Effectiveness of direct delabelling of allergy labels in type A adverse drug reactions to penicillin: a multicentre hospitalwide prospective cohort study.

BACKGROUND: Patient-reported penicillin allergy labels (PALs) are associated with adverse patient outcomes and inappropriate antibiotic prescribing. Removal of PALs via direct oral challenge (DOC) is associated with increased penicillin utilization post removal. OBJECTIVES: To assess the impact of direct delabelling (allergy label removal via medical reconciliation alone) of type A adverse drug reaction (ADR) PALs on inpatient prescribing. METHODS: From January 2019 to December 2022 at two tertiary hospitals in Melbourne, patients aged ≥18 years with type A ADR PALs, as defined by the validated Antibiotic Allergy Assessment Tool, were offered direct delabelling or single-dose DOC. The primary endpoint was antibiotic use pre- and post-assessment (during index admission and 90 days post assessment). The secondary endpoint was the proportion of patients delabelled in the direct delabelling and DOC cohorts in the electronic medical record at 90 days post assessment. RESULTS: Allergy labels (n = 4108) were assessed for 488 participants, with 490 individual type A ADR PAL assessments included. Three hundred and thirty-seven patients were directly delabelled, 69 underwent DOC and 84 were not delabelled. There was increased use of any penicillin following direct delabelling (OR 19.19, 95% CI 2.48-148.36) and DOC (OR 56.98, 95% CI 6.82-476.19) during the index admission, higher in the DOC group compared with direct delabelling (OR 2.97, 95% CI 1.39-6.37). Relabelling at 90 days was low with no statistically significant difference between direct delabelling (5/337; 1.5%) and DOC (0/69; 0%). CONCLUSIONS: Both direct delabelling and DOC of type A ADR PALs increased penicillin usage; however, the impact was greatest with DOC. Most patients remain delabelled at 90 days.

A comparison of macular ganglion cell and retinal nerve fibre layer optical coherence tomographic parameters as predictors of visual outcomes of surgery for pituitary tumours.

PURPOSE: The prognostic value of optical coherence tomography (OCT) of the macular ganglion cell layer (mGGL) versus peripapillary retinal nerve fibre layers (pRNFL) following chiasmal decompression is unclear. This study is the largest comparison of the two parameters to date and aims to clarify how their performance as covariates compare in predictive models of long-term visual outcomes following pituitary or parasellar tumour surgical resection. METHODS: This was a prospective, two-year, longitudinal cohort study in a single centre tertiary hospital setting. Participants with MRI evidence of pituitary or parasellar tumour compression of the optic chiasm who underwent surgical decompression, were enrolled. Associations between pre-operative OCT parameters and long-term visual outcomes were assessed using multivariable generalised linear mixed models and an age matched normative database. RESULTS: Final analysis included 216 eyes of 108 participants with a mean age (standard deviation) of 51.6 (17.04) years, of whom 58 (49%) were female. The superior inner mGCL was the best predictor of long-term visual field recovery, with an area under the curve of 0.90, a sensitivity of 80%, specificity of 88%, positive predictive value of 86%, and negative predictive value of 83%. CONCLUSION: mGCL performed better in predicting long-term visual field recovery post-pituitary or parasellar surgical resection. The superior inner mGCL was the best specific measure which may provide clinical utility in pre-operative counselling. In this study we clarify previously variable comparisons of mGCL and pRNFL parameters in post-operative predictive modelling.

Circulating tumor DNA for malignant peripheral nerve sheath tumors in neurofibromatosis type 1.

PURPOSE: The leading cause of early death in patients with neurofibromatosis type 1 (NF1) is malignant peripheral nerve sheath tumor (MPNST). The principles of management include early diagnosis, surgical clearance and close monitoring for tumor recurrence. Current methods for diagnosis, detection of residual disease and monitoring tumor burden are inadequate, as clinical and radiological features are non-specific for malignancy in patients with multiple tumors and lack the sensitivity to identify early evidence of malignant transformation or tumor recurrence. Circulating tumor DNA (ctDNA) is a promising tool in cancer management and has the potential to improve the care of patients with NF1. In the following article we summarise the current understanding of the genomic landscape of MPNST, report on the previous literature of ctDNA in MPNST and outline the potential clinical applications for ctDNA in NF1 associated MPNST. Finally, we describe our prospective cohort study protocol investigating the utility of using ctDNA as an early diagnostic tool for MPNSTs in NF1 patients.

P2X7 receptor antagonism inhibits tumour growth in human high-grade gliomas.

Gliomas, the most common primary brain cancer, are highly infiltrative and extremely difficult to treat. Despite advancements, current treatment is limited, with patients surviving for a median of 14-15 months post-diagnosis. Previous research has demonstrated the upregulation of a purinergic receptor, P2X7R, in human gliomas. P2X7R is expressed on both glioma cells and microglia within the glioma microenvironment. It is hypothesized that P2X7R contributes to tumour growth and proliferation via immune-mediated mechanisms involving tumour cells and surrounding microglia. We sought to elucidate the role of P2X7R in a human glioblastoma cell line (U251) and on surgically resected human glioma samples. We treated U251 and human glioma cultures for 72 h with P2X7R antagonists, Brilliant Blue G (BBG), oxidized ATP (oATP) and AZ10606120. Cell counting via fluorescence confocal microscopy was conducted to assess tumour proliferation. We observed no significant reductions in tumour cell numbers following P2X7R antagonism with BBG (20 µM) and oATP (250 µM) in both U251 cells and human glioma samples. Interestingly, there was a significant reduction in tumour cell number in both U251 cells (p = 0.0156) and human glioma samples (p = 0.0476) treated with varying concentrations of AZ10606120. When compared with the conventional chemotherapeutic agent, temozolomide, AZ10606120 was also found to more effectively inhibit tumour proliferation in U251 cells (p < 0.0001). Our pilot results demonstrate a potential trophic role of P2X7R where its inhibition by AZ10606120, a potent antagonist, hinders glioma growth directly or through the inactivation of microglia. This sheds new light on P2X7R as a therapeutic target for human gliomas.

A Multicenter, Randomized, Controlled Phase IIb Trial of Avoidance of Hyperoxemia during Cardiopulmonary Bypass.

BACKGROUND: Cardiac surgery utilizing cardiopulmonary bypass (CPB) is one of the most common forms of major surgery. Cardiac surgery-associated multiorgan dysfunction (CSA-MOD) is well recognized and includes acute kidney injury (AKI), hepatic impairment, myocardial damage, and postoperative neurologic deficit. Pathophysiology of CSA-MOD involves numerous injurious pathways linked to the use of CPB including oxidative stress and formation of reactive iron species. During cardiac surgery with CPB, arterial return blood is oxygenated to supranormal levels. This study aimed to determine whether the avoidance of arterial hyperoxemia decreased oxidative stress and reduced the severity of the multiorgan dysfunction in patients undergoing cardiac surgery utilizing CPB. METHODS: The study was a multicenter, open-label, parallel-group, randomized controlled study of the avoidance of arterial hyperoxemia versus usual care in patients undergoing cardiac surgery involving CPB. Primary outcome was the incidence and severity of AKI. Secondary outcomes included serum biomarkers for CSA-MOD, duration of mechanical ventilation, and length of intensive care and hospital stay. RESULTS: A total of 298 patients were randomized and analyzed at two hospitals in New Zealand and Australia. Mean PaO2 was significantly different between groups during CPB. There was no difference in the development of AKI (intervention arm 72.0% vs. usual care 66.2%; difference, -5.8% [95% CI, -16.1 to 4.7%]; P = 0.28), other markers of organ damage, or intensive care unit and hospital length of stay. CONCLUSIONS: Avoiding modest hyperoxemia during CPB failed to demonstrate any difference in AKI, markers of organ damage, or length of stay.

Multidisciplinary rehabilitation after primary brain tumour treatment.

BACKGROUND: Brain tumours can cause significant disability, which may be amenable to multidisciplinary rehabilitation. However, the evidence base for this is unclear. This review is an update of a previously published review in the Cochrane Database of Systematic Reviews [2013, Issue 1, Art. No. CD009509] on 'Multidisciplinary rehabilitation after primary brain tumour treatment'. OBJECTIVES: To assess the effectiveness of multidisciplinary rehabilitation in people after primary brain tumour treatment, especially the types of approaches that are effective (settings, intensity). SEARCH METHODS: For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library up to Issue 12 of 12, 2014), MEDLINE (1950 to January week 2, 2015), EMBASE (1980 to January week 2, 2015), PEDro (1985 to January week 2 2015), and LILACS (1982 to January week 2, 2015). We checked the bibliographies of papers we identified and contacted the authors and known experts in the field to seek published and unpublished trials. SELECTION CRITERIA: Controlled clinical trials (randomised and non-randomised clinical trials) that compared multidisciplinary rehabilitation in primary brain tumour with either routinely available local services or lower levels of intervention, or studies that compared multidisciplinary rehabilitation in different settings or at different levels of intensity. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed study quality, extracted data, and performed a 'best evidence ' synthesis based on methodological quality. MAIN RESULTS: We did not identify any studies for inclusion in the previous version of this review. For this update, the literature search identified one low-quality controlled clinical trial involving 106 participants. The findings from this study suggest 'low-level' evidence to support high-intensity ambulatory (outpatient) multidisciplinary rehabilitation in reducing short- and long-term motor disability (continence, mobility and locomotion, cognition), when compared with standard outpatient care. We found improvement in some domains of disability (continence, communication) and psychosocial gains were maintained at six months follow-up. We found no evidence for improvement in overall participation (quality of life and societal relationship). No adverse events were reported as a result of multidisciplinary rehabilitation. We found no evidence for improvement in quality of life or cost-effectiveness of rehabilitation. It was also not possible to suggest best 'dose' of therapy. AUTHORS' CONCLUSIONS: Since the last version of this review, one new study has been identified for inclusion. The best evidence to date comes from this CCT, which provides low quality evidence that higher intensity ambulatory (outpatient) multidisciplinary rehabilitation reduces short- and long-term disability in people with brain tumour compared with standard outpatient care. Our conclusions are tentative at best, given gaps in current research in this area. Although the strength of evidence has increased with the identification of a new controlled clinical trial in this updated review, further research is needed into appropriate and robust study designs; outcome measurement; caregiver needs; evaluation of optimal settings; type, intensity, duration of therapy; and cost-effectiveness of multidisciplinary rehabilitation in the brain tumour population.

Invasive pneumococcal disease serotype 23B1 causing multifocal septic arthritis, myositis and retroperitoneal abscess.

We describe a case of a previously healthy unvaccinated man in his 70s who developed penicillin-susceptible bacteraemic invasive pneumococcal disease due to non-vaccine serotype 23B with the unusual manifestations of multifocal myositis, intramuscular abscesses, polyarticular septic arthritis and synovitis. Blood cultures drawn prior to antibiotic therapy and culture of iliopsoas collection were helpful in making the diagnosis. At follow-up, he had persistent hip pain attributed to avascular necrosis of the head of femur, a possible late complication of his pyomyositis.

Predictive role of cardiopulmonary bypass exposure indexed to body surface area on postoperative organ dysfunction: a retrospective cohort study.

OBJECTIVES: Long cardiopulmonary bypass times are associated with adverse postoperative outcomes and increased healthcare resource use. It is likely that this effect is pronounced in smaller patients. Previous studies have been criticized for not taking into consideration that prolonged bypass times are often due to higher complexity. The purpose of this study was to investigate the relationship between bypass index (bypass time/body surface area) and adverse postoperative events. METHODS: Single-centre, retrospective cohort study including 2413 patients undergoing cardiac surgery on cardiopulmonary bypass from June 2018 to April 2020. Length of hospital stay, as surrogate marker of postoperative morbidity, was selected as primary outcome. The strength of association between bypass index and the primary outcome was assessed with linear regression analysis. Secondary outcomes included new onset renal, pulmonary or cardiac rhythm dysfunction. The predictive value of bypass index was assessed with linear regression analysis; univariate and multiple regression were used to assess the strength of association between Bi and the secondary outcomes. RESULTS: Bypass index was predictive for length of stay at univariate (Relative Risk (RR): 1.004, P < 0.001) and at multivariable (RR: 1.003, P < 0.001) analysis. The association between bypass index and new renal (mean difference: 14.1 min/m2, P < 0.001) and cardiac rhythm dysfunction (mean difference: 12.6 min/m2) was significant. This was not true of postoperative lung dysfunction (mean difference: -1.5 min/m2, P = 0.293). CONCLUSIONS: Bypass index, calculated as total bypass time/patient body surface area, is predictive of postoperative morbidity and resource utilization after cardiac surgery on pump.

The Boston Declaration 2025: Plan and Pledges for Progress in Global Neurosurgery.

Global neurosurgery has been described as the clinical and public health practice of neurosurgery with the primary purpose of ensuring timely, safe, and affordable neurosurgical care to all who need it. Global neurosurgery activities in the form of mission trips, educational partnerships, and research collaborations have been in place for decades. Still, there have been no central organizing efforts to improve the harmonization of these endeavors until recently. The 2016 Bogotà Declaration on Global Neurosurgery was the first meeting of global neurosurgery practitioners from low- and middle-income countries (LMICs) and high-income countries (HICs) to organize a consensus statement around the global gaps in neurosurgery care and goals for its future development. Since then, interest in global neurosurgery has grown dramatically among neurosurgeons, trainees, nurses, and allied professionals. Global neurosurgery has emerged as a distinct academic subspecialty within neurosurgery. However, recent evidence demonstrates that wide gaps remain in access to safe, timely, and affordable neurosurgical care. Quite as important is the current dominance of global neurosurgery discourse by HIC actors. The Boston Declaration seeks to further define a unified vision of progress as global neurosurgery continues to grow and evolve. This ambitious initiative will review existing evidence, employ on-the-ground expert experience, and seek broad inclusivity and transparency to formulate a new set of goals for global neurosurgery and a structure that shifts the agency to LMIC actors. We propose a path to developing a new consensus statement and action plan, the 2025 Boston Declaration for Global Neurosurgery.

Plasma ctDNA enables early detection of temozolomide resistance mutations in glioma.

Background: Liquid biopsy based on circulating tumor DNA (ctDNA) is a novel tool in clinical oncology, however, its use has been limited in glioma to date, due to low levels of ctDNA. In this study, we aimed to demonstrate that sequencing techniques optimized for liquid biopsy in glioma patients can detect ctDNA in plasma with high sensitivity and with potential clinical utility. Methods: We investigated 10 glioma patients with tumor tissue available from at least 2 surgical operations, who had 49 longitudinally collected plasma samples available for analysis. Plasma samples were sequenced with CAPP-seq (AVENIO) and tissue samples with TSO500. Results: Glioma-derived ctDNA mutations were detected in 93.8% of plasma samples. 25% of all mutations detected were observed in plasma only. Mutations of the mismatch repair (MMR) genes MSH2 and MSH6 were the most frequent circulating gene alterations seen after temozolomide treatment and were frequently observed to appear in plasma prior to their appearance in tumor tissue at the time of surgery for recurrence. Conclusions: This pilot study suggests that plasma ctDNA in glioma is feasible and may provide sensitive and complementary information to tissue biopsy. Furthermore, plasma ctDNA detection of new MMR gene mutations not present in the initial tissue biopsy may provide an early indication of the development of chemotherapy resistance. Additional clinical validation in larger cohorts is needed.

Improving Clinical Registry Data Quality via Linkage With Survival Data From State-Based Population Registries.

PURPOSE: Real-world data (RWD) collected on patients treated as part of routine clinical care form the basis of cancer clinical registries. Capturing accurate death data can be challenging, with inaccurate survival data potentially compromising the integrity of registry-based research. Here, we explore the utility of data linkage (DL) to state-based registries to enhance the capture of survival outcomes. METHODS: We identified consecutive adult patients with brain tumors treated in the state of Victoria from the Brain Tumour Registry Australia: Innovation and Translation (BRAIN) database, who had no recorded date of death and no follow-up within the last 6 months. Full name and date of birth were used to match patients in the BRAIN registry with those in the Victorian Births, Deaths and Marriages (BDM) registry. Overall survival (OS) outcomes were compared pre- and post-DL. RESULTS: Of the 7,346 clinical registry patients, 5,462 (74%) had no date of death and no follow-up recorded within the last 6 months. Of the 5,462 patients, 1,588 (29%) were matched with a date of death in BDM. Factors associated with an increased number of matches were poor prognosis tumors, older age, and social disadvantage. OS was significantly overestimated pre-DL compared with post-DL for the entire cohort (pre- v post-DL: hazard ratio, 1.43; P < .001; median, 29.9 months v 16.7 months) and for most individual tumor types. This finding was present independent of the tumor prognosis. CONCLUSION: As revealed by linkage with BDM, a high proportion of patients in a brain cancer clinical registry had missing death data, contributed to by informative censoring, inflating OS calculations. DL to pertinent registries on an ongoing basis should be considered to ensure accurate reporting of survival data and interpretation of RWD outcomes.

Multidisciplinary rehabilitation after primary brain tumour treatment.

BACKGROUND: Brain tumours can cause significant disability, which may be amenable to multidisciplinary rehabilitation. However, the evidence base for this is unclear. OBJECTIVES: To assess the effectiveness of multidisciplinary rehabilitation in adults after primary brain tumour treatment, especially the types of approaches that are effective (settings, intensity) and the outcomes that are affected. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (March week 2, 2012), The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 3, 2012), MEDLINE (1966 to March week 2, 2012), EMBASE (1980 to March week 2, 2012), PEDro (1982 to March 2012) and LILACS (1982 to March week 2, 2012). We checked the bibliographies of papers identified and contacted the authors and known experts in the field to seek published and unpublished trials. SELECTION CRITERIA: Controlled clinical trials (randomised and non-randomised clinical trials) that compared multidisciplinary rehabilitation in primary brain tumour with either routinely available local services or lower levels of intervention, or studies that compared multidisciplinary rehabilitation in different settings or at different levels of intensity. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed study quality, extracted data and performed a 'best evidence' synthesis based on methodological quality. MAIN RESULTS: No randomised controlled trials (RCTs) or controlled clinical trials (CCTs) were identified. AUTHORS' CONCLUSIONS: No RCTs or CCTs were available for synthesis of 'best evidence' for multidisciplinary rehabilitation after treatment for brain tumour patients. However, this does not suggest the ineffectiveness of multidisciplinary rehabilitation but rather highlights the challenges in trial design and rigour, outcome measurement and complexities of care in this population. For completeness of literature, 12 observational studies (with high risk of bias) involving patients with brain tumours were included. These studies provided 'very low level' evidence suggesting that multidisciplinary rehabilitation (inpatient, home-based) may improve functional outcomes, and ambulatory programmes (outpatient and home-based) may improve vocation and quality of life. These conclusions are tentative at best, given gaps in current research in this area. Further research is needed into appropriate and robust study designs, outcome measurement, caregiver needs, evaluation of optimal settings, type, intensity, duration of therapy, and cost-effectiveness of multidisciplinary rehabilitation in the brain tumour population.

Orbito-cranial schwannoma-a multicentre experience.

OBJECTIVES: To describe the features, management approaches, and outcomes of orbito-cranial schwannomas. METHODS: Retrospective review of ten patients with orbito-cranial schwannomas managed in six orbital services over 22 years. Data collected included demographics, presenting features, neuroimaging characteristics, histology, management approach, complications, and outcomes. RESULTS: Mean age of the patients was 41.4 ± 19.9 years, and 6 (60%) were females. The majority presented with proptosis (90%), limited extraocular motility (80%), eyelid swelling (60%), and optic neuropathy (60%). Most lesions (80%) involved the entire anterior-posterior span of the orbit, with both intra- and extraconal involvement. All tumours involved the orbital apex, the superior orbital fissure, and extended at least to the cavernous sinus. Surgical resection was performed for all. Seven (70%) of the tumours were completely or subtotally resected combining an intracapsular approach by an orbital-neurosurgical collaboration, with no recurrence on postoperative follow-up (6-186 months). Three underwent tumour debulking. Of these, two remained stable on follow-up (6-34 months) and one showed progression of the residual tumour over 9 years (cellular schwannoma on histology) necessitating stereotactic radiotherapy (SRT) for local control. Adjuncts to the orbito-cranial resection included perioperative frozen section (n = 5), endoscopic transorbital approach (n = 2), and image-guided navigation (n = 1). Post-surgical adjuvant SRT was used in three subjects. CONCLUSIONS: These results highlight the possibility of successful surgical control in complex orbito-cranial schwannomas. A combined neurosurgical/orbital approach with consideration of an intracapsular resection is recommended. Recurrence may not occur with subtotal excision and observation may be reasonable. Adjunctive SRT for progression or residual tumour can be considered.

Chronic aphasias after left-hemisphere resective surgery.

Surgical resection of brain tumours is associated with an increased risk of aphasia. However, relatively little is known about outcomes in the chronic phase (i.e., >6 months). Using voxel-based lesion symptom mapping (VLSM) in 46 patients, we investigated whether chronic language impairments are related to the location of surgical resection, residual tumour characteristics (e.g., peri-resection treatment effects, progressive infiltration, oedema) or both. Approximately 72% of patients scored below the cut-off for aphasia. Action naming and spoken sentence comprehension deficits were associated with lesions in the left anterior temporal and inferior parietal lobes, respectively. Voxel-wise analyses revealed significant associations between ventral language pathways and action naming deficits. Reading impairments were also associated with increasing disconnection of cerebellar pathways. The results indicate chronic post-surgical aphasias reflect a combination of resected tissue and tumour infiltration of language-related white matter tracts, implicating progressive disconnection as the critical mechanism of impairment.

COVID-19 infection among patients with cancer in Australia from 2020 to 2022: a national multicentre cohort study.

Background: The global COVID-19 pandemic disproportionately affected certain populations and its management differed between countries. This national study describes characteristics and outcomes of COVID-19 in patients with cancer in Australia. Methods: We performed a multicentre cohort study of patients with cancer and COVID-19 from March 2020 to April 2022. Data were analysed to determine varying characteristics between cancer types and changes in outcomes over time. Multivariable analysis was performed to determine risk factors associated with oxygen requirement. Findings: 620 patients with cancer from 15 hospitals had confirmed COVID-19. There were 314/620 (50.6%) male patients, median age 63.5 years (IQR 50-72) and majority had solid organ tumours (392/620, 63.2%). The rate of COVID-19 vaccination (≥1 dose) was 73.4% (455/620). Time from symptom onset to diagnosis was median 1 day (IQR 0-3), patients with haematological malignancy had a longer duration of test positivity. Over the study period, there was a significant decline in COVID-19 severity. Risk factors associated with oxygen requirement included male sex (OR 2.34, 95% CI 1.30-4.20, p = 0.004), age (OR 1.03, 95% CI 1.01-1.06, p = 0.005); not receiving early outpatient therapy (OR 2.78, 95% CI 1.41-5.50, p = 0.003). Diagnosis during the omicron wave was associated with lower odds of oxygen requirement (OR 0.24, 95% CI 0.13-0.43, p < 0.0001). Interpretation: Outcomes from COVID-19 in patients with cancer in Australia over the pandemic have improved, potentially related to changing viral strain and outpatient therapies. Funding: This study was supported by research funding from MSD.

Consensus core clinical data elements for meningiomas (v2021.1).

BACKGROUND: With increasing molecular analyses of meningiomas, there is a need to harmonize language used to capture clinical data across centers to ensure that molecular alterations are appropriately linked to clinical variables of interest. Here the International Consortium on Meningiomas presents a set of core and supplemental meningioma-specific common data elements (CDEs) to facilitate comparative and pooled analyses. METHODS: The generation of CDEs followed the 4-phase process similar to other National Institute of Neurological Disorders and Stroke (NINDS) CDE projects: discovery, internal validation, external validation, and distribution. RESULTS: The CDEs were organized into patient- and tumor-level modules. In total, 17 core CDEs (10 patient level and 7 tumor level) as well as 14 supplemental CDEs (7 patient level and 7 tumor level) were defined and described. These CDEs are now made publicly available for dissemination and adoption. CONCLUSIONS: CDEs provide a framework for discussion in the neuro-oncology community that will facilitate data-sharing for collaborative research projects and aid in developing a common language for comparative and pooled analyses. The meningioma-specific CDEs presented here are intended to be dynamic parameters that evolve with time and The Consortium welcomes international feedback for further refinement and implementation of these CDEs.

A normative database of A-scan data using the Heidelberg Spectralis Spectral Domain Optical Coherence Tomography machine.

PURPOSE: To develop the first normative database of macular and circumpapillary scans with reference values at the level of the A-scan using the Heidelberg Spectralis Optical Coherence Tomography (OCT) machine. METHODS: This study is a retrospective cross sectional analysis of macular and circumpapillary OCT scans of healthy individuals. All participants had a full ophthalmic examination, including best corrected visual acuity, intraocular pressure, biomicroscopy, posterior segment examination and OCT scan. The volume and thickness of each of the nine Early Treatment Diabetic Retinopathy zones at the macula were analysed for the total retinal thickness, retinal nerve fibre layer (RNFL), ganglion cell layer (GCL) and inner plexiform layer (IPL). The thickness of the circumpapillary RNFL was analysed at the disc. Associations between age, gender, refractive error and OCT measurements were explored. De-identified A-scans were extracted from the OCT machine as separate tab-separated text file and made available according to the data sharing statement. RESULTS: Two-hundred eyes from 146 participants were included of which 69 (47%) were female. The mean age (SD) was 48.52 (17.52). Participants were evenly distributed across four age groups and represented nine broad ethnic groups in proportions comparable to the local distribution. All the macular scans were 20° x 20° (5.9 mm x 5.9 mm), with a total scan density between 12,800 and 49,152 A-scans. The peripapillary scans were all 12° (3.5 mm), at a scan density of 768 A-scans. The mean retinal, GCL and IPL volumes were significantly greater in males than females. Mean peripapillary RNFL thickness did not differ significantly between males and females. Age and total retinal volume (r = -0.2561, P = 0.0003), GCL volume (-0.2911, P < 0.0001) and IPL volume (-0.3194, P < 0.0001) were negatively correlated. The IPL had the strongest three significant negatively associated segments; superior inner IPL (r = -0.3444, P < 0.0001), nasal outer IPL (r = -0.3217, P < 0.0001) and inferior inner IPL (r = -0.3179, P < 0.0001). The temporal inner macular RNFL showed a statistically significant positive correlation (r = 0.1929, P = 0.0062) with age. The only significant association between age and thickness at the peripapillary disc scan was the superior temporal sector (r = -0.1910, P = 0.0067). All retinal layers were negatively correlated for refractive error, except for the central RNFL which was positively correlated (r = 0.1426, P = 0.044). CONCLUSION: This study provides a normative database of macular and circumpapillary scans with reference values at the level of the A-scan using the Heidelberg Spectralis Optical Coherence Tomography (OCT) machine.

Pretreatment neutrophil-to-lymphocyte/monocyte-to-lymphocyte ratio as prognostic biomarkers in glioma patients.

OBJECTIVES: To evaluate the ability for pre-treatment NLR and MLR to predict overall survival (OS) and modified Rankin Scale (mRS) and to explore their relationship with clinicopathological parameters. METHODS: Retrospective analysis of pretreatment NLR and MLR from 64 glioma patients. RESULTS: Higher pretreatment NLR (>4.7) predicted higher mean admission mRS (p < 0.001) and 6-month mRS (p = 0.02). Higher pretreatment MLR (>0.35) was a risk factor for poorer OS in glioma patients (p = 0.024). Higher pretreatment NLR was significantly associated with larger tumor diameter (p = 0.02). CONCLUSION: NLR and MLR can serve as prognostic markers to predict functional outcomes and OS in glioma patients.

Melanoma brain metastases that progress on BRAF-MEK inhibitors demonstrate resistance to ipilimumab-nivolumab that is associated with the Innate PD-1 Resistance Signature (IPRES).

BACKGROUND: Melanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib-trametinib and ipilimumab-nivolumab have similar intracranial response rates (50%-55%), central nervous system (CNS) resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs around 6 months, and durable responses are only seen with combination immunotherapy. We sought to investigate the utility of ipilimumab-nivolumab after MBM progression on BRAF-MEKi and identify mechanisms of resistance. METHODS: Patients who received first-line ipilimumab-nivolumab for MBMs or second/third line ipilimumab-nivolumab for intracranial metastases with BRAFV600 mutations with prior progression on BRAF-MEKi and MRI brain staging from March 1, 2015 to June 30, 2018 were included. Modified intracranial RECIST was used to assess response. Formalin-fixed paraffin-embedded samples of BRAFV600 mutant MBMs that were naïve to systemic treatment (n=18) or excised after progression on BRAF-MEKi (n=14) underwent whole transcriptome sequencing. Comparative analyses of MBMs naïve to systemic treatment versus BRAF-MEKi progression were performed. RESULTS: Twenty-five and 30 patients who received first and second/third line ipilimumab-nivolumab, were included respectively. Median sum of MBM diameters was 13 and 20.5 mm for the first and second/third line ipilimumab-nivolumab groups, respectively. Intracranial response rate was 75.0% (12/16), and median progression-free survival (PFS) was 41.6 months for first-line ipilimumab-nivolumab. Efficacy of second/third line ipilimumab-nivolumab after BRAF-MEKi progression was poor with an intracranial response rate of 4.8% (1/21) and median PFS of 1.3 months. Given the poor activity of ipilimumab-nivolumab after BRAF-MEKi MBM progression, we performed whole transcriptome sequencing to identify mechanisms of drug resistance. We identified a set of 178 differentially expressed genes (DEGs) between naïve and MBMs with progression on BRAF-MEKi treatment (p value <0.05, false discovery rate (FDR) <0.1). No distinct pathways were identified from gene set enrichment analyses using Kyoto Encyclopedia of Genes and Genomes, Gene Ontogeny or Hallmark libraries; however, enrichment of DEG from the Innate Anti-PD1 Resistance Signature (IPRES) was identified (p value=0.007, FDR=0.03). CONCLUSIONS: Second-line ipilimumab-nivolumab for MBMs after BRAF-MEKi progression has poor activity. MBMs that are resistant to BRAF-MEKi that also conferred resistance to second-line ipilimumab-nivolumab showed enrichment of the IPRES gene signature.