Long-term control of haemorrhagic brain metastases from atrial myxoma after radiotherapy.

BACKGROUND: Cardiac myxoma is a rare, benign tumour that commonly originates in the left atrium and may lead to embolic events. Parenchymal brain metastases represent a rare neurological manifestation. While surgical intervention is commonly used, there is limited information on long-term outcomes after radiotherapy treatment. This report describes a case of successful treatment of haemorrhagic brain metastases with radiotherapy and offers a literature review of long-term results after radiotherapy treatment. CASE REPORT: A 49-year-old woman presented with multiple haemorrhagic brain lesions and a cardiac mass. Surgical removal of the cardiac mass and the symptomatic brain lesion confirmed metastatic cardiac myxoma. Post-surgery, she experienced fatigued and neurocognitive impairment and was closely monitored. However, the metastases progressed. She subsequently received whole-brain radiotherapy, resulting in complete response. Seven years later, she remains in remission, although with enduring neurocognitive impairment. CONCLUSIONS: Whole-brain radiotherapy can provide long-term control of haemorrhagic brain metastases arising from cardiac myxoma. Radiotherapy dose and treatment volume need careful consideration to reduce toxicity.

Activation of SOD-3 is involved in the antioxidant effect of a new class of ß-aryl-chalcogenium azide compounds in Caenorhabditis elegans.

Organic selenium, tellurium and sulfur compounds have been studied due to their pharmacological properties. For instance, the ß-aryl-chalcogenium azide compounds have demonstrated antitumoral action in vitro. However, yet no pharmacological actions of this class of compounds were determined in vivo. Caenorhabditis elegans is a nematode that presents innumerable advantages in relation to mammalian models, such as having a small and transparent body, which allows the visualization of its internal anatomy, besides short life and low cost. Based on that, the aim of this work was to investigate the pharmacological and toxicological properties of ß-aryl-chalcogenium azide compounds in C. elegans. As well, to evaluate the capacity of organochalcogenium compounds to repair oxidative damage induced by hydrogen peroxide and the possible mechanism of action of these compounds using CF1553 transgenic strain with superoxide dismutase (SOD-3) tagged with GFP. Our results showed that ß-aryl-chalcogenium azide have low toxicity in wild-type worms and the pre-treatment protected against the damage induced by hydrogen peroxide at higher tested concentration. Associated with this, we observed that this protection is due in part to the increased expression of the antioxidant enzyme SOD-3. In conclusion, ß-aryl-chalcogenium azide compounds caused low toxicity and induced stress-resistance by modulating SOD-3 expression in C. elegans.

Effect of Single-Fraction vs Multifraction Radiotherapy on Ambulatory Status Among Patients With Spinal Canal Compression From Metastatic Cancer: The SCORAD Randomized Clinical Trial.

Importance: Malignant spinal canal compression, a major complication of metastatic cancer, is managed with radiotherapy to maintain mobility and relieve pain, although there is no standard radiotherapy regimen. Objective: To evaluate whether single-fraction radiotherapy is noninferior to 5 fractions of radiotherapy. Design, Setting, and Participants: Multicenter noninferiority randomized clinical trial conducted in 42 UK and 5 Australian radiotherapy centers. Eligible patients (n = 686) had metastatic cancer with spinal cord or cauda equina compression, life expectancy greater than 8 weeks, and no previous radiotherapy to the same area. Patients were recruited between February 2008 and April 2016, with final follow-up in September 2017. Interventions: Patients were randomized to receive external beam single-fraction 8-Gy radiotherapy (n = 345) or 20 Gy of radiotherapy in 5 fractions over 5 consecutive days (n = 341). Main Outcomes and Measures: The primary end point was ambulatory status at week 8, based on a 4-point scale and classified as grade 1 (ambulatory without the use of aids and grade 5 of 5 muscle power) or grade 2 (ambulatory using aids or grade 4 of 5 muscle power). The noninferiority margin for the difference in ambulatory status was -11%. Secondary end points included ambulatory status at weeks 1, 4, and 12 and overall survival. Results: Among 686 randomized patients (median [interquartile range] age, 70 [64-77] years; 503 (73%) men; 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer), 342 (49.8%) were analyzed for the primary end point (255 patients died before the 8-week assessment). Ambulatory status grade 1 or 2 at week 8 was achieved by 115 of 166 (69.3%) patients in the single-fraction group vs 128 of 176 (72.7%) in the multifraction group (difference, -3.5% [1-sided 95% CI, -11.5% to ∞]; P value for noninferiority = .06). The difference in ambulatory status grade 1 or 2 in the single-fraction vs multifraction group was -0.4% (63.9% vs 64.3%; [1-sided 95% CI, -6.9 to ∞]; P value for noninferiority = .004) at week 1, -0.7% (66.8% vs 67.6%; [1-sided 95% CI, -8.1 to ∞]; P value for noninferiority = .01) at week 4, and 4.1% (71.8% vs 67.7%; [1-sided 95% CI, -4.6 to ∞]; P value for noninferiority = .002) at week 12. Overall survival rates at 12 weeks were 50% in the single-fraction group vs 55% in the multifraction group (stratified hazard ratio, 1.02 [95% CI, 0.74-1.41]). Of the 11 other secondary end points that were analyzed, the between-group differences were not statistically significant or did not meet noninferiority criterion. Conclusions and Relevance: Among patients with malignant metastatic solid tumors and spinal canal compression, a single radiotherapy dose, compared with a multifraction dose delivered over 5 days, did not meet the criterion for noninferiority for the primary outcome (ambulatory at 8 weeks). However, the extent to which the lower bound of the CI overlapped with the noninferiority margin should be considered when interpreting the clinical importance of this finding. Trial Registration: ISRCTN Identifiers: ISRCTN97555949 and ISRCTN97108008.

Productivity of CNPq Researchers from Different Fields in Biomedical Sciences: The Need for Objective Bibliometric Parameters-A Report from Brazil.

In Brazil, the CNPq (National Council for Scientific and Technological Development) provides grants, funds and fellowships to productive scientists to support their investigations. They are ranked and categorized into four hierarchical levels ranging from PQ 1A (the highest) to PQ 1D (the lowest). Few studies, however, report and analyse scientific productivity in different sub-fields of Biomedical Sciences (BS), e.g., Biochemistry, Pharmacology, Biophysics and Physiology. In fact, systematic comparisons of productivity among the PQ 1 categories within the above sub-fields are lacking in the literature. Here, the scientific productivity of 323 investigators receiving PQ 1 fellowships (A to D levels) in these sub-fields of BS was investigated. The Scopus database was used to compile the total number of articles, citations, h-index values and authorship positions (first-, co- or last-listed author) in the most cited papers by researchers granted CNPq fellowships. We found that researchers from Pharmacology had the best performance for all of the parameters analysed, followed by those in Biochemistry. There was great variability in scientific productivity within the PQ 1A level in all of the sub-fields of BS, but not within the other levels (1B, 1C and 1D). Analysis of the most cited papers of PQ 1(A-D) researchers in Pharmacology revealed that the citations of researchers in the 1C and 1D levels were associated with publications with their senior supervisors, whereas those in the 1B level were less connected with their supervisors in comparison to those in 1A. Taken together, these findings suggest that the scientific performance of PQ 1A researchers in BS is not homogenous. In our opinion, parameters such as the most cited papers without the involvement of Ph.D. and/or post-doctoral supervisors should be used to make decisions regarding any given researcher's fellowship award level.

Treatment with pentylenetetrazole (PTZ) and 4-aminopyridine (4-AP) differently affects survival, locomotor activity, and biochemical markers in Drosophila melanogaster.

PTZ is a convulsive agent that acts via selective blockage of GABAA receptor channels, whereas 4-AP leads to a convulsive episode via blockage of K+ channels. However, the mechanism(s) by which pentylenetetrazole (PTZ) and 4-aminopyridine (4-AP) cause toxicity to Drosophila melanogaster needs to be properly explored, once it will help in establishing an alternative model for development of proper therapeutic strategies and also to counteract the changes associated with exposure to both epileptic drugs. For the purpose, we investigated the effects of exposure (48 h) to PTZ (60 mM) and/or 4-AP (20 mM) on survival, locomotor performance, and biochemical markers in the body and/or head of flies. 4-AP-fed flies presented a higher incidence of mortality and a worse performance in the open field test as compared to non-treated flies. 4-AP also caused a significant increase in the reactive species (RS) and protein carbonyl (PC) content in the body and head. Also a significant increase in catalase and acetylcholinesterase (AChE) activities was observed in the body. In the same vein, PTZ exposure resulted in a significant increase in RS, thiobarbituric acid reactive substances (TBARS), PC content, and catalase activity in the body. PTZ exposure also caused a significant increase in AChE activity both in body and head. It is important to note that PTZ-treated flies also down-regulated the NRF2 expression. Moreover, both 4AP- and PTZ-fed flies presented a significant decrease in MTT reduction, down-regulation, and inhibition of SOD in body. However, SOD was significantly more active in the head of both 4-AP and PTZ-treated flies. Our findings provide evidence regarding the toxicological potential of both PTZ and/or 4-AP to flies. This model will help in decoding the underlying toxicological mechanisms of the stated drugs. It will also help to properly investigate the therapeutic strategies and to counteract the drastic changes associated with both epileptogenic drugs.

Minimal clinically important differences in the EORTC QLQ-C30 and brief pain inventory in patients undergoing re-irradiation for painful bone metastases.

PURPOSE: The EORTC QLQ-C30 and the Brief Pain Inventory (BPI) are validated tools for measuring quality of life (QOL) and the impact of pain in patients with advanced cancer. Interpretation of these instrument scores can be challenging and it is difficult to know what numerical changes translate to clinically significant impact in patients' lives. To address this issue, our study sought to establish the minimal clinically important differences (MCID) for these two instruments in a prospective cohort of patients with advanced cancer and painful bone metastases. METHODS: Both anchor-based and distribution-based methods were used to estimate the MCID scores from patients enrolled in a randomized phase III trial evaluating two different re-irradiation treatment schedules. For the anchor-based method, the global QOL item from the QLQ-C30 was chosen as the anchor. Spearman correlation coefficients were calculated for all items and only those items with moderate or better correlation (|r| ≥ 0.30) with the anchor were used for subsequent analysis. A 10-point difference in the global QOL score was used to classify improvement and deterioration, and the MCID scores were calculated for each of these categories. These results were compared with scores obtained by the distribution-method, which estimates the MCID purely from the statistical characteristics of the sample population. RESULTS: A total of 375 patients were included in this study with documented pain responses and completed QOL questionnaires at 2 months. 9/14 items in the QLQ-C30 and 6/10 items in the BPI were found to have moderate or better correlation with the anchor. For deterioration, statistically significant MCID scores were found in all items of the QLQ-C30 and BPI. For improvement, statistically significant MCID scores were found in 7/9 items of the QLQ-C30 and 2/6 items of the BPI. The MCID scores for deterioration were uniformly higher than the MCIDs for improvement. Using the distribution-based method, there was good agreement between the 0.5 standard deviation (SD) values and anchor-based scores for deterioration. For improvement, there was less agreement and the anchor-based scores were lower than the 0.5 SD values obtained from the distribution-based method. CONCLUSION: We present MCID scores for the QLQ-C30 and BPI instruments obtained from a large cohort of patients with advanced cancer undergoing re-irradiation for painful bone metastases. The results from this study were compared to other similar studies which showed larger MCID scores for improvement compared to deterioration. We hypothesize that disease trajectory and patient expectations are important factors in understanding the contrasting results. The results of this study can guide clinicians and researchers in the interpretation of these instruments.

Ilex paraguariensis crude extract acts on protection and reversion from damage induced by t-butyl hydroperoxide in human erythrocytes: a comparative study with isolated caffeic and/or chlorogenic acids.

BACKGROUND: Studies comparing the effects of phytochemicals under different regimens of exposure are necessary to give a better indication about their mechanism(s) of protection. Hence, in the present study, we investigated the preventive (pre-incubation), protective (co-incubation) and/or remediative (post-incubation) activity of chlorogenic acid and caffeic acids, in comparison with Ilex paraguariensis crude extract, against t-butyl hydroperoxide (t-BHP)-induced damage to human erythrocytes. RESULTS: We found that both caffeic and chlorogenic acids were able to prevent and revert the hemolysis associated with t-BHP exposure. By contrast, isolated compounds (alone or in combination) presented no effect on basal and/or t-BHP-induced non-protein thiol (NPSH) oxidation or production of thiobarbituric acid reactive substances (TBBARS). In turn, I. paraguariensis extract was effective to prevent, protect and revert the hemolysis associated with t-BHP exposure. Moreover, I. paraguariensis significantly protects and reverts t-BHP-induced NPSH oxidation and TBARS production. CONCLUSIONS: We have found that I. paraguariensis extract acts better with respect to the protection and reversion of t-BHP-associated changes, whereas isolated compounds are more active in preventing and reverting t-BHP pro-hemolytic action. Moreover, our data suggest that the pro-hemolytic activity of t-BHP may occur via mechanism(s) other(s) than lipid peroxidation and/or NPSH oxidation. © 2016 Society of Chemical Industry.

Revisiting classification of pain from bone metastases as mild, moderate, or severe based on correlation with function and quality of life.

PURPOSE: The objective of our study was to determine the optimal cut points for classification of pain scores as mild, moderate, and severe based on interference with function and quality of life (QOL). METHODS: We evaluated 822 patients who completed the Brief Pain Inventory (BPI) and/or the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 30 (QLQ-C30) prior to receiving repeat radiation therapy for previously irradiated painful bone metastases. Optimal cut points for mild, moderate, and severe pain were determined by the MANOVA that yielded the largest F ratio for the between category effect on the seven interference items of BPI and the six functional domains of QOL (physical, role, emotional, cognitive, social functioning, and global QOL) as indicated by Pillai's Trace, Wilk's λ, and Hostelling's Trace F statistics. RESULTS: For BPI and for QOL domains separately, the two largest F ratios for Wilk's λ, Pillai's Trace, and Hotelling's Trace F statistics were from the cut points 4, 8 and 6, 8. When combining both, the optimal cut points were 4, 8 with 1-4 (mild), 5-8 (moderate), and 9-10 (severe). With this classification, the mean scores of all the seven interference items in BPI and the six functional domains were all highly statistically different. Patients with severe pain survived significantly shorter than those with mild and moderate pain (p < 0.0001). CONCLUSION: Our analysis supports the classification of pain scores as follows: 1-4 as mild pain, 5-8 as moderate pain, and 9-10 as severe pain. This may facilitate conduct of future clinical trials.

Scientific Performance of Brazilian Researchers in Pharmacology with grants from CNPq: A comparative study within the Brazilian categories.

In Brazil, scientific performance of researchers is one important criteria for decision-making in grant allocation. In this context, this study aimed to evaluate and compare the profile of 82 seniors' investigators (graded as level 1A-D) which were receiving CNPq (National Council for Scientific and Technological Development) productivity grant in Pharmacology, by analyzing the pattern of citation of their papers and h-index. Total documents, citations (with and without self-citations) and h-index (with and without self-citations) were retrieved from the Scopus database. The results indicated a clear difference among researchers from the higher categories (1A and 1B) in most of the parameters analyzed. However, no noticeable differentiation was found between researchers from grant category 1C and 1D. The results presented here may inform the scientific community and the grant agencies on the profile of PQ 1(A-D) fellows of Pharmacology, and may help to define new differences within CNPq grant categories, and consequently, a better allocation of grants.

Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial.

BACKGROUND: Although repeat radiation treatment has been shown to palliate pain in patients with bone metastases from multiple primary origin sites, data for the best possible dose fractionation schedules are lacking. We aimed to assess two dose fractionation schedules in patients with painful bone metastases needing repeat radiation therapy. METHODS: We did a multicentre, non-blinded, randomised, controlled trial in nine countries worldwide. We enrolled patients 18 years or older who had radiologically confirmed, painful (ie, pain measured as ≥2 points using the Brief Pain Inventory) bone metastases, had received previous radiation therapy, and were taking a stable dose and schedule of pain-relieving drugs (if prescribed). Patients were randomly assigned (1:1) to receive either 8 Gy in a single fraction or 20 Gy in multiple fractions by a central computer-generated allocation sequence using dynamic minimisation to conceal assignment, stratified by previous radiation fraction schedule, response to initial radiation, and treatment centre. Patients, caregivers, and investigators were not masked to treatment allocation. The primary endpoint was overall pain response at 2 months, which was defined as the sum of complete and partial pain responses to treatment, assessed using both Brief Pain Inventory scores and changes in analgesic consumption. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00080912. FINDINGS: Between Jan 7, 2004, and May 24, 2012, we randomly assigned 425 patients to each treatment group. 19 (4%) patients in the 8 Gy group and 12 (3%) in the 20 Gy group were found to be ineligible after randomisation, and 140 (33%) and 132 (31%) patients, respectively, were not assessable at 2 months and were counted as missing data in the intention-to-treat analysis. In the intention-to-treat population, 118 (28%) patients allocated to 8 Gy treatment and 135 (32%) allocated to 20 Gy treatment had an overall pain response to treatment (p=0·21; response difference of 4·00% [upper limit of the 95% CI 9·2, less than the prespecified non-inferiority margin of 10%]). In the per-protocol population, 116 (45%) of 258 patients and 134 (51%) of 263 patients, respectively, had an overall pain response to treatment (p=0·17; response difference 6·00% [upper limit of the 95% CI 13·2, greater than the prespecified non-inferiority margin of 10%]). The most frequently reported acute radiation-related toxicities at 14 days were lack of appetite (201 [56%] of 358 assessable patients who received 8 Gy vs 229 [66%] of 349 assessable patients who received 20 Gy; p=0·011) and diarrhoea (81 [23%] of 357 vs 108 [31%] of 349; p=0·018). Pathological fractures occurred in 30 (7%) of 425 patients assigned to 8 Gy and 20 (5%) of 425 assigned to 20 Gy (odds ratio [OR] 1·54, 95% CI 0·85-2·75; p=0·15), and spinal cord or cauda equina compressions were reported in seven (2%) of 425 versus two (<1%) of 425, respectively (OR 3·54, 95% CI 0·73-17·15; p=0·094). INTERPRETATION: In patients with painful bone metastases requiring repeat radiation therapy, treatment with 8 Gy in a single fraction seems to be non-inferior and less toxic than 20 Gy in multiple fractions; however, as findings were not robust in a per-protocol analysis, trade-offs between efficacy and toxicity might exist. FUNDING: Canadian Cancer Society Research Institute, US National Cancer Institute, Cancer Council Australia, Royal Adelaide Hospital, Dutch Cancer Society, and Assistance Publique-Hôpitaux de Paris.

Copper and selenium: auxiliary measure to control infection by Haemonchus contortus in lambs.

The aim of this study was to evaluate the effects of selenium and copper on oxidative stress and its performance in lambs experimentally infected with Haemonchus contortus. Twenty-eight five-months old lambs were experimentally infected by the oral route with 5000 third-stage infective larvae and allocated into four groups, i.e., untreated animals, animals treated intramuscularly with sodium selenite (0.2 mg kg(-1)), animals treated subcutaneously with copper (3.5 mg kg(-1)), and animals treated with sodium selenite (IM; 0.2 mg kg(-1)) and copper (SC; 3.5 mg kg(-1)). These animals received oat hay (Avena sativa) and commercial concentrate, totaling 15% of crude protein, 30% being derived from oat hay and 70% of the concentrate. Lipid peroxidation, antioxidant enzymes, eggs per gram of feces (EPG) and body weight were assessed on the day of infection and after 20, 40, 60 and 80 days post-infection. The number of H. contortus adults was assessed at the end of the experiment. The selenium associated or not with copper reduced the effects of oxidative stress caused by infection. The groups supplemented with copper had increased body weight, and the combination of these two minerals reduced the EPG and number of H. contortus adults in lambs. The use of selenium associated with copper may help the control of infection by H. contortus.

Research culture in Australian and New Zealand radiation oncology: Fact or fantasy?

INTRODUCTION: Fostering a research culture is a key goal of the Royal Australian and New Zealand College of Radiologists, yet there has never been an organization-wide enquiry into the extent to which this is being realized. The purpose of this work was to address that deficit for the Radiation Oncology (RO) Faculty to serve as a baseline for future comparison. The hypothesis was that such a culture is closer to fact than fantasy. METHODS: With College approval, three de-identified Excel spreadsheets detailing 25 research-related sub-categories of the Faculty's Continuing Professional Development (CPD) database were interrogated for the 2019-21 triennium, accepting that research activity in 2020-21 would be COVID-19 suppressed. The numbers obligated to self-report CPD were 482, 496 and 511, respectively. Primary endpoints were the percentages of ROs claiming at least one research-related activity overall, and in each of the sub-categories individually, by year. Secondary endpoints were the "breadth" (number of sub-categories claimed/individual) and "depth" (percentages solely claiming in one of four lower-level sub-categories), by year. RESULTS: ROs claimed in 23/25 sub-categories. The percentages of ROs claiming at least one research-related activity were 71%, 44%, and 62% in 2019-21, respectively. The median number of sub-categories claimed by these ROs was 2 (range 1-10) in each year. The commonest activity was journal article co-author (25%, 16% and 27%, respectively). For 2019, the most representative year, other common activities were inhouse/local meeting presentation (17%), invited lecture at state level or above (15%), manuscript peer review and research project principal investigator (14% each). The percentages of ROs solely claiming in one lower-level activity ranged between 4.4% and 5.9% per year. CONCLUSION: A culture of research is arguably more fact than fantasy in ANZ. It is likely that Faculty curriculum requirements, research funding and other promotional initiatives have contributed substantively to this.

Stereotactic ablative body radiation therapy for isolated pulmonary metastases from pancreatic cancer after metastectomy with positive margins: a case report.

BACKGROUND: Isolated pulmonary oligometastases as the first site of dissemination after initial resection of pancreatic ductal adenocarcinoma (PC) is a rare event, and the treatment in this subgroup is challenging. Recurrence in the lung after initial primary tumour resection is associated with the most long-term survivors of patients with metastatic PC. Stereotactic ablative body radiation therapy (SABR) or metastectomy for pulmonary oligometastases from PC is becoming more common. However, patients with close or positive margins after metastectomy for isolated pulmonary metastatic PC are at high risk for recurrence. This requires a treatment capable of achieving high rates of local control and improved quality of life by delaying the need for systemic chemotherapy. In other settings, SABR has been shown to achieve these goals, allowing safe dose escalation with excellent conformity and short duration of treatment. CASE PRESENTATION: We report the case of a 48-year old Caucasian man with a history of locally advanced PC initially treated with neoadjuvant chemotherapy followed by Whipple's resection in August 2016. After a disease-free interval of 3 years, he developed three isolated pulmonary metastases which were treated with local resection. In the setting of microscopically positive resection margins (R1), adjuvant lung SABR was delivered to all three sites. His treated lung disease remained radiologically stable for up to twenty months after SABR. Treatment was well tolerated. In January 2021, he developed a malignant pre-tracheal node which was treated with conventionally fractionated radiotherapy and remained controlled for the duration of follow-up. A year later, he developed widespread metastatic disease including pleura, bone and adrenal gland, together with presumed progression in one of the original lung lesions, receiving palliative radiotherapy for right chest wall pain. He was later found to have an intracranial metastasis and died in February 2022, 5½ years after initial treatment. CONCLUSION: We present the case of a patient treated with SABR after R1 resection of 3 isolated pulmonary metastases from PC, with no treatment toxicities and durable local control. For well-selected patients in this setting, adjuvant lung SABR may be a safe and effective treatment option.

Cochlear sparing in LINAC-based radiosurgery for vestibular schwannoma: a dosimetric comparison of dynamic conformal arc, IMRT and VMAT treatment plans.

BACKGROUND: Stereotactic radiosurgery (SRS) is the preferred treatment for vestibular schwannoma (VS) in patients with preserved hearing and tumour diameter < 3 cm. Emerging evidence suggests restricting cochlear dose could preserve hearing. This retrospective replanning study aims to compare dynamic conformal arc therapy (DCAT), intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans for superiority of cochlear dose sparing without compromising tumour coverage. METHODS: Eligibility criteria included sporadic VS, serviceable hearing and availability of CT and MRI for planning. The original gross tumour volume and brainstem OAR volume were retained; the cochlea was newly contoured on the planning CT scan (bone window). Each case was replanned using the three above techniques, prescribing 12 Gy to the 80% isodose line. No dose constraint was applied to the cochlea. RESULTS: Eighteen patients were replanned. Mean tumour volume was 2.25 cc. Tumour coverage and tumour mean dose (DCAT: 14.2, IMRT: 14.6, VMAT: 14.5 Gy) were comparable. Paddick and RTOG conformity indices were better for DCAT (0.66 and 1.6) and VMAT (0.69 and 1.5) compared to IMRT (0.56 and 1.9). DCAT had superior gradient index (3.0) compared to VMAT (3.4) and IMRT (3.4). VMAT delivered the lowest mean brainstem maximum dose (8.3 Gy) and decreased the mean cochlear dose (3.4 Gy) by 2.3 and 2.1 Gy, and the mean cochlear maximum dose (3.6 Gy) by 2.4 and 2.5 Gy relative to DCAT and IMRT, respectively. CONCLUSION: LINAC-based SRS treatment using VMAT can achieve better cochlear dose sparing than DCAT or IMRT while maintaining tumour coverage.

Role of calcium and mitochondria in MeHg-mediated cytotoxicity.

Methylmercury (MeHg) mediated cytotoxicity is associated with loss of intracellular calcium (Ca²âº) homeostasis. The imbalance in Ca²âº physiology is believed to be associated with dysregulation of Ca²âº intracellular stores and/or increased permeability of the biomembranes to this ion. In this paper we summarize the contribution of glutamate dyshomeostasis in intracellular Ca²âº overload and highlight the mitochondrial dysfunctions induced by MeHg via Ca²âº overload. Mitochondrial disturbances elicited by Ca²âº may involve several molecular events (i.e., alterations in the activity of the mitochondrial electron transport chain complexes, mitochondrial proton gradient dissipation, mitochondrial permeability transition pore (MPTP) opening, thiol depletion, failure of energy metabolism, reactive oxygen species overproduction) that could culminate in cell death. Here we will focus on the role of oxidative stress in these phenomena. Additionally, possible antioxidant therapies that could be effective in the treatment of MeHg intoxication are briefly discussed.

Impact of Radiation Oncology Research Grants Awarded by the Royal Australian and New Zealand College of Radiologists Using the "Payback Framework".

PURPOSE: Radiation Oncology (RO) societies which provide research grants from membership dues or charitable donations owe it to their funders to assess value for money, yet very little has been published on the outcomes of such grants. A previous Royal Australian and New Zealand College of Radiologists (RANZCR) survey confirmed significant academic impact from their RO grants. The purpose of this work was to update and broaden the survey using, to our knowledge for the first time in the RO literature, the "Payback Framework", a model employed extensively elsewhere in health research. METHODS AND MATERIALS: Between funding years 2010 and 2020, 58 grants were awarded to 41 individuals, median 1 per individual (range 1-4), median AUD $20,000 (US $14,000) per grant (range AUD $5,000-$26,000). Five recipients of failed projects were excluded. The remaining 36 individuals, receiving 51 grants totaling US $660,000, were eligible for a voluntary on-line survey (SurveyMonkey) assessing project outcomes. Data collection and checking extended to 31 January 2022. RESULTS: The survey response rate was 100% (36/36). Objective academic outcomes attributable, at least in part, to the grants included 103 conference presentations, 59 publications, 21 prizes and 18 higher degrees. 27 consequential grants totaled US $4.5M, a 6.8-fold return on investment. Broader impacts included perceived contributions to guideline development (53% of recipients), changes in clinical decision making (72%) or radiotherapy techniques (61%), enabling of subsequent research (56%), development of novel research tools (19%) and recruitment of research assistant(s) (19%). The three most important factors reported to contribute to project success were the RO grant (83%), networking (81%) and local infrastructure (81%). The grant program was rated very positively. CONCLUSIONS: This updated RANZCR survey has confirmed continuing significant academic output from its RO research grants but has also revealed broader benefits using the Payback Framework. We would encourage other RO societies to report their grant outcomes using a similar framework.

Establishing a palliative Advanced Practice Radiation Therapist role: A viable alternative to a Rapid Access Palliative Radiation Therapy clinic in Australia.

INTRODUCTION: A recent survey found that Rapid Access Palliative Radiation Therapy (RAPRT) clinics have not been widely embraced in Australia and New Zealand for many reasons. The purpose of this narrative is to describe the transition of a Brisbane, Queensland, RAPRT clinic to an Advanced Practice Radiation Therapist (APRT) model to further improve access and delivery of palliative radiation therapy at that centre. METHODS: The weekly RAPRT clinic commenced in 2005, run by one Radiation Oncologist (RO). The role of the attending senior Radiation Therapist (RT) was mainly to facilitate rapid passage of patients from clinic to treatment. However, because individual ROs preferred to retain care of their own patients, capture of the relevant population was limited. It was therefore decided in 2012 to gradually transition to a model where the RT would work with all ROs and manage all palliative patients from referral to follow-up, under RO supervision. RESULTS: The steps to this palliative APRT pathway involved formulation of the role description, mentoring/training of the RT, overseas site visits, further post-graduate education, funding of the position, staff feedback surveys, evaluation studies and endorsement by professional bodies, leading to formal credentialing in 2017. Importantly, the APRT undertakes all steps in the pathway including field or volume delineation (with approval and sign-off by the responsible RO). The role has come to be highly valued by all disciplines. CONCLUSION: The successful establishment of a palliative APRT role in one Australian centre serves as a template for others wishing to create a similar position.

The Effect of Cochlear Dose on Hearing Preservation After Low-Dose Stereotactic Radiosurgery for Vestibular Schwannomas: A Systematic Review.

Purpose: Despite excellent tumor control after stereotactic radiosurgery (SRS) for vestibular schwannoma (VS), the hearing preservation rate remains unsatisfactorily low. Although many factors have been associated with hearing loss, the dose to cochlea has gained more interest in recent years. However, studies investigating the relation between cochlear dose and hearing outcomes have produced inconsistent results. The purpose of this work is to systematically review the literature and critically analyze the studies that investigated the correlation between cochlear dose and hearing loss. Methods and Materials: A literature search of Ovid MEDLINE, Embase, and Scopus was performed. Studies were included if the SRS dose used was 11 to 14 Gy and included adult patients with sporadic VS, initially serviceable hearing, and at least 24 months of mean or median follow-up. Results: Twenty-one cohort studies and 1 case-control study were eligible for inclusion, and none were considered to be truly prospective. There was substantial heterogeneity between studies in terms of baseline hearing status, cochlear dosimetry, definition and reporting of hearing outcome, and duration of follow-up, limiting comparison between studies and precluding formal meta-analysis. Eleven studies showed a statistically significant correlation between cochlear dose and hearing outcome, but there was considerable variation in the reported cochlear dose parameter that predicted hearing outcome and whether it was an independent predictor. The definition of hearing outcome and whether the outcome variable is continuous or dichotomous have a bearing on the reported correlation between cochlear dose and hearing outcome. Conclusions: Whether cochlear dose is a predictor of hearing preservation after SRS for VS could not be unequivocally determined. Future studies should use consistent cochlear dosimetry and hearing outcomes for reliable assessment. In the meantime, based on currently available data, a practical approach will be to aim for a mean cochlear dose <4 to 6 Gy without compromising tumor dose.

LINAC stereotactic radiosurgery for brain arteriovenous malformations: An updated single centre analysis of outcomes.

Arteriovenous malformations (AVM) of the brain are congenital, high pressure vascular malformations, which are at risk of haemorrhage. Stereotactic radiosurgery (SRS) can obliterate the nidus by delivering a precise high dose of ionising radiation in a single fraction. This paper updates long term AVM obliteration rates, time to obliteration and retreatment outcomes in LINAC delivered SRS treatment at the Royal Adelaide Hospital. A retrospective review of a prospectively maintained AVM SRS database supplemented by clinical case notes, patient correspondence and electronic medical records was performed. 89 AVMs received primary SRS treatment for which the crude obliteration rate was 61% (68% for 79 patients with adequate follow up). Higher marginal dose, smaller nidus size and lower Pollock-Flickinger (PF) score were significantly associated with AVM obliteration. The crude obliteration rates for patients with adequate follow-up and AVM diameter < 3 cm vs ≥ 3 cm were 76% vs 48%, respectively, and 93% with PF score < 1.0. Median time to obliteration was 36 months. Higher dose and lower PF score were associated with earlier obliteration. The crude obliteration rate after second SRS was 56% (9/16 patients) and no significant associations were found. These obliteration rates after primary and retreatment LINAC SRS are comparable to other studies. Marginal dose and PF score were the main predictors of obliteration overall as well as early (<36 months) obliteration.

Prognostic factors for survival and ambulatory status at 8 weeks with metastatic spinal cord compression in the SCORAD randomised trial.

BACKGROUND: Metastatic spinal cord compression (MSCC) carries a poor prognosis and management is based on the likelihood of maintaining mobility and predicted survival. PATIENTS AND METHOD: SCORAD is a randomised trial of 686 patients comparing a single dose of 8 Gy radiotherapy with 20 Gy in 5 fractions. Data was split into a training set (412, 60%) and a validation set (274, 40%). A multivariable Cox regression for overall survival (OS) and a logistic regression for ambulatory status at 8 weeks were performed in the training set using baseline factors and a backward selection regression to identify a parsimonious model with p ≤ 0.10. Receiver Operating Characteristic (ROC) analysis evaluated model prognostic performance in the validation set. Validation of the final survival model was performed in a separate registry dataset (n = 348). RESULTS: The survival Cox model identified male gender, lung, gastrointestinal, and other types of cancer, compression at C1-T12, presence of non-skeletal metastases and poor ambulatory status all significantly associated with worse OS (all p < 0.05). The ROC AUC for the selected model was 75% (95%CI: 69-81) in the SCORAD validation set and 68% (95%CI: 62-74) in the external validation registry data. The logistic model for ambulatory outcome identified primary tumour breast or prostate, ambulatory status grade 1 or 2, bladder function normal and prior chemotherapy all significantly associated with increased odds of ambulation at 8 weeks (all p < 0.05). The ROC AUC for the selected model was 72.3% (95% CI 62.6-82.0) in the validation set. CONCLUSIONS: Primary breast or prostate cancer, and good ambulatory status at presentation, are favourable prognostic factors for both survival and ambulation after treatment.