Gastrointestinal Stromal Tumor Patients with Molecular Testing Exhibit Superior Survival Compared to Patients without Testing: Results from the Life Raft Group (LRG) Registry.

Mutational testing for Gastrointestinal Stromal Tumor (GIST) patients remains underutilized. In this retrospective analysis, the target population (n = 1556) reported: 904 had molecular testing ("Tested") vs. 652 without testing ("Untested"). Overall survival (OS) was 14.7 vs. 12.7 years (p < 0.00001), in metastatic patients 1st line OS was 8.9 vs. 5.9 years in the Tested vs. Untested group (n = 416 vs. n = 254), respectively. From 1st - 3rd-line, no difference has been (self-)reported for progression-free survival (PFS). Dropout to/for further lines of treatment was 15% for patients with a Tested mutation vs. 47% in Untested patients.

Initial experience of left bundle branch pacing using the Abbott Agilis HisPro Catheter with stylet-driven leads.

AIMS: Conduction system pacing has gained steady interest over recent years. While the majority of tools and delivery techniques were developed for His bundle pacing (HBP), the feasibility and reproducibility of using these similar tools for left bundle branch pacing (LBBP) has yet to be determined. We describe our technique for performing LBBP using the Abbott Agilis HisPro™ Steerable Catheter. METHODS AND RESULTS: A series of 22 patients with a mean age of 71.7 years (16 males, 72.7%), underwent LBBP procedure with this catheter between May and October 2021. Nineteen patients (86%) had successful LBBP lead implantation. There were no major complications or mortality. CONCLUSION: The Agilis HisPro™ catheter along with the stylet driven Tendril STS Model 2088TC lead is a safe and feasible delivery system for LBBP.

Surveillance Colonoscopy after Appendicectomy in Patients over the Age of 40: Targeted Audit of Outcomes and Variability in Practice.

Introduction: Recent evidence suggests the need to proceed with a surveillance colonoscopy in patients above the age of 40 years who undergo appendicectomy for acute appendicitis, given the higher risk of an underlying colonic tumor. After anecdotally observing a substantial variability in terms of adaptation of these recommendations by the on-call surgical teams, we performed a clinical audit regarding our relevant endoscopic follow-up compliance rates to identify areas for improvement of our practise. Materials Methods: We performed a retrospective review of the electronic records of all patients above 40 years who had appendicectomy for acute appendicitis within a 3-year period in our institution, assessing as primary outcome the actual performance of a follow-up colonoscopy and the detected endoscopic findings. Results: Our results demonstrated that more than 80% of our patients did not have an endoscopic follow-up, as suggested by the current evidence. In addition, with respect to the subspecialisation of the parent surgical team, it seems that non-colorectal teams had lower compliance regarding the arrangement of endoscopic surveillance, when compared to specialist colorectal team. Conclusions: Emergency surgical teams need to be further educated with respect to the current practise recommendations concerning the appropriate endoscopic follow-up after the performance of appendicectomy for acute appendicitis. Establishment of dedicated bundles of postoperative care, as well as clear relevant guidance from the gastrointestinal/emergency surgery societies would be of great value in this direction.

Isolated Lambdoid Craniosynostosis.

INTRODUCTION: Lambdoid craniosynostosis is an extremely rare anomaly in which there is premature fusion of one or both lambdoid sutures. The mainstay of treatment is surgical intervention, for which various procedures have been described, but there is a paucity of data on long-term outcomes. This study examines the long-term outcomes in the surgical management of this challenging condition, showing that accurate diagnosis and careful planning can lead to safe and consistent results. MATERIALS AND METHODS: A retrospective chart review was performed looking at all cases of isolated lambdoid craniosynostosis treated with surgical intervention by the senior author from 1999 to 2016. Data collected included gender, age at diagnosis, age at surgery, length of follow up, method of diagnosis, side of affected suture, pre-operative and post-operative physical exam findings, surgical technique, complications, re-operation rate, and associated torticollis. RESULTS: Twenty-five patients (N = 25) were included in the study. All patients underwent posterior calvarial remodeling with/without barrel stave osteotomies and full thickness calvarial bone grafts. Mean length of follow up after operative intervention was 43.8 months (+/- 23.2 months). All patients were judged to have significantly improved head contour which was near-normal at conversational distance during post-operative follow up by the senior author. Residual plagiocephaly was present in 24% of patients. There were no major complications in this series. Reoperation rate was 8%. Seventy-six percent of patients also presented with torticollis, of which 37% had refractory torticollis that required sternocleidomastoid (SCM) release by the senior author. DISCUSSION: The authors present one of the largest series of operative cases of isolated lambdoid craniosynostosis to date. Our data show that with accurate diagnosis and careful planning, safe and consistent long-term results can be achieved with surgical intervention. A significant number of patients in our series also presented with concomitant torticollis. The authors recommend that all patients being evaluated for posterior plagiocephaly should also be evaluated for torticollis, because without recognition and intervention, patients may continue to have residual facial asymmetry and head shape abnormalities despite optimal surgical correction of the lambdoid synostosis.

Epicardial ablation utilizing remote magnetic navigation in a patient with Brugada syndrome and inferior early repolarization.

We report a case of epicardial ablation in a combined Brugada and inferior early repolarization syndrome patient with recurrent defibrillator therapy for spontaneous ventricular fibrillation. Electroanatomic mapping and ablation were achieved with remote magnetic navigation. Highly fractionated electrograms were seen epicardially in the anterior right ventricular outflow tract (RVOT) and at the anterior-inferior right ventricle. Ablation of the RVOT region resulted in resolution Brugada pattern electrocardiogram. The inferior early repolarization persisted despite ablation of the inferior right ventricular epicardium. Our patient remained event free at 12-months follow-up.

Wenckebach pattern in right bundle branch block - benign or not?

A Mobitz type I block (Wenckebach phenomenon) with narrow QRS complex is almost always due to a lesion in the AV node. In a type I block with wide QRS complex (>0.12sec), the block can be in the His-Purkinje system in 60-70% of the cases. Even though the progressive PR prolongation with every conducted beat suggests Wenckebach phenomenon, one needs to pay attention to the accompanying QRS complex. In the setting of persistent right bundle branch block, axis change of subsequent conducted beat before an unconducted p suggests alternating fascicular block, giving clue to unreliable infra-Hisian conduction; and in the setting of symptoms, a pacemaker should be implanted. Infra-Hisian Wenckebach block is rare with only sparse literature reports. The present case report adds to these, suggesting that wide QRS with Wenckebach block on surface ECG may indicate infra-Hisian conduction abnormalities.

Integrated pathway analysis of nasopharyngeal carcinoma implicates the axonemal dynein complex in the Malaysian cohort.

Nasopharyngeal carcinoma (NPC) is an epithelial squamous cell carcinoma on the mucosal lining of the nasopharynx. The etiology of NPC remains elusive despite many reported studies. Most studies employ a single platform approach, neglecting the cumulative influence of both the genome and transcriptome toward NPC development. We aim to employ an integrated pathway approach to identify dysregulated pathways linked to NPC. Our approach combines imputation NPC GWAS data from a Malaysian cohort as well as published expression data GSE12452 from both NPC and non-NPC nasopharynx tissues. Pathway association for GWAS data was performed using MAGENTA while for expression data, GSA-SNP was used with gene p values derived from differential expression values from GEO2R. Our study identified NPC association in the gene ontology (GO) axonemal dynein complex pathway (pGWAS-GSEA = 1.98 × 10(-2) ; pExpr-GSEA = 1.27 × 10(-24) ; pBonf-Combined = 4.15 × 10(-21) ). This association was replicated in a separate cohort using gene expression data from NPC and non-NPC nasopharynx tissues (pAmpliSeq-GSEA = 6.56 × 10(-4) ). Loss of function in the axonemal dynein complex causes impaired cilia function, leading to poor mucociliary clearance and subsequently upper or lower respiratory tract infection, the former of which includes the nasopharynx. Our approach illustrates the potential use of integrated pathway analysis in detecting gene sets involved in the development of NPC in the Malaysian cohort.

Prognostic implications of imaging in atrophic macular degeneration and its use in clinical practice and clinical trial design.

Clinical prognostic markers in atrophic age-related macular degeneration include the extent of existing atrophy, fundus autofluorescence (FAF) patterns and optical coherence tomography changes in the outer retina/retinal pigment epithelium interface. The prognostic implications of these findings may be used to determine not just the rate of disease progression but also influence the likelihood, magnitude and clinical relevance of therapy responses. FAF phenotypes have been extensively investigated; however, the pathophysiological mechanisms behind their appearance have not been fully elucidated. Optical coherence tomography imaging is additive to FAF imaging in atrophic age-related macular degeneration, allowing the visualization of detail not available through FAF imaging whilst also displaying subtle changes correlating with the FAF phenotypes themselves, thereby giving clues to their histological determinates. The developing understanding of these imaging modalities and consequent development of prognostically useful classification systems have widespread implication in clinical care and clinical trial design.

HLA-A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese.

Nasopharyngeal carcinoma (NPC) arises from the mucosal epithelium of the nasopharynx and is constantly associated with Epstein-Barr virus type 1 (EBV-1) infection. We carried out a genome-wide association study (GWAS) of 575,247 autosomal SNPs in 184 NPC patients and 236 healthy controls of Malaysian Chinese ethnicity. Potential association signals were replicated in a separate cohort of 260 NPC patients and 245 healthy controls. We confirmed the association of HLA-A to NPC with the strongest signal detected in rs3869062 (p = 1.73 × 10(-9)). HLA-A fine mapping revealed associations in the amino acid variants as well as its corresponding SNPs in the antigen peptide binding groove (p(HLA-A-aa-site-99) = 3.79 × 10(-8), p(rs1136697) = 3.79 × 10(-8)) and T-cell receptor binding site (p(HLA-A-aa-site-145) = 1.41 × 10(-4), p(rs1059520) = 1.41 × 10(-4)) of the HLA-A. We also detected strong association signals in the 5'-UTR region with predicted active promoter states (p(rs41545520) = 7.91 × 10(-8)). SNP rs41545520 is a potential binding site for repressor ATF3, with increased binding affinity for rs41545520-G correlated with reduced HLA-A expression. Multivariate logistic regression diminished the effects of HLA-A amino acid variants and SNPs, indicating a correlation with the effects of HLA-A*11:01, and to a lesser extent HLA-A*02:07. We report the strong genetic influence of HLA-A on NPC susceptibility in the Malaysian Chinese.

Establishment and Characterization of an Epstein-Barr Virus-positive Cell Line from a Non-keratinizing Differentiated Primary Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC), a cancer that is etiologically associated with the Epstein-Barr virus (EBV), is endemic in Southern China and Southeast Asia. The scarcity of representative NPC cell lines owing to the frequent loss of EBV episomes following prolonged propagation and compromised authenticity of previous models underscores the critical need for new EBV-positive NPC models. Herein, we describe the establishment of a new EBV-positive NPC cell line, designated NPC268 from a primary non-keratinizing, differentiated NPC tissue. NPC268 can undergo productive lytic reactivation of EBV and is highly tumorigenic in immunodeficient mice. Whole-genome sequencing revealed close similarities with the tissue of origin, including large chromosomal rearrangements, while whole-genome bisulfite sequencing and RNA sequencing demonstrated a hypomethylated genome and enrichment in immune-related pathways, respectively. Drug screening of NPC268 together with six other NPC cell lines using 339 compounds, representing the largest high-throughput drug testing in NPC, revealed biomarkers associated with specific drug classes. NPC268 represents the first and only available EBV-positive non-keratinizing differentiated NPC model, and extensive genomic, methylomic, transcriptomic, and drug response data should facilitate research in EBV and NPC, where current models are limited. SIGNIFICANCE: NPC268 is the first and only EBV-positive cell line derived from a primary non-keratinizing, differentiated nasopharyngeal carcinoma, an understudied but important subtype in Southeast Asian countries. This model adds to the limited number of authentic EBV-positive lines globally that will facilitate mechanistic studies and drug development for NPC.

Flavonoids from fruit and vegetables: a focus on cardiovascular risk factors.

Epidemiological studies suggest that high intakes of dietary flavonoids are associated with decreased cardiovascular disease mortality and risk factors. Less is known about the cardioprotective effects of flavonoids from fruit and vegetables. This review summarizes data from studies which examine the effects of commonly consumed fruit and vegetables on cardiovascular disease risk biomarkers in healthy volunteers or at-risk individuals. Although flavonoids from apples, berries, and onions appear to impact positively on blood pressure, vascular function, and serum lipid levels, further research is required to find out the optimal quantity and food matrix for conferring substantial clinical benefit. The benefits from citrus flavonoids are still inconclusive. Further robust, longer-term dietary intervention studies, with the inclusion of placebo or control arms, are required to improve the credibility of the findings and confirm current observations. An improved understanding of the impact of flavonoids from fruit and vegetables can help one make discerning food choices for optimal cardiovascular health.

Pacemaker failure due to loss of fluid seal in a patient with a 5/6mm pacemaker header port and a 5mm unipolar lead.

INTRODUCTION: Before IS-1 (3.2 mm) standardization of pacemaker leads and connectors, 5/6 mm connector ports accomodated 5mm or 6mm diameter lead connector pins. CASE REPORT: A patient with sick sinus syndrome underwent implantation of a 5mm unipolar atrial lead, mated to a 5/6mm connector port Medtronic Spectrax Sx 5985 pacemaker. Pulse generator reached ERI in 2006, with change out to a Medtronic Sigma SSR306 (5/6mm connector port) and preservation of the 5mm lead. She was admitted in 2010 for atrial lead non capture from blood leak and corrosion of the header-connector pin apparatus. DISCUSSION: 5/6mm pacemaker header ports have a 5mm flexible sealing ring at the port entrance to seal 5mm or 6mm lead connector pins. The inner barrel diameter of the connector port is 6mm and insertion of a 5mm lead results in a 0.5mm tolerance circumferentially. Should the seal be compromised, blood can corrode the apparatus. To minimize this, we can employ (a) a cinching tie to further seal the silicone ring (b) universal adaptor sleeves (c) splice kits (d) lead adaptor kits. Aging leads, adaptor kits or sleeves themselves can result in lead failure. It may be safer to re-implant the entire system. CONCLUSIONS: A 5/6mm configuration pacemaker header connector port allows for significant tolerances when a 5 mm lead is used. Consideration must be made to prevent leaks.

The Management of Bacillus Calmette-Guérin (BCG) Failure in High-Risk Non-muscle Invasive Bladder Cancer: A Review Article.

Non-muscle invasive bladder cancer (NMIBC) is a common urological malignancy, and bacillus Calmette-Guérin (BCG) therapy is the gold standard treatment in intermediate and high-risk groups. However, BCG failure occurs in a significant proportion of patients, emphasizing the need for effective alternative treatment modalities to address this burden. These treatments include immunotherapy, enhanced drug delivery, targeted therapy, device-assisted chemotherapy, vaccine therapy, and gene therapy, which show varying degrees of safety and efficacy. The objective of this review is to summarize the current evidence and ongoing research on these emerging therapies, offering insight into their potential for improving patient outcomes and quality of life. Although radical cystectomy remains the standard of care for high-risk NMIBC patients unresponsive to BCG, novel treatment modalities hold promise for the future management of this challenging patient population.

Outcomes of Investigating T Wave Inversion With Echocardiography in an Unselected Young Male Preparticipation Cohort.

BACKGROUND Electrocardiography (ECG) may be performed as part of preparticipation sports screening. Recommendations on screening of athletes to identify individuals with previously unrecognized cardiac disease are robust; however, data guiding the preparticipation screening of unselected populations are scarce. T wave inversion (TWI) on ECG may suggest an undiagnosed cardiomyopathy. This study aims to describe the prevalence of abnormal TWI in an unselected young male cohort and the outcomes of an echocardiography-guided approach to investigating these individuals for structural heart diseases, focusing on the yield for cardiomyopathies. METHODS AND RESULTS Consecutive young male individuals undergoing a national preparticipation cardiac screening program for 39 months were studied. All underwent resting supine 12-lead ECG. Those manifesting abnormal TWI, defined as negatively deflected T waves of at least 0.1 mV amplitude in any 2 contiguous leads, underwent echocardiography. A total of 69 714 male individuals with a mean age of 17.9±1.1 years were studied. Of the individuals, 562 (0.8%) displayed abnormal TWI. This was most frequently observed in the anterior territory and least so in the lateral territory. A total of 12 individuals (2.1%) were diagnosed with a cardiomyopathy. Cardiomyopathy diagnoses were significantly associated with deeper maximum TWI depth and the presence of abnormal TWI in the lateral territory, but not with abnormal TWI in the anterior and inferior territories. No individual presenting with TWI restricted to solely leads V1 to V2, 2 inferior leads or both was diagnosed with a cardiomyopathy. CONCLUSIONS Cardiomyopathy diagnoses were more strongly associated with certain patterns of abnormal TWI. Our findings may support decisions to prioritize echocardiography in these individuals.

Identification of a functional variant in SPLUNC1 associated with nasopharyngeal carcinoma susceptibility among Malaysian Chinese.

Nasopharyngeal carcinoma (NPC) is a multifactorial and polygenic disease with high incidence in Asian countries. Epstein-Barr virus infection, environmental and genetic factors are believed to be involved in the tumorigenesis of NPC. The association of single nucleotide polymorphisms (SNPs) in LPLUNC1 and SPLUNC1 genes with NPC was investigated by performing a two-stage case control association study in a Malaysian Chinese population. The initial screening consisted of 81 NPC patients and 147 healthy controls while the replication study consisted of 366 NPC patients and 340 healthy controls. The combined analysis showed that a SNP (rs2752903) of SPLUNC1 was significantly associated with the risk of NPC (combined P = 0.00032, odds ratio = 1.62, 95% confidence interval = 1.25-2.11). In the subsequent dense fine mapping of SPLUNC1 locus, 36 SNPs in strong linkage disequilibrium with rs2752903 (r(2) ≥ 0.85) were associated with NPC susceptibility. Screening of these variants by electrophoretic mobility shift and luciferase reporter assays showed that rs1407019 located in intron 3 (r(2) = 0.994 with rs2752903) caused allelic difference in the binding of specificity protein 1 (Sp1) transcription factor and affected luciferase activity. This SNP may consequently alter the expression of SPLUNC1 in the epithelial cells. In summary, our study suggested that rs1407019 in intronic enhancer of SPLUNC1 is associated with NPC susceptibility in which its A allele confers an increased risk of NPC in the Malaysian Chinese population.

First experiences with simultaneous skeletal and soft tissue reconstruction of noma-related facial defects.

Noma victims suffer from a three-dimensional facial soft-tissue loss. Some may also develop complex viscerocranial defects, due to acute osteitis, chronic exposure, or arrested skeletal growth. Reconstruction has mainly focused on soft tissue so far, whereas skeletal restoration was mostly avoided. After successful microvascular soft tissue free flap reconstruction, we now included skeletal restoration and mandibular ankylosis release into the initial step of complex noma surgery. One free rib graft and parascapular flap, one microvascular osteomyocutaneous flap from the subscapular system, and two sequential chimeric free flaps including vascularized bone were used as the initial steps for facial reconstruction. Ankylosis release could spare the temporomandibular joint. Complex noma reconstruction should include skeletal restoration. Avascular bone is acceptable in cases with complete vascularized graft coverage. Microsurgical chimeric flaps are preferable as they can reduce the number and complexity of secondary operations and provide viable, infection-resistant bone supporting facial growth.

Wolff-Parkinson-White Presenting as QRS Alternans and Other Differential Diagnoses in a Large Pre-Participation ECG Screening Cohort. / Wolff-Parkinson-White Apresentado como QRS Alternante e Outros Diagnósticos Diferenciais em uma Grande Coorte de Triagem de ECG Pré-Participação.

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a proarrhythmic condition that may require restriction from strenuous activities and is characterized by ECG signs, including delta waves. We observed cases of intermittent WPW patterns presenting as QRS alternans ('WPW alternans') in a large pre-participation ECG screening cohort of young men reporting for military conscription. OBJECTIVES: We aimed to determine the WPW alternans pattern, case characteristics, and the prevalence of other relevant differential diagnoses presenting as QRS alternans in a pre-participation setting. METHODS: One hundred twenty-five thousand one hundred fifty-eight prospective male military recruits were reviewed from January 2016 to December 2019. A review of electronic medical records identified cases of WPW alternans and WPW patterns or syndrome. Reviewing electronic medical records identified cases of relevant differential diagnoses that might cause QRS alternans. RESULTS: Four individuals (2.2%) had WPW alternans out of 184 individuals with a final diagnosis of WPW pattern or syndrome. Two of these individuals manifested symptoms or ECG findings consistent with supraventricular tachycardia. The overall prevalence of WPW alternans was 0.003%, and the prevalence of WPW was 0.147%. WPW alternans represented 8.7% of individuals presenting with QRS alternans, and QRS alternans had a prevalence of 0.037% in the entire population. CONCLUSIONS: WPW alternans is a variant of intermittent WPW, which comprised 2.2% of WPW cases in our pre-participation screening cohort. It does not necessarily indicate a low risk for supraventricular tachycardia. It must be recognized at ECG screening and distinguished from other pathologies that also present with QRS alternans.

FUNDAMENTO: A síndrome de Wolff-Parkinson-White (WPW) é uma condição pró-arrítmica que pode exigir restrição de atividades extenuantes e é caracterizada por sinais de ECG, incluindo ondas delta. Observamos casos de padrões intermitentes de WPW apresentando-se como QRS alternante ('WPW alternante') em uma grande coorte de triagem de ECG pré-participação de homens jovens que se candidataram ao recrutamento militar. OBJETIVOS: Nosso objetivo foi determinar o padrão de WPW alternante, as características do caso e a prevalência de outros diagnósticos diferenciais relevantes apresentando-se como alternância de QRS em um ambiente de pré-participação. MÉTODOS: Cento e vinte e cinco mil cento e cinquenta e oito recrutas militares do sexo masculino prospectivos foram revisados de janeiro de 2016 a dezembro de 2019. Uma revisão de prontuários médicos eletrônicos identificou casos de WPW alternante e padrões ou síndrome de WPW. A revisão de prontuários médicos eletrônicos identificou casos de diagnósticos diferenciais relevantes que podem causar alternância de QRS. RESULTADOS: Quatro indivíduos (2,2%) apresentaram WPW alternante em 184 indivíduos com diagnóstico final de padrão ou síndrome de WPW. Dois desses indivíduos manifestaram sintomas ou achados eletrocardiográficos compatíveis com taquicardia supraventricular. A prevalência geral de WPW alternante foi de 0,003%, e a prevalência de WPW foi de 0,147%. As WPW alternantes representaram 8,7% dos indivíduos com QRS alternantes, e QRS alternantes tiveram prevalência de 0,037% em toda a população. CONCLUSÕES: A WPW alternante é uma variante da WPW intermitente, que compreendeu 2,2% dos casos de WPW em nossa coorte de triagem pré-participação. Não indica necessariamente um baixo risco de taquicardia supraventricular. Deve ser reconhecido na triagem de ECG e distinguido de outras patologias que também apresentam QRS alternantes.