Intra-operative extracorporeal irradiation of tumour-invaded craniotomy bone flap in meningioma: a case series.

BACKGROUND: Extracorporeal irradiation of tumorous calvaria (EITC) can be performed to restore function and form of the skull after resection of bone-invasive meningioma. We sought to examine the rate of tumour recurrence and other selected outcomes in patients undergoing meningioma resection and EITC. METHODS: Retrospective single-centre study of adult patients undergoing meningioma resection and EITC between January 2015 and November 2022 at a tertiary neurosurgical centre. Patient demographics, surgery data, tumour data, use of adjuvant therapy, surgical complications, and tumour recurrences were collected. RESULTS: Eighteen patients with 11 (61%) CNS WHO grade 1, 6 (33%) grade 2, and 1 (6%) grade 3 meningiomas were included. Median follow-up was 42 months (range 3-88). Five (28%) patients had a recurrence, but none were associated with the bone flap. Two (11%) wound infections requiring explant surgery occurred. Six (33%) patients required a further operation. Two operations were for recurrences, one was for infection, one was a washout and wound exploration but no evidence of infection was found, one patient requested the removal of a small titanium implant, and one patient required a ventriculoperitoneal shunt for a persistent CSF collection. There were no cases of bone flap resorption and cosmetic outcome was not routinely recorded. CONCLUSION: EITC is feasible and fast to perform with good outcomes and cost-effectiveness compared to other reconstructive methods. We observed similar recurrence rates and lower infection rates requiring explant compared to the largest series of cranioplasty in meningioma. Cosmetic outcome is universally under-reported and should be reported in future studies.

Adult brain tumour research in 2024: Status, challenges and recommendations.

In 2015, a groundswell of brain tumour patient, carer and charity activism compelled the UK Minister for Life Sciences to form a brain tumour research task and finish group. This resulted, in 2018, with the UK government pledging £20m of funding, to be paralleled with £25m from Cancer Research UK, specifically for neuro-oncology research over the subsequent 5 years. Herein, we review if and how the adult brain tumour research landscape in the United Kingdom has changed over that time and what challenges and bottlenecks remain. We have identified seven universal brain tumour research priorities and three cross-cutting themes, which span the research spectrum from bench to bedside and back again. We discuss the status, challenges and recommendations for each one, specific to the United Kingdom.

Impact of the COVID-19 related border restrictions on influenza and other common respiratory viral infections in New Zealand.

BACKGROUND: New Zealand's (NZ) complete absence of community transmission of influenza and respiratory syncytial virus (RSV) after May 2020, likely due to COVID-19 elimination measures, provided a rare opportunity to assess the impact of border restrictions on common respiratory viral infections over the ensuing 2 years. METHODS: We collected the data from multiple surveillance systems, including hospital-based severe acute respiratory infection surveillance, SHIVERS-II, -III and -IV community cohorts for acute respiratory infection (ARI) surveillance, HealthStat sentinel general practice (GP) based influenza-like illness surveillance and SHIVERS-V sentinel GP-based ARI surveillance, SHIVERS-V traveller ARI surveillance and laboratory-based surveillance. We described the data on influenza, RSV and other respiratory viral infections in NZ before, during and after various stages of the COVID related border restrictions. RESULTS: We observed that border closure to most people, and mandatory government-managed isolation and quarantine on arrival for those allowed to enter, appeared to be effective in keeping influenza and RSV infections out of the NZ community. Border restrictions did not affect community transmission of other respiratory viruses such as rhinovirus and parainfluenza virus type-1. Partial border relaxations through quarantine-free travel with Australia and other countries were quickly followed by importation of RSV in 2021 and influenza in 2022. CONCLUSION: Our findings inform future pandemic preparedness and strategies to model and manage the impact of influenza and other respiratory viral threats.

Technical considerations and long-term results of endovascular venous stenting to control venous hypertension from meningiomas invading intracranial venous sinuses.

OBJECTIVE: Meningiomas invading the intracranial venous sinuses may cause intracranial venous hypertension, papilledema, and visual compromise. Sinus resection and graft reconstructions, however, add significant complexity to tumor surgery, with the potential for increased morbidity. In this study, the authors explored whether venous sinus stenting might provide an alternative means of controlling venous hypertension that would be sustainable over the long term. METHODS: The authors performed a retrospective review of all 16 patients with intracranial meningiomas who underwent stenting at their institution for venous sinus compromise. At presentation, all had headache and 9 had papilledema. Thirteen patients had 1 meningioma and 3 had 2 or more. Three patients had had previous tumor resection and radiotherapy. One patient had been treated with a lumboperitoneal shunt and radiotherapy. The median length of clinical follow-up was 8 years (range 4 months-18 years). RESULTS: Venous sinus narrowing was often not confined to the site of meningioma, and bilateral transverse sinus narrowing, reminiscent of that seen in idiopathic intracranial hypertension, was present in 7 patients with sagittal sinus meningiomas. Eleven patients had stents placed solely across sinus narrowing caused by meningioma. Five patients had additional stents placed at other sites of venous narrowing at the same time: in one of these patients, a stent was placed across a defect in the sagittal sinus caused by previous surgery, and in the 4 other patients, stents were placed across nontumor narrowings of the transverse sinuses. In 1 patient, the jugular vein was also stented. Nine patients developed symptomatic in-stent restenosis at the meningioma site. Eight had further stenting procedures with variable success in restoring the in-stent lumen. The remaining patient, with a late partial relapse, is being reinvestigated. Papilledema resolved in all patients after stenting. Six patients experienced prolonged and very substantial relief of all symptoms. Five patients had persistent headache despite restoration of the sinus lumen. Five had persistent symptoms associated with resistant in-stent stenosis. There were no significant complications from any of the diagnostic or therapeutic procedures. CONCLUSIONS: In patients who are symptomatic with meningiomas obstructing the venous sinuses, successful stenting of the affected segment can give a good outcome, especially in terms of relieving papilledema. However, further procedures are often necessary to maintain stent patency, other areas of venous compromise frequently coexist, and some patients remain symptomatic despite apparently successful treatment of the index lesion. Long-term surveillance is a requirement.

Imaging Glioblastoma Metabolism by Using Hyperpolarized [1-13C]Pyruvate Demonstrates Heterogeneity in Lactate Labeling: A Proof of Principle Study.

Purpose To evaluate glioblastoma (GBM) metabolism by using hyperpolarized carbon 13 (13C) MRI to monitor the exchange of the hyperpolarized 13C label between injected [1-13C]pyruvate and tumor lactate and bicarbonate. Materials and Methods In this prospective study, seven treatment-naive patients (age [mean ± SD], 60 years ± 11; five men) with GBM were imaged at 3 T by using a dual-tuned 13C-hydrogen 1 head coil. Hyperpolarized [1-13C]pyruvate was injected, and signal was acquired by using a dynamic MRI spiral sequence. Metabolism was assessed within the tumor, in the normal-appearing brain parenchyma (NABP), and in healthy volunteers by using paired or unpaired t tests and a Wilcoxon signed rank test. The Spearman ρ correlation coefficient was used to correlate metabolite labeling with lactate dehydrogenase A (LDH-A) expression and some immunohistochemical markers. The Benjamini-Hochberg procedure was used to correct for multiple comparisons. Results The bicarbonate-to-pyruvate (BP) ratio was lower in the tumor than in the contralateral NABP (P < .01). The tumor lactate-to-pyruvate (LP) ratio was not different from that in the NABP (P = .38). The LP and BP ratios in the NABP were higher than those observed previously in healthy volunteers (P < .05). Tumor lactate and bicarbonate signal intensities were strongly correlated with the pyruvate signal intensity (ρ = 0.92, P < .001, and ρ = 0.66, P < .001, respectively), and the LP ratio was weakly correlated with LDH-A expression in biopsy samples (ρ = 0.43, P = .04). Conclusion Hyperpolarized 13C MRI demonstrated variation in lactate labeling in GBM, both within and between tumors. In contrast, bicarbonate labeling was consistently lower in tumors than in the surrounding NABP. Keywords: Hyperpolarized 13C MRI, Glioblastoma, Metabolism, Cancer, MRI, Neuro-oncology Supplemental material is available for this article. Published under a CC BY 4.0 license.

A 2 and 5-Year Longitudinal Analysis of 671 Consecutive Patients Diagnosed with Unilateral Vestibular Schwannoma.

OBJECTIVE: To analyse the 2 and 5-year outcomes of a cohort of patients with newly diagnosed vestibular schwannoma patients. STUDY DESIGN: Longitudinal cohort study. SETTING: Tertiary skull base referral unit. PATIENTS: Six hundred and seventy-one consecutive patients referred to the Cambridge Skull Base Unit between 2005 and 2010. MAIN OUTCOME MEASURES: 1) Treatment outcomes, 2) hearing preservation, 3) facial nerve function, and 4) gross tumor control. RESULTS: At initial diagnosis, 440/671(65.6%) of patients entered a watch, wait and rescan (WWR) pathway, 208/671 (31%) underwent primary microsurgical excision and 23/671 (3.4%) primary radiotherapy. Of patients who entered WWR, 144/440 (32.7%) exhibited tumor growth necessitating secondary intervention at a mean of 22.7 months; 67.4% had radiotherapy and 32.6% surgery. Radiotherapy was successful at achieving tumor control in 95% of cases. Primary surgery via the translabyrinthine route was performed in the majority of cases allowing for a radiologically clear surgical resection in 93% of cases. CONCLUSION: The Cambridge philosophy of treating the newly diagnosed vestibular schwannoma aims at preserving functional status where possible. In patients with small tumors it is recommended that they are placed on to a WWR pathway, of which 67.3% will not exhibit any growth by 5 years. If small tumors grow more than 2 mm by serial scanning, radiotherapy offers a high rate of tumor control. In patients with larger tumors more than 20 mm we would advocate microsurgical excision by the translabyrinthine route which offers excellent functional outcomes and gross tumor control.

Diagnostic test accuracy and cost-effectiveness of tests for codeletion of chromosomal arms 1p and 19q in people with glioma.

BACKGROUND: Complete deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), known as 1p/19q codeletion, is a mutation that can occur in gliomas. It occurs in a type of glioma known as oligodendroglioma and its higher grade counterpart known as anaplastic oligodendroglioma. Detection of 1p/19q codeletion in gliomas is important because, together with another mutation in an enzyme known as isocitrate dehydrogenase, it is needed to make the diagnosis of an oligodendroglioma. Presence of 1p/19q codeletion also informs patient prognosis and prediction of the best drug treatment. The main two tests in use are fluorescent in situ hybridisation (FISH) and polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) assays (also known as PCR-based short tandem repeat or microsatellite analysis). Many other tests are available. None of the tests is perfect, although PCR-based LOH is expected to have very high sensitivity. OBJECTIVES: To estimate the sensitivity and specificity and cost-effectiveness of different deoxyribonucleic acid (DNA)-based techniques for determining 1p/19q codeletion status in glioma. SEARCH METHODS: We searched MEDLINE, Embase and BIOSIS up to July 2019. There were no restrictions based on language or date of publication. We sought economic evaluation studies from the results of this search and using the National Health Service Economic Evaluation Database. SELECTION CRITERIA: We included cross-sectional studies in adults with glioma or any subtype of glioma, presenting raw data or cross-tabulations of two or more DNA-based tests for 1p/19q codeletion. We also sought economic evaluations of these tests. DATA COLLECTION AND ANALYSIS: We followed procedures outlined in the Cochrane Handbook for Diagnostic Test Accuracy Reviews. Two review authors independently screened titles/abstracts/full texts, performed data extraction, and undertook applicability and risk of bias assessments using QUADAS-2. Meta-analyses used the hierarchical summary ROC model to estimate and compare test accuracy. We used FISH and PCR-based LOH as alternate reference standards to examine how tests compared with those in common use, and conducted a latent class analysis comparing FISH and PCR-based LOH. We constructed an economic model to evaluate cost-effectiveness. MAIN RESULTS: We included 53 studies examining: PCR-based LOH, FISH, single nucleotide polymorphism (SNP) array, next-generation sequencing (NGS), comparative genomic hybridisation (CGH), array comparative genomic hybridisation (aCGH), multiplex-ligation-dependent probe amplification (MLPA), real-time PCR, chromogenic in situ hybridisation (CISH), mass spectrometry (MS), restriction fragment length polymorphism (RFLP) analysis, G-banding, methylation array and NanoString. Risk of bias was low for only one study; most gave us concerns about how patients were selected or about missing data. We had applicability concerns about many of the studies because only patients with specific subtypes of glioma were included. 1520 participants contributed to analyses using FISH as the reference, 1304 participants to analyses involving PCR-based LOH as the reference and 262 participants to analyses of comparisons between methods from studies not including FISH or PCR-based LOH. Most evidence was available for comparison of FISH with PCR-based LOH (15 studies, 915 participants): PCR-based LOH detected 94% of FISH-determined codeletions (95% credible interval (CrI) 83% to 98%) and FISH detected 91% of codeletions determined by PCR-based LOH (CrI 78% to 97%). Of tumours determined not to have a deletion by FISH, 94% (CrI 87% to 98%) had a deletion detected by PCR-based LOH, and of those determined not to have a deletion by PCR-based LOH, 96% (CrI 90% to 99%) had a deletion detected by FISH. The latent class analysis suggested that PCR-based LOH may be slightly more accurate than FISH. Most other techniques appeared to have high sensitivity (i.e. produced few false-negative results) for detection of 1p/19q codeletion when either FISH or PCR-based LOH was considered as the reference standard, although there was limited evidence. There was some indication of differences in specificity (false-positive rate) with some techniques. Both NGS and SNP array had high specificity when considered against FISH as the reference standard (NGS: 6 studies, 243 participants; SNP: 6 studies, 111 participants), although we rated certainty in the evidence as low or very low. NGS and SNP array also had high specificity when PCR-based LOH was considered the reference standard, although with much more uncertainty as these results were based on fewer studies (just one study with 49 participants for NGS and two studies with 33 participants for SNP array). G-banding had low sensitivity and specificity when PCR-based LOH was the reference standard. Although MS had very high sensitivity and specificity when both FISH and PCR-based LOH were considered the reference standard, these results were based on only one study with a small number of participants. Real-time PCR also showed high specificity with FISH as a reference standard, although there were only two studies including 40 participants. We found no relevant economic evaluations. Our economic model using FISH as the reference standard suggested that the resource-optimising test depends on which measure of diagnostic accuracy is most important. With FISH as the reference standard, MLPA is likely to be cost-effective if society was willing to pay GBP 1000 or less for a true positive detected. However, as the value placed on a true positive increased, CISH was most cost-effective. Findings differed when the outcome measure changed to either true negative detected or correct diagnosis. When PCR-based LOH was used as the reference standard, MLPA was likely to be cost-effective for all measures of diagnostic accuracy at lower threshold values for willingness to pay. However, as the threshold values increased, none of the tests were clearly more likely to be considered cost-effective. AUTHORS' CONCLUSIONS: In our review, most techniques (except G-banding) appeared to have good sensitivity (few false negatives) for detection of 1p/19q codeletions in glioma against both FISH and PCR-based LOH as a reference standard. However, we judged the certainty of the evidence low or very low for all the tests. There are possible differences in specificity, with both NGS and SNP array having high specificity (fewer false positives) for 1p/19q codeletion when considered against FISH as the reference standard. The economic analysis should be interpreted with caution due to the small number of studies.

Diagnostic accuracy of 1p/19q codeletion tests in oligodendroglioma: A comprehensive meta-analysis based on a Cochrane systematic review.

Codeletion of chromosomal arms 1p and 19q, in conjunction with a mutation in the isocitrate dehydrogenase 1 or 2 gene, is the molecular diagnostic criterion for oligodendroglioma, IDH mutant and 1p/19q codeleted. 1p/19q codeletion is a diagnostic marker and allows prognostication and prediction of the best drug response within IDH-mutant tumours. We performed a Cochrane review and simple economic analysis to establish the most sensitive, specific and cost-effective techniques for determining 1p/19q codeletion status. Fluorescent in situ hybridisation (FISH) and polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) test methods were considered as reference standard. Most techniques (FISH, chromogenic in situ hybridisation [CISH], PCR, real-time PCR, multiplex ligation-dependent probe amplification [MLPA], single nucleotide polymorphism [SNP] array, comparative genomic hybridisation [CGH], array CGH, next-generation sequencing [NGS], mass spectrometry and NanoString) showed good sensitivity (few false negatives) for detection of 1p/19q codeletions in glioma, irrespective of whether FISH or PCR-based LOH was used as the reference standard. Both NGS and SNP array had a high specificity (fewer false positives) for 1p/19q codeletion when considered against FISH as the reference standard. Our findings suggest that G banding is not a suitable test for 1p/19q analysis. Within these limits, considering cost per diagnosis and using FISH as a reference, MLPA was marginally more cost-effective than other tests, although these economic analyses were limited by the range of available parameters, time horizon and data from multiple healthcare organisations.

Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review.

BACKGROUND: Detailed prevalence estimates of BRAFV600 mutations and BRAF inhibitor (BRAFi) treatment responses in V600-mutant glioma will inform trial development. METHODS: Our systematic review analyzed overall prevalence of BRAFV600 mutations in glioma and BRAFi treatment response. RESULTS: Based on 13 682 patients in 182 publications, the prevalence of BRAFV600 in epithelioid glioblastoma (eGBM) was 69% [95% CI: 45-89%]; pleomorphic xanthoastrocytoma (PXA): 56% [48-64%] anaplastic pleomorphic xanthoastrocytoma (aPXA): 38% [23-54%], ganglioglioma (GG): 40% [33-46%], and anaplastic ganglioglioma (aGG): 46% [18-76%]. Prevalence in astroblastoma was 24% [8-43%], desmoplastic infantile astrocytoma (DIA): 16% [0-57%], subependymal giant cell astrocytoma (SEGA): 8% [0-37%], dysembryoplastic neuroepithelial tumor (DNET): 3% [0-11%], diffuse astrocytoma (DA): 3% [0-9%], and pilocytic astrocytoma (PA): 3% [2-5%]. We reviewed 394 V600-mutant gliomas treated with BRAFi from 130 publications. One hundred and twenty-nine pediatric low-grade gliomas showed 4 (3.1%) complete response (CR); 53 (41.1%) partial response (PR); 64 (49.6%) stable disease (SD) and 8 (6.2%) progressive disease (PD). 25 pediatric high-grade gliomas showed CR; PR; SD; PD in 4 (16.0%); 10 (40.0%), 4 (16.0%); and 7 (28.0%) respectively. Thirty-nine adult low-grade gliomas showed CR; PR; SD; PD of 4 (10.3%); 17 (43.6%); 16 (41.0%) and 2 (5.1%) respectively. Ninety-seven adult high-grade gliomas showed CR; PR; SD; PD of 6 (6.2%); 31 (32.0%); 27 (27.8%); and 33 (34.0%) respectively. CONCLUSIONS: BRAFV600 prevalence is highest in eGBM, PXA, aPXA, GG, aGG, and lower in astroblastoma, DIA, SEGA, DNET, DA, and PA. Our data provide the rationale for adjuvant clinical trials of BRAFi in V600-mutant glioma.

Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM. METHODS: This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O6-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment. RESULTS: Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone. CONCLUSIONS: This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection. TRIAL REGISTRATION: NCT00977431 (first posted September 15, 2009).

Creating symptom-based criteria for diagnostic testing: a case study based on a multivariate analysis of data collected during the first wave of the COVID-19 pandemic in New Zealand.

BACKGROUND: Diagnostic testing using PCR is a fundamental component of COVID-19 pandemic control. Criteria for determining who should be tested by PCR vary between countries, and ultimately depend on resource constraints and public health objectives. Decisions are often based on sets of symptoms in individuals presenting to health services, as well as demographic variables, such as age, and travel history. The objective of this study was to determine the sensitivity and specificity of sets of symptoms used for triaging individuals for confirmatory testing, with the aim of optimising public health decision making under different scenarios. METHODS: Data from the first wave of COVID-19 in New Zealand were analysed; comprising 1153 PCR-confirmed and 4750 symptomatic PCR negative individuals. Data were analysed using Multiple Correspondence Analysis (MCA), automated search algorithms, Bayesian Latent Class Analysis, Decision Tree Analysis and Random Forest (RF) machine learning. RESULTS: Clinical criteria used to guide who should be tested by PCR were based on a set of mostly respiratory symptoms: a new or worsening cough, sore throat, shortness of breath, coryza, anosmia, with or without fever. This set has relatively high sensitivity (> 90%) but low specificity (< 10%), using PCR as a quasi-gold standard. In contrast, a group of mostly non-respiratory symptoms, including weakness, muscle pain, joint pain, headache, anosmia and ageusia, explained more variance in the MCA and were associated with higher specificity, at the cost of reduced sensitivity. Using RF models, the incorporation of 15 common symptoms, age, sex and prioritised ethnicity provided algorithms that were both sensitive and specific (> 85% for both) for predicting PCR outcomes. CONCLUSIONS:  If predominantly respiratory symptoms are used for test-triaging,  a large proportion of the individuals being tested may not have COVID-19. This could overwhelm testing capacity and hinder attempts to trace and eliminate infection. Specificity can be increased using alternative rules based on sets of symptoms informed by multivariate analysis and automated search algorithms, albeit at the cost of sensitivity. Both sensitivity and specificity can be improved through machine learning algorithms, incorporating symptom and demographic data, and hence may provide an alternative approach to test-triaging that can be optimised according to prevailing conditions.

Treatment options for progression or recurrence of glioblastoma: a network meta-analysis.

BACKGROUND: Glioblastoma (GBM) is a highly malignant brain tumour that almost inevitably progresses or recurs after first line standard of care. There is no consensus regarding the best treatment/s to offer people upon disease progression or recurrence. For the purposes of this review, progression and recurrence are considered as one entity. OBJECTIVES: To evaluate the effectiveness of further treatment/s for first and subsequent progression or recurrence of glioblastoma (GBM) among people who have received the standard of care (Stupp protocol) for primary treatment of the disease; and to prepare a brief economic commentary on the available evidence. SEARCH METHODS: We searched MEDLINE and Embase electronic databases from 2005 to December 2019 and the Cochrane Central Register of Controlled Trials (CENTRAL, in the Cochrane Library; Issue 12, 2019). Economic searches included the National Health Service Economic Evaluation Database (NHS EED) up to 2015 (database closure) and MEDLINE and Embase from 2015 to December 2019. SELECTION CRITERIA: Randomised controlled trials (RCTs) and comparative non-randomised studies (NRSs) evaluating effectiveness of treatments for progressive/recurrent GBM. Eligible studies included people with progressive or recurrent GBM who had received first line radiotherapy with concomitant and adjuvant temozolomide (TMZ). DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data to a pre-designed data extraction form. We conducted network meta-analyses (NMA) and ranked treatments according to effectiveness for each outcome using the random-effects model and Stata software (version 15). We rated the certainty of evidence using the GRADE approach. MAIN RESULTS: We included 42 studies: these comprised 34 randomised controlled trials (RCTs) and 8 non-randomised studies (NRSs) involving 5236 participants. We judged most RCTs to be at a low risk of bias and NRSs at high risk of bias. Interventions included chemotherapy, re-operation, re-irradiation and novel therapies either used alone or in combination. For first recurrence, we included 11 interventions in the network meta-analysis (NMA) for overall survival (OS), and eight in the NMA for progression-free survival (PFS). Lomustine (LOM; also known as CCNU) was the most common comparator and was used as the reference treatment. No studies in the NMA evaluated surgery, re-irradiation, PCV (procarbazine, lomustine, vincristine), TMZ re-challenge or best supportive care. We could not perform NMA for second or later recurrence due to insufficient data. Quality-of-life data were sparse. First recurrence (NMA findings) Median OS across included studies in the NMA ranged from 5.5 to 12.6 months and median progression-free survival (PFS) ranged from 1.5 months to 4.2 months. We found no high-certainty evidence that any treatments tested were better than lomustine. These treatments included the following. Bevacizumab plus lomustine: Evidence suggested probably little or no difference in OS between bevacizumab (BEV) combined with lomustine (LOM) and LOM monotherapy (hazard ratio (HR) 0.91, 0.75 to 1.10; moderate-certainty evidence), although BEV + LOM may improve PFS (HR 0.57, 95% confidence interval (CI) 0.44 to 0.74; low-certainty evidence). Bevacizumab monotherapy: Low-certainty evidence suggested there may be little or no difference in OS (HR 1.22, 95% CI 0.84 to 1.76) and PFS (HR 0.90, 95% CI 0.58 to 1.38; low-certainty evidence) between BEV and LOM monotherapies; more evidence on BEV is needed. Regorafenib (REG): REG may improve OS compared with LOM (HR 0.50, 95% CI 0.33 to 0.76; low-certainty evidence). Evidence on PFS was very low certainty and more evidence on REG is needed. Temozolomide (TMZ) plus Depatux-M (ABT414): For OS, low-certainty evidence suggested that TMZ plus ABT414 may be more effective than LOM (HR 0.66, 95% CI 0.47 to 0.92) and may be more effective than BEV (HR 0.54, 95% CI 0.33 to 0.89; low-certainty evidence). This may be due to the TMZ component only and more evidence is needed. Fotemustine (FOM): FOM and LOM may have similar effects on OS (HR 0.89, 95% CI 0.51 to 1.57, low-certainty evidence). Bevacizumab and irinotecan (IRI): Evidence on BEV + irinotecan (IRI) versus LOM for both OS and PFS is very uncertain and there is probably little or no difference between BEV + IRI versus BEV monotherapy (OS: HR 0.95, 95% CI 0.70 to 1.30; moderate-certainty evidence). When treatments were ranked for OS, FOM ranked first, BEV + LOM second, LOM third, BEV + IRI fourth, and BEV fifth. Ranking does not take into account the certainty of the evidence, which also suggests there may be little or no difference between FOM and LOM. Other treatments Three studies evaluated re-operation versus no re-operation, with or without re-irradiation and chemotherapy, and these suggested possible survival advantages with re-operation within the context of being able to select suitable candidates for re-operation. A cannabinoid treatment in the early stages of evaluation, in combination with TMZ, merits further evaluation. Second or later recurrence Limited evidence from three heterogeneous studies suggested that radiotherapy with or without BEV may have a beneficial effect on survival but more evidence is needed. Evidence was insufficient to draw conclusions about the best radiotherapy dosage. Other evidence suggested that there may be little difference in survival with tumour-treating fields compared with physician's best choice of treatment. We found no reliable evidence on best supportive care. Severe adverse events (SAEs) The BEV+LOM combination was associated with significantly greater risk of SAEs than LOM monotherapy (RR 2.51, 95% CI 1.72 to 3.66, high-certainty evidence), and ranked joint worst with cediranib + LOM (RR 2.51, 95% CI 1.29 to 4.90; high-certainty evidence). LOM ranked best and REG ranked second best. Adding novel treatments to BEV was generally associated with a higher risk of severe adverse events compared with BEV alone. AUTHORS' CONCLUSIONS: For treatment of first recurrence of GBM, among people previously treated with surgery and standard chemoradiotherapy, the combination treatments evaluated did not improve overall survival compared with LOM monotherapy and were often associated with a higher risk of severe adverse events. Limited evidence suggested that re-operation with or without re-irradiation and chemotherapy may be suitable for selected candidates. Evidence on second recurrence is sparse. Re-irradiation with or without bevacizumab may be of value in selected individuals, but more evidence is needed.

ANTECEDENTES: El glioblastoma (GBM) es un tumor cerebral altamente maligno que casi inevitablemente progresa o recidiva después de un tratamiento de primera línea. No hay consenso sobre el mejor o los mejores tratamientos que se pueden ofrecer a las personas que presentan progresión o recidiva de la enfermedad. A los efectos de la presente revisión, la progresión y la recidiva se consideran como una sola entidad. OBJETIVOS: Evaluar la efectividad de los tratamientos adicionales para la primera y subsiguiente progresión o recidiva del glioblastoma (GBM) entre las personas que han recibido atención estándar (protocolo Stupp) para el tratamiento primario de la enfermedad, así como preparar un breve comentario económico sobre la evidencia disponible. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en las bases de datos electrónicas de MEDLINE y Embase desde 2005 hasta diciembre de 2019 y en el Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials) (CENTRAL, en la Cochrane Library; Número 12, 2019). Las búsquedas económicas incluyeron la National Health Service Economic Evaluation Database (NHS EED) hasta 2015 (cierre de la base de datos) y MEDLINE y Embase desde 2015 hasta diciembre de 2019. CRITERIOS DE SELECCIÓN: Ensayos controlados aleatorizados (ECA) y estudios comparativos no aleatorizados (no ECA) que evaluaron la efectividad de los tratamientos para el GBM progresivo/recidivante. Los estudios elegibles incluyeron personas con GBM progresivo o recidivante que habían recibido radioterapia de primera línea con temozolomida (TMZ) concomitante y adyuvante. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión de forma independiente seleccionaron los estudios y extrajeron los datos en un formulario de extracción de datos prediseñado. Se realizaron metanálisis en red (MAR) y los tratamientos se clasificaron según la efectividad de cada desenlace, mediante el modelo de efectos aleatorios y el software Stata (versión 15). La certeza de la evidencia se evaluó mediante los criterios GRADE. RESULTADOS PRINCIPALES: Se incluyeron 42 estudios, que comprendieron 34 ensayos controlados aleatorizados (ECA) y ocho estudios no aleatorizados (no ECA), con 5236 participantes. Se consideró que la mayoría de los ECA tuvieron bajo riesgo de sesgo y que los no ECA tuvieron alto riesgo de sesgo. Las intervenciones incluyeron quimioterapia, reoperación, reirradiación y tratamientos nuevos, ya sea utilizadas solos o en combinación. Para la primera recidiva se incluyeron 11 intervenciones en el metanálisis en red (MAR) para la supervivencia general (SG), y ocho para la supervivencia sin progresión (SSP). La lomustina (LOM; también conocida como CCNU) fue el comparador más frecuente y se utilizó como tratamiento de referencia. Ningún estudio en el MAR evaluó la cirugía, la reirradiación, la PCV (procarbazina, lomustina, vincristina), la reexposición a TMZ o el mejor tratamiento de apoyo. No fue posible realizar un MAR para una segunda o posterior recidiva debido a que los datos no fueron suficientes. Los datos de calidad de vida fueron escasos. Primera recidiva (hallazgos del MAR) La mediana de la SG en los estudios incluidos en el MAR varió entre 5,5 y 12,6 meses y la mediana de la supervivencia sin progresión (SSP) varió entre 1,5 y 4,2 meses. No se encontró evidencia de certeza alta de que los tratamientos probados fueran mejores que la lomustina. Estos tratamientos incluyeron los siguientes. Bevacizumab más lomustina: La evidencia indicó probablemente poca o ninguna diferencia en la SG entre el bevacizumab (BEV) combinado con lomustina (LOM) y la monoterapia con LOM (cociente de riesgos instantáneo [CRI] 0,91; 0,75 a 1,10; evidencia de certeza moderada), aunque BEV + LOM puede mejorar la SSP (CRI 0,57; intervalo de confianza [IC] del 95%: 0,44 a 0,74; evidencia de certeza baja). Monoterapia con bevacizumab: La evidencia de certeza baja indicó que puede haber poca o ninguna diferencia en la SG (CRI 1,22; IC del 95%: 0,84 a 1,76) y la SSP (CRI 0,90; IC del 95%: 0,58 a 1,38; evidencia de certeza baja) entre las monoterapias con BEV y LOM; se necesita más evidencia sobre el BEV. Regorafenib (REG): El REG puede mejorar la SG en comparación con la LOM (CRI 0,50; IC del 95%: 0,33 a 0,76; evidencia de certeza baja). La evidencia sobre la SSP fue de certeza muy baja y se necesita más evidencia sobre el REG. Temozolomida (TMZ) más Depatux­M (ABT414): En cuanto a la SG, evidencia de certeza baja indicó que TMZ más ABT414 puede ser más efectiva que LOM (CRI 0,66; IC del 95%: 0,47 a 0,92) y puede ser más efectiva que BEV (CRI 0,54; IC del 95%: 0,33 a 0,89; evidencia de certeza baja). Lo anterior se puede deber solamente al componente de TMZ, y se necesita más evidencia. Fotemustina (FOM): FOM y LOM pueden tener efectos similares sobre la SG (CRI 0,89; IC del 95%: 0,51 a 1,57, evidencia de certeza baja). Bevacizumab e irinotecan (IRI): La evidencia sobre BEV + irinotecan (IRI) versus LOM para la SG y la SSP no está clara y probablemente hay poca o ninguna diferencia entre BEV + IRI versus la monoterapia con BEV (SG: CRI 0,95; IC del 95%: 0,70 a 1,30; evidencia de certeza moderada). Cuando los tratamientos se clasificaron según la SG, FOM se clasificó primero, BEV + LOM segundo, LOM tercero, BEV + IRI cuarto, y BEV quinto. La clasificación no tiene en cuenta la certeza de la evidencia, lo que también indica que puede haber poca o ninguna diferencia entre FOM y LOM. Otros tratamientos Tres estudios evaluaron la reoperación versus ninguna reoperación, con o sin reirradiación y quimioterapia, e indicaron posibles ventajas en la supervivencia con la reoperación, en el contexto de poder seleccionar candidatos adecuados para esta intervención. Un tratamiento con cannabinoides en las primeras etapas de evaluación, en combinación con TMZ, merece evaluación adicional. Segunda o posterior recidiva La evidencia limitada de tres estudios heterogéneos indicó que la radioterapia con o sin BEV puede tener un efecto beneficioso sobre la supervivencia, pero se necesita más evidencia. La evidencia no fue suficiente para establecer conclusiones sobre la mejor dosis de radioterapia. Otra evidencia indicó que puede haber poca diferencia en la supervivencia con los campos de tratamiento del tumor en comparación con la mejor opción de tratamiento del médico. No se encontró evidencia fiable sobre el mejor tratamiento de apoyo. Eventos adversos graves (EAG) La combinación BEV + LOM se asoció con un riesgo significativamente mayor de EAG que la monoterapia con LOM (RR 2,51; IC del 95%: 1,72 a 3,66; evidencia de certeza alta), y se clasificó peor junto con cediranib + LOM (RR 2,51; IC del 95%: 1,29 a 4,90; evidencia de certeza alta). LOM se clasificó como el mejor y REG como el segundo mejor. Agregar nuevos tratamientos al BEV se asoció generalmente con un mayor riesgo de eventos adversos graves, en comparación con BEV solo. CONCLUSIONES DE LOS AUTORES: Para el tratamiento de la primera recidiva del GBM en personas tratadas previamente con cirugía y quimiorradioterapia estándar, los tratamientos combinados evaluados no mejoraron la supervivencia general en comparación con la monoterapia con LOM, y a menudo se asociaron con un mayor riesgo de eventos adversos graves. Hay evidencia limitada que indica que la reoperación con o sin reirradiación y quimioterapia puede ser adecuada para candidatos seleccionados. La evidencia sobre la segunda recidiva es escasa. La reirradiación con o sin bevacizumab puede ser de valor en determinados individuos, pero se necesita más evidencia.

MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Systematic Review.

BACKGROUND: The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade gliomas treated with temozolomide, however, there is no consensus on which test method, methylation sites, and cutoff values to use. METHODS: We performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included (i) adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; (ii) where MGMT status was determined in tumor tissue, and assessed by 1 or more technique; and (iii) where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios (HRs). Two or more methods were compared in 32 independent cohorts with 3474 patients. RESULTS: Methylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP. CONCLUSIONS: We cannot draw strong conclusions about use of frozen tissue vs formalin-fixed paraffin-embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and PSQ at CpG sites ranging from 72 to 95. A cutoff threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in 2 of the 3 good-quality studies. About 190 studies were identified presenting HRs from survival analysis in patients in which MGMT methylation was measured by 1 technique only.

COVID-19 vaccine strategies for Aotearoa New Zealand: a mathematical modelling study.

Background: COVID-19 elimination measures, including border closures have been applied in New Zealand. We have modelled the potential effect of vaccination programmes for opening borders. Methods: We used a deterministic age-stratified Susceptible, Exposed, Infectious, Recovered (SEIR) model. We minimised spread by varying the age-stratified vaccine allocation to find the minimum herd immunity requirements (the effective reproduction number Reff<1 with closed borders) under various vaccine effectiveness (VE) scenarios and R0 values. We ran two-year open-border simulations for two vaccine strategies: minimising Reff and targeting high-risk groups. Findings: Targeting of high-risk groups will result in lower hospitalisations and deaths in most scenarios. Reaching the herd immunity threshold (HIT) with a vaccine of 90% VE against disease and 80% VE against infection requires at least 86•5% total population uptake for R0=4•5 (with high vaccination coverage for 30-49-year-olds) and 98•1% uptake for R0=6. In a two-year open-border scenario with 10 overseas cases daily and 90% total population vaccine uptake (including 0-15 year olds) with the same vaccine, the strategy of targeting high-risk groups is close to achieving HIT, with an estimated 11,400 total hospitalisations (peak 324 active and 36 new daily cases in hospitals), and 1,030 total deaths. Interpretation: Targeting high-risk groups for vaccination will result in fewer hospitalisations and deaths with open borders compared to targeting reduced transmission. With a highly effective vaccine and a high total uptake, opening borders will result in increasing cases, hospitalisations, and deaths. Other public health and social measures will still be required as part of an effective pandemic response. Funding: This project was funded by the Health Research Council [20/1018]. Research in context.

An Evaluation of the Tolerability and Feasibility of Combining 5-Amino-Levulinic Acid (5-ALA) with BCNU Wafers in the Surgical Management of Primary Glioblastoma.

Background Glioblastoma (GBM) is the commonest primary malignant brain tumour in adults and effective treatment options are limited. Combining local chemotherapy with enhanced surgical resection using 5-aminolevulinic acid (5-ALA) could improve outcomes. Here we assess the safety and feasibility of combining BCNU wafers with 5-ALA-guided surgery. Methods We conducted a multicentre feasibility study of 5-ALA with BCNU wafers followed by standard-of-care chemoradiotherapy (chemoRT) in patients with suspected GBM. Patients judged suitable for radical resection were administered 5-ALA pre-operatively and BCNU wafers at the end resection. Post-operative treatment continued as per routine clinical practice. The primary objective was to establish if combining 5-ALA and BCNU wafers is safe without compromising patients from receiving standard chemoRT. Results Seventy-two patients were recruited, sixty-four (88.9%) received BCNU wafer implants, and fifty-nine (81.9%) patients remained eligible following formal histological diagnosis. Seven (11.9%) eligible patients suffered surgical complications but only two (3.4%) were not able to begin chemoRT, four (6.8%) additional patients did not begin chemoRT within 6 weeks of surgery due to surgical complications. Eleven (18.6%) patients did not begin chemoRT for other reasons (other toxicity (n = 3), death (n = 3), lost to follow-up/withdrew (n = 3), clinical decision (n = 1), poor performance status (n = 1)). Median progression-free survival was 8.7 months (95% CI: 6.4-9.8) and median overall survival was 14.7 months (95% CI: 11.7-16.8). Conclusions Combining BCNU wafers with 5-ALA-guided surgery in newly diagnosed GBM patients is both feasible and tolerable in terms of surgical morbidity and overall toxicity. Any potential therapeutic benefit for the sequential use of 5-ALA and BCNU with chemoRT requires further investigation with improved local delivery technologies.

Use of Genomics to Track Coronavirus Disease Outbreaks, New Zealand.

Real-time genomic sequencing has played a major role in tracking the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), contributing greatly to disease mitigation strategies. In August 2020, after having eliminated the virus, New Zealand experienced a second outbreak. During that outbreak, New Zealand used genomic sequencing in a primary role, leading to a second elimination of the virus. We generated genomes from 78% of the laboratory-confirmed samples of SARS-CoV-2 from the second outbreak and compared them with the available global genomic data. Genomic sequencing rapidly identified that virus causing the second outbreak in New Zealand belonged to a single cluster, thus resulting from a single introduction. However, successful identification of the origin of this outbreak was impeded by substantial biases and gaps in global sequencing data. Access to a broader and more heterogenous sample of global genomic data would strengthen efforts to locate the source of any new outbreaks.

Prognostic value of test(s) for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for predicting overall survival in people with glioblastoma treated with temozolomide.

BACKGROUND: Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a particular modification to their DNA (called methylation) in a particular region (the O6-methylguanine-DNA methyltransferase (MGMT) promoter) respond better to treatment with chemotherapy using a drug called temozolomide. OBJECTIVES: To determine which method for assessing MGMT methylation status best predicts overall survival in people diagnosed with glioblastoma who are treated with temozolomide. SEARCH METHODS: We searched MEDLINE, Embase, BIOSIS, Web of Science Conference Proceedings Citation Index to December 2018, and examined reference lists. For economic evaluation studies, we additionally searched NHS Economic Evaluation Database (EED) up to December 2014. SELECTION CRITERIA: Eligible studies were longitudinal (cohort) studies of adults with diagnosed glioblastoma treated with temozolomide with/without radiotherapy/surgery. Studies had to have related MGMT status in tumour tissue (assessed by one or more method) with overall survival and presented results as hazard ratios or with sufficient information (e.g. Kaplan-Meier curves) for us to estimate hazard ratios. We focused mainly on studies comparing two or more methods, and listed brief details of articles that examined a single method of measuring MGMT promoter methylation. We also sought economic evaluations conducted alongside trials, modelling studies and cost analysis. DATA COLLECTION AND ANALYSIS: Two review authors independently undertook all steps of the identification and data extraction process for multiple-method studies. We assessed risk of bias and applicability using our own modified and extended version of the QUality In Prognosis Studies (QUIPS) tool. We compared different techniques, exact promoter regions (5'-cytosine-phosphate-guanine-3' (CpG) sites) and thresholds for interpretation within studies by examining hazard ratios. We performed meta-analyses for comparisons of the three most commonly examined methods (immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ)), with ratios of hazard ratios (RHR), using an imputed value of the correlation between results based on the same individuals. MAIN RESULTS: We included 32 independent cohorts involving 3474 people that compared two or more methods. We found evidence that MSP (CpG sites 76 to 80 and 84 to 87) is more prognostic than IHC for MGMT protein at varying thresholds (RHR 1.31, 95% confidence interval (CI) 1.01 to 1.71). We also found evidence that PSQ is more prognostic than IHC for MGMT protein at various thresholds (RHR 1.36, 95% CI 1.01 to 1.84). The data suggest that PSQ (mainly at CpG sites 74 to 78, using various thresholds) is slightly more prognostic than MSP at sites 76 to 80 and 84 to 87 (RHR 1.14, 95% CI 0.87 to 1.48). Many variants of PSQ have been compared, although we did not see any strong and consistent messages from the results. Targeting multiple CpG sites is likely to be more prognostic than targeting just one. In addition, we identified and summarised 190 articles describing a single method for measuring MGMT promoter methylation status. AUTHORS' CONCLUSIONS: PSQ and MSP appear more prognostic for overall survival than IHC. Strong evidence is not available to draw conclusions with confidence about the best CpG sites or thresholds for quantitative methods. MSP has been studied mainly for CpG sites 76 to 80 and 84 to 87 and PSQ at CpG sites ranging from 72 to 95. A threshold of 9% for CpG sites 74 to 78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies making such comparisons.

Medullary Thyroid Cancer Patient's Assessment of Quality of Life Tools: Results from the QaLM Study.

BACKGROUND: Medullary thyroid cancer (MTC) is a neuroendocrine tumour and a rare variant of thyroid cancer with different aetiology, presentation and treatment to differentiated thyroid cancer. Currently available thyroid cancer-specific quality of life (QoL) tools focus on issues and treatments more relevant to patients with differentiated thyroid cancer and therefore may not address issues specific to a MTC diagnosis and cancer journey. METHOD: This prospective multicentre randomised study involved 204 MTC patients completing four quality of life questionnaires (QOLQ) and stating their most and least preferred. The questionnaires were a general instrument, the EORTC QLQ-C30, two disease-specific tools, the MD Anderson Symptom Inventory (MDASI) thyroid module and the City of Hope Quality of Life Scale/THYROID (amended) and the neuroendocrine questionnaire, EORTC QLQ-GINET21. Patients were randomised to complete the four questionnaires in one of 24 possible orders and then answered questions about which tool they preferred. The primary outcome measure was patients' preferred QoL instrument for describing their concerns and for facilitating communication with their healthcare professional. Secondary analyses looked at differences between preferred QOLQs amongst patient subgroups (WHO performance status [0 and 1+], disease stage: early [T1-3, N0 or N1A], metastatic [T4, any T N1b] and advanced [any T any N M1], and type of MTC [sporadic and inherited]), identification of MTC patients' least preferred questionnaire and clinicians' views on the QoL tools in terms of their ability to highlight problems not otherwise ascertained by a standard clinical review. RESULTS: No evidence of a difference was observed for most preferred QOLQ (p = 0.650). There was however evidence of a difference in least preferred questionnaire in the cohort of 128 patients who stated their least preferred questionnaire (p = 0.042), with 36% (46/128) of patients choosing the EORTC QLQ-GI.NET21 questionnaire. Subgroup analyses showed that there was no evidence of a difference in patients' most preferred questionnaire in sporadic MTC patients (p = 0.637), patients with WHO PS 0 or 1+ (p = 0.844 and p = 0.423) nor when comparing patients with early, advanced local or metastatic disease (p = 0.132, p = 0.463 and p = 0.506, respectively). Similarly, subgroup analyses on patients' least preferred questionnaires showed no evidence of differences in sporadic MTC patients (p = 0.092), patients with WHO PS 0 or 1+ (p = 0.423 and p = 0.276), nor in early or metastatic disease patients (p = 0.682 and p = 0.345, respectively). There was however some evidence to suggest a difference in least preferred questionnaire in patients with advanced local stage disease (p = 0.059), with 43% (16/37) of these patients choosing the EORTC QLQ-GI.NET21 questionnaire. CONCLUSIONS: MTC patients regardless of their performance status, disease aetiology and disease burden did not express a preference for any one particular questionnaire suggesting any of the tools studied could be utilized in this patient cohort. The least preferred questionnaire being a gastrointestinal NET specific tool suggests that diarrhoea was not a significant symptom and concern for the population studied.

Impact of the COVID-19 nonpharmaceutical interventions on influenza and other respiratory viral infections in New Zealand.

Stringent nonpharmaceutical interventions (NPIs) such as lockdowns and border closures are not currently recommended for pandemic influenza control. New Zealand used these NPIs to eliminate coronavirus disease 2019 during its first wave. Using multiple surveillance systems, we observed a parallel and unprecedented reduction of influenza and other respiratory viral infections in 2020. This finding supports the use of these NPIs for controlling pandemic influenza and other severe respiratory viral threats.

Response to BRAF and MEK1/2 inhibition in a young adult with BRAF V600E mutant epithelioid glioblastoma multiforme: A Case Report and Literature Review.

Epithelioid glioblastoma multiforme (eGBM) is a rare and aggressive variant of glioblastoma multiforme (GBM) that predominantly affects younger patients and can be difficult to distinguish from other gliomas. Data on how patients with eGBM might be best treated are limited, although genomic analyses have shown that almost half of tumours harbour activating BRAF gene mutations. Here we present the case of a young female with BRAF V600E-mutant eGBM who had a prolonged response to targeted therapy with the BRAF and MEK1/2 inhibitors dabrafenib and trametinib. We review current knowledge about eGBM, including the emerging role for BRAF- ± MEK1/2- targeted therapy.