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Background Hepatic vascular inflow occlusion (VIO) can be applied during resection of colorectal liver metastases (CRLM) to control intra-operative blood loss, but has been linked to accelerated growth of micrometastases in experimental models. This study aimed to investigate the effects of hepatic VIO on disease-free and overall survival (DFS and OS) in patients following resection for CRLM. Methods All patients who underwent liver resection for CRLM between January 2006 and September 2015 at our center were analyzed. Hepatic VIO was performed if deemed indicated by the operating surgeon and severe ischemia was defined as ≥20 min continuous or ≥45 min cumulative intermittent VIO. Cox regression analysis was performed to identify predictive factors for DFS and OS. Results A total of 208 patients underwent liver resection for CRLM. VIO was performed in 64 procedures (31%), and fulfilled the definition of severe ischemia in 40 patients. Patients with severe ischemia had inferior DFS (5-year DFS 32% vs. 11%, P < 0.01), and inferior OS (5-year OS 37% vs. 64%, P < 0.01). At multivariate analysis, a high clinical risk score (Hazard ratio (HR) 1.60 (1.08–2.36)) and severe ischemia (HR 1.89 (1.21–2.97)) were independent predictors of worse DFS. Severe ischemia was not an independent predictor of OS. Conclusion The present cohort study suggests that prolonged hepatic VIO during liver resection for CRLM was associated with reduced DFS. A patient-tailored approach seems advisable although larger studies should confirm these findings. [ABSTRACT FROM AUTHOR]

B Background: b Data on secondary resections of colorectal liver-only metastases (CRLM) are difficult to interpret due to lack of consensus on resectability criteria. B Conclusion: b Prospective evaluation of CRLM patients by a expert panel according to uniform criteria with feedback of surgical outcomes is a unique aspect of CAIRO5. [Extracted from the article]

Implementing the Cochrane risk of bias (RoB) assessment items through standardized forms in trial registries would benefit transparency and eventually improve quality of research. This study assessed the possibilities of registration of RoB in the 5 largest trial registries and provides a proposal for the registration of RoB. B Methods: b The 5 largest trial registries were assessed for the presence and type of implementation of an option to provide information on all Cochrane collaboration RoB assessment tool items. [Extracted from the article]

B Conclusion: b Comparable disease free survival and overall survival were found in patients who underwent portal vein embolization before major liver resection compared to matched controls treated with major surgery alone. PVE is a valuable tool to improve resectability rate of patients with colorectal liver metastases and does not affect long term oncological outcomes in patients proceeding with liver resection. [Extracted from the article]

Background The objective of this study was to map referral patterns in patients with synchronous colorectal liver metastases (SCLM) and to investigate if type, volume and location of the hospital of diagnosis are associated with whether or not patients underwent liver resection. Methods This population-based study includes all patients diagnosed with SCLM between 2008 and 2012, based on the Netherlands Cancer Registry. To study inter-hospital variation, the proportion of patients undergoing liver surgery was calculated per hospital of diagnosis. Multivariable multilevel logistic regression analysis was used to investigate the association between hospital characteristics and liver resection. Results Of 10,520 patients with SCLM, 12% (n = 1259) underwent liver surgery. Of these patients, 58% (n = 733) were referred to another hospital to undergo liver surgery. In 53% of the patients (n = 647), liver resection was performed in a university hospital, in 39% (n = 482) in a dedicated liver centre and in 8% (n = 102) in a general hospital. There was a large inter-hospital variation in the proportion of patients undergoing liver resection (2–26%). In a multilevel logistic regression model, the odds of undergoing liver surgery were higher when patients were diagnosed in hospitals where liver surgery was performed compared with the general hospitals (dedicated liver centre: odds ratio 1.36 [95% confidence intervals 1.08–1.70], university hospital: odds ratio 1.69 [95% confidence intervals 1.22–2.34]). Conclusion There is a large inter-hospital and inter-regional variation in the utilisation of liver resection. Patients diagnosed with SCLM in expert centres had a higher chance of undergoing liver resection. [ABSTRACT FROM AUTHOR]

Background: This study aimed to assess the prognostic value of total tumor volume (TTV) for early recurrence (within 6 months) and overall survival (OS) in patients with colorectal liver metastases (CRLM), treated with induction systemic therapy followed by complete local treatment., Methods: Patients with initially unresectable CRLM from the multicenter randomized phase 3 CAIRO5 trial (NCT02162563) who received induction systemic therapy followed by local treatment were included. Baseline TTV and change in TTV as response to systemic therapy were calculated using the CT scan before and the first after systemic treatment, and were assessed for their added prognostic value. The findings were validated in an external cohort of patients treated at a tertiary center., Results: In total, 215 CAIRO5 patients were included. Baseline TTV and absolute change in TTV were significantly associated with early recurrence (P = 0.005 and P = 0.040, respectively) and OS in multivariable analyses (P = 0.024 and P = 0.006, respectively), whereas RECIST1.1 was not prognostic for early recurrence (P = 0.88) and OS (P = 0.35). In the validation cohort (n = 85), baseline TTV and absolute change in TTV remained prognostic for early recurrence (P = 0.041 and P = 0.021, respectively) and OS in multivariable analyses (P < 0.0001 and P = 0.012, respectively), and showed added prognostic value over conventional clinicopathological variables (increase C-statistic, 0.06; 95 % CI, 0.02 to 0.14; P = 0.008)., Conclusion: Total tumor volume is strongly prognostic for early recurrence and OS in patients who underwent complete local treatment of initially unresectable CRLM, both in the CAIRO5 trial and the validation cohort. In contrast, RECIST1.1 did not show prognostic value for neither early recurrence nor OS., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors of this manuscript declare relationships with the following companies: C.J.A.P. has an advisory role for Nordic Pharma; SAS Analytics paid for traveling expenses G. Kazemier. This funding is not related to the current research. The remaining authors declare no potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: We developed models for tumor segmentation to automate the assessment of total tumor volume (TTV) in patients with colorectal liver metastases (CRLM)., Methods: In this prospective cohort study, pre- and post-systemic treatment computed tomography (CT) scans of 259 patients with initially unresectable CRLM of the CAIRO5 trial (NCT02162563) were included. In total, 595 CT scans comprising 8,959 CRLM were divided into training (73%), validation (6.5%), and test sets (21%). Deep learning models were trained with ground truth segmentations of the liver and CRLM. TTV was calculated based on the CRLM segmentations. An external validation cohort was included, comprising 72 preoperative CT scans of patients with 112 resectable CRLM. Image segmentation evaluation metrics and intraclass correlation coefficient (ICC) were calculated., Results: In the test set (122 CT scans), the autosegmentation models showed a global Dice similarity coefficient (DSC) of 0.96 (liver) and 0.86 (CRLM). The corresponding median per-case DSC was 0.96 (interquartile range [IQR] 0.95-0.96) and 0.80 (IQR 0.67-0.87). For tumor segmentation, the intersection-over-union, precision, and recall were 0.75, 0.89, and 0.84, respectively. An excellent agreement was observed between the reference and automatically computed TTV for the test set (ICC 0.98) and external validation cohort (ICC 0.98). In the external validation, the global DSC was 0.82 and the median per-case DSC was 0.60 (IQR 0.29-0.76) for tumor segmentation., Conclusions: Deep learning autosegmentation models were able to segment the liver and CRLM automatically and accurately in patients with initially unresectable CRLM, enabling automatic TTV assessment in such patients., Relevance Statement: Automatic segmentation enables the assessment of total tumor volume in patients with colorectal liver metastases, with a high potential of decreasing radiologist's workload and increasing accuracy and consistency., Key Points: • Tumor response evaluation is time-consuming, manually performed, and ignores total tumor volume. • Automatic models can accurately segment tumors in patients with colorectal liver metastases. • Total tumor volume can be accurately calculated based on automatic segmentations., (© 2023. The Author(s).)

For patients with colorectal cancer liver metastases (CRLM), the genetic mutation status is important in treatment selection and prognostication for survival outcomes. This study aims to investigate the relationship between radiomics imaging features and the genetic mutation status (KRAS mutation versus no mutation) in a large multicenter dataset of patients with CRLM and validate these findings in an external dataset. Patients with initially unresectable CRLM treated with systemic therapy of the randomized controlled CAIRO5 trial (NCT02162563) were included. All CRLM were semi-automatically segmented in pre-treatment CT scans and radiomics features were calculated from these segmentations. Additionally, data from the Netherlands Cancer Institute (NKI) were used for external validation. A total of 255 patients from the CAIRO5 trial were included. Random Forest, Gradient Boosting, Gradient Boosting + LightGBM, and Ensemble machine-learning classifiers showed AUC scores of 0.77 (95%CI 0.62-0.92), 0.77 (95%CI 0.64-0.90), 0.72 (95%CI 0.57-0.87), and 0.86 (95%CI 0.76-0.95) in the internal test set. Validation of the models on the external dataset with 129 patients resulted in AUC scores of 0.47-0.56. Machine-learning models incorporating CT imaging features could identify the genetic mutation status in patients with CRLM with a good accuracy in the internal test set. However, in the external validation set, the models performed poorly. External validation of machine-learning models is crucial for the assessment of clinical applicability and should be mandatory in all future studies in the field of radiomics.

Background: In the DESIRE study (Discharge aftEr Surgery usIng aRtificial intElligence), we have previously developed and validated a machine learning concept in 1,677 gastrointestinal and oncology surgery patients that can predict safe hospital discharge after the second postoperative day. Despite strong model performance (area under the receiver operating characteristics curve of 0.88) in an academic surgical population, it remains unknown whether these findings can be translated to other hospitals and surgical populations. We therefore aimed to determine the generalizability of the previously developed machine learning concept., Methods: We externally validated the machine learning concept in gastrointestinal and oncology surgery patients admitted to 3 nonacademic hospitals in The Netherlands between January 2017 and June 2021, who remained admitted 2 days after surgery. Primary outcome was the ability to predict hospital interventions after the second postoperative day, which were defined as unplanned reoperations, radiological interventions, and/or intravenous antibiotics administration. Four forest models were locally trained and evaluated with respect to area under the receiver operating characteristics curve, sensitivity, specificity, positive predictive value, and negative predictive value., Results: All models were trained on 1,693 epsiodes, of which 731 (29.9%) required a hospital intervention and demonstrated strong performance (area under the receiver operating characteristics curve only varied 4%). The best model achieved an area under the receiver operating characteristics curve of 0.83 (95% confidence interval [0.81-0.85]), sensitivity of 77.9% (0.67-0.87), specificity of 79.2% (0.72-0.85), positive predictive value of 61.6% (0.54-0.69), and negative predictive value of 89.3% (0.85-0.93)., Conclusion: This study showed that a previously developed machine learning concept can predict safe discharge in different surgical populations and hospital settings (academic versus nonacademic) by training a model on local patient data. Given its high accuracy, integration of the machine learning concept into the clinical workflow could expedite surgical discharge and aid hospitals in addressing capacity challenges by reducing avoidable bed-days., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose To evaluate interobserver variability in the morphologic tumor response assessment of colorectal liver metastases (CRLM) managed with systemic therapy and to assess the relation of morphologic response with gene mutation status, targeted therapy, and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 measurements. Materials and Methods Participants with initially unresectable CRLM receiving different systemic therapy regimens from the randomized, controlled CAIRO5 trial (NCT02162563) were included in this prospective imaging study. Three radiologists independently assessed morphologic tumor response on baseline and first follow-up CT scans according to previously published criteria. Two additional radiologists evaluated disagreement cases. Interobserver agreement was calculated by using Fleiss κ. On the basis of the majority of individual radiologic assessments, the final morphologic tumor response was determined. Finally, the relation of morphologic tumor response and clinical prognostic parameters was assessed. Results In total, 153 participants (median age, 63 years [IQR, 56-71]; 101 men) with 306 CT scans comprising 2192 CRLM were included. Morphologic assessment performed by the three radiologists yielded 86 (56%) agreement cases and 67 (44%) disagreement cases (including four major disagreement cases). Overall interobserver agreement between the panel radiologists on morphology groups and morphologic response categories was moderate (κ = 0.53, 95% CI: 0.48, 0.58 and κ = 0.54, 95% CI: 0.47, 0.60). Optimal morphologic response was particularly observed in patients treated with bevacizumab ( P = .001) and in patients with RAS/BRAF mutation ( P = .04). No evidence of a relationship between RECIST 1.1 and morphologic response was found ( P = .61). Conclusion Morphologic tumor response assessment following systemic therapy in participants with CRLM demonstrated considerable interobserver variability. Keywords: Tumor Response, Observer Performance, CT, Liver, Metastases, Oncology, Abdomen/Gastrointestinal Clinical trial registration no. NCT02162563 Supplemental material is available for this article. © RSNA, 2022.

Objective: To perform a scoping review of imaging-based machine-learning models to predict clinical outcomes and identify biomarkers in patients with PDAC., Summary of Background Data: Patients with PDAC could benefit from better selection for systemic and surgical therapy. Imaging-based machine-learning models may improve treatment selection., Methods: A scoping review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses-scoping review guidelines in the PubMed and Embase databases (inception-October 2020). The review protocol was prospectively registered (open science framework registration: m4cyx). Included were studies on imaging-based machine-learning models for predicting clinical outcomes and identifying biomarkers for PDAC. The primary outcome was model performance. An area under the curve (AUC) of ≥0.75, or a P-value of ≤0.05, was considered adequate model performance. Methodological study quality was assessed using the modified radiomics quality score., Results: After screening 1619 studies, 25 studies with 2305 patients fulfilled the eligibility criteria. All but 1 study was published in 2019 and 2020. Overall, 23/25 studies created models using radiomics features, 1 study quantified vascular invasion on computed tomography, and one used histopathological data. Nine models predicted clinical outcomes with AUC measures of 0.78-0.95, and C-indices of 0.65-0.76. Seventeen models identified biomarkers with AUC measures of 0.68-0.95. Adequate model performance was reported in 23/25 studies. The methodological quality of the included studies was suboptimal, with a median modified radiomics quality score score of 7/36., Conclusions: The use of imaging-based machine-learning models to predict clinical outcomes and identify biomarkers in patients with PDAC is increasingly rapidly. Although these models mostly have good performance scores, their methodological quality should be improved., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Although the role of artificial intelligence (AI) in medicine is increasingly studied, most patients do not benefit because the majority of AI models remain in the testing and prototyping environment. The development and implementation trajectory of clinical AI models are complex and a structured overview is missing. We therefore propose a step-by-step overview to enhance clinicians' understanding and to promote quality of medical AI research., Methods: We summarised key elements (such as current guidelines, challenges, regulatory documents and good practices) that are needed to develop and safely implement AI in medicine., Conclusion: This overview complements other frameworks in a way that it is accessible to stakeholders without prior AI knowledge and as such provides a step-by-step approach incorporating all the key elements and current guidelines that are essential for implementation, and can thereby help to move AI from bytes to bedside., Competing Interests: Competing interests: DG received speaker's fees and travel expenses from Dräger, GE Healthcare (medical advisory board 2009–2012), Maquet, and Novalung (medical advisory board 2015–2018). JH currently works as industry expert healthcare at SAS Institute. EvU currently works as principal analytics consultant at SAS Institute. No financial relationships exist that could be construed as a potential conflict of interest. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Somatic KRAS mutations occur in approximately half of the patients with metastatic colorectal cancer (mCRC). Biologic tumor characteristics differ on the basis of the KRAS mutation variant. KRAS mutations are known to influence patient prognosis and are used as predictive biomarker for treatment decisions. This study examined clinical features of patients with mCRC with a somatic mutation in KRAS G12, G13, Q61, K117, or A146., Methods: A total of 419 patients with colorectal cancer with initially unresectable liver-limited metastases, who participated in a multicenter prospective trial, were evaluated for tumor tissue KRAS mutation status. For the subgroup of patients who carried a KRAS mutation and were treated with bevacizumab and doublet or triplet chemotherapy (N = 156), pretreatment circulating tumor DNA levels were analyzed, and total tumor volume (TTV) was quantified on the pretreatment computed tomography images., Results: Most patients carried a KRAS G12 mutation (N = 112), followed by mutations in G13 (N = 15), A146 (N = 12), Q61 (N = 9), and K117 (N = 5). High plasma circulating tumor DNA levels were observed for patients carrying a KRAS A146 mutation versus those with a KRAS G12 mutation, with median mutant allele frequencies of 48% versus 19%, respectively. Radiologic TTV revealed this difference to be associated with a higher tumor load in patients harboring a KRAS A146 mutation (median TTV 672 cm 3 [A146] v 74 cm 3 [G12], P = .036). Moreover, KRAS A146 mutation carriers showed inferior overall survival compared with patients with mutations in KRAS G12 (median 10.7 v 26.4 months; hazard ratio = 2.5; P = .003)., Conclusion: Patients with mCRC with a KRAS A146 mutation represent a distinct molecular subgroup of patients with higher tumor burden and worse clinical outcomes, who might benefit from more intensive treatments. These results highlight the importance of testing colorectal cancer for all KRAS mutations in routine clinical care., Competing Interests: Remond J. A. Fijneman Research Funding: Merck BV (Inst), Personal Genome Diagnostics (Inst), Delfi Diagnostics (Inst), Cergentis (Inst) Patents, Royalties, Other Intellectual Property: Several Patents pending (Inst) No other potential conflicts of interest were reported. Remond J. A. Fijneman Research Funding: Merck BV (Inst), Personal Genome Diagnostics (Inst), Delfi Diagnostics (Inst), Cergentis (Inst) Patents, Royalties, Other Intellectual Property: Several Patents pending (Inst) No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Objectives: Compare total tumor volume (TTV) response after systemic treatment to Response Evaluation Criteria in Solid Tumors (RECIST1.1) and assess the prognostic value of TTV change and RECIST1.1 for recurrence-free survival (RFS) in patients with colorectal liver-only metastases (CRLM)., Background: RECIST1.1 provides unidimensional criteria to evaluate tumor response to systemic therapy. Those criteria are accepted worldwide but are limited by interobserver variability and ignore potentially valuable information about TTV., Methods: Patients with initially unresectable CRLM receiving systemic treatment from the randomized, controlled CAIRO5 trial (NCT02162563) were included. TTV response was assessed using software specifically developed together with SAS analytics. Baseline and follow-up computed tomography (CT) scans were used to calculate RECIST1.1 and TTV response to systemic therapy. Different thresholds (10%, 20%, 40%) were used to define response of TTV as no standard currently exists. RFS was assessed in a subgroup of patients with secondarily resectable CRLM after induction treatment., Results: A total of 420 CT scans comprising 7820 CRLM in 210 patients were evaluated. In 30% to 50% (depending on chosen TTV threshold) of patients, discordance was observed between RECIST1.1 and TTV change. A TTV decrease of >40% was observed in 47 (22%) patients who had stable disease according to RECIST1.1. In 118 patients with secondarily resectable CRLM, RFS was shorter for patients with less than 10% TTV decrease compared with patients with more than 10% TTV decrease ( P = 0.015), while RECIST1.1 was not prognostic ( P = 0.821)., Conclusions: TTV response assessment shows prognostic potential in the evaluation of systemic therapy response in patients with CRLM., Competing Interests: C.J.A.P. has an advisory role for Nordic Pharma. This funding is not related to the current research. The remaining authors declare no potential conflicts of interest. The CAIRO5 study is supported by unrestricted scientific grants from Roche and Amgen. The funders had no role in the design, conduct, and submission of the study, or in the decision to submit the manuscript for publication., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Histologic examination of resected pancreatic cancer after neoadjuvant therapy (NAT) is used to assess the effect of NAT and may guide the choice for adjuvant treatment. However, evaluating residual tumor burden in pancreatic cancer is challenging given tumor response heterogeneity and challenging histomorphology. Artificial intelligence techniques may offer a more reproducible approach., Methods: From 64 patients, one H&E-stained slide of resected pancreatic cancer after NAT was digitized. Three separate classes were manually outlined in each slide (i.e., tumor, normal ducts, and remaining epithelium). Corresponding segmentation masks and patches were generated and distributed over training, validation, and test sets. Modified U-nets with varying encoders were trained, and F1 scores were obtained to express segmentation accuracy., Results: The highest mean segmentation accuracy was obtained using modified U-nets with a DenseNet161 encoder. Tumor tissue was segmented with a high mean F1 score of 0.86, while the overall multiclass average F1 score was 0.82., Conclusions: This study shows that artificial intelligence-based assessment of residual tumor burden is feasible given the promising obtained F1 scores for tumor segmentation. This model could be developed into a tool for the objective evaluation of the response to NAT and may potentially guide the choice for adjuvant treatment.

Background: A significant proportion of surgical inpatients is often admitted longer than necessary. Early identification of patients who do not need care that is strictly provided within hospitals would allow timely discharge of patients to a postoperative nursing home for further recovery. We aimed to develop a model to predict whether a patient needs hospital-specific interventional care beyond the second postoperative day., Methods: This study included all adult patients discharged from surgical care in the surgical oncology department from June 2017 to February 2020. The primary outcome was to predict whether a patient still needs hospital-specific interventional care beyond the second postoperative day. Hospital-specific care was defined as unplanned reoperations, radiological interventions, and intravenous antibiotics administration. Different analytical methods were compared with respect to the area under the receiver-operating characteristics curve, sensitivity, specificity, positive predictive value, and negative predictive value., Results: Each model was trained on 1,174 episodes. In total, 847 (50.5%) patients required an intervention during postoperative admission. A random forest model performed best with an area under the receiver-operating characteristics curve of 0.88 (95% confidence interval 0.83-0.93), sensitivity of 79.1% (95% confidence interval 0.67-0.92), specificity of 80.0% (0.73-0.87), positive predictive value of 57.6% (0.45-0.70) and negative predictive value of 91.7% (0.87-0.97)., Conclusion: This proof-of-concept study found that a random forest model could successfully predict whether a patient could be safely discharged to a nursing home and does not need hospital care anymore. Such a model could aid hospitals in addressing capacity challenges and improve patient flow, allowing for timely surgical care., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction In the current situation, clinical patient data are often siloed in multiple hospital information systems. Especially in the intensive care unit (ICU), large volumes of clinical data are routinely collected through continuous patient monitoring. Although these data often contain useful information for clinical decision making, they are not frequently used to improve quality of care. During, but also after, pressing times, data-driven methods can be used to mine treatment patterns from clinical data to determine the best treatment options from a hospitals own clinical data. Methods In this implementer report, we describe how we implemented a data infrastructure that enabled us to learn in real time from consecutive COVID-19 ICU admissions. In addition, we explain our step-by-step multidisciplinary approach to establish such a data infrastructure. Conclusion By sharing our steps and approach, we aim to inspire others, in and outside ICU walls, to make more efficient use of data at hand, now and in the future., Competing Interests: Competing interests: DG has received speakers fees and travel expenses from Dräger, GE Healthcare (medical advisory board 2009–12), Maquet and Novalung (medical advisory board 2015–18). JH currently works as industry expert healthcare at SAS Institute. No financial relationships exists that could be construed as a potential conflict of interest. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Recurrence rates after resection of colorectal cancer liver metastases (CRLM) are high and correlate with worse survival. Postoperative circulating tumour DNA (ctDNA) is a promising prognostic biomarker. Focusing on patients with resected CRLM, this study aimed to evaluate the association between the detection of postoperative ctDNA, pathologic response and recurrence-free survival (RFS)., Methods: Twenty-three patients were selected from an ongoing phase-3 trial who underwent resection of RAS-mutant CRLM after induction systemic treatment. CtDNA analysis was performed by droplet digital PCR using blood samples collected at baseline, before and after resection. Pathologic response of CRLM was determined via the Tumour Regression Grading system., Findings: With a median follow-up of 19.6 months, the median RFS for patients with detectable (N = 6, [26%]) and undetectable (N = 17, [74%]) postoperative ctDNA was 4.8 versus 12.1 months, respectively. Among 21 patients with available tumour tissue, pathologic response in patients with detectable compared to undetectable postoperative ctDNA was found in one of six (17%) and 15 of 15 (100%) patients, respectively (p < 0.001). In univariable Cox regression analyses both postoperative detectable ctDNA (HR = 3.3, 95%CI = 1.1-9.6, p = 0.03) and pathologic non-response (HR = 4.6, 95%CI = 1.4-15, p = 0.01) were associated with poorer RFS and were strongly correlated (r = 0.88, p < 0.001). After adjusting for clinical characteristics in pairwise multivariable analyses, postoperative ctDNA status remained associated with RFS., Interpretation: The detection of postoperative ctDNA after secondary resection of CRLM is a promising prognostic factor for RFS and appeared to be highly correlated with pathologic response., Funding: None., Competing Interests: Declaration of Competing Interest C.J.A.P. has an advisory role for Nordic Pharma. This funding is not related to the current research. G.A.M. reports non-financial support from Exact Sciences, non-financial support from Sysmex, non-financial support from Sentinel CH. SpA, non-financial support from Personal Genome Diagnostics (PGDX), other from Hartwig Medical Foundation, grants from CZ (OWM Centrale Zorgverzekeraars groep Zorgverzekeraar u.a), other from Royal Philips, other from GlaxoSmithKline, other from Keosys SARL, other from Open Clinica LLC, other from Roche Diagnostics Nederland BV, other from The Hyve BV, other from Open Text, other from SURFSara BV, other from Vancis BV, other from CSC Computer Sciences BV, outside the submitted work; In addition, G.A.M. has several patents pending. R.J.A.F. reports grants and non-financial support from Personal Genome Diagnostics, grants from MERCK BV, non-financial support from Pacific Biosciences, non-financial support from Cergentis BV, outside the submitted work; In addition, R.J.A.F. has several patents pending. The remaining authors declare no potential conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To present short-term outcomes of liver surgery in patients with initially unresectable colorectal liver metastases (CRLM) downsized by chemotherapy plus targeted agents., Background: The increase of complex hepatic resections of CRLM, technical innovations pushing boundaries of respectability, and use of intensified induction systemic regimens warrant for safety data in a homogeneous multicenter prospective cohort., Methods: Patients with initially unresectable CRLM, who underwent complete resection after induction systemic regimens with doublet or triplet chemotherapy, both plus targeted therapy, were selected from the ongoing phase III CAIRO5 study (NCT02162563). Short-term outcomes and risk factors for severe postoperative morbidity (Clavien Dindo grade ≥ 3) were analyzed using logistic regression analysis., Results: A total of 173 patients underwent resection of CRLM after induction systemic therapy. The median number of metastases was 9 and 161 (93%) patients had bilobar disease. Thirty-six (20.8%) 2-stage resections and 88 (51%) major resections (>3 liver segments) were performed. Severe postoperative morbidity and 90-day mortality was 15.6% and 2.9%, respectively. After multivariable analysis, blood transfusion (odds ratio [OR] 2.9 [95% confidence interval (CI) 1.1-6.4], P = 0.03), major resection (OR 2.9 [95% CI 1.1-7.5], P = 0.03), and triplet chemotherapy (OR 2.6 [95% CI 1.1-7.5], P = 0.03) were independently correlated with severe postoperative complications. No association was found between number of cycles of systemic therapy and severe complications ( r = -0.038 , P = 0.31)., Conclusion: In patients with initially unresectable CRLM undergoing modern induction systemic therapy and extensive liver surgery, severe postoperative morbidity and 90-day mortality were 15.6% and 2.7%, respectively. Triplet chemotherapy, blood transfusion, and major resections were associated with severe postoperative morbidity., Competing Interests: Disclosure: C.J.A.P. has an advisory role for Nordic Pharma. The other authors declare that they have nothing to disclose. The CAIRO5 study (NCT02162563) was supported by unrestricted scientific grants from Roche and Amgen. The funders had no role in the design, conduct and submission of the study, nor in the decision to submit the manuscript for publication., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Advanced medical image analytics is increasingly used to predict clinical outcome in patients diagnosed with gastrointestinal tumors. This review provides an overview on the value of radiomics in predicting response to treatment in patients with gastrointestinal tumors., Methods: A systematic review was conducted, according to PRISMA guidelines. The protocol was prospectively registered (PROSPERO: CRD42019128408). PubMed, Embase, and Cochrane databases were searched. Original studies reporting on the value of radiomics in predicting response to treatment in patients with a gastrointestinal tumor were included. A narrative synthesis of results was conducted. Results were stratified by tumor type. Quality assessment of included studies was performed, according to the radiomics quality score., Results: The comprehensive literature search identified 1360 unique studies, of which 60 articles were included for analysis. In 37 studies, radiomics models and individual radiomic features showed good predictive performance for response to treatment (area under the curve or accuracy > 0.75). Various strategies to construct predictive models were used. Internal validation of predictive models was often performed, while the majority of studies lacked external validation. None of the studies reported predictive models implemented in clinical practice., Conclusion: Radiomics is increasingly used to predict response to treatment in patients suffering from gastrointestinal cancer. This review demonstrates its great potential to help predict response to treatment and improve patient selection and early adjustment of treatment strategy in a non-invasive manner.

Background: The coronavirus disease 2019 (COVID-19) pandemic is a challenge for intensive care units (ICU) in part due to the failure to identify risks for patients early and the inability to render an accurate prognosis. Previous reports suggest a strong association between hypercoagulability and poor outcome. Factors related to hemostasis may, therefore, serve as tools to improve the management of COVID-19 patients., Aim: The purpose of this report is to develop a model to determine whether it is possible to early identify COVID-19 patients at risk for thromboembolic complications (TCs)., Methods: We analyzed electronic health record data of 108 consecutive COVID-19 patients admitted to the adult ICU of the Erasmus University Medical Center between February 27 and May 20, 2020. By training a decision tree classifier on 66% of the available data, a model for the prediction of TCs was developed., Results: The median (interquartile range) age was 62 (53-70) years and 73% were male. Forty-three patients (40%) developed a TC during their ICU stay. Mortality was higher for patients in the TCs group compared to the control group (26% vs. 8%, P =0.03). Lactate dehydrogenase, standardized bicarbonate, albumin, and leukocytes were identified by the Decision Tree classifier as the most powerful predictors for TCs 2 days before the onset of the TC, with a sensitivity of 73% and a positive likelihood ratio of 2.7 on the test dataset., Conclusions: Clinically relevant TCs frequently occur in critically ill COVID-19 patients. These can successfully be predicted using a decision tree model. Although this model could be of special importance to aid clinical decision making, its generalizability and clinical impact should be determined in a larger population., Relevance for Patients: Recently, severe TCs were observed in COVID-19 patients with progressive respiratory failure warranting ICU treatment. Timely identification of patients at risk of developing TCs is critical inasmuch as it would enable clinicians to initiate potentially salvaging therapeutic anticoagulation., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright: © Whioce Publishing Pte. Ltd.)

Introduction: Registration of clinical trials has been initiated in order to assess adherence of the reported results to the original trial protocol. This study aimed to investigate the publication rates, timely dissemination of results, and the prevalence of consistency in hypothesis, sample size, and primary endpoint of Dutch investigator-initiated randomized controlled clinical trials (RCTs)., Methods: All Dutch investigator-initiated RCTs with a completion date between December 31, 2010, and January 1, 2012, and registered in the Trial Register of The Netherlands database were included. PubMed was searched for the publication of these RCT results until September 2016, and the time to the publication date was calculated. Consistency in hypothesis, sample size, and primary endpoint compared with the registry data were assessed., Results: The search resulted in a total of 168 Dutch investigator-initiated RCTs. In September 2016, the results of 129 (77%) trials had been published, of which 50 (39%) within 2 years after completion of accrual. Consistency in hypothesis with the original protocol was observed in 108 (84%) RCTs; in 71 trials (55%), the planned sample size was reached; and 103 trials (80%) presented the original primary endpoint. Consistency in all three parameters was observed in 50 studies (39%)., Conclusion: This study shows that approximately one out of four Dutch investigator-initiated RCTs remains unpublished 5 years after initiation. The observed low overall consistency with the initial study outline is a matter of concern and warrants improvements in trial design and assessment of trial feasibility., (© 2019 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.)

Background: Decision making on optimal treatment strategy in patients with initially unresectable colorectal cancer liver metastases (CRLM) remains complex because uniform criteria for (un)resectability are lacking. This study reports on the feasibility and short-term outcomes of The Dutch Colorectal Cancer Group Liver Expert Panel., Study Design: The Expert Panel consists of 13 hepatobiliary surgeons and 4 radiologists. Resectability assessment is performed independently by 3 randomly assigned surgeons, and CRLM are scored as resectable, potentially resectable, or permanently unresectable. In absence of consensus, 2 additional surgeons are invited for a majority consensus. Patients with potentially resectable or unresectable CRLM at baseline are evaluated every 2 months of systemic therapy. Once CRLM are considered resectable, a treatment strategy is proposed., Results: Overall, 398 panel evaluations in 183 patients were analyzed. The median time to panel conclusion was 7 days (interquartile range [IQR] 5-11 days). Intersurgeon disagreement was observed in 205 (52%) evaluations, with major disagreement (resectable vs permanently unresectable) in 42 (11%) evaluations. After systemic treatment, 106 patients were considered to have resectable CRLM, 84 of whom (79%) underwent a curative procedure. R0 resection (n = 41), R0 resection in combination with ablative treatment (n = 26), or ablative treatment only (n = 4) was achieved in 67 of 84 (80%) patients., Conclusions: This study analyzed prospective resectability evaluation of patients with CRLM by a panel of radiologists and liver surgeons. The high rate of disagreement among experienced liver surgeons reflects the complexity in defining treatment strategies for CRLM and supports the use of a panel rather than a single-surgeon decision., (Copyright © 2019 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: ALPPS is a two-stage hepatectomy that induces more rapid liver growth compared to conventional strategies. This report aims to establish a risk-score to avoid adverse outcomes of ALPPS only for patients with colorectal liver metastases (CRLM) as primary indication for ALPPS., Methods: All patients with CRLM included in the ALPPS registry were included. Risk score analysis was performed for 90-day mortality after ALPPS, defined as death within 90 days after either stage. Two risk scores were generated i.e. one for application before stage-1, and one for application before stage-2. Logistic regression analysis was performed to establish the risk-score., Results: In total, 486 patients were included, of which 35 (7%) died 90 days after stage-1 or 2. In the stage-1 risk score, age ≥67 years (OR 3.7), FLR/BW ratio <0.40 (OR 2.9) and total center-volume (OR 2.4) were included. For the stage-2 score age ≥67 years (OR 3.7), FLR/BW ratio <0.40 (OR 2.8), bilirubin 5 days after stage-1 >50 μmol/L (OR 2.4), and stage-1 morbidity grade IIIA or higher (OR 6.3) were included., Conclusions: The CRLM risk-score to predict mortality after ALPPS demonstrates that older patients with small remnant livers in inexperienced centers, especially after experiencing morbidity after stage-1 have adverse outcomes. The risk score may be used to restrict ALPPS to low-risk patient populations., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background and Aim: Both the number and complexity of medical trials are increasing vastly. To facilitate easy access to concise trial information, a freely available mobile application including all ongoing clinical trials of the Dutch Colorectal Cancer Group (DCCG) was developed. The aim of this study was to investigate the use and user satisfaction over the first 2 years., Methods: The application was launched in January 2015 on iOS and Android platforms. Google Analytics was used to monitor anonymous user data up to February 2017. In addition, an online survey regarding the use and satisfaction among health-care professionals and research affiliates active in the field of colorectal cancer in the Netherlands was conducted., Results: A total of 6173 unique users were identified, of which 1822 (30%) were from the Netherlands, representing a total of 16,065 and 10,987 (68%) sessions, respectively. The median session duration per day was 01:47 min (IQR 0:51-03:03). The mobile application was mostly used on Monday, Tuesday, and Thursday, and the number of sessions was highest during the following time frames: 12-13 pm (9%), 17-18 pm (9%), and 13-14 pm (8%). Of 121 survey responses, most were medical doctors (47%), nurses (25%), or researchers (9%), working either in a teaching (40%), academic hospital (32%), or general hospital (19%). 83% of all respondents rated the application 4 or higher for satisfaction on a 5-point scale. Highest reported reasons of the use were urgent trial inquiry (57%) and usage during multi-disciplinary meetings (49%)., Conclusion: The DCCG Trials application is frequently used, and the majority of users is highly satisfied., Relevance for Patients: Clustering trial information into one platform, such as DCCG trials app, has shown to be useful for medical professionals treating patients with colorectal carcinoma in the Netherlands.

Introduction: There is an ongoing controversy surrounding portal vein embolization (PVE) regarding the short-term safety of PVE and long-term oncological benefit. This study aims to compare survival outcomes of patients subjected to major liver resection for colorectal liver metastases (CRLM) with or without PVE., Methods: All consecutive patients who underwent major liver resection for CRLM in four high volume liver centres between January 2000 and December 2015 were included. Major liver resection was defined as resection of at least three Couinaud liver segments. To reduce selection bias, propensity score matching was performed for PVE and non-PVE patients with overall and disease-free survival as primary endpoints. For matching, all patients who underwent PVE followed by a major liver resection were selected. Patients were matched to patients who had undergone major liver resection without PVE., Results: Of 745 patients undergoing major liver resection for CRLM, 53 patients (7%) underwent PVE before liver resection. In the overall cohorts, PVE patients had inferior DFS and a trend towards inferior OS. A total of 46 PVE patients were matched to 46 non-PVE patients to create comparable cohorts and between these two matched cohorts no differences in DFS (3-year DFS 16% vs 9%, p = 0.776) or OS (5-year OS 14% vs 14%, p = 0.866) were found., Conclusions: This retrospective, matched analysis does not suggest a negative impact of PVE on long-term outcomes after liver resection in patients with CRLM., (Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with stage I or II disease. Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients. In patients with resectable colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival. These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Discrepancies are often noted between management of perihilar cholangiocarcinoma (PHC) in regional hospitals and the eventual treatment plan in specialized centers., Objective: The objective of this article is to evaluate whether regional centers adhere to guideline recommendations following implementation in 2013., Methods: Data were analyzed from all consecutive patients with suspected PHC referred to our academic center between June 2013 and December 2015. Frequency and quality of biliary drainage and imaging at referring centers were assessed as well as the impact of inadequate initial drainage., Results: Biliary drainage was attempted at regional centers in 83 of 158 patients (52.5%), with a technical and therapeutic success rate of 79.5% and 50%, respectively, and a complication rate of 45.8%. The computed tomography protocol was not in accordance with guidelines in 52.8% of referrals. In 45 patients (54.2%) who underwent drainage in regional centers, additional drainage procedures were required after referral. Initial inadequate biliary drainage at a regional center was significantly associated with more procedures and a prolonged waiting time until surgery. A trend toward more drainage-related complications was observed among patients with inadequate initial drainage (54.7% vs. 39.0%, p  = 0.061)., Conclusion: Despite available guidelines, suboptimal management of PHC persists in many regional centers and affects eventual treatment strategies.

Background: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) allows the resection of colorectal liver metastases with curative intent which would otherwise be unresectable and only eligible for palliative systemic therapy. This study aimed to compare outcomes of ALPPS in patients with otherwise unresectable colorectal liver metastases with matched historic controls treated with palliative systemic treatment., Methods: All patients with colorectal liver metastases from the international ALPPS registry were identified and analyzed. Survival data were compared according to the extent of disease. Otherwise unresectable ALPPS patients were defined by at least 2 of the following criteria: ≥6 metastasis, ≥2 future remnant liver metastasis, ≥6 involved segments excluding segment 1. These patients were matched with patients included in 2, phase 3, metastatic, colorectal cancer trials (CAIRO and CAIRO2) using propensity scoring in order to compare survival., Results: Of 295 patients with colorectal liver metastases in the ALPPS registry, 70 patients had otherwise unresectable disease defined by the proposed criteria. Two-year overall survival was 49% and 72% for patients with ≥2 and <2 criteria, respectively (P = .002). Median disease-free survival was 6 months compared to 12 months (P < .001) in the ≥2 and <2 criteria groups, respectively. Median overall survival was comparable between ALPPS patients with ≥2 criteria and case-matched patients who received palliative treatment (24.0 vs 17.6 months, P = .088)., Conclusion: Early oncologic outcomes of patients with advanced liver metastases undergoing ALPPS were not superior to results of matched patients receiving systemic treatment with palliative intent. Careful patient selection is essential in order to improve outcomes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Transaminase levels are usually measured as markers of hepatocellular injury following liver resection, but recent evidence was unclear on their clinical value. This study aimed to identify factors that determine peak postoperative transaminase levels and correlated transaminase levels to postoperative complications., Study Design: All liver resections performed at a single center between 2006 and 2015 were included in the analysis. Multivariate analysis was used to identify factors that determine peak ALT and AST levels and postoperative morbidity and mortality. An ALT and AST cutoff for the prediction of mortality was determined using receiver operating characteristic curves analysis., Results: A total of 539 resections were included. Clavien-Dindo grade III or higher complications, intraoperative transfusion, and operative duration were identified as determinants of peak transaminases. A peak AST cut-off value for predicting mortality was defined at 828 U/L, with an area under the curve of 0.81 (0.73-0.89). The cut-off was an independent predictor of mortality (P < 0.01) along with (intraoperative) transfusion (P < 0.01), fifty-fifty criteria (P < 0.01), and age (P < 0.01)., Conclusion: Postoperative transaminase levels are independent predictors of postoperative morbidity and mortality and therefore clinically relevant. Transaminase levels usually peak during the first 24 h after surgery and thus possess early prognostic power in terms of postoperative mortality., (Copyright © 2016 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Colorectal cancer patients with unresectable liver-only metastases may be cured after downsizing of metastases by neoadjuvant systemic therapy. However, the optimal neoadjuvant induction regimen has not been defined, and the lack of consensus on criteria for (un)resectability complicates the interpretation of published results., Methods/design: CAIRO5 is a multicentre, randomised, phase 3 clinical study. Colorectal cancer patients with initially unresectable liver-only metastases are eligible, and will not be selected for potential resectability. The (un)resectability status is prospectively assessed by a central panel consisting of at least one radiologist and three liver surgeons, according to predefined criteria. Tumours of included patients will be tested for RAS mutation status. Patients with RAS wild type tumours will be treated with doublet chemotherapy (FOLFOX or FOLFIRI) and randomised between the addition of either bevacizumab or panitumumab, and patients with RAS mutant tumours will be randomised between doublet chemotherapy (FOLFOX or FOLFIRI) plus bevacizumab or triple chemotherapy (FOLFOXIRI) plus bevacizumab. Radiological evaluation to assess conversion to resectability will be performed by the central panel, at an interval of two months. The primary study endpoint is median progression-free survival. Secondary endpoints are the R0/1 resection rate, median overall survival, response rate, toxicity, pathological response of resected lesions, postoperative morbidity, and correlation of baseline and follow-up evaluation with respect to outcomes by the central panel., Discussion: CAIRO5 is a prospective multicentre trial that investigates the optimal systemic induction therapy for patients with initially unresectable, liver-only colorectal cancer metastases., Trial Registration: CAIRO 5 is registered at European Clinical Trials Database (EudraCT) (2013-005435-24). CAIRO 5 is registered at ClinicalTrials.gov: NCT02162563 , June 10, 2014.