Delay in the Diagnosis of Pediatric Brain Tumors in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Vague symptoms and a lack of pathognomonic features hinder the timely diagnosis of pediatric brain tumors (PBTs). However, patients in low- and middle-income countries (LMICs) must also bear the brunt of a multitude of additional factors contributing to diagnostic delays and subsequently affecting survival. Therefore, this study aims to assess these factors and quantify the durations associated with diagnostic delays for PBTs in LMICs. METHODS: A systematic review of extant literature regarding children from LMICs diagnosed with brain tumors was conducted. Articles published before June 2023 were identified using PubMed, Google Scholar, Scopus, Embase, Cumulative Index to Nursing and Allied Health Literature, and Web of Science. A meta-analysis was conducted using a random-effects model through R Statistical Software. Quality was assessed using the Newcastle Ottawa Scale. RESULTS: A total of 40 studies including 2483 patients with PBT from 21 LMICs were identified. Overall, nonspecific symptoms (62.5%) and socioeconomic status (45.0%) were the most frequently reported factors contributing to diagnostic delays. Potential sources of patient-associated delay included lack of parental awareness (45.0%) and financial constraints (42.5%). Factors contributing to health care system delays included misdiagnoses (42.5%) and improper referrals (32.5%). A pooled mean prediagnostic symptomatic interval was calculated to be 230.77 days (127.58-333.96), the patient-associated delay was 146.02 days (16.47-275.57), and the health care system delay was 225.05 days (-64.79 to 514.89). CONCLUSION: A multitude of factors contribute to diagnostic delays in LMICs. The disproportionate effect of these factors is demonstrated by the long interval between symptom onset and the definitive diagnosis of PBTs in LMICs, when compared with high-income countries. While evidence-based policy recommendations may improve the pace of diagnosis, policy makers will need to be cognizant of the unique challenges patients and health care systems face in LMICs.

Brain Drain: A Cross-Sectional Study Evaluating Migration Intentions of Neurosurgery Trainees in Pakistan.

Background Pakistan has a significant proportion of medical graduates who intend to leave the country for better opportunities abroad, leading to a brain drain. However, the push and pull factors within neurosurgery remain unexplored, emphasizing the need for evaluation to enact policy changes. Materials and Methods We conducted a nationwide survey across 22 College of Physicians and Surgeons of Pakistan accredited neurosurgery training centers in all provinces of Pakistan. SPSS version 26 and STATA 15 were used for data analysis. Results We collected responses from 120 neurosurgery trainees across Pakistan. Trainees were categorized into two groups: those intending to leave (64%) and those intending to stay (36%) in Pakistan. A significant association was observed between the availability of fellowship training in the residents' hospital and the decision to leave or remain in Pakistan ( p = 0.034). About 67.5% of our respondents did not have any publication, and among the intention to leave group, a greater percentage had academic involvement, when compared with the stay group. A significant association ( p = 0.012) was also observed between the decision to leave or remain in Pakistan and the number of publications in nonindexed journals. Conclusion There remains a need for improvement in the standard of training provided by neurosurgery programs across the country. Our study found that disparities in research and academic exposure, as well as the lack of fellowship opportunities, may serve as stimuli for residents to leave Pakistan.

Association Between Ki-67 Proliferative Index and Oncotype-Dx Recurrence Score in Hormone Receptor-Positive, HER2-Negative Early Breast Cancers. A Systematic Review of the Literature.

Background: Oncotype-Dx (ODx) is a 21-gene assay used as a prognostic and predictive tool for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative, node-negative, or 1 to 3 lymph node-positive early breast cancers (EBCs). The cost of the test, which is not available in low-middle income countries (LMICs), is not within the means of most individuals. The Ki-67 index is a marker of tumor proliferation that is cost-effective and easily performed and has been substituted in many cases to obtain prognostic information. Objective: We aimed to identify the correlation between the ODx recurrence score (RS) and the Ki-67 index in HR-positive EBCs and to determine whether Ki-67, like the ODx, can help facilitate clinical decision-making. Design: Systematic review correlating Ki-67 index and ODx in HR-positive and HER2-negative EBCs as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data sources and methods: We searched different databases between January 2010 and May 2023 and included retrospective/prospective cohorts, clinical trials, case-control, and cross-sectional studies involving HR-positive and HER2-negative EBCs correlating the Ki-67 index and ODx RS categories. Results: Of the 18 studies included, 16 indicated a positive or weakly positive correlation between ODx and the Ki-67 index. The combined P value of the included studies is <0.05 (P = .000), which shows a statistical significance between the 2. Our review also discusses the potential of machine learning and artificial intelligence (AI) in Ki-67 assessment, offering a cost-effective and reproducible alternative. Conclusion: Even although there are limitations, studies indicate a favorable association between ODx and the Ki-67 index in specific situations. This implies that Ki-67 can offer important predictive details, especially regarding the likelihood of relapse in HR-positive EBC. This is particularly significant in LMICs where financial constraints often hinder the availability of costly diagnostic tests.

Comparing Ki-67 and Oncotype-Dx Tests for Predicting Early Breast Cancer Outcomes: A Comprehensive Review The study explored the correlation between the expensive Oncotype-Dx (ODx) test and the more affordable Ki-67 index in predicting outcomes for certain breast cancers. Results from 16 out of 18 studies indicated a significant link between the 2 tests, suggesting Ki-67 could be a cost-effective alternative, especially in low- to middle-income countries.

Human RAD52 stimulates the RAD51-mediated homology search.

Homologous recombination (HR) is a DNA repair mechanism of double-strand breaks and blocked replication forks, involving a process of homology search leading to the formation of synaptic intermediates that are regulated to ensure genome integrity. RAD51 recombinase plays a central role in this mechanism, supported by its RAD52 and BRCA2 partners. If the mediator function of BRCA2 to load RAD51 on RPA-ssDNA is well established, the role of RAD52 in HR is still far from understood. We used transmission electron microscopy combined with biochemistry to characterize the sequential participation of RPA, RAD52, and BRCA2 in the assembly of the RAD51 filament and its activity. Although our results confirm that RAD52 lacks a mediator activity, RAD52 can tightly bind to RPA-coated ssDNA, inhibit the mediator activity of BRCA2, and form shorter RAD51-RAD52 mixed filaments that are more efficient in the formation of synaptic complexes and D-loops, resulting in more frequent multi-invasions as well. We confirm the in situ interaction between RAD51 and RAD52 after double-strand break induction in vivo. This study provides new molecular insights into the formation and regulation of presynaptic and synaptic intermediates by BRCA2 and RAD52 during human HR.

In vivo reduction of RAD51-mediated homologous recombination triggers aging but impairs oncogenesis.

Homologous recombination (HR) is a prominent DNA repair pathway maintaining genome integrity. Mutations in many HR genes lead to cancer predisposition. Paradoxically, the implication of the pivotal HR factor RAD51 on cancer development remains puzzling. Particularly, no RAD51 mouse models are available to address the role of RAD51 in aging and carcinogenesis in vivo. We engineered a mouse model with an inducible dominant-negative form of RAD51 (SMRad51) that suppresses RAD51-mediated HR without stimulating alternative mutagenic repair pathways. We found that in vivo expression of SMRad51 led to replicative stress, systemic inflammation, progenitor exhaustion, premature aging and reduced lifespan, but did not trigger tumorigenesis. Expressing SMRAD51 in a breast cancer predisposition mouse model (PyMT) decreased the number and the size of tumors, revealing an anti-tumor activity of SMRAD51. We propose that these in vivo phenotypes result from chronic endogenous replication stress caused by HR decrease, which preferentially targets progenitors and tumor cells. Our work underlines the importance of RAD51 activity for progenitor cell homeostasis, preventing aging and more generally for the balance between cancer and aging.

Method combining BAC film and positive staining for the characterization of DNA intermediates by dark-field electron microscopy.

DNA intermediate structures are formed in all major pathways of DNA metabolism. Transmission electron microscopy (TEM) is a tool of choice to study their choreography and has led to major advances in the understanding of these mechanisms, particularly those of homologous recombination (HR) and replication. In this article, we describe specific TEM procedures dedicated to the structural characterization of DNA intermediates formed during these processes. These particular DNA species contain single-stranded DNA regions and/or branched structures, which require controlling both the DNA molecules spreading and their staining for subsequent visualization using dark-field imaging mode. Combining BAC (benzyl dimethyl alkyl ammonium chloride) film hyperphase with positive staining and dark-field TEM allows characterizing synthetic DNA substrates, joint molecules formed during not only in vitro assays mimicking HR, but also in vivo DNA intermediates.