Clinical experience of a tattoo application device.

Introduction: The use of tattoos for radiation therapy (RT) treatment is common practice. The Comfort Marker 2.0 (CQ Medical, Iowa, USA) has been designed to apply tattoos with a controlled depth injection, potentially resulting in tattoos that fade over time. The aim of this study was to investigate the clinical implementation of the Comfort Marker 2.0 tattoo device including the patient experience and clinical workflow. Methods: Patients undergoing RT treatment for breast cancer were invited to participate in this prospective pilot study. Patients completed a questionnaire after the planning session rating the level of pain experienced during tattoo application. Staff rated ease of use after each patient recording any feedback regarding the device. To evaluate tattoo fading, patients were followed up at 6 and 12 months after treatment to assess if tattoos could be visualised. Results: Between August and December 2021, 50 breast cancer patients were recruited to the study. All patients received at least 3 tattoos. The majority of patients (80%) rated their pain between not hurting or hurting a little. More than 85% of staff indicated the device was easy or very easy to use. The three most common areas staff identified for improvement were: cordless device (39.1%), pen size (20.3%) and consumable rubbish (13.0%). All tattoos remained visible at the final follow up appointment. Conclusion: Clinical implementation of the Comfort Marker tattoo device has been successful. Overall, patients found the process reasonably painless and staff found the device easy to use, providing a consistent result.

Long-Term Outcomes of TROG 13.01 SAFRON II Randomized Trial of Single- Versus Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In a randomized phase II clinical trial, the Trans Tasman Radiation Oncology Group compared single- versus multifraction stereotactic ablative body radiotherapy (SABR) in 90 patients with 133 oligometastases to the lung. The study found no differences in safety, efficacy, systemic immunogenicity, or survival between arms, with single-fraction SABR picked as the winner on the basis of cost-effectiveness. In this article, we report the final updated survival outcome analysis. The protocol mandated no concurrent or post-therapy systemic therapy until progression. Modified disease-free survival (mDFS) was defined as any progression not addressable by local therapy, or death. At a median follow-up of 5.4 years, the 3- and 5-year estimates for overall survival (OS) were 70% (95% CI, 59 to 78) and 51% (95% CI, 39 to 61). There were no significant differences between the multi- and single-fraction arms for OS (hazard ratio [HR], 1.1 [95% CI, 0.6 to 2.0]; P = .81). The 3- and 5-year estimates for disease-free survival were 24% (95% CI, 16 to 33) and 20% (95% CI, 13 to 29), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.6]; P = .92). The 3- and 5-year estimates for mDFS were 39% (95% CI, 29 to 49) and 34% (95% CI, 24 to 44), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.8]; P = .90). In this patient population, where patients receive SABR in lieu of systemic therapy, one-in-three patients are alive without disease in the long term. There were no differences in outcomes by fractionation schedule.

Case report: ISL2 is involved in malignant transformation in a patient with multiple relapsed oligodendroglioma.

The majority of oligodendrogliomas exhibit an intrinsic tendency to develop into malignant high-grade tumors. Angiogenesis is a major factor contributing to the malignant transformation of oligodendroglioma, and its molecular regulatory mechanism needs further study. We provide a case report of an oligodendroglioma patient with two recurrences whose disease progressed from WHO grade II to grade III. We showed that the expression of insulin gene enhancer protein (ISL2) and its angiogenic ability were positively correlated with the progression of oligodendroglioma. In Low-grade glioma (LGG) patients, including oligodendroglioma patients, overexpression of ISL2 was correlated with poor prognosis, and this correlation was not affected by gender or isocitrate dehydrogenase 1(IDH1) mutation status. ISL2 expression and ISL2-mediated angiogenic pathway activity are ideal biomarkers for the malignant transformation of oligodendroglioma. Anti-ISL2 therapy is also a potential treatment option for malignantly transformed oligodendroglioma.

Acute toxicity and patient-reported outcomes in anal canal cancer: results of a pilot study.

INTRODUCTION: Anal canal cancer (ACC) is uncommon. The gold standard of care is chemoradiotherapy treatment. However, this treatment is associated with considerable acute and late side effects. The aim of this pilot study was to evaluate acute toxicity and patient-reported outcomes (PRO) in these patients from planning to 3 months after treatment. METHODS: Sixteen patients were recruited to this prospective observational study from March 2015 to December 2017. All patients received volumetric modulated arc therapy (VMAT) in 30#. Toxicity data were graded by a Radiation Oncologist using the Common Terminology Criteria for Adverse Effects (CTCAE) version 4 at planning, weekly during treatment, 6-week and 3-month post-treatment. PRO data were collected using the EORTC QLQ C30 and CR29 questionnaires completed by patients at planning, mid and end treatment and 3-month post-treatment. RESULTS: The majority of toxicity and PRO items peaked in severity at the end of treatment (week 6). Skin was the only item where >50% of patients had ≥ grade 2 toxicity at any point with 75% having ≥ grade 2 at week 6. Patient-reported embarrassment significantly increased over time (P < 0.001). No meaningful relationships were found between PRO and CTCAE results. CONCLUSION: After reaching their maximum severity at the end of treatment, the majority of toxicity and PRO items approached baseline levels by 3-month post-treatment. The results of this study suggest that PROs are an important complementary tool to CTCAE and provide greater understanding of patients' perception of treatment side effects.

Erratum to "Ulinastatin alleviates traumatic brain injury by reducing endothelin-1".

[This corrects the article DOI: 10.1515/tnsci-2021-0001.].

Single-Fraction vs Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases (SAFRON II): The Trans Tasman Radiation Oncology Group 13.01 Phase 2 Randomized Clinical Trial.

IMPORTANCE: Evidence is lacking from randomized clinical trials to guide the optimal approach for stereotactic ablative body radiotherapy (SABR) in patients with pulmonary oligometastases. OBJECTIVE: To assess whether single-fraction or multifraction SABR is more effective for the treatment of patients with pulmonary oligometastases. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, unblinded, phase 2 randomized clinical trial of 90 patients across 13 centers in Australia and New Zealand enrolled patients with 1 to 3 lung oligometastases less than or equal to 5 cm from any nonhematologic malignant tumors located away from the central airways, Eastern Cooperative Oncology Group performance status 0 or 1, and all primary and extrathoracic disease controlled with local therapy. Enrollment was from January 1, 2015, to December 31, 2018, with a minimum patient follow-up of 2 years. INTERVENTIONS: Single fraction of 28 Gy (single-fraction arm) or 4 fractions of 12 Gy (multifraction arm) to each oligometastasis. MAIN OUTCOMES AND MEASURES: The main outcome was grade 3 or higher treatment-related adverse events (AEs) occurring within 1 year of SABR. Secondary outcomes were freedom from local failure, overall survival, disease-free survival, and patient-reported outcomes (MD Anderson Symptom Inventory-Lung Cancer and EuroQol 5-dimension visual analog scale). RESULTS: Ninety participants were randomized, of whom 87 were treated for 133 pulmonary oligometastases. The mean (SD) age was 66.6 [11.6] years; 58 (64%) were male. Median follow-up was 36.5 months (interquartile range, 24.8-43.9 months). The numbers of grade 3 or higher AEs related to treatment at 1 year were 2 (5%; 80% CI, 1%-13%) in the single-fraction arm and 1 (3%; 80% CI, 0%-10%) in the multifraction arm, with no significant difference observed between arms. One grade 5 AE occurred in the multifraction arm. No significant differences were found between the multifraction arm and single-fraction arm for freedom from local failure (hazard ratio [HR], 0.5; 95% CI, 0.2-1.3; P = .13), overall survival (HR, 1.5; 95% CI, 0.6-3.7; P = .44), or disease-free survival (HR, 1.0; 95% CI, 0.6-1.6; P > .99). There were no significant differences observed in patient-reported outcomes. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, neither arm demonstrated evidence of superior safety, efficacy, or symptom burden; however, single-fraction SABR is more efficient to deliver. Therefore, single-fraction SABR, as assessed by the most acceptable outcome profile from all end points, could be chosen to escalate to future studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01965223.

Ulinastatin alleviates traumatic brain injury by reducing endothelin-1.

BACKGROUND: Brain edema is one of the major causes of fatality and disability associated with injury and neurosurgical procedures. The goal of this study was to evaluate the effect of ulinastatin (UTI), a protease inhibitor, on astrocytes in a rat model of traumatic brain injury (TBI). METHODOLOGY: A rat model of TBI was established. Animals were randomly divided into 2 groups - one group was treated with normal saline and the second group was treated with UTI (50,000 U/kg). The brain water content and permeability of the blood-brain barrier were assessed in the two groups along with a sham group (no TBI). Expression of the glial fibrillary acidic protein, endthelin-1 (ET-1), vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) were measured by immunohistochemistry and western blot. Effect of UTI on ERK and PI3K/AKT signaling pathways was measured by western blot. RESULTS: UTI significantly decreased the brain water content and extravasation of the Evans blue dye. This attenuation was associated with decreased activation of the astrocytes and ET-1. UTI treatment decreased ERK and Akt activation and inhibited the expression of pro-inflammatory VEGF and MMP-9. CONCLUSION: UTI can alleviate brain edema resulting from TBI by inhibiting astrocyte activation and ET-1 production.

Neoadjuvant chemotherapy or chemoradiotherapy for adenocarcinoma of the esophagus.

BACKGROUND: The optimal treatment strategy for patients with esophageal adenocarcinoma (EAC) remains undetermined. This study compared outcomes in patients undergoing neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) for EAC. METHODS: Patients who underwent nCT or nCRT followed by surgery for EAC were identified from a prospective database (2000-2017) and included. After propensity score matching, the impact of the treatments on postoperative complications, in-hospital mortality, pathological outcomes, and survival rates were compared. RESULTS: Of the 396 eligible patients, 262 patients were analysed following matching with 131 patients in both groups. There were no significant differences between the nCT and nCRT groups for overall complications (59% vs 57%, P = 0.802) or in-hospital mortality (2% vs 0%, P = 0.156). Patients who had nCRT had more R0 resections (93% vs 83%, P = 0.013), and higher pathological complete response rates (15% vs 5%, P < 0.001). No differences in 5-year overall survival rates (nCT vs nCRT; 44% vs 33%, P = 0.645) were found. CONCLUSION: In this study no differences between nCT and nCRT were seen in postoperative complications and in-hospital mortality in patients treated for EAC. Inspite of improved complete resection and pathological response there was no difference in the overall survival between the treatment modalities.

Spared Nerve Injury Increases the Expression of Microglia M1 Markers in the Prefrontal Cortex of Rats and Provokes Depression-Like Behaviors.

Pain and depression are frequently co-existent in clinical practice, yet the underlying mechanisms remain largely to be determined. Microglia activation and subsequent pro-inflammatory responses play a crucial role in the development of neuropathic pain and depression. The process of microglia polarization to the pro-inflammatory M1 or anti-inflammatory M2 phenotypes often occurs during neuroinflammation. However, it remains unclear whether M1/M2 microglia polarization is involved in the neuropathic pain induced by spared nerve injury (SNI). In the present study, the mechanical withdrawal threshold, forced swim test, sucrose preference test, and open field test were performed. The levels of microglia markers including ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation 11b (CD11b), M1 markers including CD68, inducible nitric oxide synthase (iNOS), interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-a (TNF-α), 8-hydroxy-2-deoxyguanosine (8-OH-dG), and M2 markers including CD206, arginase 1 (Arg1), IL-4 in the prefrontal cortex were determined on day 14 after SNI. The results showed that SNI produced mechanical allodynia and depressive-like behaviors, and also increased the expressions of microglia markers (Iba1, CD11b) and M1 markers (CD68, iNOS, IL-1ß, TNF-α, and 8-OH-dG) in the prefrontal cortex. Notably, minocycline administration reversed these abnormalities. In addition, minocycline also promoted M2 microglia polarization as evidenced by up-regulation of CD206 and Arg1. In conclusion, data from our study suggest that SNI can lead to depression-like behaviors, while M1 polarization and consequent overproduction of pro-inflammatory cytokines plays a key role in the pathogenesis of neuropathic pain. The data furthermore indicate that modulation of inflammation by inhibition of M1 polarization could be a strategy for treatment of neuropathic pain, and might prevent the induction of neuropathic pain-induced depression symptoms.

Increased Renal Clearance of Rocuronium Compensates for Chronic Loss of Bile Excretion, via upregulation of Oatp2.

Requirement for rocuronium upon surgery changes only minimally in patients with end-stage liver diseases. Our study consisted of both human and rat studies to explore the reason. The reduction rate of rocuronium infusion required to maintain neuromuscular blockade during the anhepatic phase (relative to paleohepatic phase) was examined in 16 children with congenital biliary atresia receiving orthotopic liver transplantation. Pharmacodynamics and pharmacokinetics of rocuronium were studied based on BDL rats. The role of increased Oatp2 and decrease Oatp1 expressions in renal compensation were explored. The reduction of rocuronium requirements significantly decreased in obstructively jaundiced children (24 ± 9 vs. 39 ± 11%). TOF50 in BDL rats was increased by functional removal of the kidneys but not the liver, and the percentage of rocuronium excretion through urine increased (20.3 ± 6.9 vs. 8.6 ± 1.8%), while that decreased through bile in 28d-BDL compared with control group. However, this enhanced renal secretion for rocuronium was eliminated by Oatp2 knock-down, rather than Oatp1 overexpression (28-d BDL vs. Oatp1-ShRNA or Oatp2-ShRNA, 20.3 ± 6.9 vs. 17.0 ± 6.6 or 9.3 ± 3.2%). Upon chronic/sub-chronic loss of bile excretion, rocuronium clearance via the kidneys is enhanced, by Oatp2 up-regulation.

A Comparison of Non-coplanar Three-dimensional Conformal Radiation Therapy, Intensity Modulated Radiation Therapy, and Volumetric Modulated Radiation Therapy for the Delivery of Stereotactic Ablative Radiation Therapy to Peripheral Lung Cancer.

AIM: The objective of the study was to compare three noncoplanar delivery techniques (three-dimensional conformal radiation therapy [3DCRT], intensity-modulated radiation therapy [IMRT], and volumetric-modulated arc therapy [VMAT]) for the delivery of lung stereotactic ablative radiation therapy to peripheral lung tumours. METHODS AND MATERIALS: The plans were compared by assessing the planning target volume coverage, doses to organs at risk, high and intermediate dose constraints (D2cm and R50%) and delivery times using analysis of variance for repeated measurements or Friedman's test when appropriate. RESULTS: Mean PTV54 Gy coverage was found to be 95.6%, 95.7%, and 95.6% for the 3DCRT, IMRT, and VMAT techniques, respectively. No deviations to the intermediate dose constraints were found in 65%, 65%, and 85% of the patients for the 3DCRT, IMRT, and VMAT plans, respectively. Mean treatment times (excluding setup and imaging) were 20.0 minutes (±1.67), 25.2 minutes (±2.15), and 11.7 (±2.0) minutes respectively for 3DCRT, IMRT, and VMAT. CONCLUSION: A noncoplanar VMAT technique was found to provide superior intermediate dose sparing with comparable prescription dose coverage when compared with noncoplanar 3DCRT or IMRT. In addition, VMAT was found to reduce the treatment times of stereotactic ablative radiation therapy delivery for peripheral lung tumours.

Risk factors of infected pancreatic necrosis secondary to severe acute pancreatitis.

BACKGROUND: Severe acute pancreatitis (SAP) remains a clinical challenge with considerable morbidity and mortality. An early identification of infected pancreatic necrosis (IPN), a life-threatening evolution secondary to SAP, is obliged for a more preferable prognosis. Thus, the present study was conducted to identify the risk factors of IPN secondary to SAP. METHODS: The clinical data of patients with SAP were retrospectively analyzed. Univariate and multivariate logistic regression analyses were sequentially performed to assess the associations between the variables and the development of IPN secondary to SAP. A receiver operating characteristic (ROC) curve was created for each of the qualified independent risk factors. RESULTS: Of the 115 eligible patients, 39 (33.9%) progressed to IPN, and the overall in-hospital mortality was 11.3% (13/115). The early enteral nutrition (EEN) (P=0.0092, OR=0.264), maximum intra-abdominal pressure (IAP) (P=0.0398, OR=1.131) and maximum D-dimer level (P=0.0001, OR=1.006) in the first three consecutive days were independent risk factors associated with IPN secondary to SAP. The area under ROC curve (AUC) was 0.774 for the maximum D-dimer level in the first three consecutive days and the sensitivity was 90% and the specificity was 58% at a cut-off value of 933.5 µg/L; the AUC was 0.831 for the maximum IAP in the first three consecutive days and the sensitivity was 95% and specificity was 58% at a cut-off value of 13.5 mmHg. CONCLUSIONS: The present study suggested that the maximum D-dimer level and/or maximum IAP in the first three consecutive days after admission were risk factors of IPN secondary to SAP; an EEN might be helpful to prevent the progression of IPN secondary to SAP.

Prophylactic cranial irradiation in small cell lung cancer: A single institution experience.

AIM: To compare patient demographics, prophylactic cranial irradiation (PCI) utilization and overall survival (OS) of patients with small cell lung cancer (SCLC) referred to a large tertiary center with those reported in large clinical trials. PATIENTS AND METHODS: A retrospective review was conducted of consecutive patients with limited stage (LS) and extensive stage (ES) SCLC diagnosed at the Princess Alexandra Hospital between January 2008 and December 2013. RESULTS: Two hundred and three patients with a mean age of 65.4 (±10.7) years were followed for a median duration of 7.6 months (range 0.5-76.5). At diagnosis, 129 (64%) patients had ES-SCLC, including 39 (19.2%) with cerebral metastases. Median OS in LS-SCLC patients receiving PCI was 18.8 months (0.9-69.4), compared with 8.2 months (0.1-34.4) in patients who did not receive PCI (P < 0.001). Median OS in the ES-SCLC cohort receiving PCI was 13.6 months (5.2-37.5) compared to 5.6 months (0.1-73.6) in patients who did not receive the therapy (P < 0.001). There was a significant improvement in intracranial disease-free survival of 7.1 months in patients with ES-SCLC who received PCI. Forty-two LS-SCLC patients (57%) did not receive PCI due to patient suitability. CONCLUSIONS: In our SCLC cohort, median OS following PCI in LS-SCLC and ES-SCLC is comparable to published data. PCI use at our institution was lower than utilization rates in large meta-analyses, predominately due to poor chemotherapy tolerance and patient suitability. This may be more representative of patients treated in clinical practice rather than those recruited into large phase III trials.

A comparison of three different VMAT techniques for the delivery of lung stereotactic ablative radiation therapy.

INTRODUCTION: The purpose of this study was to investigate coplanar and non-coplanar volumetric modulated arc therapy (VMAT) delivery techniques for stereotactic ablative radiation therapy (SABR) to the lung. METHODS: For ten patients who had already completed a course of radiation therapy for early stage lung cancer, three new SABR treatment plans were created using (1) a coplanar full arc (FA) technique, (2) a coplanar partial arc technique (PA) and (3) a non-coplanar technique utilising three partial arcs (NCA). These plans were evaluated using planning target volume (PTV) coverage, dose to organs at risk, and high and intermediate dose constraints as incorporated by radiation therapy oncology group (RTOG) 1021. RESULTS: When the FA and PA techniques were compared to the NCA technique, on average the PTV coverage (V 54Gy) was similar (P = 0.15); FA (95.1%), PA (95.11%) and NCA (95.71%). The NCA resulted in a better conformity index (CI) of the prescription dose (0.89) when compared to the FA technique (0.88, P = 0.23) and the PA technique (0.83, P = 0.06). The NCA technique improved the intermediate dose constraints with a statistically significant difference for the D 2cm and R 50% when compared with the FA (P < 0.03 and <0.0001) and PA (P < 0.04 and <0.0001) techniques. The NCA technique reduced the maximum spinal cord dose by 2.72 and 4.2 Gy when compared to the PA and FA techniques respectively. Mean lung doses were 4.09, 4.31 and 3.98 Gy for the FA, PA and NCA techniques respectively. CONCLUSION: The NCA VMAT technique provided the highest compliance to RTOG 1021 when compared to coplanar techniques for lung SABR. However, single FA coplanar VMAT was suitable for 70% of patients when minor deviations to both the intermediate dose and organ at risk (OAR) constraints were accepted.

The effect of beam arrangements and the impact of non-coplanar beams on the treatment planning of stereotactic ablative radiation therapy for early stage lung cancer.

INTRODUCTION: The aim of this study was to compare various coplanar and non-coplanar 3-dimensional conformal radiation therapy (3DCRT) beam arrangements for the delivery of stereotactic ablative radiation therapy (SABR) to patients with early stage lung cancer, based on the dosimetric criteria from the Radiation Therapy Oncology Group (RTOG) 1021 protocol. METHODS: Ten medically inoperable lung cancer patients eligible for SABR were re-planned using three different coplanar and three different non-coplanar beam arrangements. The plans were compared by assessing planning target volume (PTV) coverage, doses to normal tissues, the high-dose conformity (conformity index) and intermediate dose spillage as defined by the D2cm, (the dose at any point 2 cm away from the PTV), and the R50% (the ratio of the volume of half the prescription dose to the volume of the PTV). RESULTS: Sixty plans in total were assessed. Mean PTV coverage with the prescription isodose was similar between coplanar (95.14%) and non-coplanar (95.26%) techniques (P = 0.47). There was significant difference between all coplanar and all non-coplanar fields for the R50% (P < 0.0001) but none for the D2cm (P = 0.19). The seven and nine field beam arrangements with two non-coplanar fields had less unacceptable protocol deviations (10 and 7) than the seven and nine field plans with only coplanar fields (13 and 8). The 13 field coplanar fields did not improve protocol compliance with eight unacceptable deviations. The 10 field non-coplanar beam arrangement achieved best compliance with the RTOG 1021 dose criteria with only one unacceptable deviation (maximum rib dose). CONCLUSION: A 3DCRT planning technique using 10 fields with ≥6 non-coplanar beams best satisfied high and intermediate dose constraints stipulated in the RTOG 1021 trial. Further investigations are required to determine if minor protocol deviations should be balanced against efficiency with the extended treatment times required to deliver non-coplanar fields and if treatment times can be improved using novel intensity modulated techniques.

A randomised phase II trial of Stereotactic Ablative Fractionated radiotherapy versus Radiosurgery for Oligometastatic Neoplasia to the lung (TROG 13.01 SAFRON II).

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is emerging as a non-invasive method for precision irradiation of lung tumours. However, the ideal dose/fractionation schedule is not yet known. The primary purpose of this study is to assess safety and efficacy profile of single and multi-fraction SABR in the context of pulmonary oligometastases. METHODS/DESIGN: The TROG 13.01/ALTG 13.001 clinical trial is a multicentre unblinded randomised phase II study. Eligible patients have up to three metastases to the lung from any non-haematological malignancy, each < 5 cm in size, non-central targets, and have all primary and extrathoracic disease controlled with local therapies. Patients are randomised 1:1 to a single fraction of 28Gy versus 48Gy in four fractions of SABR. The primary objective is to assess the safety of each treatment arm, with secondary objectives including assessment of quality of life, local efficacy, resource use and costs, overall and disease free survival and time to distant failure. Outcomes will be stratified by number of metastases and origin of the primary disease (colorectal versus non-colorectal primary). Planned substudies include an assessment of the impact of online e-Learning platforms for lung SABR and assessment of the effect of SABR fractionation on the immune responses. A total of 84 patients are required to complete the study. DISCUSSION: Fractionation schedules have not yet been investigated in a randomised fashion in the setting of oligometastatic disease. Assuming the likelihood of similar clinical efficacy in both arms, the present study design allows for exploration of the hypothesis that cost implications of managing potentially increased toxicities from single fraction SABR will be outweighed by costs associated with delivering multiple-fraction SABR. TRIALS REGISTRATION: ACTRN12613001157763 , registered 17th October 2013.

Protective effect of stellate ganglion block on delayed cerebral vasospasm in an experimental rat model of subarachnoid hemorrhage.

Stellate ganglion block (SGB) is a blockade of sympathetic ganglia innervating the head and neck, and is known to function through vasodilation of the target region. However, the effectiveness of SGB in relieving cerebral vasospasm (CVS) through dilation of intracerebral vessels has not been evaluated. The aim of the present study is to investigate the therapeutic effects of SGB in a rat model of subarachnoid hemorrhage (SAH) complicated by delayed CVS, and explore the underlying mechanisms. The SAH model was established by double injection of autologous arterial blood into the cisterna magna. We simulated SGB by transection of the cervical sympathetic trunk (TCST), and measured changes in the diameter, perimeter and cross-sectional area of the basilar artery (BA) and middle cerebral artery (MCA) to evaluate its vasodilatory effect. To investigate the underlying mechanisms, we determined the expression level of vasoactive molecules endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP) in the plasma, and apoptotic modulators Bcl-2 and Bax in the hippocampus. We found a significant increase in the diameter, perimeter and cross-sectional area of the BA and right MCA in SAH rats subjected to TCST. Application of SGB significantly reduced the expression of ET-1 while increasing that of CGRP in SAH rats. We also found a significant increase in the expression of Bcl-2 and decrease in the expression of Bax in the hippocampus of SAH rats subjected to TCST, when compared to untreated SAH rats. The mechanism of action of SGB is likely mediated through alterations in the ratio of ET-1 and CGRP, and Bax and Bcl-2. These results suggest that SGB can alleviate the severity of delayed CVS by inducing dilation of intracerebral blood vessels, and promoting anti-apoptotic signaling. Our findings provide evidence supporting the use of SGB as an effective and well-tolerated approach to the treatment of CVS in various clinical settings.

Resveratrol pretreatment attenuates the isoflurane-induced cognitive impairment through its anti-inflammation and -apoptosis actions in aged mice.

Although the underlying mechanisms of isoflurane-induced cognitive impairments remain largely to be determined, neuronal inflammation and apoptosis are thought to be major contributors. Resveratrol is a naturally available herbal compound for the treatment of inflammatory and neurodegenerative diseases. We therefore aimed to investigate the effects of resveratrol on the isoflurane-induced cognitive impairments and the associated hippocampal inflammation responses and neuronal apoptosis in the aged mice. Fifteen-month-old male C57BL/6 mice received 2 h of 1.5 % isoflurane or oxygen exposure 24 h after the intraperitoneal injection of resveratrol or saline daily for 7 consecutive days. Here, we showed that the isoflurane anesthesia decreased the freezing time to context significantly at 48 h after the isoflurane exposure in the fear conditioning test. The hippocampal levels of IL-1ß, TNF-α, NLRP3, cleaved caspase-3, and Bax increased significantly while the hippocampal levels of IkBα and Bcl-2 decreased significantly at 6 and/or 48 h after the isoflurane anesthesia. All these effects induced by isoflurane were attenuated by resveratrol pretreatment. However, the isoflurane anesthesia had no significant effect on the hippocampal Sirt1. In conclusion, our results suggest that resveratrol attenuates the hippocampus-dependent cognitive impairment induced by isoflurane anesthesia through its anti-inflammation and anti-apoptosis effects in aged mice.

[Disruption of the microfilament cytoskeleton induced by simulated microgravity affects NO/NOS system of osteoblasts].

OBJECTIVE: To study the effect of microfilament cytoskeleton changes induced by simulated microgravity on the NO/NOS system of osteoblasts, and explore the mechanism of weightlessness leading to osteoporosis. METHODS: Mouse osteoblast-like cell line MC3T3-E1 were divided into simulated microgravity (by rotating clinostat) group, 0.5 microg/ml cytochalasins B group, simulated microgravity+cytochalasins B group, and normal gravity group. After cell culture for 48 h with corresponding treatments, immunofluorescence staining of the cells by FITC-phallacidin was performed to observe the changes of microfilament under laser confocal microscope. NOS activity of the cells was tested with NOS detection kit, and the NO concentration in the cell supernatant was measured with nitrate reductase method. RESULTS: Depolymerization of the microfilament cytoskeleton with irregular arrangement and reduced tension fibers occurred in the cells except for those in the normal gravity group, which was especially obvious in the microgravity+cytochalasins B group. Compared with the normal gravity group, the cells in the other groups showed increased iNOS activity and NO concentration but decreased eNOS activity, especially obvious in simulated microgravity+ cytochalasins B group. CONCLUSION: Disruption of the microfilament cytoskeleton induced by simulated microgravity can regulate the NO/NOS system to influence the signal transduction of the osteoblasts.