High Incidence Research Articles

Patterns of Gene Expression Profiles Associated with Colorectal Cancer in Colorectal Mucosa by Using Machine Learning Methods.

Colorectal cancer (CRC) has a very high incidence and lethality rate and is one of the most dangerous cancer types. Timely diagnosis can effectively reduce the incidence of colorectal cancer. Changes in para-cancerous tissues may serve as an early signal for tumorigenesis. Comparison of the differences in gene expression between para-cancerous and normal mucosa can help in the diagnosis of CRC and understanding the mechanisms of development. This study aimed to identify specific genes at the level of gene expression, which are expressed in normal mucosa and may be predictive of CRC risk. A machine learning approach was used to analyze transcriptomic data in 459 samples of normal colonic mucosal tissue from 322 CRC cases and 137 non-CRC, in which each sample contained 28,706 gene expression levels. The genes were ranked using four ranking methods based on importance estimation (LASSO, LightGBM, MCFS, and mRMR) and four classification algorithms (decision tree [DT], K-nearest neighbor [KNN], random forest [RF], and support vector machine [SVM]) were combined with incremental feature selection [IFS] methods to construct a prediction model with excellent performance. The top-ranked genes, namely, HOXD12, CDH1, and S100A12, were associated with tumorigenesis based on previous studies. This study summarized four sets of quantitative classification rules based on the DT algorithm, providing clues for understanding the microenvironmental changes caused by CRC. According to the rules, the effect of CRC on normal mucosa can be determined.

Healthcare Experiences of African American Women with the Fragile X Premutation.

This study aims to understand the healthcare experiences of African American women with a fragile X premutation (PM). PM carriers are at risk for fragile X-associated conditions, including primary ovarian insufficiency (FXPOI) and neuropsychiatric disorders (FXAND). There is no racial/ethnic association with carrying a PM, but African American women historically experience barriers receiving quality healthcare in the USA. Obstacles to care may increase mental health conditions like anxiety and depression. Eight African American women with a PM were interviewed to explore disparities in receiving healthcare and to learn about psychosocial experiences during and after their diagnoses. Interviews were transcribed verbatim and independently coded by two researchers. A deductive-inductive approach was used, followed by thematic analysis to determine prominent themes. The average participant age was 52.3 ± 8.60 years, with a mean age at premutation diagnosis of 31 ± 5.95 years. Seven participants had children with FXS. Themes from interviews included healthcare experiences, family dynamics, and emotional/mental health after their diagnosis. Participants reported concerns about not being taken seriously by providers and mistrust of the medical institutions. Within families, participants reported denial, insensitivity, and isolation. Participants reported a high incidence of anxiety and depression. Both are symptoms of FXAND and stresses of systemic racism and sexism. The reported family dynamics around the news of a genetic diagnosis stand apart from other racial cohorts in fragile X research: interventions like family counseling sessions and inclusive support opportunities from national organizations could ease the impacts of a PM for African American women.

Role of different examination methods in colorectal cancer screening: Insights and future directions

Colorectal cancer is a malignant tumor with the third and second highest incidence and mortality rates worldwide, and its mortality rate is increasing annually. Colorectal cancer evolves gradually over a long period of time. The evolving process from colorectal adenoma to colorectal cancer takes approximately 10-15 years, providing a sufficiently long "window period" for early screening and diagnosis of colorectal cancer. The recurrence and mortality rates can be controlled at a low level with an early intervention. Metaxas et al sum-marized existing screening methods and their applicable scope in a recent publication. Moreover, they provide suggestions on how to improve adherence. This editorial provides a commentary on their article and discuss the roles of different screening methods in the early screening of colorectal cancer.

Analysis of therapeutic effect of cell reduction combined with intraperitoneal thermoperfusion chemotherapy in treatment of peritoneal pseudomyxoma

BACKGROUND Pseudomyxoma peritonei is a rare tumor that can produce a biological behavior similar to that of a malignant tumor. Surgical resection combined with chemotherapy is the traditional treatment method, but the effect is not good. Cell reduction (CRS) combined with intraperitoneal thermoperfusion chemotherapy (HIPEC) has become a new method for the treatment of peritoneal pseudomyxoma (PMP). AIM To find out if CRS and HIPEC can be used safely and effectively to treat PMP. METHODS This is an observational study. Clinical data of PMP patients treated with CRS + HIPEC at our hospital from January 2013 to June 2023 was collated and analyzed. The main outcome measures were overall survival (OS), and the secondary outcome measures were the incidence of surgical complications and serious adverse events. Complications were graded according to common adverse event evaluation criteria. Peritoneal tumor staging was performed using the peritoneal tumor index (PCI) scoring system, and a cell reduction degree (CCR) score was performed after CRS. CCR-0 and CCR-1 were considered satisfactory CRS. RESULTS A total of 186 patients with PMP were included, with a median age of 56 (48-64) years, 65 (34.9%) years in males, and 121 (65.1%) years in females. The median PCI score was 28 (20-34) points. The median operative time was 300 (211-430) minutes, and no significant complications occurred. 91.4% (170/186) were from the appendix, 53.2% (99/186) were from the low grade, and 30.6% (57/186) were from the high grade. CCR scores showed that 55 patients (29.6%) achieved satisfactory CRS, and 113 patients (60.8%) did not achieve satisfactory CRS. The fatality rate at 30 days after surgery was 2.7% (5/186), 1.6% (3/186) needed a second operation, and the fatality rate at 90 days was 4.3% (8/186). The total incidence of III-IV complications was 43.0% (80/186), among which the higher incidence was mainly anemia (27.4%, 51/186), electrolyte disturbance (11.6%, 21/181), and albumin decrease (7.5%, 14/186). The main complications associated with abdominal surgery were gastrointestinal anastomotic leakage (2.2%, 4/186), abdominal hemorrhage (2.2%, 4/186), and abdominal infection (4.3%, 8/186). The median follow-up was 38.1 (95%CI: 31.2-45.1) months. The 5-year OS of PMP patients treated with CRS + HIPEC was 50.3% (95%CI: 40.7%-59.9%), and the median survival time was 66.1 (95%CI: 43.1-89.1) months. The results of the survival analysis showed that patients with a low pathological grade, a low PCI, and a satisfactory CCR score had a higher survival rate (all P < 0.05). 5-year OS was 88.9% (95%CI: 68.3%-100.0%) in CCR-0 patients, 77.6% (95%CI: 62.7%-92.5%) in CCR-1 patients, and 42.0% (95%CI: 29.5%-54.5%) in CCR-2/3 patients. CONCLUSION The application of CRS + HIPEC in PMP is safe and feasible, and the survival benefit is high, especially in those who achieve satisfactory CRS, which can significantly extend the OS.

Intracerebral hemorrhage

Background: Compared to ischemic stroke, intracerebral hemorrhage (ICH) has higher mortality and more severe disability. Asian such as Chinese and Japanese and Mexican Americans, Latin Americans, African Americans, Native Americans have higher incidences than do white Americans. So, ICH is an important cerebrovascular disease in Asia. Summary: ICH accounts for approximately 10-20% of all strokes. The incidence of ICH is higher in low- and middle-income than high-income countries and is estimated 8-15% in western countries like USA, UK and Australia, and 18-24% in Japan, Taiwan and Korea. The ICH incidence increases exponentially with age, and old age especially over 80 years is a major predictor of mortality independent of ICH severity. Females are older at the onset of ICH and have higher clinical severity than males. Modifiable risk factors include blood pressure, smoking, alcohol consumption, lipid profiles, use of anticoagulants, antiplatelet agents and sympathomimetic drugs. Non-modifiable risk factors constitute old age, male gender, Asian ethnicity, cerebral amyloid angiopathy, cerebral microbleed, and chronic kidney disease. Blood pressure is the most important risk factor of ICH. Imaging markers may help predict ICH outcome, which include black hole sign, blend sign, iodine sign, island sign, leakage sign, satellite sign, spot sign, spot-tail sign, swirl sign, and hypodensities. ICH prognostic scoring system such as ICH scoring system and ICH grading scale scoring system in Chinese and Osaka prognostic score and Naples prognostic score has been used to predict ICH outcome. Early minimally invasive removal of ICH can be recommended for lobar ICH of 30–80 mL within 24 hours after onset. Decompressive craniectomy without clot evacuation might benefit ICH patients aged 18–75 years with 30–100 mL at basal ganglia or thalamus. However, clinical studies are needed to investigate the effect of surgery on patients with smaller or larger ICH, ICH in non-lobar locations, and for older patients or patients with preexisting disability. Surgical treatment is usually associated with neurological sequels if survived. For medical treatment, blood pressure lowering should be careful titrated to secure continuous smooth and sustained control and avoid peaks and large variability in systolic blood pressure. Stroke and cancer are the most common causes of death in Asian ICH patients, compared to stroke and cardiac disease in non-Asian patients. Key Messages: The incidence and outcome are different between Asian and non-Asian patients, and more clinical studies are needed to investigate the best management for Asian ICH patients.

Characteristics of patients with drug-resistant epilepsy in a tertiary hospital

Drug-resistant epilepsy has a cumulative incidence between 14 and 20% of patients with epilepsy. It is associated with more comorbidities and with higher healthcare expenditure and impact on quality of life. A retrospective longitudinal descriptive study was performed covering the period from 01/01/2010 to 02/28/2024. All patients with epilepsy seen in the Pediatric Neurology unit of our center were collected and a review of medical records was carried out to collect the characteristics and evolution during the study period. The classification and definitions used were those established by the International League Against Epilepsy. A total of 325 patients with epilepsy were identified, with a cumulative incidence of DRE of 29%. The most frequent etiology was structural both in all patients with epilepsy (22%), and in drug-resistant epilepsy (36%). A statistically significant association was established between refractoriness and genetic and structural causes, and between having status epilepticus and the development of drug-resistant epilepsy. Seventy-nine percent of patients with drug-resistant epilepsy developed epileptic encephalopathy. The most commonly used antiseizure drug was valproic acid (90%), 19% received a ketogenic diet and 4.2% received epilepsy surgery. In our setting the incidence of drug-resistant epilepsy is high, more so than previously described. Genetic and structural etiologies are associated with a higher incidence. Having suffered status epilepticus is associated with refractoriness. A higher incidence was observed in patients with defined electroclinical syndromes, probably influenced by epileptic and developmental encephalopathies.

Epidemiology of Orofacial Clefts: A Spatio-Temporal Descriptive Analysis in Tripoli, Libya, 2017-2021

Orofacial clefts are the most common congenital anomalies affecting the orofacial region. An abnormal facial development causes this congenital deformity during gestation; its aetiology is multifactorial. It is crucial to understand the prevalence of craniofacial anomalies in each community to determine the size of the problem, enhance the life standards for the patients, and assess the efficacy of interventions. In this study, we aimed to provide a picture of the prevalence of orofacial clefts in Tripoli, Libya. Also, it provides a useful reference for cleft-type distribution with their etiological risk factors. The data was collected from the archives of cleft babies referred to major specialized hospitals in Tripoli, Libya, from 2017 to 2021. Variables were collected and analyzed, including data related to cleft cases and their parents. During the study period, the incidence of orofacial clefts was 1.06 per 1,000 live births. The prevalence of cleft lip was 38.3%, cleft palate was 42.2%, and cleft lip with palate was 19.6%. The results showed that 2017 had the highest incidence rate, reaching 32.2%, while it was 8.3% in 2021. The prevalence was generally higher among males than females, at a difference rate of 3.47%. A history of folic acid deficiency and unsupervised drug intake during pregnancy was noted (58.3% and 61.7%, respectively). In addition, the higher prevalence was more common among mothers older than 34. Moreover, it has observed that 46.8% of patients` fathers were smokers. The study concluded that the incidence of cleft defects in Tripoli, Libya, was relatively low, and the role of the predisposing factors in increasing the incidence of cleft deformity remains uncertain. Further studies are recommended to find out the root cause.

The dietary phytochemical index and its relation to polycystic ovary syndrome: a case-control study.

Polycystic ovary syndrome (PCOS), a hormonal disorder affecting women of reproductive age, can be significantly impacted by diet. This study explores the relationship between a diet rich in phytochemicals, measured by the Dietary Phytochemical Index (DPI), and PCOS, along with associated health markers. A case-control study design was implemented with 480 individuals diagnosed with PCOS based on the Rotterdam criteria, paired with 480 controls matched in terms of age and BMI. The evaluation encompassed dietary intake, anthropometric measurements, and hormonal/metabolic markers. Additionally, the DPI score was determined based on the consumption of phytochemical-rich foods. The study also examined PCOS-related complications like acne and irregular menstrual cycles, as well as mental health using the Beck Depression Inventory (BDI-II) scores. Women with PCOS had significantly lower DPI scores (32.42 vs 43.87, p < 0.001) compared to the control group, indicating a less phytochemical-rich diet. The DPI scores coincided with higher levels of hormones typically associated with PCOS, including Luteinizing Hormone (LH), Dehydroepiandrosterone Sulfate (DHEA-S), and testosterone. Additionally, these scores were associated with markers of metabolic dysfunction such as C-reactive Protein (CRP), Fasting Blood Sugar (FBS), and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), while positively correlating with Sex Hormone-Binding Globulin (SHBG) (all p < 0.050).). Higher DPI scores were associated with a significantly reduced risk of PCOS (OR: 0.13, 95% CI: 0.08, 0.23, P for trend: 0.001) and its complications, including acne and irregular menstrual cycles. Interestingly, a positive association emerged, suggesting better mental health (lower BDI-II scores) with higher DPI scores. In conclusion, this study indicates that lower DPI scores are associated with a higher incidence and severity of PCOS, suggesting that a phytochemical-rich diet could potentially benefit the management of PCOS by enhancing hormonal profiles, metabolic health, and mental well-being in women.

Evaluation of the osteoarthritis disease burden in China from 1990 to 2021: based on the Global Burden of Disease Study 2021

ObjectiveThis study aims to understand the current status and trend of the disease burden of osteoarthritis (OA) in people over 30 years old in China from 1990 to 2021 and identify the priority population groups, to provide reference data for the prevention and treatment of OA in China.MethodsThe Global Burden of Disease Study 2021 was used to describe the incidence, prevalence, and disability-adjusted life years (DALYs) of OA in adult aged 30 years or older in China by sex and age groups, which was used to analyze the disease burden of OA from 1990 to 2021. The joinpoint regression model and age-period-cohort model were used to characterize the temporal trend.ResultsIn 2021, the number of OA prevalence in China was about 152.85 million, and the number of incidences was about 11.65 million. The age-standardized prevalence rate (ASPR), age-standardized incidence rate (ASIR) and age-standardized DALYs rate (ASDR) of OA in China are lower than those in developed countries such as Korea, the United States of America and Japan, but higher than those in India. Knee osteoarthritis had the highest ASPR and ASDR. The highest incidence rate was 50–54 years, and the highest prevalence and DALYs rate were in the age group of patients over 95 years old. The incidence rate of women in all age groups is higher than that of men. From 1990 to 2021, the ASIR, ASPR and ASDR of OA in China roughly showed an increasing trend year by year. The age-period-cohort analysis showed that the peak age groups for longitudinal age incidence of OA in China from 1992 to 2021 were 50–54 years and 80–84 years. We found that the OA incidence was highest in the period 2017–2021.ConclusionThe disease burden of OA in those over 30 years old in China from 1990 to 2021 will become more and more serious, and the target population for primary prevention is the female population under 50 years old. The development of a scientific and effective comprehensive prevention and treatment program for OA is imminent.

Epidemiology, trends, and survival of ocular and orbital rhabdomyosarcoma: a nationwide study in the USA (1996-2018) : Ocular and orbital rhabdomyosarcoma in the USA.

Rhabdomyosarcoma (RMS) is a rare malignancy that affects both children and young adults. Therefore, the current incidence and mortality rates of ocular and orbital rhabdomyosarcoma (ORMS) need to be clarified. We aimed to explore the epidemiology, trends, and survival outcomes of ORMS in the United States population spanning over two decades, from 1996 to 2018. We retrospectively reviewed 92,633 patients with ocular and adnexal malignancies and identified 640 ORMS cases from the North American Association of National Cancer Registries. Demographics, tumor characteristics, treatment modalities, and survival outcomes were analyzed. Most ORMS cases (71.7%) were reported in children aged-0-9 years. The age-adjusted incidence of ORMS was 0.1 per million population (ppm), with males demonstrating a higher incidence (0.12 ppm) than females (0.09 ppm). Whites had the highest incidence rate (0.11 ppm). Embryonal ORMS is the most common histological subtype. The incidence trend over the 22-year study period revealed a decline in ORMS from 0.124 to 0.076, in contrast with the incidence of whole-body RMS, which showed an insignificant increase. The 5-year relative survival rates of patients with ORMS were 89.7%, whereas the 10-year relative survival rate was 87.2%. The 5-year relative survival trend for ORMS increased but was insignificant. ORMS primarily affects young children and males, with the embryonal subtype being the most common. Despite the declining incidence, survival rates have remained stable, underscoring the need for further research on the risk factors, diagnostics, and management strategies to improve patient outcomes. What is known Ocular and Orbital Rhabdomyosarcoma (ORMS) predominantly affects children, especially males, and is the most frequent primary tumor in the orbit during childhood. The embryonal subtype is the most common histological subtype of ORMS. What is new A significant decline in the incidence of ORMS was observed over the 22-yearstudy period, in contrast to the overall incidence of whole-body rhabdomyosarcoma. It has a characteristic bigeminal distribution with a peak at 3-4 and another at 6 years. Patients receiving combined treatment modalities showed improved survival rates, while those undergoing surgery alone had poorer outcomes. Despite advancements in treatment, there has been no significant increase in the 5-year relative survival trends for ORMS.

OCCURRENCE OF HUMAN PAPILLOMAVIRUS (HPV) IN WOMEN OF LGBTQIA+ COMMUNITY TREATED IN MANAUS, AMAZONAS

Human papillomavirus (HPV) is a significant etiological factor for several types of cancer, including cervical carcinoma, with 80% of cases of cervical cancer occurring in Latin America. In Brazil, cervical carcinoma is the third most prevalent cancer among women, and the northern region and the state of Amazonas have the highest incidence in the country. However, not all women benefit from cervical cancer screening measures. Most women in the LGBTQIA+ community do not seek gynecological health services since they often face barriers related to female homosexuality when accesing sexual health services. Using PCR, this study perfomed the molecular detection and genotyping of HPV in thirty-six patients (20 homosexual and 16 bisexual women) from Manaus, Amazonas, Brazil. Samples of the cervical epithelium were taken during the preventive examination and genotyping was perfomed to detect HPV 16, 18, 31 and 58. Of the thirty-six patients analyzed in this study, 88% of bisexual women (n=14) and 60% of homosexual women (n=12) tested positive for HPV. The HPV 18 genotype was the most frequent among the findings. The results indicate that homosexual and bisexual women are more vulnerable to HPV infections due to the lack of more specific gynecological care directed to this group, which includes the lack of training of professionals to deal with the particularities of this population group. Therefore, more HPV screening studies for LGBTQIA+ women and improved training for specialized health professionals are needed.

High frequency post-pause word choices and task-dependent speech behavior characterize connected speech in individuals with mild cognitive impairment.

Alzheimer's disease (AD) is characterized by progressive cognitive decline, including impairments in speech production and fluency. Mild cognitive impairment (MCI), a prodrome of AD, has also been linked with changes in speech behavior but to a more subtle degree. This study aimed to investigate whether speech behavior immediately following both filled and unfilled pauses (post-pause speech behavior) differs between individuals with MCI and healthy controls (HCs), and how these differences are influenced by the cognitive demands of various speech tasks. Transcribed speech samples were analyzed from both groups across different tasks, including immediate and delayed narrative recall, picture descriptions, and free responses. Key metrics including lexical and syntactic complexity, lexical frequency and diversity, and part of speech usage, both overall and post-pause, were examined. Significant differences in pause usage were observed between groups, with a higher incidence and longer latencies following these pauses in the MCI group. Lexical frequency following filled pauses was higher among MCI participants in the free response task but not in other tasks, potentially due to the relative cognitive load of the tasks. The immediate recall task was most useful at differentiating between groups. Predictive analyses utilizing random forest classifiers demonstrated high specificity in using speech behavior metrics to differentiate between MCI and HCs. Speech behavior following pauses differs between MCI participants and healthy controls, with these differences being influenced by the cognitive demands of the speech tasks. These post-pause speech metrics can be easily integrated into existing speech analysis paradigms.

Abstract Su702: Association Between In-hospital Cardiac Arrest Incidence and Survival in Older Patients

Background: Survival after an in-hospital cardiac arrest (IHCA) varies markedly across hospitals in the U.S. Whether hospitals with IHCA survival also excel in ‘preventing’ IHCA remains unclear. Methods: Using 2013-2019 data from the Get-With-The-Guidelines–Resuscitation (GWTG-R) registry linked with Medicare and American Hospital Association data, we identified all patients &gt; 65 years with IHCA at participating hospitals. Using two-level hierarchical multivariable regression models, we calculated hospital rates of IHCA incidence, adjusted for case-mix index, and risk-standardized survival to discharge (RSSR) for IHCA, adjusted for patient and cardiac arrest variables. We also examined the association of IHCA incidence and RSSR with hospital variables. Results: Among &gt;10 million admissions at 335 hospitals during 2013-2019, 77676 patients experienced an IHCA. The median hospital rate of IHCA incidence was 6.9 per 1000 admissions, and the median case-survival rate among those with IHCA was 21.9%. After case-mix adjustment, the median IHCA incidence was 7.9 per 1000 admissions with considerable variation across hospitals: IQR: 5.8-10.3 per 1000 admissions, range 1.2 to 25.4 per 1000 admissions. The median RSSR for IHCA was 22.3%, which varied from 11.5% to 35.7% across hospitals (IQR: 19.5%-24.9%). There was a weak negative correlation between risk-adjusted hospital IHCA incidence and its RSSR (rho = -0.11; p = 0.037) (Figure 1). Adjustment for hospital variables attenuated the negative association between IHCA incidence and RSSR (rho = -0.08; p = 0.13). The nurse-patient ratio was the only modifiable factor significantly associated with lower IHCA incidence (OR = 0.97; p = 0.004) and higher RSSR (OR = 1.05; p &lt;.0001). Conclusion: Even after case-mix adjustment, hospital IHCA incidence and survival rates varied markedly. Notably, hospitals with higher survival rates for IHCA did not have a higher incidence. Since case-survival rates for IHCA have plateaued in recent years, our findings highlight that efforts focused on reducing IHCA incidence may yield additional gains in reducing resuscitation deaths in hospitals.

Abstract 4146312: Global Burden and Trend of Atrial Fibrillation and Flutter in the 27 European Union Countries from 1990-2021: A Systematic analysis for the Global Burden of Disease Study 2021

Introduction: Atrial Fibrillation (Afib) and Flutter ranks as the fifth leading cause of death among all cardiovascular diseases (CVD). Given the scarcity of consistent previous estimates, this study is the first to assess the burden of Afib and Flutter in the European Union (EU) over the past three decades, including the initial two years of the COVID-19 pandemic. Methods: Using global burden of disease study 2021 meta tool, we estimated prevalence, incidence, deaths, disability adjusted life years (DALYs), years lived with disability (YLDs) due to Afib and Flutter by age, sex, year and location across the 27 EU countries from 1990-2021. Results: The total number of prevalence rose from 5 million (95% uncertainty interval: 3.9-6.4 million) in 1990 to 8.6 million (7.2-10.3 million) in 2021. The total percentage of change (TPC) in deaths increased by 130% (110%-143%), and YLDs by 69% (56%-84%) from 1990-2021. Austria saw the highest increase in age-standardized incidence rates (ASIR) at 83%, followed by Czechia at 50%. Sweden experienced the largest rise in mortality rates (ASMR) at 93%, with Estonia at 35%, and in YLD rates (ASYLDR), Austria led with a 90% increase followed by Sweden at 49%. In terms of age, individuals aged 55 and older recorded the highest death toll at 70,269 (57,793-77,019) and the highest incidence at 607,960 (397,686-868,122) in 2021. Regarding gender, males showed an increased TPC in overall burden compared to females, with males observing an increase and females a decreasing trend in ASIR (5% vs -7%), ASMR (7% vs -4%), and ASYLDR (7% vs -5%) from 1990-2021. Conclusion: Deaths due to Afib and Flutter accounted for 4.26% of all CVD in EU. The escalating prevalence and mortality rates of Afib and Flutter across the EU highlight an urgent need for comprehensive healthcare strategies. Effective management should focus on bolstering preventive measures, advancing diagnostic techniques, and enhancing patient care frameworks, particularly for the aging demographic most at risk. Strategic collaboration across sectors, including innovative public health initiatives and policy reinforcement, is essential to curb this growing trend and safeguard public health.

IMMU-64. SEX-SPECIFIC ROLES OFYAP1 AND CD276/B7-H3 IN MEDULLOBLASTOMA IMMUNE SUPPRESSION

Abstract The molecular mechanism governing sex disparities in cancer prevalence, progression, and treatment outcomes represents an important yet understudied area of research with significant implications for cancer treatment. Medulloblastoma (MB), the most prevalent pediatric brain malignancy, exhibits a notable sex bias in incidence and survival rates. Males have a higher incidence rate across all age groups and have worse prognoses than their females for age groups over three years old. Here, we report an unanticipated sex-biased role of the oncogene Yap1 in SHH medulloblastoma. Our results reveal that Yap1 deletion significantly prolongs survival in male, but not female mice with SmoM2-driven SHH MB. Employing an integrated multi-omics approach, we demonstrate that YAP1 is required to maintain cancer stem cells simultaneously activating stemness genes (such as Sox2) and repressing differentiation genes (such as Neurod1 and Zic1/2) in both sexes. In contrast, Yap1 plays a more critical role in immune evasion in males than in females. Specifically, YAP1 regulates the expression of the immune checkpoint molecule Cd276/B7-H3, which suppresses cytotoxic T cell function. In males, CD276 blockade or Yap1 deletion in MB cells is enough to reverse T cell suppression effectively. In females, neither CD276 blockade nor Yap1 deletion alone in MB cells can reverse T cell suppression. Furthermore, YAP1’s direct transcriptional target gene signatures, including CD276, predict survival across multiple human cancers in male patients. These findings suggest broader implications of our findings beyond medulloblastoma and indicate a highly conserved mechanism across species. Our study provides compelling evidence for the male-biased efficacy of Yap1 or CD276 inhibitors and presents novel insights into sex-specific mechanisms of cancer immune evasion.

SURG-22. BRAIN METASTASIS FROM ADVANCED GASTRIC CANCERS: HIGH INCIDENCE OF LEPTOMENINGEAL DISSEMINATION AND ITS CLINICAL IMPACT ON SURVIVAL

Abstract OBJECTIVE Advanced gastric cancer is one of the most common and fatal cancers worldwide, and due to its highest incidence rate in Eastern Asian, it is steadily considered important. However, brain metastasis from advanced gastric cancer is very rare, and its incidence is reported as less than 1% of patients with primary advanced gastric cancer. There have been very few studies describing on the incidence and clinical outcome of patients with brain metastasis from advanced gastric cancers. METHOD We retrospectively analyzed 128 patients diagnosed as brain metastasis from advanced gastric cancers, and then underwent treatment from 2005 to 2021 April in our institution. Patients’ survival and its associated prognostic factors were evaluated. Especially, subgroup analysis on patients with leptomeningeal dissemination (LMD) was performed. RESULT Of total 128 patients of advanced gastric cancer with brain metastasis, 74 patients (58%) were diagnosed with LMD. Overall survival of LMD group was significantly shorter than that of non-LMD group (p&amp;lt;0.001). Patients treated with tumor removal (TR) followed by whole brain radiotherapy (WBRT) showed superior overall survival than patients with WBRT alone (p=0.002). Among 74 LMD patients, those who underwent WBRT combined with intrathecal methotrexate (IT MTX) showed better outcome than patients with WBRT alone (p=0.025). Specifically, for the 51 pure LMD patients without parenchymal brain metastasis, the superiority of adjuvant IT TMX on survival outcome was more apparent (p=0.011). CONCLUSION The incidence of LMD has been underestimated as 58% of patient with brain metastasis from advanced gastric cancers presented LMD on radiological and cytological studies. If the brain tumor is surgically resectable, TR followed by WBRT can be the first choice of treatment provides survival benefit. Patients with LMD are most benefited from IT MTX combined with WBRT.

Global, regional, and national burden of tuberculosis and attributable risk factors for 204 countries and territories, 1990-2021: a systematic analysis for the Global Burden of Diseases 2021 study.

Tuberculosis (TB) remains a major global health threat. Despite ongoing efforts to control and eradicate TB, various factors including socioeconomic issues, policy modifications, and unexpected public health crises like COVID-19 pandemic have posed new obstacles to achieving TB elimination. This study aims to analyze the changes in global tuberculosis burden over the past 32 years, and provide scientific support for global initiatives targeting the eradication of TB in the post-pandemic period. The data for this study were obtained from the Global Burden of Disease (GBD) 2021 database, with age-standardized incidence rate (ASIR), prevalence rate (ASPR), mortality rate (ASDR), and disability-adjusted life years (DALYs) as the primary assessment indicators. Dynamic changes in the TB burden were analyzed by estimating the annual percentage changes (EAPCs). The attributable ratios of six main risk factors to TB burden were calculated, and the correlation between the Socio-Demographic Index (SDI) and the TB burden was analyzed using Pearson correlation tests. The global TB incidence decreased from 8.6million cases in 1990 to 8.4million cases in 2021, with a corresponding decline in deaths. However, the TB burden remains higher among men than women. The highest incidence and mortality rates were observed in the age group of 15-69 years, with a notable gender disparity, especially in Eastern Europe. These rates were generally elevated in low-income and lower-middle-income regions, with significantly higher Age-Standardized Incidence Rates and Age-Standardized Death Rates in males compared to females. A significant negative correlation was found between SDI values and TB burden. Analyzing risk factors from the Global Burden of Disease study, it was determined that globally, dietary risks, high body-mass index, high fasting plasma glucose, low physical activity, tobacco, and alcohol use were the main contributors to TB age-standardized Disability-Adjusted Life Years, with tobacco and alcohol use having the most significant impact. Analysis of risk factors suggests that tailored public health interventions for specific genders and regions can effectively lessen the TB burden.

CNSC-68. SEX DIFFERENCES IN GLYCINE BIOSYNTHESIS DRIVE RESPONSES TO COMBINED NUTRIENT DEPRIVATION AND PHARMACOLOGICAL INHIBITION IN PEDIATRIC HGG

Abstract In children and adults, high-grade gliomas (HGGs) are the most common and deadly primary brain malignancies. Generally, male HGGs occur at higher incidence and demonstrate more rapid proliferation, resulting in shorter overall male survival. Obscurity of molecular mechanisms driving this phenomenon prevents implementation of clinically effective treatments. Recently, a positive correlation between HGG cellular proliferation and metabolic reprogramming toward glycine biosynthesis was identified. By analyzing pediatric and adult HGG patient data, we discovered significantly worse outcomes unique to pediatric males bearing upregulation of serine and glycine biosynthesis transcripts. Previously, we have identified differential flux of glucose into serine and glycine biosynthesis drives sex differences in lung cancer. Therefore, we sought to confirm and target this paradigm in our NF1-/- DNp53 model of HGG. By performing metabolic tracing with [13C]-labeled glucose in male and female cells, we identified higher enrichment of [13C]-labeled serine and glycine in male cells relative to female cells. Through Western blotting, we identify male-specific upregulation of serine and glycine biosynthetic pathway enzymes in transformed cells, supporting our labelling results. Next, we sought to determine if inhibition of de-novo serine and glycine biosynthesis was similarly sex-biased. Utilizing serine-and-glycine-deprived media conditions, we identified a male-biased decrease in proliferation following pharmacological inhibition of de-novo serine and glycine biosynthesis. More precisely, in the absence of exogenous glycine, we discovered that inhibition of de-novo synthesis of glycine from serine drove male-specific decreases in proliferation. Additionally, we identified that transformed female cell robustness against inhibition of glycine biosynthesis is driven by the uptake of exogenous nucleotide precursors. These data confirm that sex differences in de-novo glycine biosynthesis drive sex differences in HGG cellular proliferation. As well, our work suggests that dietary restriction of serine and glycine, in-combination with pharmacological inhibition of de-novo glycine biosynthesis, represents a novel treatment paradigm.

Giardia lamblia risk factors and burden in children with acute gastroenteritis in a Nicaraguan birth cohort.

Giardia lamblia is an intestinal protozoan estimated to cause ~200 million symptomatic infections annually, mainly in children in low- and middle-income countries associated with intestinal damage, increased permeability, and malabsorption. We describe here the epidemiology, incidence, clinical characteristics, and risk factors of acute gastroenteritis episodes (AGE) with G. lamblia detection (GAGE) using a birth cohort of 443 Nicaraguan children followed weekly until 36 months of life. From June 2017 to July 2021, 1385 AGE samples were tested by qPCR. G. lamblia was detected in 104 (7.5%) of AGE episodes. In all, 69 (15.6%) children experienced at least one GAGE episode, and 25 of them (36.2%) experienced more than one episode. The incidence rate of the first episode of GAGE was 6.8/100 child-years (95% CI, 4.5-9.1). During GAGE, bloody stools, vomiting, and fever were uncommon, and children were less likely to be treated at a primary care clinic, suggesting that GAGE is typically mild and most cases did not receive medical attention, which could facilitate higher parasite loads with increased possibilities of establishing chronic carriage. GAGE was more common in children 12-24 months of age (13.9/100 child-years [95% CI, 10.7-17.1]) as compared to other age groups. In our birth-cohort, children living in a home with an indoor toilet (aHR, 0.52 [95%CI, 0.29-0.92]), and being breastfed in the first year of life (aHR: 0.10 [95%IC, 0.02, 0.57]) had a lower incidence of GAGE. In contrast, being breastfed for ≤ 6 months was associated with a higher incidence if the children were living in houses without indoor toilets and earthen floors (HR, 7.79 [95% CI, 2.07, 29.3]). Taken together, GAGE is more frequent under poor household conditions. However, breastfeeding significantly reduces the incidence of GAGE in those children.

EPCO-47. SEX-BIASED BRD4 ACTIVITY DRIVES TUMORIGENESIS IN GLIOBLASTOMA

Abstract Consistent sex differences in incidence and outcome have been reported in cancers including brain tumors. Glioblastoma (GBM), the most common and aggressive primary brain tumor, occurs with higher incidence and shorter survival in males compared to females. Brd4 is essential for regulating transcriptome-wide gene expression and specifying cell identity. Using an isogenic murine GBM model, we have reported correlated transcriptome-wide sex differences in gene expression, Brd4-bound enhancer usage, and Brd4 localization to oncogenic and tumor suppressor transcription factors binding sites in male and female GBM cells, respectively. Sex-biased gene expression patterns were also evident in human glioblastoma. Inhibiting Brd4 function abrogates sex differences in these transcriptional states and concomitant differences in tumorigenic phenotype. Thus, sex-biased Brd4 activity drives sex differences in GBM rendering males and females differentially sensitive to BET inhibitors. These data indicate that Brd4 can exhibit dual functions as an oncogene or tumor suppressor, dependent upon cellular sex. To better understand how to globally target Brd4, we interrogated the role played by master transcriptional Brd4 regulators in coordinating this dual phenotype in GBM. Motif-based analysis revealed that Brd4 co-localized with oncogenes such as Bach1, and Klf5 at male-biased enhancers whereas female-biased enhancers were co-occupied with tumor suppressors, such as Smad4 and p53. Knockdown of Bach1 decreased clonogenic frequency in males and females. Conversely, knockdown of Smad4 increased proliferation and clonogenicity in males, further inducing the male tumorigenic phenotype, while no change was observed in females. These results indicate that Smad4 might be necessary but not sufficient to provide females with resistance to transformation. Ongoing epitranscriptomics investigating Brd4 re-localization and enhancer usage in knockdown cells will increase our understanding of Brd4 mechanism in GBM. Targeting sex-biased Brd4 function will identify novel combinatorial sex-specific therapeutics for brain tumors and could have immediate impact on the clinical treatment of GBM patients.