Citations

Abstract Enhancer is a critical epigenetic feature in head and neck squamous cell carcinoma (HNSCC), yet the functional roles of individual enhancers remain poorly understood. Here, we conducted an integrative multi-omics analysis based on publicly available ATAC-seq, H3K27ac ChIP-seq, transcriptomic profiling, and genetic association datasets to systematically map HNSCC-associated enhancers and their target genes. Integrating ATAC-seq and H3K27ac ChIP-seq, we identified 20,362 enhancers and 18,040 enhancer-associated genes, highlighting widespread regulatory complexity. Functional characterization of the TERT -associated enhancer GH05J001312 (GRCh38/hg38: chr5:1312099-1317743) revealed strong transcriptional activity in HNSCC. CRISPR-mediated deletion of a core sequence significantly reduced TERT expression, impaired cellular proliferation in vitro , and suppressed tumor growth in vivo , confirming its role as a key cis-regulatory element. RNA-seq analysis of enhancer-edited cells uncovered 742 differentially expressed genes enriched in cancer-related pathways, including MAPK and IL-17 signaling, indicating a broad transcriptional impact. Collectively, our findings establish GH05J001312 as a functional enhancer driving oncogenic programs in HNSCC and suggest enhancer-targeted strategies as a potential therapeutic avenue.

Abstract Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

Abstract Background Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology‐based topics spanning the field. Methods In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence‐Based Review with Recommendations, Evidence‐Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses format, and completed sections underwent a thorough and iterative consensus‐building process. The final document underwent rigorous synthesis and review prior to publication. Results The ICSNT document consists of four major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology‐based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention. Conclusion As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses.

AbstractBackgroundComprehensive analysis of trauma care between high‐, middle‐, and low‐income countries (HIC/MIC/LIC) is needed to improve global health. Comparison of HIC and MIC outcomes after damage control laparotomy (DCL) for patients is unknown. We evaluated DCL utilization among patients treated at high‐volume trauma centers in the USA and South Africa, an MIC, hypothesizing similar mortality outcomes despite differences in resources and setting.MethodsPost hoc analysis of prospectively collected trauma databases from participating centers was performed. Injury severity, physiologic, operative data and post‐operative outcomes were abstracted. Univariate and multivariable analyses were performed to assess differences between HIC/MIC for the primary outcome of mortality.ResultsThere were 967 HIC and 602 MIC patients who underwent laparotomy. DCL occurred in 144 MIC patients (25%) and 241 HIC (24%) patients. Most sustained (58%) penetrating trauma with higher rates in the MIC compared to the HIC (71 vs. 32%, p = 0.001). Between groups, no differences were found for admission physiology, coagulopathy, or markers of shock except for increased presence of hypotension among patients in the HIC. Crystalloid infusion volumes were greater among MIC patients, and MIC patients received fewer blood products than those in the HIC. Overall mortality was 30% with similar rates between groups (29 in HIC vs. 33% in MIC, p = 0.4). On regression, base excess and penetrating injury were independent predictors of mortality but not patient residential status.ConclusionUse and survival of DCL for patients with severe abdominal trauma was similar between trauma centers in HIC and MIC settings despite increased penetrating trauma and less transfusion in the MIC center. While the results overall suggest no gap in care for patients requiring DCL in this MIC, it highlights improvements that can be made in damage control resuscitation.

Abstract Background The pediatric resuscitation and trauma outcome (PRESTO) model was developed to aid comparisons of risk‐adjusted mortality after injury in low‐ and middle‐income countries (LMICs). We sought to validate PRESTO using data from a middle‐income country (MIC) trauma registry and compare its performance to the Pediatric Trauma Score (PTS), Revised Trauma Score, and pediatric age‐adjusted shock index (SIPA). Methods We included children (age < 15 years) admitted to a single trauma center in South Africa from December 2012 to January 2019. We excluded patients missing variables necessary for the PRESTO model—age, systolic blood pressure, pulse, oxygen saturation, neurologic status, and airway support. Trauma scores were assigned retrospectively. PRESTO's previously high‐income country (HIC)‐validated optimal threshold was compared to MIC‐validated threshold using area under the receiver operating characteristic curves (AUROC). Prediction of in‐hospital death using trauma scoring systems was compared using ROC analysis. Results Of 1160 injured children, 988 (85%) had complete data for calculation of PRESTO. Median age was 7 (IQR: 4, 11), and 67% were male. Mortality was 2% ( n = 23). Mean predicted mortality was 0.5% (range 0–25.7%, AUROC 0.93). Using the HIC‐validated threshold, PRESTO had a sensitivity of 26.1% and a specificity of 99.7%. The MIC threshold showed a sensitivity of 82.6% and specificity of 89.4%. The MIC threshold yielded superior discrimination (AUROC 0.86 [CI 0.78, 0.94]) compared to the previously established HIC threshold (0.63 [CI 0.54, 0.72], p < 0.0001). PRESTO showed superior prediction of in‐hospital death compared to PTS and SIPA (all p < 0.01). Conclusion PRESTO can be applied in MIC settings and discriminates between children at risk for in‐hospital death following trauma. Further research should clarify optimal decision thresholds for quality improvement and benchmarking in LMIC settings.

AbstractIntroductionWe aimed to expand on the global surgical discussion around splenic trauma in order to understand locally and clinically relevant factors for operative (OP) and non‐operative management (NOM) of splenic trauma in a South African setting.MethodsA retrospective cohort study was performed using 2013–2017 data from the Pietermaritzburg Metropolitan Trauma Service. All adult patients (≥15 years) were included. Those managed with OP or NOM for splenic trauma were identified and analyzed descriptively. Multiple logistic regression analysis identified patients and clinical factors associated with management type.ResultsThere were 127 patients with splenic injury. Median age was 29 [19–35] years with 42 (33%) women and 85 (67%) men. Blunt injuries occurred in the majority (81, 64%). Organ Injury Scale (OIS) grades included I (25, 20%), II (43, 34%), III (36, 28%), IV (15, 11%), and V (8, 6%). Nine patients expired. On univariate analysis, increasing OIS was associated with OP management, need for intensive care unit (ICU) admission, and hospital and ICU duration of stay, but not mortality. In patients with a delayed compared to early presentation, ICU utilization (62% vs. 36%, p = 0.008) and mortality (14% vs. 4%, p = 0.03) were increased. After adjusting for age, sex, presence of shock, and splenic OIS, penetrating trauma (adjusted odds ratio, 5.7; 95%CI, 1.7–9.8) and admission lactate concentration (adjusted odds ratio, 1.4; 95%CI 1.1–1.9) were significantly associated with OP compared to NOM (p = 0.002; area under the curve 0.81).ConclusionsWe have identified injury mechanism and admission lactate as factors predictive of OP in South African patients with splenic trauma. Timely presentation to definitive care affects both ICU duration of stay and mortality outcomes. Future global surgical efforts may focus on expanding non‐operative management protocols and improving pre‐hospital care in patients with splenic trauma.

AbstractBackgroundSnake envenomation is associated with major morbidity especially in low‐ and middle‐income countries and may require fasciotomy. We determined patient factors associated with the need for fasciotomy after venomous snake bites in children located in KwaZulu‐Natal, South Africa.MethodsSingle institutional review of historical data (2012–2017) for children (<18 years) sustaining snake envenomation was performed. Clinical data, management, and outcomes were abstracted. Syndromes after snake bite were classified according to Blaylock nomenclature: progressive painful swelling (PPS), progressive weakness (PW), or bleeding (B), as it is difficult to reliably identify the species of snake after a bite. Comparative and multivariable analyses to determine factors associated with fasciotomy were performed.ResultsThere were 72 children; mean age was 7 (±3) years, 59% male. Feet were most commonly affected (n = 27, 38%) followed by legs (n = 18, 25%). Syndromes (according to Blaylock) included PPS (n = 63, 88%), PW (n = 5, 7%), and B (n = 4, 5%). Eighteen patients underwent fasciotomy, and one required above knee amputation. Nine patients received anti‐venom. Few patients (15%) received prophylactic beta‐lactam antibiotics. Hemoglobin < 11 mg/dL, leukocytosis, INR >1.2, and age‐adjusted shock index were associated with fasciotomy. On regression, age‐adjusted shock index and hemoglobin concentration < 11 mg/dL, presentation >24 h after snake bite, and INR >1.2 were independently associated with fasciotomy. Model sensitivity was 0.89 and demonstrated good fit.ConclusionsPatient factors were associated with the fasciotomy. These factors, coupled with clinical examination, may identify those who need early operative intervention. Improving time to treatment and the appropriate administration of anti‐venom will minimize the need for surgery.Level of evidenceIII

Abstract Lung cancer has the highest mortality across all cancers in the world. Epidermal growth factor receptor (EGFR) is commonly mutated in lung adenocarcinomas from Asian non-smoking females. These tumors usually respond to EGFR tyrosine kinase inhibitors (EGFR-TKI), but the outcomes vary in different patients. Though EGFR T790M, amplification of MET and other mechanisms have been shown to confer EGFR-TKI resistance, the molecular mechanisms in around 30% of patients are still unknown. To uncover novel candidate pathways of EGFR-TKI resistance, we analyzed the whole exome mutation profiles of pre-treatment, EGFR T790M-free lung adenocarcinomas with typical activating mutations (L858R, exon 19 deletions). Amongst 19 non-responding (NR) tumors without significant shrinkage after gefitinib or erlotinib treatment, 67 cancer-related genes showed coding region non-synonymous single nucleotide variations (SNV) or insertion-deletions (indels) but they were not detected in 22 responding tumors. Gene set enrichment analysis (GSEA) showed 14 of the 67 genes were involved in the EGFR and WNT signaling network (false discovery rate q=1.14 e-8 for EGFR and q=4.3 e-9 for WNT), including well-known TKI resistance-related genes PIK3CA, PTEN and NF1. Notably, ARID1A, which encodes a subunit of the chromatin remodeling complex, showed nonsense mutations in 2 NR but not responding tumors, which were validated by Sanger sequencing. More than 40% of ARID1A mutations in lung adenocarcinomas recorded in COSMIC were nonsense mutations or frameshift indels. Loss of function mutations of ARID1A have also been reported in various cancers, together suggesting ARID1A might be a tumor suppressor but its involvement in EGFR mutant lung cancers is unknown. To investigate the potential role of ARID1A, its expression was first studied using Kaplan-Meier plotter. Low expression of ARID1A is associated with significantly better overall survival than high expression level in lung adenocarcinoma patients (p=8.5 e-7). To test whether loss of ARID1A could cause TKI resistance, ARID1A was knocked down by shRNA in HCC827 lung cancer cell line harboring EGFR exon19 deletion. MTT cell viability assay using gefitinib showed increase of IC50. Western blot assay further showed ARID1A knockdown increased phosphorylation of AKT at Ser473. Together, the findings suggest loss of ARID1A could lead to EGFR bypass and promote activation of the downstream PI3K/AKT pathway, leading to EGFR TKI resistance. Overall, our findings suggest EGFR-TKI resistance mutations could be detected before TKI drug selection. Resistant gene mutations present in pre-treatment tumors could help to predict the treatment response. More specifically, our study identified a promising gene list involved in EGFR-TKI resistance, and suggested ARID1A loss could be a novel EGFR-TKI resistance mechanism. Citation Format: Xuyuan Gao, Hang Xu, James CM Ho, Oscar SH Chan, Feng Xu, Junwen Wang, Victor HF Lee, Vicky PC Tin, Zhijie Xiao, Siqi Wang, Judy WP Yam, Maria P Wong. EGFR-mutant lung adenocarcinomas mutation profiles reveal ARID1A might be a novel tyrosine kinase resistance pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-196.

AbstractBackgroundAcute appendicitis is a common pediatric surgical emergency; however, there are few grading systems to assign disease severity. The American Association for the Surgery of Trauma (AAST) recently developed a grading system for a variety of emergency surgical conditions, including appendicitis. The severity of acute appendicitis in younger patients in KwaZulu‐Natal (South Africa) is unknown. We aimed to describe the disease severity in this patient population using the AAST grading system hypothesizing that the AAST grade would correlate with morbidity, management type, and duration of stay.MaterialsSingle institutional review of patients <18 years old with a final diagnosis of acute appendicitis during 2010–2016 in KwaZulu‐Natal, South Africa, was performed. Demographics, physiologic and symptom data, procedural details, postoperative complications, and Clavien–Dindo classification were abstracted. AAST grades were generated based on intraoperative findings. Summary, univariate, and nominal logistic regression analyses were performed to compare AAST grade and outcomes.ResultsA total of 401 patients were identified with median [IQR] age of 11 [5–13], 65% male. Appendectomy was performed in all patients; 2.4% laparoscopic, 37.6% limited incision, and 60% midline laparotomy. Complications occurred in 41.6%, most commonly unplanned relaparotomy (22.4%), surgical site infection (8.9%), pneumonia (7.2%), and acute renal failure (2.9%). Complication rate and median length of stay increased with greater AAST grade (all p < 0.001). AAST grade was independently associated with increased risk of complications.ConclusionPediatric appendicitis is a morbid disease in a developing middle‐income country. The AAST grading system is generalizable and accurately corresponds with management strategies as well as key clinical outcomes.Level of evidenceRetrospective study, Level IV.Study typeRetrospective single institutional study.

AbstractBackgroundThe American Association for the Surgery of Trauma (AAST) anatomic severity grading system for adhesive small bowel obstruction (ASBO) has demonstrated to be a valid tool in North American patient populations. Using a multi‐national patient cohort, we retrospectively assessed the validity the AAST ASBO grading system and estimated disease severity in a global population in order to correlate with several key clinical outcomes.MethodsMulticenter retrospective review during 2012–2016 from four centers, Minnesota USA, Bologna Italy, Pietermaritzburg South Africa, and Bucharest Romania, was performed. Adult patients (age ≥ 18) with ASBO were identified. Baseline demographics, physiologic parameters, laboratory results, operative and imaging details, outcomes were collected. AAST ASBO grades were assigned by independent reviewers. Univariate and multivariable analyses with odds ratio (OR) and 95% confidence intervals (CIs) were performed.ResultsThere were 789 patients with a median [IQR] age of 58 [40–75] years; 47% were female. The AAST ASBO grades were I (n = 180, 23%), II (n = 443, 56%), III (n = 87, 11%), and IV (n = 79, 10%). Successful non‐operative management was 58%. Conversion rate from laparoscopy to laparotomy was 33%. Overall mortality and complication and temporary abdominal closure rates were 2, 46, and 4.7%, respectively. On regression, independent predictors for mortality included grade III (OR 4.4 95%CI 1.1–7.3), grade IV (OR 7.4 95%CI 1.7–9.4), pneumonia (OR 5.6 95%CI 1.4–11.3), and failing non‐operative management (OR 2.4 95%CI 1.3–6.7).ConclusionThe AAST EGS grade can be assigned with ease at any surgical facility using operative or imaging findings. The AAST ASBO severity grading system has predictive validity for important clinical outcomes and allows for standardization across institutions, providers, and future research. Disease severity and outcomes varied between countries.Level of evidence IIIStudy type Retrospective multi‐institutional cohort study.