A systematic review of high impact CpG sites and regions for MGMT methylation in glioblastoma [A systematic review of MGMT methylation in GBM].

BACKGROUND: MGMT (O 6 -methylguanine-DNA methyltransferase) promoter methylation is a commonly assessed prognostic marker in glioblastoma (GBM). Epigenetic silencing of the MGMT gene by promoter methylation is associated with greater overall and progression free survival with alkylating agent regimens. To date, there is marked heterogeneity in how MGMT promoter methylation is tested and which CpG sites are interrogated. METHODS: To further elucidate which MGMT promoter CpG sites are of greatest interest, we performed comprehensive searches in PubMed, Web of Science, and Embase and reviewed 2,925 article abstracts. We followed the GRADE scoring system to assess risk of bias and the quality of the studies we included. RESULTS: We included articles on adult glioblastoma that examined significant sites or regions within MGMT promoter for the outcomes: overall survival, progression free survival, and/or MGMT expression. We excluded systemic reviews and articles on lower grade glioma. fifteen articles met inclusion criteria with variable overlap in laboratory and statistical methods employed, as well as CpG sites interrogated. Pyrosequencing or BeadChip arrays were the most popular methods utilized, and CpG sites between CpG's 70-90 were most frequently investigated. Overall, there was moderate concordance between the CpG sites that the studies reported to be highly predictive of prognosis. Combinations or means of sites between CpG's 73-89 were associated with improved OS and PFS. Six studies identified CpG sites associated with prognosis that were closer to the transcription start site: CpG's 8, 19, 22, 25, 27, 32,38, and CpG sites 21-37, as well as low methylation level of the enhancer regions. CONCLUSION: The following systematic review details a comprehensive investigation of the current literature and highlights several potential key CpG sites that demonstrate significant association with OS, PFS, and MGMT expression. However, the relationship between extent of MGMT promoter methylation and survival may be non-linear and could be influenced by potential CpG hotspots, the extent of methylation at each CpG site, and MGMT enhancer methylation status. There were several limitations within the studies such as smaller sample sizes, variance between methylation testing methods, and differences in the various statistical methods to test for association to outcome. Further studies of high impact CpG sites in MGMT methylation is warranted.

A scoping review of Ayurvedic rasayana adaptogens in oncology.

INTRODUCTION: Rasayanas are Ayurvedic natural products that have adaptogenic effects. The extensive research on rasayanas in oncology is not currently well summarized. The aim of this review is to investigate the range and nature of the current body of research, identify gaps in knowledge, and to summarize the existing literature as it relates to Ayurvedic rasayanas and oncology. MATERIALS AND METHODS: A comprehensive literature search of fifteen Ayurvedic adaptogen rasayanas was conducted using three main concepts: Ayurvedic herbal terms, neoplasm terms, and oncological pathways. After screening was performed, key variables were extracted (tagged) including type of adaptogen, cancer type, type of study design, constituent type, and mechanisms of action (MOA). The results were synthesized and summarized using descriptive statistics and narrative summaries. RESULTS: Five hundred and eighty-four articles were reviewed and tagged. The two most tagged adaptogens were Glycyrrhiza glabra (Yashthimadhu/licorice) (n = 166 (28.4 %)) and Withania somnifera (Ashwagandha) (n = 151 (25.9 %)). The most frequently tagged cancer diagnostic categories were gastrointestinal (n = 175 (30 %)), and breast (n = 126 (21 %)). Most of the articles focused on in vitro studies (n = 470 (80.3 %)). Of the 12 MOA tags, the most frequently tagged was apoptosis (n = 298 (29.2 %)). CONCLUSION: A large body of pre-clinical literature exists on adaptogen rasayanas in oncology, indicating this field of research is still in its early phase. Comparatively few studies focused on the effects on the immune system. Given the growing interest in immuno-oncology therapeutics and the potential impact of adaptogen rasayanas on the immune system, future research may focus more in this area, along with work that is more directly linked to future clinical studies.

Diabetes and incidence of breast cancer and its molecular subtypes: A systematic review and meta-analysis.

Diabetes mellitus (DM) has been proposed to be positively associated with breast cancer (BCa) risk due to shared risk factors, metabolic dysfunction, and the use of antidiabetic medications. We conducted a systematic review and meta-analysis to evaluate the association between DM and BCa risk. We searched PubMed, Embase, and Web of Science for cohort and case-control studies assessing the association between DM and BCa published before 10 December 2021. Two reviewers independently screened the studies for inclusion, abstracted article data, and rated study quality. Random effects models were used to estimate summary risk ratios (RRs) and 95% confidence intervals (CIs). From 8396 articles identified in the initial search, 70 independent studies were included in the meta-analysis. DM was associated with an overall increased risk of BCa (RR = 1.20, 95% CI: 1.11-1.29). The 24 case-control studies demonstrated a stronger association (RR = 1.26, 95% CI: 1.13-1.40) than the 46 cohort studies (RR = 1.15, 95% CI: 1.05-1.27). Studies reporting risk by menopausal status found that postmenopausal women had an elevated risk of developing BCa (RR = 1.12, 95% CI: 1.07-1.17). No association between DM and BCa risk was observed among premenopausal women (RR = 0.95, 95% CI: 0.85-1.05). In addition, DM was associated with significantly increased risks of oestrogen receptor (ER)+ (RR = 1.09, 95% CI: 1.00-1.20), ER- (RR = 1.16, 95% CI: 1.04-1.30), and triple negative BCa (RR = 1.41, 95% CI: 1.01-1.96). The association estimate for human epidermal growth factor 2-positive BCa was also positive (RR = 1.21, 95% CI: 0.52-2.82), but the CI was wide and crossed the null. Our meta-analysis confirms a modest positive association between DM and BCa risk. In addition, our results suggest that the association between DM and BCa may be modified by menopausal status, and that DM may be differentially associated with BCa subtypes defined by receptor status. Additional studies are warranted to investigate the mechanisms underlying these associations and any influence of DM on BCa receptor expression.

Cancer-directed surgery in patients with metastatic cancer: A systematic review and meta-analysis of randomized evidence.

PURPOSE: To assess the impact of primary-site surgery plus systemic therapy compared to systemic therapy alone on overall survival in common metastatic cancer types. METHODS: Data sources included Embase, PubMed, and Web of Science (January 1, 1995-March 22, 2023). Randomized controlled trials were included that enrolled patients diagnosed with the 10 most common de novo metastatic cancer types in the Surveillance, Epidemiology, and End Results database and randomized patients to resection of the primary site and systemic therapy versus systemic treatment alone. Random-effects models were used to pool associations by cancer type. RESULTS: Eight studies with 1774 patients evaluating the efficacy of surgery in breast, renal, stomach, and colorectal cancer were included. There was no statistically significant reduction in risk of all-cause mortality associated with surgical intervention for metastatic breast (HR = 0.94, 95% CI 0.63-1.40) or renal cancer (HR = 0.79, 95% CI 0.53-1.20), although results were heterogeneous (I2 = 73.7% and 80.6%, respectively). One study evaluating gastrectomy in metastatic stomach cancer found no benefit (HR = 1.09, 95% CI 0.78-1.52), while a small trial suggested that surgery and hyperthermic intraperitoneal chemotherapy might be beneficial for colorectal cancer with peritoneal metastasis (HR = 0.55, 95% CI 0.32-0.95). CONCLUSIONS: Few randomized trials have evaluated cancer-directed surgery among patients with metastatic solid malignancies.

Biologic Therapies in HIV/AIDS Patients with Inflammatory Diseases: A Systematic Review of the Literature.

Biologic therapies have been increasingly developed and used for the treatment of severe inflammatory diseases. However, the safety and efficacy profile of biologic drugs in patients with HIV is not well established as this patient population is historically excluded from clinical trials. We review the available evidence of biologic use in people with HIV. We conducted a systematic review of the literature up to June 29, 2022 and included studies that treated patients with HIV who have inflammatory disease using biologic drugs. Clinical data regarding safety and efficacy were abstracted into tables. One hundred twelve studies were included, and 179 patients were included in our study. Nearly all classes of biologics drugs had a favorable safety profile with minimal or minor adverse events. Anti-CD-20 inhibitors and TNF-alpha inhibitors were associated with opportunistic infections. Transient increase in HIV viral load was noted with use of some agents such as TNF-alpha inhibitors. The quality of evidence is low, restricted to case reports and retrospective reviews. However, the safety profile of biologics observed in these patients with HIV was overall favorable.

Radiation-induced Fistulas in Patients With Prior Pelvic Radiotherapy for Prostate Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: To systematically aggregate and summarize existing data on fistula prevalence among patients with a history of pelvic radiotherapy for prostate cancer. MATERIALS AND METHODS: We queried PubMed, Embase, and Web of Science on October 7, 2020 for peer-reviewed publications pertaining to radiation-induced fistulas in the pelvis. For meta-analysis, we used the random-effects model. We used the I2 statistic to quantify heterogeneity and the Newcastle-Ottawa Scale to assess risk of bias. RESULTS: Our final meta-analysis included 6 cohort studies with a total of 7665 patients exposed to pelvic radiotherapy between 1967 and 2013. Median follow-up time was 35.5 months (IQR 33.5-57.5). Pooled prevalence of radiation-induced fistula across all 6 cohort studies was 0.2% (95% CI: 0.1-0.4, I2 = 0.000%, P < .608). In subgroup analysis, we did not detect significant heterogeneity in fistula prevalence in patients who were re-irradiated (0.3%, 95% CI: 0.1-0.4; P = .762) or patients on concurrent chemotherapy (0.4%, 95% CI: -0.3 -1.2; P = .664) compared to those receiving their first course of radiotherapy alone. No randomized controlled trials met inclusion criteria due to ambiguous and inconsistent reporting language for fistula occurrence. CONCLUSION: There is limited published literature reporting fistula as an adverse event of prostate cancer radiotherapy, especially in the medium and long-term period. Patients undergoing pelvic radiotherapy for prostate cancer appear at low short-term risk for developing fistulas. Adverse event reporting in randomized controlled trials merits greater granularity where fistulas should be reported with specificity rather than aggregating into broad categories of genitourinary or gastrointestinal adverse events.

The effects of microbiome-targeted therapy on cognitive impairment and postoperative cognitive dysfunction-A systematic review.

BACKGROUND: The gut-brain axis involves bidirectional communication between the gut-microbiota and central nervous system. This study aimed to investigate whether probiotics and/or prebiotics, known as Microbiome-targeted Therapies (MTTs), improve cognition and prevent postoperative cognitive dysfunction (POCD). METHODS: Relevant animal and human studies were identified using a systematic database search (PubMed, EMBASE, Cochrane Library, and Web of Science), focusing on the effects of MTTs on inflammation, perioperative and non-perioperative cognitive impairment. Screening and data extraction were conducted by two independent reviewers. The Risk of bias was assessed using the SYRCLE's risk of bias tool for animal studies. The revised Cochrane risk of bias tool (RoB 2) was used for human studies. RESULTS: A total of 24 articles were selected; 16 of these involved animal studies, and 8 described studies in humans. In these papers, the use of MTTs consistently resulted in decreased inflammation in perioperative and non-perioperative settings. Out of 16 animal studies, 5 studies (2 associated with delirium and 3 studies related to POCD) were conducted in a perioperative setting. MTTs improved perioperative cognitive behavior and reduced inflammation in all 5 animal studies. Eleven animal studies were conducted in a non-perioperative setting. In all of these studies, MTTs showed improvement in learning and memory function. MTTs showed a positive effect on levels of pro-inflammatory cytokines and biomarkers related to cognitive function. Among the 8 human studies, only one study examined the effects of perioperative MTTs on cognitive function. This study showed a reduced incidence of POCD along with improved cognitive function. Of the remaining 7 studies, 6 suggested that MTTs improved behavioral test results and cognition in non-perioperative environments. One study failed to show any significant differences in memory, biomarkers of inflammation, or oxidative factors. CONCLUSION: In the studies we examined, most showed that MTTs decrease inflammation by down-regulating inflammatory cytokines and oxidative stress in both perioperative and non-perioperative settings. In general, MTTs also seem to have a positive effect on cognition through neural, immune, endocrine, and metabolic pathways. However, these effects have not yet resulted in a consensus regarding preventative strategies or treatments. Based on these current research results, MTTs could be a potential new preventative strategy for cognitive impairment after surgery.

Making the Financial Case for Surgical Resident Well-being: A Scoping Review.

OBJECTIVE: To conduct a scoping review of literature on financial implications of surgical resident well-being. BACKGROUND: Surgeon well-being affects clinical outcomes, patient experience, and health care economics. However, our understanding of the relationship between surgical resident well-being and organizational finances is limited. METHODS: Authors searched PubMed, Web of Science, and Embase with no date or language restrictions. Searches of the gray literature included hand references of articles selected for data extraction and reviewing conference abstracts from Embase. Two reviewers screened articles for eligibility based on title and abstract then reviewed eligible articles in their entirety. Data were extracted and analyzed using conventional content analysis. RESULTS: Twenty-five articles were included, 5 (20%) published between 2003 and 2010, 12 (48%) between 2011 and 2018, and 8 (32%) between 2019 and 2021. One (4%) had an aim directly related to the research question, but financial implications were not considered from the institutional perspective. All others explored factors impacting well-being or workplace sequelae of well-being, but the economics of these elements were not the primary focus. Analysis of content surrounding financial considerations of resident well-being revealed 5 categories; however, no articles provided a comprehensive business case for investing in resident well-being from the institutional perspective. CONCLUSIONS: Although the number of publications identified through the present scoping review is relatively small, the emergence of publications referencing economic issues associated with surgical resident well-being may suggest a growing recognition of this area's importance. This scoping review highlights a gap in the literature, which should be addressed to drive the system-level change needed to improve surgical resident well-being.

Three-dimensional morphologic changes in the temporomandibular joint in asymptomatic patients who undergo orthodontic treatment: A systematic review.

OBJECTIVE: This systematic review aimed to summarize the morphologic changes in the temporomandibular joint (TMJ) in patients who underwent orthodontic treatment and were assessed by 3-dimensional (3D) imaging techniques (e.g., magnetic resonance imaging, cone beam computed tomography, and multidetector computed tomography). STUDY DESIGN: The authors searched PubMed, Web of Science, and Embase databases to identify original articles from 2014 to 2021 containing keywords for morphologic changes in the TMJ, orthodontic treatment, and three-dimensional imaging methods. Prospective and retrospective studies, including observational, cross-sectional, randomized, and nonrandomized clinical trials, cohort studies, and case-control studies, were reviewed. The review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The risk of bias was assessed in studies selected for the full-text review. RESULTS: The search strategy yielded 294 publications. After an initial screening and the application of exclusion criteria, 13 studies were selected for the final review. CONCLUSION: Differences were found in condylar positioning, typically in an anterior position; condylar morphology, primarily with increased diameter or head height; and articular disk position within the anterior-posterior plane post-treatment. Changes in the glenoid fossa were not consistent between the studies. The overall risk of bias among studies was moderate. The influence of orthodontic treatment on morphologic changes in the TMJ remains unclear.

Navigation programs relevant for African American men with prostate cancer: a scoping review protocol.

BACKGROUND: The excess incidence and mortality due to prostate cancer that impacts African American men constitutes the largest of all cancer disparities. Patient navigation is a patient-centered healthcare system intervention to eliminate barriers to timely, high-quality care across the cancer continuum and improves health outcomes among vulnerable patients. However, little is known regarding the extent to which navigation programs include cultural humility to address prostate cancer disparities among African American men. We present a scoping review protocol of an in-depth examination of navigation programs in prostate cancer care-including navigation activities/procedures, training, and management-with a special focus on cultural context and humility for African American men to achieve health equity. METHODS: We will conduct comprehensive searches of the literature in PubMed, Embase, Web of Science, and CINAHL Complete, using keywords and index terms (Mesh and Emtree) within the three main themes: prostate cancer, patient navigation, and African American men. We will also conduct a search of the gray literature, hand-searching, and reviewing references of included papers and conference abstracts. In a two-phase approach, two authors will independently screen titles and abstracts, and full-text based on inclusion/exclusion criteria. All study designs will be included that present detailed data about the elements of navigation programs, including intervention content, navigator training, and/or management. Data will be extracted from included studies, and review findings will be synthesized and summarized. DISCUSSION: A scoping review focused on cultural humility in patient navigation within the context of eliminating disparities in PCa care among African American men does not yet exist. This review will synthesize existing evidence of patient navigation programs for African American prostate cancer patients and the inclusion of cultural humility. Results will inform the development and implementation of future programs to meet the unique needs of vulnerable prostate cancer patients in safety net settings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2021 CRD42021221412.

Earlier initiation of palliative care in the disease trajectory of people living with dementia: a scoping review protocol.

INTRODUCTION: While the need for palliative care for people living with dementia has widely been recognised, they continue to be a disadvantaged group when it comes to timely initiation, and controversies remain regarding appropriate timing, or what elements constitute high quality palliative care early in the disease trajectory. To date, no literature review has summarised this debate or offered insights. The aim of this scoping review is to provide a general overview of research regarding palliative care in mild or moderate dementia, to identify existing controversies, and to examine what are key components of palliative care in dementia, specifically when initiated earlier in the disease trajectory. METHODS AND ANALYSIS: Consistent with recent guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews, we carried out a search for academic literature in PubMed, CINAHL, EMBASE, Cochrane Library, PsycINFO, Web of Science; on 5 November 2019 and an updated search on 2 February 2021. We will include studies with different study designs published in English over the last decade that focused on palliative care in early stages of dementia. We will include models targeting at least one outcome domain of palliative care (physical, psychological, social or spiritual) and advance care planning, and will exclude hospice models with limited prognosis similar to the requirements in the USA. We will report study characteristics and quality. We aim to apply narrative synthesis techniques to develop a theoretical model of how, for whom and why palliative care can be relevant in early stages of dementia, and what are facilitators and barriers. We anticipate to also describe if and how the concept of (early) palliative care in dementia changed across time and studies. ETHICS AND DISSEMINATION: No ethical review required. Results will identify research gaps and lay out basic principles for conceptualising palliative care in early stages of dementia.

Examining reporting and representation of patients with cancer in COVID-19 clinical trials.

BACKGROUND: Patients with cancer are particularly vulnerable in the current COVID-19 pandemic. Emerging evidence suggests that patients with a cancer diagnosis are three times more likely to die from COVID-19 compared to non-cancer patients. Due to these observed risks, it is critical that emerging COVID-19 therapies demonstrate safety and efficacy among patients with cancer. AIM: This study sought to examine reporting and representation of patients with cancer among published COVID-19 treatment-related research studies. METHODS AND RESULTS: All published COVID-19 treatment-related clinical research studies published from March 1 to August 20, 2020 recruiting from North America and Europe were identified. The date published, study design, therapeutics studied, and study population were evaluated. Of the 343 studies identified through initial search and researcher knowledge, 55 (16%) reported on COVID-19 treatments. Twenty-one COVID-19 therapeutic studies (n = 15, prospective; n = 6, retrospective) that recruited from the United States and Europe were identified. Among these studies, eight (38%) reported on the number of trial participants with a cancer diagnosis in the publication and two (10%) specified tumor type. Four of the studies (19%) did not collect cancer history. Among studies where cancer history was available, patients with a cancer diagnosis participated at a proportion higher than overall cancer prevalence and greater than the known proportion of COVID-19 patients with cancer. CONCLUSION: This study observed that cancer history was not uniformly collected or reported among published COVID-19 therapeutic studies. Among reported publications, we observed that patients with a cancer diagnosis were generally overrepresented. However, patients with a cancer diagnosis were notably underrepresented in outpatient COVID-19 therapeutic studies.

Diagnosis, Staging, Radiation Treatment Response Assessment, and Outcome Prognostication of Head and Neck Cancers Using PET Imaging: A Systematic Review.

This systematic review summarizes the current applications of 18F-FDG PET imaging in the diagnosis, staging, radiation treatment response assessment, and outcome prognostication of head and neck cancers. For head and neck cancers of unknown primary origin, 18F-FDG PET/CT increases the likelihood of identifying the primary tumor and establishing the diagnosis. 18F-FDG PET/CT is important in the accurate staging of locoregionally advanced cases of HNSCC, which can greatly affect recommendations for treatment. Following definitive chemoradiation, 18F-FDG PET/CT is validated as a means of treatment response assessment. Emerging PET tracers of hypoxia and their potential applications are reviewed.

Palliative Oncologic Care Curricula for Providers in Resource-Limited and Underserved Communities: a Systematic Review.

Familiarity with principles of palliative care, supportive care, and palliative oncological treatment is essential for providers caring for cancer patients, though this may be challenging in global communities where resources are limited. Herein, we describe the scope of literature on palliative oncological care curricula for providers in resource-limited settings. A systematic literature review was conducted using PubMed, Embase, Cochrane Library, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Med Ed Portal databases, and gray literature. All available prospective cohort studies, case reports, and narratives published up to July 2017 were eligible for review. Fourteen articles were identified and referenced palliative care education programs in Argentina, Uganda, Kenya, Australia, Germany, the USA, or multiple countries. The most common teaching strategy was lecture-based, followed by mentorship and experiential learning involving role play and simulation. Education topics included core principles of palliative care, pain and symptom management, and communication skills. Two programs included additional topics specific to the underserved or American Indian/Alaskan Native community. Only one program discussed supportive cancer care, and no program reported educational content on resource-stratified decision-making for palliative oncological treatment. Five programs reported positive participant satisfaction, and three programs described objective metrics of increased educational or research activity. There is scant literature on effective curricula for providers treating cancer patients in resource-limited settings. Emphasizing supportive cancer care and palliative oncologic treatments may help address gaps in education; increased outcome reporting may help define the impact of palliative care curriculum within resource-limited communities.

Survival outcomes in pediatric recurrent high-grade glioma: results of a 20-year systematic review and meta-analysis.

Recurrent pediatric high-grade glioma is a leading cause of cancer-related death in children. We report results of a systematic review and meta-analysis investigating survival outcome in pediatric patients with recurrent high-grade glioma over the last 20 years. MEDLINE/PubMed, EMBASE, Web of Science and Cochrane Review databases were searched for relevant studies reporting on survival outcomes for pediatric patients with recurrent high-grade glioma treated between 1996 and 2016. Progression-free survival (PFS) and overall survival (OS) were calculated cumulatively over all studies, by therapy subgroup, and by decade of treatment. Random effects models were used to control for heterogeneity as measured by the I2 statistic. A total of 17 studies across 4 treatment strategies were included. Eleven investigated traditional chemotherapy, 1 investigated targeted therapy, 3 investigated immunotherapy, and 2 investigated radiotherapy. A total of 129 patients were included with a median age of 10.0 years. Cumulative PFS was 3.5 months (95% CI 2.1-5.0). Cumulative OS was 5.6 months (95% CI 3.9-7.3). OS was 4.0 months (95% CI 1.9-6.1) using traditional chemotherapy, 9.3 months using targeted therapies (95% CI 5.4-13), 6.9 months using immunotherapy (95% CI 2.1-12), and 14 months using reirradiation (95% CI 2.8-25). OS between 1996 and 2006 was 4.2 months (95% CI 2.1-6.2) compared to 8.5 months (95% CI 5.6-11) after 2006. Pediatric patients with recurrent high-grade glioma suffer from poor PFS and OS, regardless of therapy. There may be a trend towards improved OS in the last decade.