Citations

A new systems approach to diseased states and wellness result in a new branch in the healthcare services, namely, Personalized and Precision Medicine (PPM). To achieve the implementation of PPM concept, it is necessary to create a fundamentally new strategy based upon the recogni-tion of biomarkers and thus the targets to secure the grand future of drug design and drug dis-covery.Each decision-maker values the impact of their decision to use PPM on their own budget and well-being, which may not necessarily be optimal for society as a whole. It would be extremely useful to integrate data harvesting from different databanks for applications to provide more tai-lored measures for the patients resulting in improved patient outcomes, reduced adverse events, and more cost-effective use of the latest health care resources including diagnostic (companion ones or theranostics), preventive and therapeutic (targeted molecular and cellular) etc.Meanwhile, along with the impact of genomics and bioinformatics, pathology is the central specialty of PPM-related resources. Coupled with IT, the upgraded tools are ever more efficient and robust within clinical cancer settings. The latest algorithms may be able to identify and vali-date patterns which humans are not capable of quantifying easily, such as slight differences in textures or morphologies. In this sense, the impact of pathology allows a modular approach, as its various aspects are under development in several areas of PPM.Among the above-mentioned medical specialists involved in PPM, the pathologists play an im-portant and key role in the implementation and development of PPM-driven resources that are in the center of decision of many therapeutic choices. Recent advances in systems biology have tremendously affected the practice of precision pathology, gradually transforming it from a morphology-based into a precise molecular-based discipline. The enormous development of precision pathology research (integrating molecular OMICS and digital approaches) has raised great expectations concerning its impact on PPM aiming to custom-ize medical practice with a focus on the individual, based on the use of molecular tests, identifi-cation of genomic biomarkers, and development of targeted drugs.The precision pathology process introduces a new paradigm in pathology by leveraging digital imaging and IT technologies, and provides significant advancements in accuracy, efficiency, and collaboration. Among the latest innovations the precision pathology supported by digital tools, would dictate the implementation of high-resolution imaging, image analysis tools and integra-tion with molecular OMICS data. Integration of the approaches and resources will provide a true challenge for the future, requiring collaboration between oncologists, pathologists, biodesigners and bioengineers and remaining a challenge to precision cancer practice and profiled bioindustry.The latter requires precision pathologists highly trained in pre-analytic processes, tumor area mi-crodissection for tumor cell enrichment, methodology analysis and results. The in-depth study of molecular alterations in patients allows optimizing molecular diagnosis and selecting candidates for receive novel treatments against specific molecular targets. These patients would benefit from multidisciplinary approach and learning. In this sense, molecular diagnostics has a long tradition in pathology, especially in clinical one, where various OMICS-analyses of cancers are incorpo-rated into diagnostic and decision-making algorithms to secure a way where the pathologists con-tinue to play an essential role in developing and implementing molecular profiling tests in practice and communicate the results and their relevance with cancer practitioners.Cancer pathology is the central specialty of personalized and precision oncology (PPO). Meanwhile, the combination of comprehensive biobanking and the next wave of theranostic pathology technologies provides a natural, externally visible infrastructure that now allows pa-thology as a discipline – to engage directly with the biotechnology and pharma sector. We’re at an exciting junction in precision cancer pathology’s growth as a medical specialty, and pathology-driven biobanking is becoming both central to our core expertise and, even more importantly, a powerful enabler for many of the most promising growth areas of our discipline: PPM healthcare, clinical trials and drug development, theranostics, and functional assessment and monitoring of disease. In the context of these changes and challenges, the precision cancer pathology can play a fundamental role in both PPO-guided clinical practice and biodesign-driven cancer research.

3069 Background: Molecular targeted agents have revolutionized cancer diagnosis and treatment. Intraoperative molecular imaging (IMI) is a novel technique that entails performing real-time, in vivo optical imaging during surgery to ensure cancer clearance. A multicenter clinical trial was conducted using abenacianine, a cathepsin targeted near-infrared (NIR) IMI agent to visualize pulmonary nodules during surgery. The primary objective was to assess the efficacy of abenacianine in localizing pulmonary lesions, evaluating surgical margin, and identifying unsuspected disease. Methods: Participants scheduled to undergo surgery for known or suspected cancer in the lung received abenacianine (0.32 mg/kg intravenous) preoperatively 12 to 36 hours before surgery. During a standard-of-care surgery, the lung underwent IMI and additional disease not identified by conventional methods were identified and analyzed. Efficacy was measured by frequency of clinically significant events (CSEs) defined as localization of lesions not found by standard surgical techniques, identification of additional cancers, identification of positive surgical margins confirmed by histology, and detection of cancerous lymph nodes. Results: 89 participants were included in the study. The mean age was 67 years and 57 (64%) were female. Of 89 participants administered abenacianine who underwent standard of care surgical resection for known or suspected cancer in the lung, 40 (45%) had at least one CSE. Abenacianine with NIR imaging identified lesions that were not found by standard surgical methods in 34 (38%) participants, synchronous and occult cancers that were not found by pre-operative imaging in 2 (2%), margins within 10 mm of the closest staple line in 8 (9%), and lymph nodes determined to be cancerous in 1 (1%) participant. Tumors visualized by IMI with abenacianine included non-small cell lung cancers (adenocarcinoma, squamous cell carcinoma, neuroendocrine tumor) and cancers that metastasized to the lung (breast, colorectal, prostate, thymoma, renal cell, sarcoma). Abenacianine was safe and well tolerated in this study; there were no drug-related serious adverse events. Conclusions: This Phase 2 multicenter study demonstrated that using IMI with abenacianine during standard-of-care lung cancer surgery markedly improved clinical outcomes. Abenacianine localized tumors intraoperatively, identified synchronous and occult lesions, helped assess negative margin status, and identified cancerous lymph nodes enabling a more complete oncologic resection. Clinical trial information: NCT06145048 .

Abstract Background Tumor necrosis factor-like ligand 1A (TL1A) is upregulated in inflammatory bowel disease and believed to promote inflammation and intestinal fibrosis. RO7790121, an anti-TL1A antibody, showed promising results in the phase IIa TUSCANY trial.1 Here we report post-hoc analyses of patient-reported outcomes from the TUSCANY-2 trial. Methods This phase IIb, multicenter, randomized, double-blind, treat-through, dose-ranging study evaluated RO7790121 in patients (pts) aged 18–75 years with moderately to severely active ulcerative colitis (UC) (total Mayo score [MS] ≥6, endoscopic subscore ≥2). Pts were randomized to receive subcutaneous (SC) RO7790121 50mg, 150mg, 450mg or matched placebo (PBO) monthly during the 12-week induction period, and SC RO7790121 50mg, 150mg or 450mg monthly during the 40-week treat-through maintenance period. To assess efficacy of RO7790121 in supporting pts achieving early symptomatic improvement, rectal bleeding (RB), stool frequency (SF) and partial modified MS (RB+SF) were evaluated at baseline and Weeks 2, 4, 8, 12 and 14. The exploratory endpoint of symptomatic remission, defined as a RB subscore of 0 and a SF subscore of 0 or 1, was assessed throughout induction. Safety was assessed throughout the study. Results Overall, 245 pts received ≥1 dose of RO7790121 or PBO. At Week 2, pts receiving RO7790121 were more likely to report a RB subscore of 0 (34% RO7790121; 20% PBO) and less likely to report a RB subscore of 2 or 3 (25% RO7790121; 40% PBO) (Figure). Improvements in SF increased from Week 2 and throughout induction, with ~60% of pts receiving RO7790121 reporting a SF subscore of 0 or 1 at Weeks 12 and 14, vs ~40% for PBO. Greater rates of symptomatic remission were observed in pts receiving RO7790121 vs PBO throughout induction and from Week 2 (17.5% RO7790121; 8.9% PBO) (Table). Treatment-emergent adverse events (TEAEs) were reported during induction in 117/245 pts, the most common (reported in ≥5% of pts in any treatment group) were nausea, urinary tract infection and UC (highest in the 50mg arm), anemia (highest in the placebo arm) and fatigue, headache and pyrexia (highest in the 450mg arm). Serious TEAEs were reported in ten pts during induction (PBO=4; 50mg=3; 450mg=3); two were treatment related (PBO=1; 450mg=1). There were six treatment discontinuations due to TEAEs and a generally similar safety profile was observed during the maintenance period. Conclusion Greater and earlier improvements in RB and SF were observed in pts receiving RO7790121 vs PBO. These results indicate early symptom relief and a favorable safety profile for pts treated with RO7790121, supporting its further clinical development. RO7790121 is currently being evaluated in phase III studies (NCT06589986 and NCT06588855). References 1.Danese S, Klopocka M, Scherl EJ, et al. Anti-TL1A antibody PF-06480605 safety and efficacy for ulcerative colitis: A phase 2a single-arm study. Clin GastroenterolHepatol. 2021;19(11):2324-2332.e6. http://doi.org/10.1016/j.cgh.2021.06.011

ABSTRACTBackgroundAnemia is frequently observed as a comorbidity in atrial fibrillation (AF), especially in elderly patients and in those on anticoagulation. This has been associated with poor clinical outcomes. We aim to investigate the impact of anemia on clinical outcomes in patients with AF on oral anticoagulation.MethodsWe comprehensively searched PubMed, WOS, SCOPUS, EMBASE, and CENTRAL through March 2024 and conducted a prognostic systematic review and meta‐analysis. All analyses were performed using R V. 4.3.1. This meta‐analysis was registered at PROSPERO (CRD42024556023).ResultsWe included 23 studies comprising 286,781 patients for analysis. Anemia had a significant association with an 84% increase in risk of major bleeding (HR: 1.84 with 95% CI [1.59, 2.13], p < 0.01), a 32% increase in the risk of intracranial hemorrhage (HR: 1.32 with 95% CI [1.10, 1.58], p < 0.01), a 98% increase in the risk of gastrointestinal bleeding (HR: 1.98 with 95% CI [1.67, 2.35], p < 0.01), and a 91% increase in the risk of all‐cause mortality (HR: 1.91 with 95% CI [1.46, 2.51], p < 0.01). However, the impact of anemia did not significantly affect the risk of stroke, transient ischemic stroke (TIA), or systemic embolism (HR: 1.07 with 95% CI [0.93, 1.22], p = 0.36).ConclusionAnemia was significantly associated with an increased risk of major bleeding, intracranial hemorrhage, gastrointestinal bleeding, and all‐cause mortality. However, anemia did not significantly impact stroke, TIA, or systemic embolism.

Background: Among patients (pts) with coronary artery disease (CAD) who are candidates for coronary artery bypass graft surgery (CABG), a reduced ejection fraction (EF) identifies a high-risk group. The profile of pre-operative, intra-operative and post-operative factors contributing to 30 day (d) mortality in pts with low EF undergoing CABG has not been well characterized. Methods: The STICH trial enrolled 2136 pts with CAD amenable to CABG with an LVEF < 35% who were treated with medical therapy (MED) alone, MED with CABG, or with MED plus CABG and surgical ventricular resconstruction (SVR). Multivariable logistic regression models utilizing extensive baseline, intra-operative and post-operative care variables were developed to determine factors associated with mortality at 30d in a landmark analysis among pts surviving the first 36 hours (h). Results: Among those enrolled, 1460 pts received CABG; 673 (46.1%) on pump, 160 (11.0%) off pump, 132 (9.0%) with a mitral valve procedure (MVR), 393 (26.9%) with SVR, and 102 (7.0%) received CABG with SVR and MVR. Mortality in the operating room (OR) was 0.3 %, within the first 36h was 1.0%, and at 30d was 5.1%. The rate of in-hospital acute myocardial infarction was 0.8%, stroke 1.6%, mediastinitis 1.7%, worsening renal insufficiency 8.4%, and return to OR was 6.9%. Inotropes were used in 43.6% and intra-aortic balloon pump in 18.6%. At 36h, 148 pts (10.2%) remained intubated. Among pts who survived to 36h, a robust multivariable model (Table, c-statistic 0.89) was developed to predict 30d mortality. A prolonged intubation time (>36h) was the strongest marker of 30d mortality (odds ratio 7.4, 95% CI 3.8, 14.5, p<0.0001). Conclusions: Among pts with ischemic heart failure, CABG can be performed with a low rate of complications and intra-operative mortality. Prolonged intubation time (>36h) after CABG is an integrated clincal marker that may serve to identify those pts with the least likelihood of survival to 30d.

Abstract MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN and enhanced colony formation in a MYCN-dependent manner. Using molecular modeling, surface plasmon resonance, and mutagenesis studies, we mapped the MYCN–PA2G4 interaction site to a 14 amino acid MYCN sequence and a surface crevice of PA2G4. Competitive chemical inhibition of the MYCN–PA2G4 protein–protein interface had potent inhibitory effects on neuroblastoma tumorigenesis in vivo. Treated tumors showed reduced levels of both MYCN and PA2G4. Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease. Significance: Competitive chemical inhibition of the PA2G4–MYCN protein interface provides a basis for drug design of small molecules targeting MYC and MYCN-binding partners in malignancies driven by MYC family oncoproteins.

Surgery remains the cornerstone of rectal cancer treatment. However, there is significant morbidity and mortality associated with pelvic surgery, and the past decade has illustrated that a cohort of rectal cancer patients sustain a remission of local disease with chemoradiation alone. Thus, questions remain regarding the optimal management for rectal cancer; namely, accurately identifying patients who have a complete pathologic response and determining the oncologic safety of the observational approach for this patient group. This review aims to summarize the current evidence to provide an overview to the ‘watch and wait’ approach in rectal cancer patients with a complete response to neoadjuvant chemoradiation therapy.