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The incidence and prevalence of brain tumours have steadily increased within low- and middle-income countries, similar to patterns seen in high-income countries. In addition to the epidemiological landscape of brain tumours in Pakistan, it is important to consider the economics of brain tumour diagnosis and management to inform policy on neuro-oncological healthcare service delivery. The challenges associated with conducting economic evaluations in LMICs include the ability to receive funding for country-specific estimates, dearth of existing data and methodological development, and the need for investment in economic evaluations of health. Economic evaluations are most useful when funding support is given to country-specific initiatives to allocate resources. Cost and cost components must also be meticulously collected to enable accurate calculations of economic evidence for the decision-making process. To put neuro-oncological care at the forefront of the national health agenda, it is crucial for vigorous epidemiological and economic evidence to be available for policymakers.

Guidelines for low- and middle-income countries (LMICs) are needed in complex, multidisciplinary areas such as oncology, requiring mobilising considerable resources and specialists for coordinated care. Neuro-oncology guidelines have been primarily established in countries where technological advancements and robust care pathways facilitate broad resource utilisation. In contrast, LMICs require complex and region-specific interventions to provide equitable care. The present opinion paper is a culmination of our own centre's experience collaborating and developing loco-regional guidelines for brain tumour care, keeping in mind LMIC experiences and expertise available. We intend for the process and methodology to apply to a broader audience of other LMIC authors and clinicians collaborating with LMIC institutions to develop guidelines and clinical recommendations.

Glioblastoma (GBM) is the most common lethal primary brain cancer in adults. Despite treatment regimens including surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy, growth of residual tumor leads to therapy resistance and death. At recurrence, a quarter to a third of all gliomas have hypermutated genomes, with mutational burdens orders of magnitude greater than in normal tissue. Here, we quantified the mutational landscape progression in a patient's primary and recurrent GBM, and we uncovered Cas9-targetable repeat elements. We show that CRISPR-mediated targeting of highly repetitive loci enables rapid elimination of GBM cells, an approach we term "genome shredding." Importantly, in the patient's recurrent GBM, we identified unique repeat sequences with TMZ mutational signature and demonstrated that their CRISPR targeting enables cancer-specific cell ablation. "Cancer shredding" leverages the non-coding genome and therapy-induced mutational signatures for targeted GBM cell depletion and provides an innovative paradigm to develop treatments for hypermutated glioma., Competing Interests: Declaration of interests The Regents of the University of California and the J. David Gladstone Institutes have filed a patent related to this work, on which C.F. is listed as inventor. Silico Therapeutics has filed a patent related to this work, on which A.R.P. and X.S. are listed as inventors. J.A.D. is a co-founder of Caribou Biosciences, Editas Medicine, Intellia Therapeutics, Scribe Therapeutics, and Mammoth Biosciences. J.A.D. is a scientific advisory board member of Caribous Biosciences, Intellia Therapeutics, eFFECTOR Therapeutics, Scribe Therapeutics, Synthego, Metagenomi, Mammoth Biosciences, and Inari. J.A.D. is a member of the board of directors at Driver and Johnson & Johnson. C.F. is a co-founder of Mirimus, Inc., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To provide information about brain tumour epidemiology in Pakistan and potential associated risk factors due to family, medical and social characteristics., Methods: A retrospective cross-sectional nationwide study was designed by the Pakistan Society of Neuro-oncology, to include patients diagnosed with brain tumours in Pakistan retrospectively, from January 1, 2019- December 31, 2019. The study intended to involve data from all age groups for all brain tumour cases, irrespective of histopathology which would determine the national prevalence and incidence of these tumours., Results: A total of 2750 brain tumour cases were recorded, of which 1897 (69%) were diagnosed in the public sector. MRIs were a more common radiological study compared to CT scans. Gliomas were the most common tumours 778 (28.29%), while pineal tumours were the least common 19 (0.69%). The median age at diagnosis for males was 36 (24-49), while the median age at diagnosis for females was 37 (24-48). Hypertension was the most common co-morbidity in patients diagnosed with a brain tumour, 524 (51.89%), and smoking was the most frequent social behaviour, 355 (62.02%). Findings indicate a low metastasis frequency and few females seeking care., Conclusions: The PBTES and the PBTC have presented an opportunity and platform for hospitals and health professionals to work together to strengthen cancer care health systems, ensure implementation of treatment guidelines and conduct regular cancer registration.

Objective: To examine the effect of distance travelled for brain tumour surgery on patient outcomes in an LMIC., Methods: Data were collected as part of the Pakistan Brain Tumour Epidemiology Study (PBTES) for brain tumour patients who underwent surgery in 2019. Mapping software was used to calculate the distance travelled by each patient from their primary address to the hospital. This was analysed in correlation with outcomes (change in KPS score, current status) and demographic variables., Results: Of 2366 patients, the median distance travelled across the country was 104 km (IQR: 9.07 - 304). Only 970 (41%) patients had access to brain tumour surgical care within 50 km of their primary address. A total of 372 (15.7%) patients requiring brain tumour surgery had to travel more than 500 km to reach their primary care hospital. Patients travelling more than 50 km for brain tumour surgery had better pre- and post-surgery Karnofsky performance scores (p<0.001) than those travelling less than 50 km. The overall survival for these patients was also better (82.4% vs 75.7%, p= 0.002) compared to patients travelling less than 50 km., Conclusions: The distance to a hospital dictates a patient's access to continuity of care through adjuvant chemoradiotherapy and regular follow-ups. Less than half of brain tumour patients in Pakistan had access to brain tumour surgery care within 50 km of their homes. Overall outcomes were significantly better in patients travelling more than 50km for neurosurgical care - suggesting a distance bias effect.

Objective: To ascertain the age and gender differences, treatment, and management of meningiomas across Pakistan.., Methods: Data were collected as part of the PBTES, and patients with a histopathological diagnosis of an intracranial meningioma in 2019 that presented at these centres were included in this cohort study sub-analysis. Thirty-two centres participated in the study. Medical students, residents, and faculty collated data from medical records., Results: Our data indicate that meningiomas constitute 15.6% of all intracranial tumours in Pakistan and occur more often in females (236, 55%) than in males. The mean age at diagnosis was 43.7 ± 19.9 years. Meningiomas had a slightly higher preponderance in the right hemisphere of the brain at 203 (47.32%) tumours and 267 (62.2%) of the tumours in the frontal and parietal lobes. We found that 174 (61.3%) of all meningiomas diagnosed in Pakistan in 2019 were grade I tumours, which was also the most commonly occurring tumour grade. Adjuvant chemoradiotherapy for meningiomas was rarely observed in Pakistan., Conclusions: The PBTES reveals a low hospital-based incidence of meningiomas in 2019 when compared to the incidence in high-income countries but found evidence similar to those of other LMICs. Tumour characteristics, such as location, grading and surgical procedures, were similar to global literature.

Objective: To observe the patient characteristics and centres providing neuro-oncological care in public and private health hospitals in Pakistan., Method: The Pakistan Association of Neuro-oncology carried out a retrospective, cross-sectional study in 2019 on patients admitted to 32 hospitals in Pakistan, with dedicated neurosurgical facilities. Patients with a histopathological diagnosis of an intracranial tumour were included., Results: Public health care facilities catered for 84% patients with ages between 20 and 60 years and children having intracranial tumours. Private centres were utilised by 66.7% patients from the upper socioeconomic sector. More patients were lost to follow-up in the public sector (n = 784) versus in the private sector (n = 356). Mortality was also higher in the public sector hospitals, (13.9%) as compared to 9.6% in the private sector., Conclusions: Public and private sector health services for neuro-oncological care in Pakistan still have a long way to go to cover the gaps for unmet needs. Strengthening health systems for brain tumour care is imperative to increase both the access to care and the quality of care to fulfil this need.

Objectives: To combat the lack of brain tumour registries, the Pakistan Brain Tumour Epidemiology Study (PBTES) was conducted without any funding from an external source., Methods: A retrospective analysis of patient data, including patients of all age groups diagnosed with all histopathological types of brain tumours from all over Pakistan, was performed. For this, Pakistan Brain Tumour Consortium (PBTC) was established, including 32 neurosurgical centres from around the country. Data was collected online through a proforma that included variables such as patient demographics, clinical characteristics, operative details, postoperative complications, survival indices, and current functional status. The data collection and analysis team included principal investigators, core leads, regional leads, regional associates, and student facilitators. Despite logistical concerns and lack of resources, the PBTES was conducted successfully, and a formal brain tumour surveillance database was formed without any external funding, which remains unheard of., Conclusions: The methods applied in this study are reproducible and can be employed not just to develop more robust brain tumour and other cancer registries but also to study the epidemiology of communicable and non-communicable diseases in resource-limited settings, both locally and globally.

Objective: To identify populations at risk for lost to follow-up while undergoing management of brain tumours in a low-resource setting., Methods: A retrospective study was conducted at the neurosurgical centre on patients presenting with a brain tumour from January 1, 2019, to December 31, 2019. Data on demographic characteristics, surgical characteristics, treatment, and outcomes such as mortality status, were collected by manual chart review. LTFU was defined as patients discontinuing clinical follow-up at the institute of surgical consultation within two years from the initial visit. Univariate (odds ratio) and multivariate (b-coefficient) logistic regression were used to determine factors' significance for LTFU., Results: From a total of 2750 patients from 32 centres, 1140 (41.4%) were LTFU during the study period. Of these 1140 LTFU patients, 156 (13.7%) were LTFU without any intervention, 984 (86.3%) were LTFU after the primary surgery, and 872 (76.5%) patients were LTFU without any adjuvant treatment. On univariate analysis annual hospital case volume (p< 0.001), older age group (15-39 years (p=0.037) and ?40 years (p= 0.016)), and non-surgical treatment (p<=0.026) correlated with a higher risk of LTFU. Belonging to the middle-class cohort was correlated with a better chance of follow up (p=0.001). Multivariate analysis demonstrated that larger centres had the largest b-coefficient of 1.53 (95% CI= 1.3-1.8, p< 0.001)., Conclusions: Our study demonstrated that almost half of patients diagnosed with brain tumours were LTFU within two years of diagnosis. Larger centres, non-surgical treatment, and older age seem to be associated with higher LTFU. Identifying vulnerable populations will allow the need-based provision of care and follow-up to improve health outcomes.

Objective: To investigate waiting times for brain tumour surgery in Pakistan from a nationwide sample and highlight specific affected patient populations., Method: A nationwide study was conducted as part of the Pakistan Brain Tumour Epidemiology Study; data from 32 high-volume neurosurgical centres were collected. The national sample included 2,750 patients. Time to surgery was calculated by the difference in dates recorded for radiological diagnosis and the date of the first surgery. This was further stratified according to demographic factors, histopathological diagnosis, type of surgical procedure performed and survival outcomes., Results: The data of 1,474 patients for time to surgery was available. Patients travelling to public hospitals had significantly longer mean wait times (94.07 (CI: 85.29, 102.84) vs 75.14 (CI: 54.72, 95.56) days, p<0.001). Significant differences were seen between patients of various age groups, as adolescents (116.63 (CI: 65.27, 167.98) days) and young adults (103.34 (CI: 85.96, 120.72) days) had higher waiting times compared to middle-aged (72.44 (CI: 61.26, 83.61) days) and older (48.58 (CI: 31.17, 65.98) days) adults. No difference was seen between the genders. A significantly longer time to surgery was observed for middle- and lower-socioeconomic class patients. Those undergoing gross total resection of the tumour had significantly (p<0.001) longer waiting times for surgery when compared to STR (sub-total resection), biopsy, and CSF-diversion procedures, for all tumour types. Patients diagnosed with meningioma had the most prolonged waiting periods (106 (CI: 76, 95) days). Gliomas had a mean waiting period of 88 (CI: 73, 103) days across the country. Low-grade gliomas had significantly (p=0.031) longer mean waiting times (99.73 (CI: 61.91, 127.36) days) in comparison to high-grade gliomas (70.13 (CI: 43.39, 89.69 ) days). A significant difference was seen between waiting times for patients who survived surgical procedures for a brain tumour on the most recent follow-up and those who had expired (91.87 (CI: 79, 107.74) vs 77.41 (CI: 59.90, 94.91) days, p<0.001)., Conclusions: Prolonged delays to surgery are a significant barrier within low-and-middle-income countries, leading to adverse outcomes for patients. Patients undergoing brain tumour surgery at public hospitals from lower or middle SES and electing for gross resections were more likely to have longer delays.

Objective: To identify the surgical incidence and prevalence of schwannoma in our region and quantify the demographic, surgical, neoplastic, and outcome characteristics of the patients diagnosed with schwannoma.., Methods: A retrospective cross-sectional study was conducted from January 1 to December 31, 2019. Enrolled were 32 of the highest volume neurosurgical centres in Pakistan. Patients with a histopathological diagnosis of schwannoma and radiological imaging were included in the study. Medical records were reviewed for data, and SPSS version 25 was used for statistical analysis. Patients were followed up for one year, which was the duration of the study., Results: From 2750 patients diagnosed with brain tumours, 148 patients had schwannomas. Out of these, 84 (56.8%) patients were male, and 64 (43.2%) patients were female. The mean age of the patients was 39 ± 14 years. The socioeconomic statuses of the enrolled patients were lower in 72 (53.3%) patients, middle in 57 (42.2%) patients, and upper middle to upper in 6 (4.4%) patients. All patients underwent surgery, 14 patients received radiotherapy, and two patients received chemotherapy. In our cohort, 115 (77.7%) patients presented to public sector hospitals, with only 33 (22.3%) patients presenting to private hospitals. At the end of the study period, 60 (40.5%) patients had been lost to follow-up. Of the remaining 88 patients, 75 (85.2%) were alive. The mortality rate on a one-year follow-up was 14.8%., Conclusions: Schwannoma comprises a larger percentage of the brain tumours in our regions than reported in the literature. The high mortality rate is of particular concern and warrants further investigation to improve patient care and outcomes.

Objective: To quantify the metastatic brain tumour burden presenting to tertiary care neurosurgical centres, the demographics and mortality rate, and the type of metastatic tumours commonly presenting to neurosurgical practice., Method: A cross-section retrospective study was conducted on patients diagnosed with brain tumours from 32 neurosurgical centres across Pakistan between January 1, 2019, to December 31, 2019. At least one neurosurgical resident and one neurosurgical faculty member were recruited from each centre as members of the Pakistan Brain tumour consortium. Mean with standard deviation or median with interquartile range was reported as variables., Results: Of 2750 patients in this cohort, 77 (2.8%) were diagnosed with metastatic brain tumours. The median age of these patients was 52 (IQR= 43-60) years; 9 (14%) adults were aged 20-39 years, 37 (57%) were aged 40-59, and 19 (29%) were aged 60 and above. There were 62 (82.7%) married patients with 4% unmarried. The median KPS score both pre and post-surgery was 80 (IQR= 60-90, 70-90 respectively), and 43 (55.8%) patients were lost to follow-up. The mortality rate for patients that followed up was 50%, 17 patients were alive, and 17 were deceased at the end of the study period. The 30-day mortality rate amongst our patients was 11.8% (n=4)., Conclusions: The number of patients presenting to neurosurgical care with brain metastases is much lower than the expected incidence of metastatic brain lesions. Multidisciplinary integration and the establishment of a registry to track patients diagnosed with brain tumours is the first step in ensuring better care for these patients.

Objective: To build a comprehensive brain tumour database that will allow us to analyse in detail the prevalence, demographics, and outcomes of the disease in paediatric, adolescent, and young adult age groups., Method: A national cross-sectional study was conducted at 32 centres, and data regarding patient demographics and brain tumours were collected. This data was then stratified based on age groups, healthcare sectors, socioeconomic status, tumour types, and surgical outcomes., Results: Most of the patients who were diagnosed with brain tumours belonged to a lower socioeconomic background and went to public sector hospitals. More males were diagnosed with and treated for brain tumours in the paediatric, adolescent, and young adult populations. The most common tumour in the paediatric population was medulloblastoma (23.7%) and the most common tumour in the adolescent (27.8%) and young adult population (34.7%) was glioma. Significant improvement in KPS scores were seen for: craniopharyngioma (p = 0.001), meningioma (p < 0.0005) and pituitary adenoma (p < 0.0005)., Conclusions: This study shows that in all three age groups, there was a greater prevalence in males. Most of the patients belonged to a lower-middle-income class background and most patients presented to public sector hospitals. Greater knowledge of these parameters unique to each age group is the key to understanding and alleviating the burden of disease. Cancer registries, specifically brain tumour registries that keep up-to-date records of these patients, are essential to identify and keep track of these unique parameters to advance medical research and treatment strategies, ultimately lowering the disease burden.

Objective: To explore the differences in demographic, surgical, and prognostic characteristics between the two genders in patients with brain tumours in Pakistan., Method: This study was a retrospective cross-sectional analysis of patients with a histopathological brain tumour diagnosis across 32 high-volume hospitals in Pakistan. The study period was from January 1, 2019, to December 31, 2019. There were no restrictions on inclusion apart from time.., Results: From 2750 patients enrolled in the study, 1605 (58.4%) were male, and 1142 (41.6%) were female . The median age amongst males was 36 (24-49), while the median age amongst females was 37 (24-48). The ratio of married to unmarried patients was 2.7:1 for females and 1.3:1 for males. Surgical treatment was carried out for 1430 (58.1%) males and 1013 (41.9%) females. The median time to surgery was 25 (4-107) days for males and 31 (5-98) days for females. The greatest disparity in tumour malignancy was in grade IV gliomas., Conclusions: Males generally have a higher incidence of brain tumours in our experience, apart from meningiomas, which favour females. The mortality rate and glioblastoma incidence rate are both higher amongst males. However, post-treatment cure is also witnessed. Sociocultural norms play a prominent role in accessing healthcare. Women are generally at a disadvantage compared to their male counterparts, which may impact reporting of brain tumour cases and treatment outcomes.

Objective: To quantify the frequency of craniopharyngiomas presenting to tertiary care neurosurgical centres, the demographics and mortality rate, and commonly presenting to neurosurgical practice., Method: Our study was a retrospective cross-sectional analysis of patients admitted at 32 neurosurgical centres between January 1, 2019, and December 31, 2019, with brain tumour. Kruskal Wallis analysis was used to determine normality; normally distributed variables were reported as means with standard deviation, while median with interquartile range was used for non-normally distributed variables., Results: Of 2750 patients with brain tumours, 114 patients presented with craniopharyngioma. The median age at diagnosis was 18 years, with 42 (42.8%) patients below the age of 15, 40 (40.9%) patients aged 15-39, and 16 (16.3%) patients aged 40 and above. There were 70 (61.4%) males and 44 (38.6%) females in our cohort. Gross total resection was performed in 42(36.8%), 45 (39.5%) underwent subtotal resection, 9 (7.9%) underwent CSF diversion only, and 2 (1.8%) had a biopsy. Most of our patients 94(82.5%) presented to public hospitals, with 20 (17.5%) patients presenting to private hospitals (p=0.002). The overall survival at two years was 86.8% in patients with known outcomes, and only 10% of patients died within 30 days of surgery., Conclusions: Craniopharyngiomas comprised a small portion of all brain tumours in our region. They are more common in males and in patients from the lower socioeconomic class. These patients mainly presented to public sector hospitals, and the three highest volume centres were all public sector institutions. The overall survival rate at two years in our region is lower than in other regions.

Objective: To define the landscape of treatment patterns and current epidemiological data regarding gliomas in Pakistan., Methods: As part of the Pakistan Brain Tumour Epidemiology Study (PBTES), data were collected from 32 neurosurgical centres across the country. Our retrospective study looked at patients who underwent surgical procedures for gliomas in 2019 in neurosurgical centres. The data was collated and analysed using STATA version 15., Results: A total of 781 patients with gliomas were identified 479(61.8%) in public sector hospitals, 302(39.1%) in the private sector). The most common histopathological subtypes were glioblastoma 262 (33.5%), followed by astrocytoma 147(18.8%) and oligodendroglioma 93(11.9%). Gender distribution was skewed towards men 508(65%). Private institution hospitals performed surgical biopsies as the first surgical procedure 75(23%) more often than public hospitals 38(9%). Chemotherapy was given to 115(29.8%) patients, and there was no data regarding 467(53%) of patients. Similarly, only 202(43.9%) patients received radiation therapy, and there was no data for 469(60%) of patients. For high-grade gliomas specifically, only 95(31.8%) patients with HGG have a record of receiving radiation therapy, and only 57(18.9%) had a record of being started on chemotherapy., Conclusion: Our study highlighted gaps in glioma management within Pakistan, with only around half of our patients receiving chemotherapy and radiotherapy, despite it being indicated. In our experience, high-grade tumours were diagnosed at a younger age than in high-income countries, but overall, glioblastoma was a smaller constituent of our tumour sample than expected.

Objective: To enumerate the burden of ependymoma in our region and identify the demographic, tumoural, surgical, clinical characteristics, and outcomes of patients diagnosed with ependymoma., Methods: This retrospective cross-sectional study included patients admitted under neurosurgical service between January 1 and December 31, 2019. The inclusion criterion for the study was a histopathological diagnosis of the brain lesion. The experience of the ependymal brain tumours observed at the 32 participating sites in Pakistan is presented., Results: A total of 2750 patients with brain tumours were seen in 2019 at our centres of whom 58(2.1%) had a histopathological diagnosis of ependymoma. The median age at diagnosis was nine (IQR= 4.5-24.5) years. The median time to surgery from date of radiological diagnosis was 38.5 (IQR= 4-93.8) days. The median KPS score at presentation was 70 (IQR= 60-80), and post-surgery was 90 (IQR= 70-100), showing an average increase of 20. Our population's overall mortality rate for ependymoma was 31.1%, with the 30-day mortality rate being 2.2% (lower than the 4.5% on average for all brain tumours in our cohort)., Conclusions: Ependymomas were predominantly found in the paediatric population in the presented cohort. While gender distribution and histopathological grading seemed to follow international trends, this study had a much higher mortality rate and a much lower gross total resection rate than centres in high-income countries.