PRDM16 Suppresses MLL1r Leukemia via Intrinsic Histone Methyltransferase Activity.

PRDM16 is a transcription co-factor that plays critical roles in development of brown adipose tissue, as well as maintenance of adult hematopoietic and neural stem cells. Here we report that PRDM16 is a histone H3K4 methyltransferase on chromatin. Mutation in the N-terminal PR domain of PRDM16 abolishes the intrinsic enzymatic activity of PRDM16. We show that the methyltransferase activity of PRDM16 is required for specific suppression of MLL fusion protein-induced leukemogenesis both in vitro and in vivo. Mechanistic studies show that PRDM16 directly activates the SNAG family transcription factor Gfi1b, which in turn downregulates the HOXA gene cluster. Knockdown Gfi1b represses PRDM16-mediated tumor suppression, while Gfi1b overexpression mimics PRDM16 overexpression. In further support of the tumor suppressor function of PRDM16, silencing PRDM16 by DNA methylation is concomitant with MLL-AF9-induced leukemic transformation. Taken together, our study reveals a previously uncharacterized function of PRDM16 that depends on its PR domain activity.

Interventions for undergraduate and postgraduate medical learners with academic difficulties: A BEME systematic review update: BEME Guide No. 85.

BACKGROUND: Clinical teachers often struggle to record trainee underperformance due to lacking evidence-based remediation options. OBJECTIVES: To provide updated evidence-based recommendations for addressing academic difficulties among undergraduate and postgraduate medical learners. METHODS: A systematic review searched databases including MEDLINE, CINAHL, EMBASE, ERIC, Education Source, and PsycINFO (2016-2021), replicating the original Best Evidence Medical Education 56 review strategy. Original research/innovation reports describing intervention(s) for medical learners with academic difficulties were included. Data extraction used Michie's Behaviour Change Techniques (BCT) Taxonomy and program evaluation models from Stufflebeam and Kirkpatrick. Quality appraised used the Mixed Methods Appraisal Tool (MMAT). Authors synthesized extracted evidence by adapting GRADE approach to formulate recommendations. RESULTS: Eighteen articles met the inclusion criteria, primarily addressing knowledge (66.7%), skills (66.7%), attitudinal problems (50%) and learner's personal challenges (27.8%). Feedback and monitoring was the most frequently employed BCT. Study quality varied (MMAT 0-100%). We identified nineteen interventions (UG: n = 9, PG: n = 12), introducing twelve new thematic content. Newly thematic content addressed contemporary learning challenges such as academic procrastination, and use of technology-enhanced learning resources. Combined with previous interventions, the review offers a total dataset of 121 interventions. CONCLUSION: This review offers additional evidence-based interventions for learners with academic difficulties, supporting teaching, learning, faculty development, and research efforts.

Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia.

Here we report a comprehensive characterization of our recently developed inhibitor MM-401 that targets the MLL1 H3K4 methyltransferase activity. MM-401 is able to specifically inhibit MLL1 activity by blocking MLL1-WDR5 interaction and thus the complex assembly. This targeting strategy does not affect other mixed-lineage leukemia (MLL) family histone methyltransferases (HMTs), revealing a unique regulatory feature for the MLL1 complex. Using MM-401 and its enantiomer control MM-NC-401, we show that inhibiting MLL1 methyltransferase activity specifically blocks proliferation of MLL cells by inducing cell-cycle arrest, apoptosis, and myeloid differentiation without general toxicity to normal bone marrow cells or non-MLL cells. More importantly, transcriptome analyses show that MM-401 induces changes in gene expression similar to those of MLL1 deletion, supporting a predominant role of MLL1 activity in regulating MLL1-dependent leukemia transcription program. We envision broad applications for MM-401 in basic and translational research.

Molecular basis underlying histone H3 lysine-arginine methylation pattern readout by Spin/Ssty repeats of Spindlin1.

Histone modification patterns and their combinatorial readout have emerged as a fundamental mechanism for epigenetic regulation. Here we characterized Spindlin1 as a histone effector that senses a cis-tail histone H3 methylation pattern involving trimethyllysine 4 (H3K4me3) and asymmetric dimethylarginine 8 (H3R8me2a) marks. Spindlin1 consists of triple tudor-like Spin/Ssty repeats. Cocrystal structure determination established concurrent recognition of H3K4me3 and H3R8me2a by Spin/Ssty repeats 2 and 1, respectively. Both H3K4me3 and H3R8me2a are recognized using an "insertion cavity" recognition mode, contributing to a methylation state-specific layer of regulation. In vivo functional studies suggest that Spindlin1 activates Wnt/ß-catenin signaling downstream from protein arginine methyltransferase 2 (PRMT2) and the MLL complex, which together are capable of generating a specific H3 "K4me3-R8me2a" pattern. Mutagenesis of Spindlin1 reader pockets impairs activation of Wnt target genes. Taken together, our work connects a histone "lysine-arginine" methylation pattern readout by Spindlin1-to-Wnt signaling at the transcriptional level.

Point-of-care ultrasound for evaluation of vaginal bleeding or abdominal pain in early pregnancy: Use by family physicians following focused training and certification.

OBJECTIVE: To evaluate the use of point-of-care ultrasound (POCUS) for the assessment of patients experiencing first-trimester bleeding or abdominal pain by family physicians working in family medicine clinics following first-trimester POCUS training and certification. DESIGN: Multisite, retrospective chart review. SETTING: Two hospital-affiliated academic family medicine clinics in Toronto, Ont. PARTICIPANTS: Twelve family physicians who completed a first-trimester POCUS training and certification course. MAIN OUTCOME MEASURES: The primary outcome was the proportion of family physicians using POCUS during their evaluations of patients in the first trimester of pregnancy in the 6 months following the FPs' successful completion of the Family Medicine Obstetrical Ultrasound (FaMOUS) course. Secondary outcomes included indications for POCUS use, diagnostic accuracy of POCUS compared with radiologist-interpreted ultrasound, pregnancy outcomes, and emergency department visits within 10 days of the index family medicine clinic visit. RESULTS: Of the 12 certified family physicians, 7 (58.3%) used POCUS during their assessments of first-trimester patients during the study period. The FPs used POCUS with 56 patients for the following indications: 11 (19.6%) had only vaginal bleeding, 5 (8.9%) had only abdominal pain, and 8 (14.3%) had both vaginal bleeding and abdominal pain; the indication for 32 patients (57.1%) was unclear. Forty-six patients (82.1%) underwent a subsequent radiologist-interpreted ultrasound within 10 days of the index POCUS test. Compared with radiologist-interpreted ultrasound, POCUS had a sensitivity of 91.3% (95% CI 79.2% to 97.6%) for documenting intrauterine pregnancy and a sensitivity of 81.4% (95% CI 66.6% to 91.6%) for documenting the presence of fetal cardiac activity. CONCLUSION: Following a first-trimester POCUS certification course, family physicians used POCUS for the assessment of first-trimester patients with varying frequency and for indications other than vaginal bleeding or abdominal pain. Further study is needed to assess the clinical impact of office-based POCUS, unforeseen barriers and facilitators to its use, and patient and provider preferences.

Survival of colorectal cancer patients in Brunei Darussalam: comparison between 2002-09 and 2010-17.

BACKGROUND: Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide. It is the second leading cause of cancer death in men and women in Brunei Darussalam in 2017, posing a major burden on society. METHODS: This retrospective cohort study (n = 1035 patients diagnosed with CRC in Brunei Darussalam from 1st January 2002 until 31st December 2017) aims to compare the overall survival rates of CRC patients (2002-2017), to compare survival rates between two study periods (2002-2009 and 2010-2017) and to identify prognostic factors of CRC. Kaplan-Meier estimator and log-rank tests were performed to analyse the overall survival rates of CRC patients. Multiple Cox regression was performed to determine the prognostic factors of CRC with adjusted hazard ratios (Adj. HRs) reported. RESULTS: The 1-, 3- and 5-year survival rates of CRC patients are 78.6, 62.5, and 56.0% respectively from 2002 to 2017. The 1-, 3-, and 5-year survival rates of CRC patients for 2002-2009 are 82.2, 69.6, and 64.7%; 77.0, 59.1, and 51.3% for 2010-2017 respectively. A significant difference in CRC patients' survival rate was observed between the two study periods, age groups, ethnic groups, cancer stages, and sites of cancer (p < 0.05). The Adjusted Hazard Ratios (Adj. HRs) were significantly higher in the 2010-17 period (Adj. HR = 1.78, p < 0.001), older age group ( ≥ 60 years) (Adj. HR = 1.93, p = 0.005), distant cancer (Adj. HR = 4.69, p < 0.010), tumor at transverse colon and splenic flexure of colon (Adj. HR = 2.44, p = 0.009), and lower in the Chinese(Adj. HR = 0.63, p = 0.003). CONCLUSION: This study highlights the lower survival rates of CRC patients in 2010-2017, Malays, older patients, distant cancer, and tumors located at the latter half of the proximal colon (transverse colon), and predominantly LCRC (splenic flexure, descending colon, sigmoid colon, overlapping lesion colon and colon (NOS), as well as the rectosigmoid junction and rectum (NOS)). Age, ethnicity, cancer stage, and tumor location are significant prognostic factors for CRC. These findings underscore the importance of public health policies and programmes to enhance awareness on CRC from screening to developing strategies for early detection and management, to reduce CRC-associated mortality.

ASH2L regulates ubiquitylation signaling to MLL: trans-regulation of H3 K4 methylation in higher eukaryotes.

Crosstalk between H2B ubiquitylation (H2Bub) and H3 K4 methylation plays important roles in coordinating functions of diverse cofactors during transcription activation. The underlying mechanism for this trans-tail signaling pathway is poorly defined in higher eukaryotes. Here, we show the following: (1) ASH2L in the MLL complex is essential for H2Bub-dependent H3 K4 methylation. Deleting or mutating K99 of the N-terminal winged helix (WH) motif in ASH2L abrogates H2Bub-dependent regulation. (2) Crosstalk can occur in trans and does not require ubiquitin to be on nucleosomes or histones to exert regulatory effects. (3) trans-regulation by ubiquitin promotes MLL activity for all three methylation states. (4) MLL3, an MLL homolog, does not respond to H2Bub, highlighting regulatory specificity for MLL family histone methyltransferases. Altogether, our results potentially expand the classic histone crosstalk to nonhistone proteins, which broadens the scope of chromatin regulation by ubiquitylation signaling.

The medico-legal helpline: A content analysis of postgraduate medical trainee advice calls.

CONTEXT: Available literature exploring medical liability and postgraduate medical education consistently posits that postgraduate trainees worry about their exposure to medico-legal liability. This assumption has formed the basis for research and curriculum development. OBJECTIVES: The aim of this study was to describe the encounters that lead physicians-in-training to seek external medico-legal guidance. We sought to provide empirical evidence on trends and themes related to medico-legal advice requests from physicians-in-training. METHODS: Our primary dataset consisted of records of calls from physicians-in-training to the medico-legal helpline of the Canadian Medical Protective Association (CMPA), a national mutual defence organisation providing medico-legal advice and liability protection for over 95% of Canada's physicians. We conducted a trend analysis of the frequency of calls for advice over 10 years from physician-in-training compared with non-trainee physicians. Furthermore, we performed a content analysis of calls made over the most recent 2 years (2016-2017) to elucidate the concerns that led to trainees seeking medico-legal advice. RESULTS: The 10-year trend analysis revealed that the annual growth in the number of physician-in-training advice calls (8.8%) exceeded other CMPA physician groups and was in excess of trainee population growth over the same period. The content analysis identified four core themes: managing confidential information, complex care situations, academic matters and patient safety incidents. CONCLUSIONS: Our findings indicate that trainees are asking questions about their medico-legal liability with increasing frequency. This study contributes new evidence on the issues that lead to trainees seeking help. We believe that understanding trainees' medico-legal advice requests will support medical educators to tailor quality improvement education to learners' needs.

Facile target validation in an animal model with intracellularly expressed monobodies.

Rapidly determining the biological effect of perturbing a site within a potential drug target could guide drug discovery efforts, but it remains challenging. Here, we describe a facile target validation approach that exploits monobodies, small synthetic binding proteins that can be fully functionally expressed in cells. We developed a potent and selective monobody to WDR5, a core component of the mixed lineage leukemia (MLL) methyltransferase complex. The monobody bound to the MLL interaction site of WDR5, the same binding site for small-molecule inhibitors whose efficacy has been demonstrated in cells but not in animals. As a genetically encoded reagent, the monobody inhibited proliferation of an MLL-AF9 cell line in vitro, suppressed its leukemogenesis and conferred a survival benefit in an in vivo mouse leukemia model. The capacity of this approach to readily bridge biochemical, structural, cellular characterization and tests in animal models may accelerate discovery and validation of druggable sites.

Interventions for undergraduate and postgraduate medical learners with academic difficulties: A BEME systematic review: BEME Guide No. 56.

Background: Clinical teachers often struggle to report unsatisfactory trainee performance, partly because of a lack of evidence-based remediation options. Objectives: To identify interventions for undergraduate (UG) and postgraduate (PG) medical learners experiencing academic difficulties, link them to a theory-based framework and provide literature-based recommendations around their use. Methods: This systematic review searched MEDLINE, CINAHL, EMBASE, ERIC, Education Source and PsycINFO (1990-2016) combining these concepts: medical education, professional competence/difficulty and educational support. Original research/innovation reports describing intervention(s) for UG/PG medical learners with academic difficulties were included. Data extraction employed Michie's Behavior Change Techniques (BCT) Taxonomy and program evaluation models from Stufflebeam and Kirkpatrick. Quality appraisal used the Mixed Methods Appraisal Tool (MMAT). The authors synthesized extracted evidence by adapting the GRADE approach to formulate recommendations. Results: Sixty-eight articles met the inclusion criteria, most commonly addressing knowledge (66.2%), skills (53.9%) and attitudinal problems (26.2%), or learner personal issues (41.5%). The most common BCTs were Shaping knowledge, Feedback/monitoring, and Repetition/substitution. Quality appraisal was variable (MMAT 0-100%). A thematic content analysis identified 109 interventions (UG: n = 84, PG: n = 58), providing 24 strong, 48 moderate, 26 weak and 11 very weak recommendations. Conclusion: This review provides a repertoire of literature-based interventions for teaching/learning, faculty development, and research purposes.

Videos in clinical medicine. Insertion of an intraosseous needle in adults.

Intraosseous needle insertion is used as a temporary measure when intravascular access cannot be achieved through peripheral or central venous routes. The intraosseous needle may remain in situ for 72 to 96 hours, but it is best removed within 6 to 12 hours, as soon as an alternative site of intravascular access has been established. The intraosseous route provides fast and reliable vascular access in emergency medical situations. The use of the appropriate technique will ensure that the procedure is performed as safely and effectively as possible.

Cellular Reparative Mechanisms of Mesenchymal Stem Cells for Retinal Diseases.

The use of multipotent mesenchymal stem cells (MSCs) has been reported as promising for the treatment of numerous degenerative disorders including the eye. In retinal degenerative diseases, MSCs exhibit the potential to regenerate into retinal neurons and retinal pigmented epithelial cells in both in vitro and in vivo studies. Delivery of MSCs was found to improve retinal morphology and function and delay retinal degeneration. In this review, we revisit the therapeutic role of MSCs in the diseased eye. Furthermore, we reveal the possible cellular mechanisms and identify the associated signaling pathways of MSCs in reversing the pathological conditions of various ocular disorders such as age-related macular degeneration (AMD), retinitis pigmentosa, diabetic retinopathy, and glaucoma. Current stem cell treatment can be dispensed as an independent cell treatment format or with the combination of other approaches. Hence, the improvement of the treatment strategy is largely subjected by our understanding of MSCs mechanism of action.

Micro-Computed Tomography Detection of Gold Nanoparticle-Labelled Mesenchymal Stem Cells in the Rat Subretinal Layer.

Mesenchymal stem cells are widely used in many pre-clinical and clinical settings. Despite advances in molecular technology; the migration and homing activities of these cells in in vivo systems are not well understood. Labelling mesenchymal stem cells with gold nanoparticles has no cytotoxic effect and may offer suitable indications for stem cell tracking. Here, we report a simple protocol to label mesenchymal stem cells using 80 nm gold nanoparticles. Once the cells and particles were incubated together for 24 h, the labelled products were injected into the rat subretinal layer. Micro-computed tomography was then conducted on the 15th and 30th day post-injection to track the movement of these cells, as visualized by an area of hyperdensity from the coronal section images of the rat head. In addition, we confirmed the cellular uptake of the gold nanoparticles by the mesenchymal stem cells using transmission electron microscopy. As opposed to other methods, the current protocol provides a simple, less labour-intensive and more efficient labelling mechanism for real-time cell tracking. Finally, we discuss the potential manipulations of gold nanoparticles in stem cells for cell replacement and cancer therapy in ocular disorders or diseases.

Parasitic Mistletoes of the Genera Scurrula and Viscum: From Bench to Bedside.

The mistletoes, stem hemiparasites of Asia and Europe, have been used as medicinal herbs for many years and possess sophisticated systems to obtain nutrients from their host plants. Although knowledge about ethnomedicinal uses of mistletoes is prevalent in Asia, systematic scientific study of these plants is still lacking, unlike its European counterparts. This review aims to evaluate the literature on Scurrula and Viscum mistletoes. Both mistletoes were found to have anticancer, antimicrobial, antioxidant and antihypertensive properties. Plants from the genus Scurrula were found to inhibit cancer growth due to presence of phytoconstituents such as quercetin and fatty acid chains. Similar to plants from the genus Viscum, Scurrula also possesses TNFα activity to strengthen the immune system to combat cancer. In line with its anticancer activity, both mistletoes are rich in antioxidants that confer protection against cancer as well as neurodegeneration. Extracts from plants of both genera showed evidence of vasodilation and thus, antihypertensive effects. Other therapeutic effects such as weight loss, postpartum and gastrointestinal healing from different plants of the genus Scurrula are documented. As the therapeutic effects of plants from Scurrula are still in exploration stage, there is currently no known clinical trial on these plants. However, there are few on-going clinical trials for Viscum album that demonstrate the functionalities of these mistletoes. Future work required for exploring the benefits of these plants and ways to develop both parasitic plants as a source of pharmacological drug are explained in this article.

One-pot refolding of core histones from bacterial inclusion bodies allows rapid reconstitution of histone octamer.

We report an optimized method to purify and reconstitute histone octamer, which utilizes high expression of histones in inclusion bodies but eliminates the time consuming steps of individual histone purification. In the newly modified protocol, Xenopus laevis H2A, H2B, H3, and H4 are expressed individually into inclusion bodies of bacteria, which are subsequently mixed together and denatured in 8M guanidine hydrochloride. Histones are refolded and reconstituted into soluble octamer by dialysis against 2M NaCl, and metal-affinity purified through an N-terminal polyhistidine-tag added on the H2A. After cleavage of the polyhistidine-tag, histone octamer is further purified by size exclusion chromatography. We show that the nucleosomes reconstituted using the purified histone octamer above are fully functional. They serve as effective substrates for the histone methyltransferases DOT1L and MLL1. Small angle X-ray scattering further confirms that the reconstituted nucleosomes have correct structural integration of histone octamer and DNA as observed in the X-ray crystal structure. Our new protocol enables rapid reconstitution of histone octamer with an optimal yield. We expect this simplified approach to facilitate research using recombinant nucleosomes in vitro.

Dose-dependent neuroprotection of VEGF165 in Huntington's disease striatum.

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by abnormal polyglutamine expansion in the huntingtin protein (Exp-Htt). Currently, there are no effective treatments for HD. We used bidirectional lentiviral transfer vectors to generate in vitro and in vivo models of HD and to test the therapeutic potential of vascular endothelial growth factor 165 (VEGF165). Lentiviral-mediated expression of Exp-Htt caused cell death and aggregate formation in human neuroblastoma SH-SY5Y and rat primary striatal cultures. Lentiviral-mediated VEGF165 expression was found to be neuroprotective in both of these models. Unilateral stereotaxic vector delivery of Exp-Htt vector in adult rat striatum led to progressive inclusion formation and striatal neuron loss at 10 weeks post-transduction. Coinjection of a lower dose VEGF165 significantly attenuated DARPP-32(+) neuronal loss, enhanced NeuN staining and reduced Exp-Htt aggregation. A tenfold higher dose VEGF165 led to overt neuronal toxicity marked by tissue damage, neovascularization, extensive astrogliosis, vascular leakage, chronic inflammation and distal neuronal loss. No overt behavioral phenotype was observed in these animals. Expression of VEGF165 at this higher dose in the brain of wild-type rats led to early mortality with global neuronal loss. This report raises important safety concerns about unregulated VEGF165 CNS applications.

Therapeutic induction of autophagy to modulate neurodegenerative disease progression.

There is accumulating evidence that aggregating, misfolded proteins may have an impact on autophagic function, suggesting that this could be a secondary pathological mechanism in many diseases. In this review, we focus on the role of autophagy in four major neurodegenerative diseases: Alzheimer disease (AD), Huntington's disease (HD), Parkinson's disease (PD) and amyotropic lateral sclerosis.

Medico-legal issues related to emergency physicians' documentation in Canadian emergency departments.

OBJECTIVES: Physician documentation plays a central role in the delivery of safe patient care. It describes a physician's clinical decision-making and supports essential communication between healthcare providers within the patient's circle of care. Good documentation can potentially also decrease a physician's medico-legal risk. This study provides examples of documentation issues attributed to physicians practicing emergency medicine as identified by peer experts in civil legal actions, regulatory authority complaints (College) and hospital complaints (collectively, medico-legal cases) in Canada. METHODS: We conducted a descriptive study and content analysis of medico-legal cases involving emergency department physicians from a national repository at the Canadian Medical Protective Association. Cases with peer expert criticism of an emergency physician's documentation, which were closed between 2016 and 2020, and occurred in an emergency department were included in our analysis. RESULTS: Of the 1628 cases involving emergency medicine, our inclusion criteria identified that absent or insufficiently detailed documentation was present in 24% of cases (391/1,628). A detailed review of 20% of the cases (79/391), selected randomly, found that documentation issues were most often associated with the assessment and investigation stage of care. This pertained to documenting details of the clinical examination, relevant medical history, diagnosis, and differential diagnosis. CONCLUSIONS: For physicians practicing emergency medicine, criticism of documentation was frequently observed in medico-legal cases. Based on the findings of this study and the expert criticism related to documentation, emergency medicine physicians may consider reflecting upon their documentation of the care provided to determine if their documentation provides a clear and accurate chronicle of the care and the rationale for their clinical decisions.

RéSUMé: OBJECTIFS: La tenue des dossiers joue un rôle crucial dans la prestation de soins sécuritaires. Elle témoigne des décisions cliniques des médecins et favorise une bonne communication entre les membres des différentes professions de la santé faisant partie du cercle de soins. Une bonne tenue des dossiers peut également réduire les risques médico-légaux auxquels les médecins sont exposés. Cette étude présente certains des problèmes relevés par les médecins experts dans la tenue des dossiers de médecins d'urgence. Elle a été réalisée à partir de dossiers d'action civile, de plaintes auprès d'organismes de réglementation de la médecine (Collège) et de plaintes auprès d'hôpitaux (dossiers médico-légaux) au Canada. MéTHODES: Nous avons réalisé une étude descriptive et une analyse du contenu des dossiers médico-légaux ciblant des médecins d'urgence de la base de données nationale de l'Association canadienne de protection médicale. L'analyse incluait les dossiers conclus entre 2016 et 2020 dans lesquels les expertes et experts consultés avaient émis des critiques à l'égard de la tenue des dossiers de médecins d'urgence. RéSULTATS: D'après nos critères d'inclusion, la tenue des dossiers avait été omise ou était insuffisante dans 391 (24%) des 1 628 dossiers ciblant des médecins d'urgence. Une analyse approfondie de 20% des dossiers (79/391), choisis au hasard, a révélé que les problèmes dans la tenue des dossiers étaient le plus souvent associés aux stades d'évaluation et d'investigation des soins. Plus précisément, les renseignements concernant les examens cliniques, les antécédents médicaux, le diagnostic et le diagnostic différentiel n'avaient pas été versés aux dossiers. CONCLUSIONS: Dans les dossiers médico-légaux, les critiques formulées à l'encontre des médecins d'urgence concernaient souvent la tenue des dossiers. À la lumière des résultats de cette étude et des critiques formulées par les médecins experts quant à la tenue des dossiers, les médecins d'urgence devraient porter attention à la consignation des soins qui sont prodigués et se demander si la tenue de leurs dossiers illustre, de façon claire et précise, la chronologie des soins ainsi que les raisons motivant leurs décisions cliniques.

Survival of cervical cancer patients in Brunei Darussalam: 2002-2017.

Objective: Cervical cancer is the fourth leading cause of cancer deaths among Bruneian women. This study aims to investigate the survival rate of cervical cancer patients in Brunei Darussalam between 2002 and 2017, to compare survival of cervical cancer patients between two periods: 2002-2009 and 2010-2017 and to identify prognostic factors of cervical cancer. Methods: A retrospective cohort study on cervical cancer patients registered in Brunei Darussalam Cancer Registry between 2002 and 2017. De-identified data from the registry was extracted and survival analysis was performed using Kaplan-Meier estimator, log-rank test and multiple Cox regression analysis. Results: The 1-, 3- and 5-year survival rates of cervical cancer patients in Brunei Darussalam were 87.3%, 77.4% and 72.5% respectively from 2002 to 2017. The 5-year survival rate for 2002-2009 and 2010-2017 were 77.3% and 69.1% respectively. The risk of mortality was significantly higher in 2010-2017 compared to 2002-2009 after adjusting for variables (Adjusted HR = 1.59; 95% CI: 1.08, 2.40; p = 0.019). Patients with distant cancer (Adjusted HR = 11.21; 95% CI: 6.18, 20.30; p < 0.001) had the highest risk of mortality. Conclusion: The 5-year survival rate of cervical cancer patients in Brunei Darussalam was 72.5%, which ranks relatively high globally. However, increased mortality among elderly patients, and patients diagnosed with cervical cancers at the later stages, calls for public health efforts to raise awareness, early detection, and disease management.