Citations

ABSTRACT Complete esophageal obstruction is a rare but serious complication of endoscopic variceal band ligation (EVBL). We present the case of a 75-year-old man with cirrhosis and esophageal varices who developed acute esophageal obstruction following EVBL, which was successfully managed with a combination of endoscopic scissors to cut the band and through-the-scope balloon dilation, restoring luminal patency and recanalization of the esophagus. This case highlights the importance of prevention, early recognition, and timely management of this rare but important complication of EVBL. Key management options addressed include preventive, conservative, and interventional strategies to improve patient outcomes.

Abstract Background Presacral tumours are rare and heterogeneous lesions arising within a complex anatomical space, resulting in variability in diagnosis and management. Increasing incidental detection and evolving surgical and oncological strategies have highlighted the need for contemporary guidance. The aim of this study was to establish an international expert consensus on the optimal diagnosis and management of presacral tumours. Methods An international panel of colorectal surgeons from high-volume units was convened. Evidence- and practice-based statements were developed after domain-based literature reviews and refined through five online and two in-person meetings. Consensus was achieved using a modified Delphi process with anonymous voting. Results In total, 16 colorectal surgeons participated in the study. Ten domains were identified resulting in the development of 22 statements based on expert opinion and retrospective studies. After two rounds, unanimous (100%) agreement was achieved for all statements. High-resolution MRI with structured synoptic reporting is endorsed as central to risk stratification. Selective image-guided transperineal or parasacral biopsy is recommended for high-risk lesions where histology would alter management. Complete surgical resection is defined as the operative goal, with approach tailored to tumour biology and anatomy; minimally invasive surgery is considered appropriate in selected cases. Non-operative surveillance is supported for carefully selected asymptomatic, low-risk cystic lesions. Postoperative surveillance is recommended in a risk-adapted manner according to histopathology and margin status. Conclusion This international consensus provides a pragmatic, risk-stratified framework for the multidisciplinary diagnosis and management of presacral tumours. These recommendations aim to reduce practice variation, support decision-making in specialized centres, and inform future prospective collaborative research.

ABSTRACT BACKGROUND Point-of-care (POC) high-sensitivity cardiac troponin (hs-cTn) testing has the potential to expedite decision-making and reduce emergency department (ED) length of stay for patients presenting with possible myocardial infarction (MI) by ensuring that results are consistently available when looked for by clinicians. We assessed the real-life effectiveness and safety of implementing POC hs-cTn testing in the ED. METHODS We conducted a pragmatic, stepped-wedge cluster randomized trial. The control arm was usual care with an accelerated diagnostic pathway utilizing a single-sample rule-out step with a central laboratory hs-cTn assay. The intervention arm used the same pathway with a POC hs-cTnI. The primary effectiveness outcome was ED length of stay assessed using a generalized linear mixed model, and the safety outcome was 30-day MI or cardiac death. RESULTS Six sites participated with 59,980 ED presentations (44,747 individuals, 61±19 years, 49.5% female) from February 2023 to January 2025, in which 31,392 presentations were during the intervention arm. After adjustment for co-variates associated with length of stay, the intervention reduced length of stay by 13% (95% confidence intervals [CI], 9 to 16%. P<0.001), corresponding to a reduction of 47 minutes (95%CI, 33 to 61 minutes) from a mean length of stay in the control arm of 376 minutes. The 30-day MI or cardiac death rate was similar in the control and intervention arms (0.39% and 0.39% respectively, P=0.54). CONCLUSIONS Implementation of whole-blood hs-cTnI testing at the POC into an accelerated diagnostic pathway was safe and reduced length of stay in the ED compared with laboratory testing. (Australia New Zealand Clinical Trials Registry ACTRN12619001189112) Clinical Perspective What is new? Point-of-care troponin assays with good precision have become available and received regulatory approval as high-sensitivity assays. A pragmatic stepped-wedge cluster randomized trial implementing the validated Siemens VTLi high-sensitivity point-of-care assay into 6 emergency departments investigating ∼60,000 patients, was conducted to ascertain if the rapid turnaround time reduced lengths of stay. Introduction of the VTLi high-sensitivity point-of-care assay into clinical pathways reduced emergency department lengths of stay by an average 13% (47 minutes) without compromising safety. What are the clinical implications? Early decision-making using a point-of-care high-sensitivity troponin assay within a structured clinical pathway was safe. Faster turnaround means troponin results are consistently available when clinicians first seek them. This can facilitate earlier decisions and reduce patient length of stay.

Abstract Background Atypical hemolytic uremic syndrome (aHUS) is a rare, complement-mediated disorder. Disease-associated variants have been found in complement factor H-related genes and complement regulatory genes. Particularly, homozygous deletions of CFHR1, CFHR3, or CFHR4 have been associated with aHUS. Generally, multiplex ligation-dependent probe amplification (MLPA) is used to detect copy number changes in the CFH and CFHR regions. We have developed a cost-effective droplet digital PCR (ddPCR) method for measuring copy number variations (CNVs) in these genes. Methods A total of 41 DNA samples were analyzed using both ddPCR and MLPA to assess large deletions in the CFHR1, CFHR3, CFHR4 regions. The ddPCR primers were designed to avoid rare single nucleotide polymorphisms to enhance hybridization efficiency and accurate identification of deletions within the CFHR regions. The MLPA probe mix (Probemix P236 CFH Region) targeting CFHR regions was purchased from MRC Holland. Results Multiple heterozygous deletions were observed in the CFHR1, CFHR3, and CFHR4 genes. Homozygous deletions of CFHR1 and CFHR3 were seen in 2 cases, while 2 other cases showed homozygous CFHR1 and heterozygous CFHR3 deletions. All 41 samples demonstrated 100% concordance in copy number results between ddPCR and MLPA, as well as consistent reproducibility in both inter- and intratechnologist evaluations. Conclusions Our findings demonstrate that ddPCR is a robust platform to identify large deletions in the CFHR regions. Future studies are needed to evaluate its ability to distinguish full vs partial deletions and to further establish its clinical diagnostic value.

Abstract Purpose: Immune checkpoint blockade (ICB) induces frequent and durable responses in metastatic deficient DNA mismatch repair (dMMR) colorectal cancer, yet substantial molecular heterogeneity and resistance remain. We sought to identify candidate tumor- and immune-related biomarkers associated with clinical outcomes following anti–PD-1 therapy. Experimental Design: Consecutive patients with metastatic dMMR colorectal cancer (N = 39) treated with anti–PD-1 therapy underwent tumor profiling using a validated immune-enhanced exome and transcriptome platform. Microsatellite instability (MSI) burden was quantified as the percentage of unstable microsatellite loci using MSIsensor-pro. Associations with objective response were evaluated, and progression-free survival (PFS) and overall survival (OS) were analyzed using Cox proportional hazards models. Results: Higher MSI burden was associated with improved objective response (P = 0.018) and survival. The dichotomized MSI level (Q2–4 vs. Q1) was associated with longer PFS [hazard ratio (HR), 0.18; 95% confidence interval (CI), 0.06–0.56; P = 0.003] and OS (HR, 0.20; 95% CI, 0.07–0.58; P = 0.003), with similar results when modeled continuously. MSI burden correlated with neoantigen clonality but not burden (R = 0.53, P = 0.01). Responders exhibited significantly greater T-cell receptor repertoire diversity; both T- and B-cell receptor diversities were associated with survival. Although human leukocyte antigen (HLA) A, HLA-B, and HLA-C expression was not prognostic, the HLA-B*07:02 allele was associated with the best overall response. In contrast, overexpression of immune exhaustion–related genes and cytotoxic T-cell and natural killer cell exhaustion phenotypes were associated with ICB resistance and poorer prognosis. Conclusions: Integrated exome/transcriptome profiling with MSI quantification identified MSI burden and adaptive immune repertoire diversity as potential correlates of response and survival following ICB. These findings suggest a mechanistic link among genomic instability, antigen recognition diversity, and immunotherapy benefit.

Abstract Background and Aims Acute myocarditis (AM) is a T cell-mediated myocardial disease with clinical manifestations ranging from mild chest pain to cardiogenic shock. Reliable biomarkers to stratify patients and guide therapy are currently lacking. In particular, the extent of the dysregulation of inflammatory pathways, and the impact on myocardial dysfunction, remain elusive. Methods Serum analyses were performed in prospectively recruited AM patients (n = 103) from two independent cohorts. Multimodal data integration combining profiling of cytokine and chemokine dysregulation with clinical biomarkers was used to define clinical phenotypes with distinct inflammatory signatures. Machine-learning and regression models were applied to determine biomarkers that indicate clinical severity. Results Immuno-proteomic profiling revealed conserved inflammatory patterns across AM cohorts, dominated by T cell-related cytokines and chemokines. In addition, AM patients showed dysregulation of fibroblast-derived cytokines, including hepatocyte growth factor (HGF), bone morphogenic protein 4 (BMP4) and the BMP4 inhibitors Gremlin-1 (GREM1) and Gremlin-2 (GREM2). Data integration and unsupervised clustering revealed two immuno-clinical phenotypes, linking T cell activation and fibroblast dysregulation to disease severity. Machine learning-based analysis identified CXCL10, GREM2 and LVEF as critical parameters for stratifying disease severity. Conclusions These findings highlight a systemic T cell activation signature as diagnostic hallmark of AM. In addition, dysregulation of fibroblast-derived tissue cytokines serves as an indicator for distinct immuno-clinical phenotypes in myocardial inflammatory disease. Thus, the clinically relevant link between T cell-driven immune activation, myocardial inflammation and fibroblast-driven remodelling provides a versatile set of parameters to identify severe manifestations of AM. Graphical Abstract Key Question: Are serological immune signatures linked to clinical severity in acute myocarditis and do they enable patient stratification? Key Findings: T cell- and fibroblast associated proteomic signatures indicate disease severity in acute myocarditis. Novel immuno-clinical phenotypes stratify patients according to distinct immune responses and clinical manifestations. CXCL10, GREM2 and LVEF are the most important parameters to identify immuno-clinical phenotypes. Take Home Message: CXCL10, GREM2 and LVEF emerge as key determinants for a severe immuno-clinical phenotype in acute myocarditis, highlighting the role of T cell-fibroblast interaction in the disease process and linking T cell activation, fibroblastic tissue remodelling and impaired cardiac function.

Objective We investigated potential racial disparities in the effects of audiometric hearing loss and its treatment on dementia and mortality among 3,602 older adults aged 68–89 years, 22% of whom were self-identified Black race. Methods Adjudicated all-cause dementia was determined using neurocognitive test data, proxy reports, and surveillance of hospital records and death certificates. Audiometric hearing loss, defined as the better-ear averaged pure-tone threshold (0.5–4 kHz), was categorized using clinical cutpoints. Multivariable-adjusted Cox proportional hazards models included hearing loss–race interaction terms. Results Dementia risk associated with moderate-to-severe hearing loss did not differ by race [Black participants: hazard ratio (HR): 1.66; 95% confidence interval (CI): 1.05, 2.61; White participants: HR: 1.71; 95% CI: 1.16, 2.51; P -interaction = 0.92]. However, moderate-to-severe hearing loss was associated with a 2.3-fold increase in mortality among Black participants only (95% CI: 1.17, 4.60). Conclusions Our findings emphasize the importance of including minoritized populations in hearing treatment research to build an evidence base for policy development and clinical decision-making. Hearing loss affects the health of both Black and White Americans. Racial disparities in hearing healthcare should be addressed to advance health equity for all older adults.

Abstract The INFORM trial (NCT01670500) was a randomized, two-arm Phase II neoadjuvant study comparing the efficacy of a platinum-based regimen (cisplatin) versus an anthracycline (AC)-based regimen in participants with germline BRCA1/2 mutations and early-stage, HER2-negative breast cancer. MicroRNAs (miRNAs) are emerging as promising non-invasive biomarkers for disease detection and treatment monitoring. The initial aim of this study was to evaluate whether pretreatment plasma miRNA profiles were associated with treatment outcomes in the INFORM trial cohort. Pretreatment plasma samples from 97 INFORM participants (n=53 cisplatin and n=44 AC) were screened for 352 miRNAs commonly implicated in cancer using the qPCR-based ID3EALTM Cancer Panel. Twenty out of 53 participants achieved residual cancer burden (RCB) score of 0 or 1 with cisplatin and 20/44 with AC. Higher plasma miR-362-3p expression was associated with a favorable response to cisplatin (1.7-fold; p&lt;0.01), but not to AC. MiR-362-3p expression in paired pretreatment tumor biopsies (n=79) did not significantly correlate with plasma expression and was not associated with RCB 0/1 (p&gt;0.05). In TCGA, miR-362-3p expression was higher in breast tumors than in adjacent normal tissue, and higher in triple negative breast cancers (TNBCs) compared with hormone receptor-positive tumors (both FDR&lt;0.001), independent of BRCA mutation or Single Base Substitution Signature 3 (SBS3) status. The miR-362-3p findings in INFORM did not replicate in a sister trial, TBCRC 030 (NCT01982448; 11 out of 46 cisplatin-treated patients achieved RCB 0/1, p=0.46). These results suggest that while miR-362-3p is unsuitable as a circulating biomarker for cisplatin response, it may play an important biological role in mediating cisplatin sensitivity in TNBCs, independent of BRCA1/2 mutations. Functional studies demonstrated that miR-362-3p is expressed and secreted by TNBC cell lines, operates as a tumor suppressor, and generally correlates with cisplatin sensitivity. Overexpression of miR-362-3p rendered MDA-MB-231 and CAL-51 cells cisplatin sensitive, while knockdown induced resistance in MDA-MB-436 cells. Ongoing studies are testing whether these effects translate in xenograft models. In silico and functional assays identified BCLAF1, a DNA damage response (DDR) regulator, as a direct target of miR-362-3p. Overexpression of miR-362-3p suppresses BCLAF1 mRNA and protein levels. Our findings demonstrate that miR-362-3p enhances cisplatin responsiveness by targeting BCLAF1. A miR-362-3p-based therapeutic may be useful as a co-agent to enhance tumor responses to platinum-based chemotherapy. Citation Format: Zhaoji Liu, Shizhong Ke, Xiaohui Li, Catherine Wu, Madison M. Uyemura, Brian R. Sardella, Erica S. Massicott, Lin Wang, Emily K. Aronson, Dimitra Karagkouni, Nikolas Kalavros, Ioannis S. Vlachos, Felipe Batalini, Cristina S. Bogsan, Jit Kong Cheong, Lihan Zhou, He Cheng, Phillip Munson, Erica L. Mayer, Judy E. Garber, Stuart J. Schnitt, Nadine M. Tung, Andrea L. Kasinski, Frank J. Slack, Gerburg M. Wulf, Yujing J. Heng. MiR-362-3p enhances platinum response in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7903.

Abstract Background: The BRAF(V600E) mutation in colorectal cancer (CRC) is associated with treatment resistance and a poor prognosis. CDK2/9 is frequently activated in human cancers, and we have previously shown that BRAFV600E can upregulate MCL-1, which can be suppressed by the selective CDK2/9 inhibitor fadraciclib. Herein, we determined whether targeting CDK2/9 by fadraciclib can be enhanced by concurrent Bcl-2/Bcl-xL inhibition using LP-118, which minimizes platelet toxicity in patients, compared to the Bcl-2 inhibitor venetoclax. Effects of the drugs on apoptosis, colony formation and tumor growth were studied in a zebrafish model. Methods: We utilized isogenic human RKO (BRAFV600E/V600E/WT) and T29 (BRAFWT/−/−) CRC cell lines in addition to HCT-116 (BRAFWT) and Bax knockout (HCT-116Bax-/-) CRC cells. Cells were treated for 24h with fadraciclib (500nM) plus encorafenib (500nM) in the presence or absence of LP-118 (1µM) or venetoclax (1µM). Apoptosis and cell growth inhibition were assessed using annexin V/PI staining and colony formation assays, respectively. Expression of MCL-1, Bcl-xL, Bcl-2, PARP, and cleaved caspase-3 (Asp175) proteins was analyzed. In a zebrafish tumor xenograft model, the effects of the drugs on caspase-3 cleavage and tumor growth were then evaluated. Results: Fadraciclib suppressed MCL-1 expression, induced apoptosis and significantly inhibited colony formation in all CRC cell lines. However, this effect was enhanced by encorafenib only in RKO (BRAFV600E/V600E/WT) cells. The addition of LP-118 to fadraciclib plus encorafenib potently enhanced apoptosis induction, shown by annexin V and cleavage of PARP, caspase-3, in RKO and HCT-116 cell lines, which was synergistic and Bax dependent. Treatment with LP-118 combined with fadraciclib and encorafenib suppressed both Bcl-xL and MCL-1 expression in RKO cells. The addition of LP-118 to fadraciclib plus encorafenib enhanced apoptosis (annexin V) to a greater extent than did venetoclax. In a zebrafish tumor xenograft model, the addition of LP-118 to fadraciclib plus encorafenib significantly enhanced caspase-3 activation and reduced the tumor xenograft size. Conclusion: LP-118 synergistically enhanced the antitumor activity of fadraciclib plus encorafenib in BRAFV600E human CRC cells, and to a greater extent than did venetoclax. Mechanistically, targeting Bcl-2/Bcl-xL concurrent with inhibition of MCL-1 and CDK2/9 by fadraciclib potently induced apoptosis and suppressed tumor cell growth. These findings suggest a novel and effective therapeutic strategy for BRAFV600E human CRCs. Citation Format: Md Mohiuddin, Vanda Póvoa, Beatriz Sebo, Rita Fior, Frank A. Sinicrope. Novel Bcl-2/Bcl-xL inhibitor, LP-118, enhances apoptosis induction by the CDK2/9 inhibitor, fadraciclib, in BRAF(V600E) human colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4658.