Stratifying risk of failure to achieve textbook outcomes among patients undergoing hepatectomy for hepatocellular carcinoma: A multicenter score validation study.

BACKGROUND AND AIMS: The concept of textbook outcomes (TOs) has gained increased attention as a critical metric to assess the quality and success of outcomes following complex surgery. A simple yet effective scoring system was developed and validated to predict risk of not achieving textbook outcomes (non-TOs) following hepatectomy for hepatocellular carcinoma (HCC). METHODS: Using a multicenter prospectively collected database, risk factors associated with non-TO among patients who underwent hepatectomy for HCC were identified. A predictive scoring system based on factors identified from multivariate regression analysis was used to risk stratify patients relative to non-TO. The score was developed using 70 % of the overall cohort and validated in the remaining 30 %. RESULTS: Among 3681 patients, 1458 (39.6 %) failied to experience a TO. Based on the derivation cohort, obesity, American Society of Anaesthesiologists score(ASA score), Child-Pugh grade, tumor size, and extent of hepatectomy were identified as independent predictors of non-TO. The scoring system ranged from 0 to 10 points. Patients were categorized into low (0-3 points), intermediate (4-6 points), and high risk (7-10 points) of non-TO. In the validation cohort, the predicted risk of developing non-TOs was 39.0 %, which closely matched the observed risk of 39.9 %. There were no differences among the predicted and observed risks within the different risk categories. CONCLUSIONS: A novel scoring system was able to predict risk of non-TO accurately following hepatectomy for HCC. The score may enable early identification of individuals at risk of adverse outcomes and inform surgical decision-making, and quality improvement initiatives.

Chronological and Geographical Variations in the Incidence and Acceptance of COVID-19-Positive Donors and Outcomes Among Abdominal Transplant Patients.

INTRODUCTION: Given the importance of understanding COVID-19-positive donor incidence and acceptance, we characterize chronological and geographic variations in COVID-19 incidence relative to COVID-19-positive donor acceptance. METHODS: Data on deceased donors and recipients of liver and kidney transplants were obtained from the UNOS database between 2020 and 2023. Hierarchical cluster analysis was used to assess trends in COVID-19-positive donor incidence. Posttransplant graft and patient survival were assessed using Kaplan-Meier curves. RESULTS: From among 38 429 deceased donors, 1517 were COVID-19 positive. Fewer kidneys (72.4% vs. 76.5%, p < 0.001) and livers (56.4% vs. 62.0%, p < 0.001) were used from COVID-19-positive donors versus COVID-19-negative donors. Areas characterized by steadily increased COVID-19 donor incidence exhibit the highest transplantation acceptance rates (92.33%), followed by intermediate (84.62%) and rapidly increased (80.00%) COVID-19 incidence areas (p = 0.016). Posttransplant graft and patient survival was comparable among recipients, irrespective of donor COVID-19 status. CONCLUSIONS: Regions experiencing heightened rates of COVID-19-positive donors are associated with decreased acceptance of liver and kidney transplantation. Similar graft and patient survival is noted among recipients, irrespective of donor COVID-19 status. These findings emphasize the need for adaptive practices and unified medical consensus in navigating a dynamic pandemic.

A data science roadmap for open science organizations engaged in early-stage drug discovery.

The Structural Genomics Consortium is an international open science research organization with a focus on accelerating early-stage drug discovery, namely hit discovery and optimization. We, as many others, believe that artificial intelligence (AI) is poised to be a main accelerator in the field. The question is then how to best benefit from recent advances in AI and how to generate, format and disseminate data to enable future breakthroughs in AI-guided drug discovery. We present here the recommendations of a working group composed of experts from both the public and private sectors. Robust data management requires precise ontologies and standardized vocabulary while a centralized database architecture across laboratories facilitates data integration into high-value datasets. Lab automation and opening electronic lab notebooks to data mining push the boundaries of data sharing and data modeling. Important considerations for building robust machine-learning models include transparent and reproducible data processing, choosing the most relevant data representation, defining the right training and test sets, and estimating prediction uncertainty. Beyond data-sharing, cloud-based computing can be harnessed to build and disseminate machine-learning models. Important vectors of acceleration for hit and chemical probe discovery will be (1) the real-time integration of experimental data generation and modeling workflows within design-make-test-analyze (DMTA) cycles openly, and at scale and (2) the adoption of a mindset where data scientists and experimentalists work as a unified team, and where data science is incorporated into the experimental design.

Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10.

Antiviral signaling, immune response and cell metabolism are dysregulated by SARS-CoV-2, the causative agent of COVID-19. Here, we show that SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes with critical roles in mitochondrial function and morphology. On the other hand, all four ORFs altered mitochondrial dynamics and function, but only ORF3a and ORF9c induced a marked alteration in mitochondrial cristae structure. Genome-Scale Metabolic Models identified both metabolic flux reprogramming features both shared across all accessory proteins and specific for each accessory protein. Notably, a downregulated amino acid metabolism was observed in ORF9b, ORF9c and ORF10, while an upregulated lipid metabolism was distinctly induced by ORF3a. These findings reveal metabolic dependencies and vulnerabilities prompted by SARS-CoV-2 accessory proteins that may be exploited to identify new targets for intervention.

Procedural and Intermediate-term Results of the Electroanatomical-guided Cardioneuroablation for the Treatment of Supra-Hisian Second- or Advanced-degree Atrioventricular Block: the PIRECNA multicentre registry.

AIMS: Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB. METHODS AND RESULTS: This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up. CONCLUSION: This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings.

More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-a]pyrimidine Host CSNK2 Inhibitors for Combatting ß-Coronavirus Replication.

The pyrazolo[1,5-a]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against ß-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5-a]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor 53. Despite excellent in vitro metabolic stability, rapid decline in plasma concentration of 53 in vivo was observed and may be attributed to lung accumulation, although in vivo pharmacological effect was not observed. Further optimization of this novel chemotype may validate CSNK2 as an antiviral target in vivo.

Resolution Enhancement of Metabolomic J-Res NMR Spectra Using Deep Learning.

J-Resolved (J-Res) nuclear magnetic resonance (NMR) spectroscopy is pivotal in NMR-based metabolomics, but practitioners face a choice between time-consuming high-resolution (HR) experiments or shorter low-resolution (LR) experiments which exhibit significant peak overlap. Deep learning neural networks have been successfully used in many fields to enhance quality of natural images, especially with regard to resolution, and therefore offer the prospect of improving two-dimensional (2D) NMR data. Here, we introduce the J-RESRGAN, an adapted and modified generative adversarial network (GAN) for image super-resolution (SR), which we trained specifically for metabolomic J-Res spectra to enhance peak resolution. A novel symmetric loss function was introduced, exploiting the inherent vertical symmetry of J-Res NMR spectra. Model training used simulated high-resolution J-Res spectra of complex mixtures, with corresponding low-resolution spectra generated via blurring and down-sampling. Evaluation of peak pair resolvability on J-RESRGAN demonstrated remarkable improvement in resolution across a variety of samples. In simulated plasma data, 100% of peak pairs exhibited enhanced resolution in super-resolution spectra compared to their low-resolution counterparts. Similarly, enhanced resolution was observed in 80.8-100% of peak pairs in experimental plasma, 85.0-96.7% in urine, 94.4-98.9% in full fat milk, and 82.6-91.7% in orange juice. J-RESRGAN is not sample type, spectrometer or field strength dependent and improvements on previously acquired data can be seen in seconds on a standard desktop computer. We believe this demonstrates the promise of deep learning methods to enhance NMR metabolomic data, and in particular, the power of J-RESRGAN to elucidate overlapping peaks, advancing precision in a wide variety of NMR-based metabolomics studies. The model, J-RESRGAN, is openly accessible for download on GitHub at https://github.com/yanyan5420/J-RESRGAN.

The nature of the last universal common ancestor and its impact on the early Earth system.

The nature of the last universal common ancestor (LUCA), its age and its impact on the Earth system have been the subject of vigorous debate across diverse disciplines, often based on disparate data and methods. Age estimates for LUCA are usually based on the fossil record, varying with every reinterpretation. The nature of LUCA's metabolism has proven equally contentious, with some attributing all core metabolisms to LUCA, whereas others reconstruct a simpler life form dependent on geochemistry. Here we infer that LUCA lived ~4.2 Ga (4.09-4.33 Ga) through divergence time analysis of pre-LUCA gene duplicates, calibrated using microbial fossils and isotope records under a new cross-bracing implementation. Phylogenetic reconciliation suggests that LUCA had a genome of at least 2.5 Mb (2.49-2.99 Mb), encoding around 2,600 proteins, comparable to modern prokaryotes. Our results suggest LUCA was a prokaryote-grade anaerobic acetogen that possessed an early immune system. Although LUCA is sometimes perceived as living in isolation, we infer LUCA to have been part of an established ecological system. The metabolism of LUCA would have provided a niche for other microbial community members and hydrogen recycling by atmospheric photochemistry could have supported a modestly productive early ecosystem.

Heli-SMACC: Helicase-targeting SMAll Molecule Compound Collection.

Helicases have emerged as promising targets for the development of antiviral drugs; however, the family remains largely undrugged. To support the focused development of viral helicase inhibitors we identified, collected, and integrated all chemogenomics data for all available helicases from the ChEMBL database. After thoroughly curating and enriching the data with relevant annotations we have created a derivative database of helicase inhibitors which we dubbed Heli-SMACC ( Heli case-targeting SMA ll Molecule C ompound C ollection). The current version of Heli-SMACC contains 20,432 bioactivity entries for viral, human, and bacterial helicases. We have selected 30 compounds with promising viral helicase activity and tested them in a SARS-CoV-2 NSP13 ATPase assay. Twelve compounds demonstrated ATPase inhibition and a consistent dose-response curve. The Heli-SMACC database may serve as a reference for virologists and medicinal chemists working on the development of novel helicase inhibitors. Heli-SMACC is publicly available at https://smacc.mml.unc.edu . Highlights: We created a curated Helicase-Targeting SMAll Molecule Compound Collection (Heli-SMACC).Heli-SMACC covers 29 human, viral, and bacterial helicases.Twelve of thirty selected compounds demonstrated inhibitory activity in a SARS-CoV-2 NSP13 ATPase Assay. Heli-SMACC is freely available online at https://smacc.mml.unc.edu .

Myokine secretion during moderate-intensity physical activity: Dose-response of interleukin 6 to walking duration.

During vigorous physical activity, contracting muscles secrete a variety of immunomodulatory and metabolic factors called myokines that perform a variety of functions. Foremost among these is interleukin 6 (IL-6), which increases fatty acid mobilization and stimulates anti-inflammatory cytokine release. Despite being well characterized in vigorous exercise contexts, whether IL-6 is secreted during moderate-intensity activities such as walking is unclear. This is especially pertinent as regular walking is one of the oldest and most common forms of physical activity and comes with a variety of health benefits, which may be coordinated in part by IL-6 signaling. To test the hypothesis that IL-6 release occurs during evolutionarily normal physical activity contexts like long distance walking, we performed a dose-response experiment to test the effect of walking duration on IL-6 secretion. Thirteen participants completed four moderate-intensity walking trials (55% HRmax) of varying durations (30 min, 1 h, 2 h, and 3 h) in a randomized order with intervening washout periods of at least 1 week. Using a linear mixed effects model, we found that IL-6 levels modestly increased during only the 2 h and 3 h walking trials. These results suggest that small frequent increases in IL-6 signaling may be an important mechanism underlying the health benefits of regular walking. Furthermore, this finding raises the possibility that IL-6 secretion is an adaptation to fuel physical activity, especially during periods of negative energy balance.

Predictors of Therapy Success in Weekly Adalimumab for Refractory Uveitis: A Retrospective Cohort Study.

PURPOSE: To determine predictors of treatment success after dose escalation of adalimumab, including measurement of anti-adalimumab antibodies as a predictor of success DESIGN: Retrospective clinical cohort study SETTING: Single-center academic institution STUDY POPULATION: Patients with noninfectious uveitis who were inadequately controlled or developed recurrent disease on biweekly adalimumab and required dose escalation or therapy modification OBSERVATION PROCEDURES: Patients who had anti-adalimumab antibodies checked with resultant low to intermediate levels were compared to patients who had no testing performed prior to adalimumab dose escalation. Of note, patients with testing and resultant high levels of anti-adalimumab antibodies were not escalated. Predictors of escalation success and utility of antibody testing prior to escalation were analyzed using Kaplan Meier survival analysis and Cox proportional hazard models. MAIN OUTCOME MEASURES: Treatment success defined as anterior chamber grade ≤0.5+ cell, topical corticosteroids ≤1 drop/day, oral prednisone ≤5 mg/day, resolution of macular edema, and resolution of angiographic signs of inflammation without any addition or escalation of therapy. RESULTS: 24 patients had antibodies tested with low to intermediate levels (average: 32.3 ng/mL, range: 0 - 154), while 41 did not have antibody testing. A greater treatment success rate post escalation was observed among the "low antibody" group compared to the "no testing" group (HR: 2.63, standard error: 1.19, p=0.031, 95% CI 1.09 - 6.37). Among the entire cohort, patients with panuveitis (n = 14) had a lower treatment success rate compared to the reference of anterior uveitis (n = 26) (HR: 0.09, standard error: 0.11, p = 0.05, 95% CI 0.01 - 0.99). CONCLUSIONS: Patients with low anti-adalimumab antibodies had a greater treatment success compared to patients in whom antibodies were not checked. This suggests a utility to checking antibodies prior to dose escalation and that low levels of antibodies may confer a success advantage. Overall, patients with panuveitis had a lower rate of success after escalation while patients with anterior uveitis patients had a very high rate of success suggesting that certain disease characteristics may guide clinicians when determining who to escalate versus changing therapy.

Towards pharmacokinetic boosting of phenoxymethylpenicillin (penicillin-V) using probenecid for the treatment of bacterial infections.

In the face of increasing antimicrobial tolerance and resistance there is a global obligation to optimise oral antimicrobial dosing strategies including narrow spectrum penicillins, such as penicillin-V. We conducted a randomised, crossover study in healthy volunteers to characterise the influence of probenecid on penicillin-V pharmacokinetics and estimate the pharmacodynamics against Streptococcus pneumoniae. Twenty participants took six doses of penicillin-V (250 mg, 500 mg or 750 mg four times daily) with and without probenecid. Total and free concentrations of penicillin-V and probenecid were measured at two timepoints. A pharmacokinetic model was developed, and the probability of target attainment (PTA) calculated. The mean difference (95% CI) between penicillin-V alone and in combination with probenecid for serum total and free penicillin-V concentrations was significantly different at both timepoints (total: 45 min 4.32 (3.20-5.32) mg/L p < 0.001, 180 min 2.2 (1.58-3.25) mg/L p < 0.001; free: 45 min 1.15 (0.88-1.42) mg/L p < 0.001, 180 min 0.5 (0.35-0.76) mg/L p < 0.001). There was no difference between the timepoints in probenecid concentrations. PTA analysis shows probenecid allows a fourfold increase in MIC cover. Addition of probenecid was safe and well tolerated. The data support further research into improved dosing structures for complex outpatient therapy and might also be used to address penicillin supply shortages.

Effect of prior gestational diabetes on the risk of cardiovascular disease and death in women with type 2 diabetes: The Fremantle Diabetes Study Phase II.

BACKGROUND: To examine whether prior gestational diabetes mellitus (GDM) is associated with prevalent coronary heart disease (CHD), cerebrovascular disease (CeVD) and peripheral arterial disease (PAD), and all-cause mortality, in community-based women with type 2 diabetes. METHODS: Baseline prevalences of CHD/CeVD/PAD/prior GDM were determined in 718 females (mean ± SD age 65.5 ± 11.9 years) from the Fremantle Diabetes Study Phase II. Deaths between baseline (2008-2011) and end-2016 were ascertained. Cox regression identified predictors of mortality with GDM as a candidate variable. RESULTS: Compared to the 673 women without GDM, the 39 (5.4 %) with prior GDM were younger, more likely Aboriginal, smokers and obese, had longer diabetes duration and higher HbA1c levels, and were more dyslipidemic (P ≤ 0.046). Prevalences of CHD (24.6 versus 23.1 %), CeVD (7.5 % versus 2.6 %) and PAD (27.5 % versus 23.7 %) were not significantly different in those without versus with prior GDM (P ≥ 0.35). There were 116 deaths (16.2 %) during 6.8 ± 1.6 years of follow-up. Age, Aboriginal ethnicity, marital status, current smoking, heart rate, estimated glomerular filtration rate, CHD and PAD were independently associated with all-cause mortality (P ≤ 0.023); GDM status did not add to the most parsimonious model (P = 0.62). CONCLUSIONS: Prior GDM does not increase CVD risk or all-cause mortality in women with type 2 diabetes.

Tumor-localized interleukin-2 and interleukin-12 combine with radiation therapy to safely potentiate regression of advanced malignant melanoma in pet dogs.

PURPOSE: Interleukin-2 and -12 cytokines have potent anti-cancer activity, but suffer a narrow therapeutic window due to off-tumor immune cell activation. Engineering cytokines with the ability to bind and associate with tumor collagen after intratumoral injection potentiated response without toxicity in mice, and was previously safe in pet dogs with sarcoma. Here we sought to test the efficacy of this approach with in dogs with advanced melanoma. EXPERIMENTAL DESIGN: This study examined fifteen client-owned dogs with histologically- or cytologically-confirmed malignant melanoma who received a single 9 Gray fraction of radiation therapy, followed by six cycles of combined collagen-anchored IL-2 and IL-12 therapy Q2W. Cytokine dosing followed a 3+3 dose escalation design, with the initial cytokine dose chosen from prior evaluation in canine sarcomas. No exclusion criteria for tumor stage or metastatic burden, age, weight, or neuter status were applied for this trial. RESULTS: Median survival regardless of tumor stage or dose level was 256 days and 10/13 (76.9%) dogs that completed treatment had CT-measured tumor regression at the treated lesion. In dogs with metastatic disease, 8/13 (61.5%) dogs had partial responses across their combined lesions, evidence of locoregional response. Profiling by Nanostring of treatment-resistant dogs revealed that B2m loss was predictive of poor response to this therapy. CONCLUSIONS: Collectively, these results confirm the ability of locally administered tumor-anchored cytokines to potentiate responses at regional disease sites when combined with radiation. This evidence supports the clinical translation of this approach and highlights the utility of comparative investigation in canine cancers.

COVID-19 Across Pandemic Variant Periods: The Severe Acute Respiratory Infection-Preparedness (SARI-PREP) Study.

IMPORTANCE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has evolved through multiple phases in the United States, with significant differences in patient centered outcomes with improvements in hospital strain, medical countermeasures, and overall understanding of the disease. We describe how patient characteristics changed and care progressed over the various pandemic phases; we also emphasize the need for an ongoing clinical network to improve the understanding of known and novel respiratory viral diseases. OBJECTIVES: To describe how patient characteristics and care evolved across the various COVID-19 pandemic periods in those hospitalized with viral severe acute respiratory infection (SARI). DESIGN: Severe Acute Respiratory Infection-Preparedness (SARI-PREP) is a Centers for Disease Control and Prevention Foundation-funded, Society of Critical Care Medicine Discovery-housed, longitudinal multicenter cohort study of viral pneumonia. We defined SARI patients as those hospitalized with laboratory-confirmed respiratory viral infection and an acute syndrome of fever, cough, and radiographic infiltrates or hypoxemia. We collected patient-level data including demographic characteristics, comorbidities, acute physiologic measures, serum and respiratory specimens, therapeutics, and outcomes. Outcomes were described across four pandemic variant periods based on a SARS-CoV-2 sequenced subsample: pre-Delta, Delta, Omicron BA.1, and Omicron post-BA.1. SETTING: Multicenter cohort of adult patients admitted to an acute care ward or ICU from seven hospitals representing diverse geographic regions across the United States. PARTICIPANTS: Patients with SARI caused by infection with respiratory viruses. MAIN OUTCOMES AND RESULTS: Eight hundred seventy-four adult patients with SARI were enrolled at seven study hospitals between March 2020 and April 2023. Most patients (780, 89%) had SARS-CoV-2 infection. Across the COVID-19 cohort, median age was 60 years (interquartile range, 48.0-71.0 yr) and 66% were male. Almost half (430, 49%) of the study population belonged to underserved communities. Most patients (76.5%) were admitted to the ICU, 52.5% received mechanical ventilation, and observed hospital mortality was 25.5%. As the pandemic progressed, we observed decreases in ICU utilization (94% to 58%), hospital length of stay (median, 26.0 to 8.5 d), and hospital mortality (32% to 12%), while the number of comorbid conditions increased. CONCLUSIONS AND RELEVANCE: We describe increasing comorbidities but improved outcomes across pandemic variant periods, in the setting of multiple factors, including evolving care delivery, countermeasures, and viral variants. An understanding of patient-level factors may inform treatment options for subsequent variants and future novel pathogens.

Implementing evidence-based restrictive neonatal intensive care unit platelet transfusion guidelines.

Platelet transfusions are life-saving treatments for specific populations of neonates. However, recent evidence indicates that liberal prophylactic platelet transfusion practices cause harm to premature neonates. New efforts to better balance benefits and risks are leading to the adoption of more restrictive platelet transfusion guidelines in neonatal intensive care units (NICU). Although restrictive guidelines have the potential to improve outcomes, implementation barriers exist. We postulate that as neonatologists become more familiar with the data on the harm of liberal platelet transfusions, enthusiasm for restrictive guidelines will increase and barriers to implementation will decrease. Thus, we focused this educational review on; (1) the adverse effects of platelet transfusions to neonates, (2) awareness of platelet transfusion "refractoriness" in thrombocytopenic neonates and its association with poor outcomes, and (3) the impetus to find alternatives to transfusing platelets from adult donors to NICU patients.

Preoperative and postoperative predictive models of early recurrence for colorectal liver metastases following chemotherapy and curative-intent one-stage hepatectomy.

INTRODUCTION: Accurate prediction of patients at risk for early recurrence (ER) among patients with colorectal liver metastases (CRLM) following preoperative chemotherapy and hepatectomy remains limited. METHODS: Patients with CRLM who received chemotherapy prior to undergoing curative-intent resection between 2000 and 2020 were identified from an international multi-institutional database. Multivariable Cox regression analysis was used to assess clinicopathological factors associated with ER, and an online calculator was developed and validated. RESULTS: Among 768 patients undergoing preoperative chemotherapy and curative-intent resection, 128 (16.7 %) patients had ER. Multivariable Cox analysis demonstrated that Eastern Cooperative Oncology Group Performance status ≥1 (HR 2.09, 95%CI 1.46-2.98), rectal cancer (HR 1.95, 95%CI 1.35-2.83), lymph node metastases (HR 2.39, 95%CI 1.60-3.56), mutated Kirsten rat sarcoma oncogene status (HR 1.95, 95%CI 1.25-3.02), increase in tumor burden score during chemotherapy (HR 1.51, 95%CI 1.03-2.24), and bilateral metastases (HR 1.94, 95%CI 1.35-2.79) were independent predictors of ER in the preoperative setting. In the postoperative model, in addition to the aforementioned factors, tumor regression grade was associated with higher hazards of ER (HR 1.91, 95%CI 1.32-2.75), while receipt of adjuvant chemotherapy was associated with lower likelihood of ER (HR 0.44, 95%CI 0.30-0.63). The discriminative accuracy of the preoperative (training: c-index: 0.77, 95%CI 0.72-0.81; internal validation: c-index: 0.79, 95%CI 0.75-0.82) and postoperative (training: c-index: 0.79, 95%CI 0.75-0.83; internal validation: c-index: 0.81, 95%CI 0.77-0.84) models was favorable (https://junkawashima.shinyapps.io/CRLMfollwingchemotherapy/). CONCLUSIONS: Patient-, tumor- and treatment-related characteristics in the preoperative and postoperative setting were utilized to develop an online, easy-to-use risk calculator for ER following resection of CRLM.