Beginning at 24 h post irradiation, the AEOL 10150 cohort (n = 7) received daily subcutaneous injections of the catalytic antioxidant at a concentration of 5 mg kg for a total of 4 wk. All animals received medical management, including dexamethasone, based on clinical signs during the planned 180-d in-life phase of the study. All decedent study animals were euthanized for failure to maintain saturation of peripheral oxygen > 88% on room air. Exposure of the whole thorax to 11.5 Gy resulted in radiation-induced lung injury in all animals. AEOL 10150, as administered in this pilot study, demonstrated potential efficacy as a mitigator against fatal radiation-induced lung injury. Treatment with the drug resulted in 28.6% survival following exposure to a radiation dose that proved to be 100% fatal in the control cohort (n = 6). Computed tomography scans demonstrated less quantitative radiographic injury (pneumonitis, fibrosis, effusions) in the AEOL 10150-treated cohort at day 60 post-exposure, and AEOL 10150-treated animals required less dexamethasone support during the in-life phase of the study. Analysis of serial plasma samples suggested that AEOL 10150 treatment led to lower relative transforming growth factor-Beta-1 levels when compared with the control animals. The results of this pilot study demonstrate that treatment with AEOL 10150 results in reduced clinical, radiographic, anatomic, and molecular evidence of radiation-induced lung injury and merits further study as a medical countermeasure against radiation-induced pulmonary injury.
IntroductionHelicobacter pylori colonization is present in half of the world’s population and can lead to numerous gastrointestinal diseases if left untreated, including peptic ulcer disease and gastric cancer. Although concurrent triple therapy remains the recommended treatment regimen for H. pylori eradication, its success rate and efficacy have been declining. Recent studies have shown that the addition of probiotics can significantly increase eradication rates by up to 50%. This meta-analysis examines the impact of probiotic supplementation on the efficacy of standard triple therapy in eradicating H. pylori.MethodsA comprehensive literature search was conducted using PubMed, Cochrane Central Registry of Controlled Trials, and Google Scholar (time of inception to 2016) to identify all published randomized control trials (RCTs) assessing the use of probiotics in addition to triple therapy for the treatment of H. pylori. Searches were conducted using the keywords “probiotics”, “triple therapy”, and “Helicobacter pylori”. RCTs comparing the use of probiotics and standard triple therapy with standard triple therapy alone for any duration in patients of any age diagnosed with H. pylori infection were included. H. pylori eradication rates (detected using urea breath test or stool antigen) were analyzed as-per-protocol (APP) and intention-to-treat (ITT).ResultsA total of 30 RCTs involving 4,302 patients APP and 4,515 patients ITT were analyzed. The addition of probiotics significantly increased eradication rates by 12.2% (relative risk [RR] =1.122; 95% confidence interval [CI], 1.091–1.153; P<0.001) APP and 14.1% (RR =1.141; 95% CI, 1.106–1.175; P<0.001) ITT. Probiotics were beneficial among children and adults, as well as Asians and non-Asians. No significant difference was observed in efficacy between the various types of probiotics. The risk of diarrhea, nausea, vomiting, and epigastric pain was also reduced.ConclusionThe addition of probiotics is associated with improved H. pylori eradication rates in both children and adults, as well as Asians and non-Asians. Lactobacillus, Bifidobacterium, Saccharomyces, and mixtures of probiotics appear beneficial in H. pylori eradication. Furthermore, the reduction in antibiotic-associated side effects such as nausea, vomiting, diarrhea, and epigastric pain improves medication tolerance and patient compliance. Given the consequences associated with chronic H. pylori infection, the addition of probiotics to the concurrent triple therapy regimen should be considered in all patients with H. pylori infection. However, further studies are required to identify the optimal probiotic species and dose.
Background/Aims: Primary chordomas, rare cancers arising from the notochord remnants, are extremely rare in the pediatric population. This study examined a large cohort of primary chordoma patients to determine factors impacting prognosis and survival. Methods: Demographic and clinical data on 1,358 primary chordoma patients (86 pediatric patients ≤19 years of age and 1,272 adult patients ≥20 years of age) were abstracted from the Surveillance, Epidemiology, and End Result (SEER) database (1973-2011). Results: Pediatric primary chordomas present most often as small tumors <4 cm in the cranium of male Caucasians. Despite the majority of primary chordomas presenting with locoregional involvement (90.4%), pediatric patients had more distant disease (14.8 vs. 9.2%, p < 0.05). Survival among pediatric patients having surgery only was significantly longer than for adults (22.5 vs. 14.3 years, p < 0.001). Overall survival was longer (17.2 vs. 12.6 years) and overall mortality was lower in pediatric patients (38.4 vs. 49.8%), but cancer-specific mortality was higher (37.2 vs. 28.6%, p < 0.005). Conclusions: Pediatric primary chordomas present most often as small tumors <4 cm in the cranium of male Caucasians. Despite having a higher rate of metastasis, they have prolonged survival compared to adults. Surgical resection significantly improves survival in pediatric primary chordoma patients, and should be considered as first-line therapy in all eligible children.
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