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Background: The aim of this study was to develop a prediction model for 10-year overall survival (OS) after resection of colorectal liver metastasis (CRLM) based on patient, tumour and treatment characteristics. Methods: Consecutive patients after complete resection of CRLM were included from two centres (1992-2019). A prediction model providing 10-year OS probabilities was developed using Cox regression analysis, including KRAS, BRAF and histopathological growth patterns. Discrimination and calibration were assessed using cross-validation. A web-based calculator was built to predict individual 10-year OS probabilities. Results: A total of 4112 patients were included. The estimated 10-year OS was 30% (95% CI 29 -32). Fifteen patient, tumour and treatment characteristics were independent prognostic factors for 10-year OS; age, gender, location and nodal status of the primary tumour, disease-free interval, number and diameter of CRLM, preoperative CEA, resection margin, extrahepatic disease, KRAS and BRAF mutation status, histopathological growth patterns, perioperative systemic chemotherapy and hepatic arterial infusion pump chemotherapy. The discrimination at 10-years was 0.73 for both centres. A simplified risk score identified four risk groups with a 10-year OS of 57%, 38%, 24%, and 12%. Conclusions: Ten-year OS after resection of CRLM is best predicted with a model including 15 patient, tumour, and treatment characteristics. The web-based calculator can be used to inform patients. This model serves as a benchmark to determine the prognostic value of novel biomarkers. (C) 2022 The Author(s). Published by Elsevier Ltd.

Background The practice of adjuvant hepatic arterial infusion chemotherapy (HAIC) for colorectal liver metastasis (CRLM) varies widely. This meta-analysis investigates the effectiveness of adjuvant HAIC and the influence of variations in HAIC treatment in patients with resected CRLM. Methods PRISMA guidelines were followed for this study. The search was limited to comparative studies (HAIC vs non-HAIC) for overall survival. Subgroup meta-analyses using random-effects were performed for type of intra-arterial drug, method of catheter insertion, use of concomitant adjuvant systemic chemotherapy, and study design. Results Eighteen eligible studies were identified. After excluding overlapping cohorts, fifteen studies were included in the quantitative analysis, corresponding to 3,584 patients. HAIC was associated with an improved overall survival (pooled hazard ratio (HR) 0.77; 95%CI 0.64-0.93). Survival benefit of HAIC was most pronounced in studies using floxuridine (HR 0.76; 95%CI: 0.62-0.94), surgical catheter insertion with subcutaneous pump (HR 0.71; 95%CI: 0.61-0.84), and concomitant adjuvant systemic chemotherapy (HR 0.75; 95%CI: 0.59-0.96). The pooled HR of RCTs was 0.91 (95%CI 0.72-1.14), of which only 3 used floxuridine. Discussion Adjuvant HAIC is a promising treatment for patients with resectable CRLM, in particular HAIC with floxuridine using a surgically placed catheter and a subcutaneous pump, and concomitant systemic chemotherapy.

Histopathological growth patterns (HGPs) are a reliable, reproducible, and strong prognostic biomarker that can be assessed on haematoxylin and eosin-stained sections of resected colorectal liver metastases (CRLM). Assessment estimates the relative fraction of the tumour–liver interface for each of the three growth patterns; the desmoplastic HGP reflects good prognosis. Whether preoperative chemotherapy affects the HGP is currently unclear. The present international multicentre study evaluates this in an original cohort of 877 consecutive patients treated in the Netherlands, an external validation cohort of 1,203 consecutive patients treated in the USA, and a post hoc analysis from the phase III randomised controlled European Organization for Research and Treatment of Cancer (EORTC) 40983 trial (n = 70). All patients underwent resection of CRLM with or without preoperative systemic chemotherapy. Trial patients were randomised between perioperative chemotherapy and resection or resection alone. HGPs were determined according to consensus guidelines and compared for preoperative treatment status. Data from three separate tumour regression grading systems were available for the trial cohort. These were correlated with HGP stratified for treatment arm. In the original cohort, the average presence of desmoplastic HGP was 43% for chemo-naïve versus 67% for preoperatively treated patients (p < 0.001). A significant association between chemotherapy and desmoplastic HGP was found on multivariable analysis (β [95% confidence interval, CI]: 24.57 [18.28–30.87], p < 0.001). In the validation cohort, the average presence of desmoplastic HGP was 40% for chemo-naïve versus 63% for preoperatively treated patients (p < 0.001). This association remained on multivariable analysis (β [95% CI]: 24.18 [18.70–29.66], p < 0.001). In the EORTC 40983 trial, the average desmoplastic HGP presence was 33% in the resection arm versus 61% in the chemotherapy arm (p = 0.005). Chemotherapy was independently associated with an increase in desmoplastic HGP (β [95% CI]: 23.29 [1.78–44.79], p = 0.022). All three tumour regression gradings were significantly associated with the desmoplastic HGP in the chemotherapy arm (all p < 0.04). None were associated in the resection arm (all p > 0.11). Preoperative chemotherapy induces histopathological changes that alter the HGP of CRLM.

BACKGROUND: Floxuridine's high hepatic extraction ratio and short elimination half-life allows maximum liver exposure with minimal systemic side-effects. This study attempts to quantify the systemic exposure of floxuridine.METHODS: Patients undergoing continuous hepatic arterial infusion pump (HAIP) floxuridine after resection of colorectal liver metastases (CRLM) in two centres underwent six cycles of floxuridine at start dose 0.12 mg/kg/day. No concomitant systemic chemotherapy was administered. Peripheral venous blood samples were drawn during the first two cycles: pre-dose (only in the second cycle), 30 min, 1 h, 2 h, 7 h, and 15 days after floxuridine infusion. Foxuridine concentration in the residual pump reservoir was measured on day 15 of both cycles. A floxuridine assay with a lower boundary of detection of 0.250 ng/mL was developed.RESULTS: 265 blood samples were collected in the 25 patient included in this study. Floxuridine was mostly measurable at day 7 and day 15 (86 % and 88 % of patients respectively). The median dose corrected concentrations were 0.607 ng/mL [IQR: 0.472-0.747] for cycle 1 day 7, 0.579 ng/mL [IQR: 0.470-0.693] for cycle 1 day 15, 0.646 ng/mL [IQR: 0.463-0.8546] for cycle 2 day 7, and 0.534 ng/mL [IQR: 0.4257-0.7075] for cycle 2 day 15. One patient had remarkably high floxuridine concentrations reaching up to 44 ng/mL during the second cycle, without a clear explanation. The floxuridine concentration in the pump decreased by 14.7 % (range 0.5 %-37.8 %) over a period of 15 days (n = 18).CONCLUSION: Overall, negligible systemic concentrations of floxuridine were detected. However, remarkably increased levels were detected in one patient. Floxuridine concentration in the pump decreases over time.

Background: This study investigated the effect of the reduced dose of systemic chemotherapy (SYS) on recurrence patterns in patients receiving adjuvant hepatic artery infusion (HAI) chemotherapy after complete colorectal liver metastases (CRLM) resection. Methods: Patients undergoing complete CRLM resection between 2000 and 2007 were selected from a prospectively maintained database and categorized as receiving SYS or HAI + SYS. Those with pre and/or intraoperative extrahepatic disease, documented death, or recurrence within 30 days of CRLM resection were excluded. Competing risk, Fine and Gray's tests were used to compare SYS versus HAI + SYS for time‐to‐organ recurrence. Results: Of 361 study patients, 153 (42.4%) received SYS and 208 (57.6%) received HAI + SYS. The median follow‐up for survivors was 100 (range = 12–185) and 156 months (range = 18–217) for SYS and HAI + SYS, respectively. The 5‐year cumulative incidence (CI) of any liver recurrence was greater for those receiving SYS (SYS = 41.9% vs. HAI + SYS = 28.6%, p = .005). The 5‐year CI of developing any lung or extrahepatic recurrence for SYS patients was 36.2% and 47.9% compared with 44.5% (p = .242) and 51.7% (p = .551), respectively, in patients receiving HAI + SYS. Conclusion: Despite the reduced dose of SYS, adjuvant HAI + SYS after CRLM resection is not associated with a significantly increased risk of extrahepatic recurrence.

BACKGROUND: The objective was to investigate the impact of adjuvant hepatic arterial infusion pump (HAIP) chemotherapy on the rates and patterns of recurrence and survival in patients with resected colorectal liver metastases (CRLM).METHODS: Recurrence rates, patterns, and survival were compared between patients treated with and without adjuvant HAIP using competing risk analyses.RESULTS: 2128 patients were included, of which 601 patients (28.2%) received adjuvant HAIP and systemic chemotherapy (HAIP + SYS). The overall recurrence rate was similar with HAIP + SYS or SYS (63.5% versus 64.2%,p = 0.74). The 5-year cumulative incidence of initial intrahepatic recurrences was lower with HAIP + SYS (22.9% versus 38.4%,p < 0.001). The 5-year cumulative incidence of initial extrahepatic recurrences was higher with HAIP + SYS (48.5% versus 40.3%,p = 0.005), because patients remained at risk for extrahepatic recurrence in the absence of intrahepatic recurrence, which was largely attributable to more pulmonary recurrences with HAIP + SYS (33.6% versus 23.7%,p < 0.001). HAIP was an independent prognostic factor for DFS (adjusted HR 0.69, 95% CI 0.60-0.79, p < 0.001), and OS (adjusted HR 0.67, 95% CI 0.57-0.78,p < 0.001).CONCLUSION: Adjuvant HAIP chemotherapy is associated with lower intrahepatic recurrence rates and better DFS and OS after resection of CRLM.

Background The aim of this study was to investigate the effectiveness of adjuvant hepatic arterial infusion pump (HAIP) chemotherapy after complete resection or ablation of recurrent colorectal liver metastases (CRLM). Methods A retrospective cohort study was conducted of patients from two centers who were treated with resection and/or ablation of recurrent CRLM only between 1992 and 2018. Overall survival (OS) and hepatic disease-free survival (hDFS) were estimated using the Kaplan–Meier method. The Cox regression method was used to calculate hazard ratios (HRs) with corresponding 95% confidence intervals (CI). Results Of 374 eligible patients, 81 (22%) were treated with adjuvant HAIP chemotherapy. The median follow-up for survivors was 65 months (IQR 32–118 months). Patients receiving adjuvant HAIP were more likely to have multifocal disease and receive perioperative systemic chemotherapy at time of resection for recurrence. A median hDFS of 46 months (95% CI 29–81 months) was found in patients treated with adjuvant HAIP compared with 18 months (95% CI 15–26 months) in patients treated with resection and/or ablation alone (p = 0.001). The median OS and 5-year OS were 89 months (95% CI 52–126 months) and 66%, respectively, in patients treated with adjuvant HAIP compared with 57 months (95% CI 47–67 months) and 47%, respectively, in patients treated with resection and/or ablation only (p = 0.002). Adjuvant HAIP was associated with superior hDFS (adjusted HR 0.599, 95% CI 0.38–0.93, p = 0.02) and OS (adjusted HR 0.59, 95% CI 0.38–0.92, p = 0.02) in multivariable analysis. Conclusion Adjuvant HAIP chemotherapy after resection and/or ablation of recurrent CRLM is associated with superior hDFS and OS.

BACKGROUND: Histopathological growth patterns (HGPs) of colorectal liver metastases (CRLM) may be an expression of biological tumour behaviour impacting the risk of positive resection margins. The current study aimed to investigate whether non-desmoplastic growth pattern (non-dHGP) is associated with a higher risk of positive resection margins after resection of CRLM. METHODS: All patients treated surgically for CRLM between January 2000 and March 2015 at the Erasmus MC Cancer Institute and between January 2000 and December 2012 at the Memorial Sloan Kettering Cancer Center were considered for inclusion. Positive resection margin (R1) was defined as tumour cells at the resection margin. RESULTS: Of all patients (n=1302) included for analysis, 13% (n=170) had positive resection margins. Factors independently associated with positive resection margins were the non-dHGP (odds ratio (OR): 1.79, 95% confidence interval (CI): 1.11-2.87, p=0.016) and a greater number of CRLM (OR: 1.15, 95% CI: 1.08-1.23 p

BACKGROUND: After resection of colorectal liver metastases (CRLM), recurrent disease in the liver is a major cause of death, but may be reduced with the addition of adjuvant hepatic arterial infusion (HAI) chemotherapy to systemic chemotherapy (SYS). OBJECTIVE: This study investigates organ-specific causes of death in patients receiving adjuvant HAI and SYS compared with adjuvant SYS alone. METHODS: Between 2000 and 2007, patients undergoing complete CRLM resection were identified from a prospectively maintained liver resection database and categorized as receiving HAI+SYS or SYS only. Using newly constructed definitions, mortality was attributed to specific organs (liver, lung, peritoneum, and brain) or infection. Univariate models and cumulative incidence functions were generated using competing risks methods. RESULTS: Of 361 eligible patients, 208 (57.6%) received HAI+SYS and 153 (42.4%) received SYS. The median follow-up among survivors was 142 months (range= 12–217 months). Ten-year overall survival was 50.6% in the HAI+SYS group compared to 30.9% in those receiving SYS (p= 0.004). The 5-year cumulative incidence of liver-related mortality was 6.8% in the HAI+SYS group compared to 14.3% in SYS group (p= 0.007). CONCLUSION: The addition of HAI to systemic chemotherapy after CRLM resection is associated with a 50% reduction in liver-related mortality at 5 years.

BACKGROUND: This study investigated the impact of perioperative systemic chemotherapy on the recurrence rate and pattern following resection of colorectal liver metastases.METHODS: A retrospective cohort study was conducted in two centers. Rates and patterns of recurrence and overall survival (OS) were compared between patients treated with and without perioperative systemic chemotherapy. The clinical risk score (CRS) was used to stratify patients in low risk (CRS 0-2) and high risk (CRS 3-5) of recurrence.RESULTS: A total of 2020 patients were included, of whom 1442 (71%) received perioperative systemic chemotherapy. The median follow-up was 88 months, and 1289 patients (64%) developed a recurrence. The recurrence pattern was independent of chemotherapy in low-risk patients: intrahepatic recurrences (30% vs. 30%, p = 0.97) and extrahepatic recurrences (38% vs. 39%, p = 0.52). In high-risk patients, no difference in intrahepatic recurrences was found (48% vs. 50%, p = 0.59). However, a lower rate of extrahepatic recurrences (43% vs. 55%, p = 0.007) was observed with perioperative systemic chemotherapy, mainly due to a reduction in pulmonary recurrences (25% vs. 35%, p = 0.007). In competing risk analysis, the cumulative incidence of extrahepatic recurrence was significantly lower with perioperative systemic chemotherapy in high-risk patients only (5-year cumulative incidence 44% vs. 59%, p CONCLUSIONS: Perioperative systemic chemotherapy had no association with intrahepatic recurrence, but was associated with fewer pulmonary recurrences and superior OS in high-risk patients only.

Introduction: Recurrence risk after curative surgery for colorectal liver metastases (CRLM) remains high, underlining the need for novel prognostic markers. Liquid biopsies provide promising biomarkers to detect minimal residual disease (MRD) after local treatment. The aim of this study was to determine and compare the characteristics of cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) in liquid biopsies taken before and after surgical treatment of CRLM. Materials & Methods: Patients with isolated CRLM were recruited before undergoing potentially curative hepatic resection. Only patients who did not receive per-operative chemotherapy were selected. Peripheral blood samples were collected in CellSave preservative tubes at four different time points and processed into plasma within 96 hours after withdrawal. Subsequently, cfDNA was isolated from 4mL plasma, in which the total cfDNA concentration was measured. Mutations characterizing ctDNA were determined before surgery by next generation sequencing (NGS) using a colon-specific targeted panel (Oncomine Colon cfDNA assay, 14 genes). Samples were sequenced at >20.000 average reads depth and variants were called mutations when the variant allele frequency was above their predefined limit of detection. Longitudinal blood samples of ctDNA-positive patients were evaluated by digital PCR (dPCR) using mutation-specific assays, in which samples were considered ctDNA positive when >5 mutant copies were detected. Results: Blood samples of 231 patients were collected one day before surgery (T0), and were repeated one day (T1), one week (T2), and three weeks (T3) after surgery. The cfDNA yields per mL plasma were higher at T1 and T2 (median 93 ng and 64 ng, respectively) compared to T0 (6 ng, p Discussion/Conclusion: ctDNA is a potential biomarker to detect MRD after curative treatment for CRLM. Our results demonstrate that out of all patients with detectable ctDNA at baseline (before surgery), ctDNA is still present in 36% of patients three weeks after resection. Citation Format: Lissa Wullaert, Maurice P. Jansen, Jaco Kraan, Jan M. van Rees, Corine M. Beaufort, Yannick M. Meyer, Boris Galjart, Pieter M. Nierop, Florian E. Buisman, Diederik J. Höppener, Erik P. van der Stok, Gianmarco Motta, Dirk J. Grünhagen, Henk M. Verheul, Stefan Sleijfer, Saskia M. Wilting, Cornelis Verhoef, John W. Martens. Circulating tumor DNA in colorectal cancer patients with resectable liver metastases: Preliminary results of the MIRACLE study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5715.

Background The 10-year overall survival with adjuvant hepatic arterial infusion pump (HAIP) chemotherapy after resection of colorectal liver metastases (CRLMs) was 61% in clinical trials from Memorial Sloan Kettering Cancer Center. A pilot study was performed to evaluate the safety and feasibility of adjuvant HAIP chemotherapy in patients with resectable CRLMs. Study Design A phase II study was performed in two centers in The Netherlands. Patients with resectable CRLM without extrahepatic disease were eligible. All patients underwent complete resection and/or ablation of CRLMs and pump implantation. Safety was determined by the 90-day HAIP-related postoperative complications from the day of pump placement (Clavien–Dindo classification, grade III or higher) and feasibility by the successful administration of the first cycle of HAIP chemotherapy. Results A total of 20 patients, with a median age of 57 years (interquartile range [IQR] 51–64) were included. Grade III or higher HAIP-related postoperative complications were found in two patients (10%), both of whom had a reoperation (without laparotomy) to replace a pump with a slow flow rate or to reposition a flipped pump. No arterial bleeding, arterial dissection, arterial thrombosis, extrahepatic perfusion, pump pocket hematoma, or pump pocket infections were found within 90 days after surgery. After a median of 43 days (IQR 29–52) following surgery, all patients received the first dose of HAIP chemotherapy, which was completed uneventfully in all patients. Conclusion Pump implantation is safe, and administration of HAIP chemotherapy is feasible, in patients with resectable CRLMs, after training of a dedicated multidisciplinary team.

The WORC database consists in total of 930 patients composed of six datasets gathered at the Erasmus MC, consisting of patients with: 1) well-differentiated liposarcoma or lipoma (115 patients); 2) desmoid-type fibromatosis or extremity soft-tissue sarcomas (203 patients); 3) primary solid liver tumors, either malignant (hepatocellular carcinoma or intrahepatic cholangiocarcinoma) or benign (hepatocellular adenoma or focal nodular hyperplasia) (186 patients); 4) gastrointestinal stromal tumors (GISTs) and intra-abdominal gastrointestinal tumors radiologically resembling GISTs (246 patients); 5) colorectal liver metastases (77 patients); and 6) lung metastases of metastatic melanoma (103 patients). For each patient, either a magnetic resonance imaging (MRI) or computed tomography (CT) scan, collected from routine clinical care, one or multiple (semi-)automatic lesion segmentations, and ground truth labels from a gold standard (e.g., pathologically proven) are available. All datasets are multicenter imaging datasets, as patients referred to our institute often received imaging at their referring hospital. The dataset can be used to validate or develop radiomics methods, i.e., using machine or deep learning to relate the visual appearance to the ground truth labels, and automatic segmentation methods. See also the research article related to this dataset: Starmans et al.,Reproducible radiomics through automated machine learning validated on twelve clinical applications, Submitted.Specifications Table

Background After resection of colorectal cancer liver metastases (CRLM), 2 main histopathological growth patterns can be observed: a desmoplastic and a nondesmoplastic subtype. The desmoplastic subtype has been associated with superior survival. These findings require external validation. Methods An international multicenter retrospective cohort study was conducted in patients treated surgically for CRLM at 3 tertiary hospitals in the United States and the Netherlands. Determination of histopathological growth patterns was performed on hematoxylin and eosin–stained sections of resected CRLM according to international guidelines. Patients displaying a desmoplastic histopathological phenotype (only desmoplastic growth observed) were compared with patients with a nondesmoplastic phenotype (any nondesmoplastic growth observed). Cutoff analyses on the extent of nondesmoplastic growth were performed. Overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan-Meier and multivariable Cox analysis. All statistical tests were 2-sided. Results In total 780 patients were eligible. A desmoplastic phenotype was observed in 19.1% and was associated with microsatellite instability (14.6% vs 3.6%, P = .01). Desmoplastic patients had superior 5-year OS (73.4%, 95% confidence interval [CI] = 64.1% to 84.0% vs 44.2%, 95% CI = 38.9% to 50.2%, P .1). Conclusions This external validation study confirms the remarkably good prognosis after surgery for CRLM in patients with a desmoplastic phenotype. The extent of nondesmoplastic growth does not affect prognosis.

Histopathological growth patterns (HGPs) are independent prognosticators for colorectal liver metastases (CRLM). Currently, HGPs are determined postoperatively. In this study, we evaluated radiomics for preoperative prediction of HGPs on computed tomography (CT), and its robustness to segmentation and acquisition variations. Patients with pure HGPs [i.e. 100% desmoplastic (dHGP) or 100% replacement (rHGP)] and a CT-scan who were surgically treated at the Erasmus MC between 2003–2015 were included retrospectively. Each lesion was segmented by three clinicians and a convolutional neural network (CNN). A prediction model was created using 564 radiomics features and a combination of machine learning approaches by training on the clinician’s and testing on the unseen CNN segmentations. The intra-class correlation coefficient (ICC) was used to select features robust to segmentation variations; ComBat was used to harmonize for acquisition variations. Evaluation was performed through a 100 × random-split cross-validation. The study included 93 CRLM in 76 patients (48% dHGP; 52% rHGP). Despite substantial differences between the segmentations of the three clinicians and the CNN, the radiomics model had a mean area under the curve of 0.69. ICC-based feature selection or ComBat yielded no improvement. Concluding, the combination of a CNN for segmentation and radiomics for classification has potential for automatically distinguishing dHGPs from rHGP, and is robust to segmentation and acquisition variations. Pending further optimization, including extension to mixed HGPs, our model may serve as a preoperative addition to postoperative HGP assessment, enabling further exploitation of HGPs as a biomarker. Supplementary Information The online version contains supplementary material available at 10.1007/s10585-021-10119-6.

BACKGROUND: Recently numerous studies have reported primary tumor location as a potential prognostic factor after surgery for colorectal liver metastases (CRLM). The aim of this study was to comprehensively review and analyze all the available literature on the impact of primary tumor location in patients after local treatment of CRLM.METHODS: Studies examining the association of right- and left-sided colorectal cancer and overall survival (OS) and recurrence free survival (RFS) after local treatment (resection and/or ablation) of CRLM were identified. Random-effects models were used for both clinicopathological and outcome variables. Pooled hazard ratios (HR) with 95% confidence intervals (95% CI) were shown for both OS and RFS.RESULTS: Ten studies (including 11 patient cohorts) were eligible for inclusion, representing 3962 patients. Right-sided tumors (i.e. proximal to the splenic flexure) were observed in 1340 patients (33.8%). Median follow-up ranged from 25 to 137 months. Patients with right-sided tumors had a significantly decreased OS (HR 1.60, 95% CI 1.30-1.98, p < 0.001) and RFS (HR 1.35, 95% CI 1.04-1.77, p = 0.03), when compared to patients with left-sided tumors.CONCLUSION: This meta-analysis suggests that patients with right-sided primaries suffer from a worse prognosis, compared to patients with left-sided primaries in patients after local treatment of CRLM.

Adjuvant systemic chemotherapy (CTx) is widely administered in patients with colorectal liver metastases (CRLM). Histopathological growth patterns (HGPs) are an independent prognostic factor for survival after complete resection. This study evaluates whether HGPs can predict the effectiveness of adjuvant CTx in patients with resected CRLM. Two main types of HGPs can be distinguished; the desmoplastic type and the non-desmoplastic type. Uni- and multivariable analyses for overall survival (OS) and disease-free survival (DFS) were performed, in both patients treated with and without preoperative chemotherapy. A total of 1236 patients from two tertiary centers (Memorial Sloan Kettering Cancer Center, New York, USA; Erasmus MC Cancer Institute, Rotterdam, The Netherlands) were included (period 2000–2016). A total of 656 patients (53.1%) patients received preoperative chemotherapy. Adjuvant CTx was only associated with a superior OS in non-desmoplastic patients that had not been pretreated (adjusted hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.37–0.73, p

BACKGROUND: Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM.METHODS: This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 μg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4-12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and a reduction of costs, compared to resection alone.DISCUSSION: If this PUMP trial demonstrates that adjuvant HAIP chemotherapy improves survival in low-risk patients, this treatment approach may be implemented in the standard of care of patients with resected CRLM since adjuvant systemic chemotherapy alone has not improved survival.TRIAL REGISTRATION: The PUMP trial is registered in the Netherlands Trial Register (NTR), number: 7493 . Date of registration September 23, 2018.

INTRODUCTION: While preoperative chemotherapy (pCT) is utilized in many intra-abdominal cancers, the use of pCT among patients with intrahepatic cholangiocarcinoma (ICC) remains ill defined. As such, the objective of the current study was to examine the impact of pCT among patients undergoing curative-intent resection for ICC. METHODS: Patients who underwent hepatectomy for ICC were identified from a multi-institutional international cohort. The association between pCT with peri-operative and long-term clinical outcomes was assessed. RESULTS: Of the 1 057 patients who were identified and met the inclusion criteria, 62 patients (5.9%) received pCT. These patients were noticed to have more advanced disease. Median OS (pCT:46.9 months vs no pCT:37.4 months; P = 0.900) and DFS (pCT: 34.1 months vs no pCT: 29.1 months; P = 0.909) were similar between the two groups. In a subgroup analysis of propensity-score matched patients, there was longer OS (pCT:46.9 months vs no pCT:29.4 months) and DFS (pCT:34.1 months vs no pCT:14.0 months); however this did not reach statistical significance (both P > 0.05). CONCLUSION: In conclusion, pCT utilization among patients with ICC was higher among patients with more advanced disease. Short-term post-operative outcomes were not affected by pCT use and receipt of pCT resulted in equivalent OS and DFS following curative-intent resection. info:eu-repo/semantics/publishedVersion

Background Breast cancer is a common malignancy, but metastases to the breast of extramammary malignancies are very rare. Treatment and prognosis are different. The aim of the study is to report the incidence of lymphomas and metastases to the breast of extramammary malignancies in our 30-year archive. Methods The pathology database of a single institute was reviewed for all breast neoplasms which were coded in our system as a metastasis in the period 1985–2014. Metastatic tumors from primary breast carcinoma were excluded. Results A total of 47 patients were included (7 men/40 women, mean age 63 years). The majority originated from lymphoma (n = 18) and primary melanoma (n = 11). Other primary tumor sites included the ovary (n = 6), lung (n = 6), colon (n = 3), kidney (n = 1), stomach (n = 1), and chorion (n = 1). In 24/47 patients (51 %), metastasis was the first sign of the specific malignant disease. In seven patients (15 %) surgery was performed, the diagnosis of metastatic disease was adjusted in four patients (9 %) postoperatively. Conclusions It is important to distinguish lymphomas and metastases to the breast from common primary breast carcinoma for proper treatment and prognosis. Therefore, we emphasize the need for a histological or cytopathological diagnosis before any treatment is commenced. The pathologist plays a key role in considering the diagnosis of metastasis if the histological features are unusual for a primary breast carcinoma. The pathologist should therefore be properly informed by the clinical physician although lymphomas and metastases to the breast are the first presentation of malignant disease in half the cases.

Introduction The Neer classification is the most commonly used fracture classification system for proximal humeral fractures. Inter- and intra-observer agreement is limited, especially for comminuted fractures. A possibly more straightforward and reliable classification system is the Hertel classification. The aim of this study was to compare the inter- and intra-observer variability of the Hertel with the Neer classification in comminuted proximal humeral fractures. Materials and methods Four observers evaluated blinded radiographic images (X-rays, CT-scans, and CT-scans with 3D-reconstructions) of 60 patients. After at least two months classification was repeated. Results Inter-observer agreement on plain X-rays was fair for both Hertel (κ = 0.39; 95% CI 0.23–0.62) and Neer (κ = 0.29; 0.09–0.42). Inter-observer agreement on CT-scans was substantial (κ = 0.63; 0.56–0.72) for Hertel and moderate for Neer (κ = 0.51; 0.29–0.68). Inter-observer agreement on 3D-reconstructions was moderate for both Hertel (κ = 0.60; 0.53–0.72) and Neer (κ = 0.51; 0.39–0.58). Intra-observer agreement on plain X-rays was fair for both Hertel (κ = 0.38; 0.27–0.59) and Neer (κ = 0.40; 0.15–0.52). Intra-observer agreement on CT-scans was moderate for both Hertel (κ = 0.50; 0.38–0.66) and Neer (κ = 0.42; 0.35–0.52). Intra-observer agreement on 3D-reconstructions was moderate for Hertel (κ = 0.55; 0.45–0.64) and substantial for Neer (κ = 0.63; 0.48–0.79). Conclusions The Hertel and Neer classifications showed a fair to substantial inter- and intra-observer agreement on the three diagnostic modalities used. Although inter-observer agreement was highest for Hertel classification on CT-scans, Neer classification had the highest intra-observer agreement on 3D-reconstructions. Data of this study do not confirm superiority of either classification system for the classification of comminuted proximal humeral fractures.

A 39-year-old woman presented with extensive soft tissue injury involving her upper legs and her left hand caused by the explosion of her cell phone. She suffered second and third-degree burns. She underwent surgery. She underwent surgical removal of metal slivers, wound debridement and repair of the soft tissue injury.