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OBJECTIVE: To examine the impact of an active surveillance (AS) approach on health-related quality of life (HRQoL) of patients with desmoid-type fibromatosis (DTF). SUMMARY BACKGROUND DATA: AS is recommended as initial approach in DTF patients. AS might however negatively affect HRQoL due to physical symptoms or stress and anxiety. METHODS: In a prospective observational study, the GRAFITI trial (NTR4714), DTF patients were followed during an initial AS approach for three years. HRQoL was assessed by the EORTC QLQ-C30 at baseline, 6, 12 and 24-month follow-up. Patients who completed questionnaires at≥1 time point were included in this analysis of the secondary endpoint. A multivariable linear mixed-effects model with random intercept was conducted to assess trends of HRQoL scores over time and to explore the effect of treatment strategy on HRQoL. RESULTS: All 105 patients enrolled in the GRAFITI trial were eligible for the HRQoL analyses. During 24-month follow-up, 75 patients (71%) continued AS and 30 patients (29%) started an active treatment (AT). DTF patients who continued AS demonstrated relatively stable HRQoL scores during follow-up. HRQoL scores of patients who started AT worsened compared to patients who continued AS, although no significant changes in HRQoL score over time were found in the mixed-model analyses. Overall, DTF patients who started AT scored significantly worse on pain (β=10.08, P=0.039) compared to patients who continued AS. CONCLUSIONS: An initial AS approach did not impair HRQoL of DTF patients who continued AS over time, therefore providing further support for AS as the frontline approach in DTF patients. Longitudinal assessment of HRQoL should be part of clinical follow-up to identify patients who may need a change in treatment strategy.

Background Consensus on resectability criteria for colorectal cancer liver metastases (CRLM) is lacking, resulting in differences in therapeutic strategies. This study evaluated variability of resectability assessments and local treatment plans for patients with initially unresectable CRLM by the liver expert panel from the randomised phase III CAIRO5 study. Methods The liver panel, comprising surgeons and radiologists, evaluated resectability by predefined criteria at baseline and 2-monthly thereafter. If surgeons judged CRLM as resectable, detailed local treatment plans were provided. The panel chair determined the conclusion of resectability status and local treatment advice, and forwarded it to local surgeons. Results A total of 1149 panel evaluations of 496 patients were included. Intersurgeon disagreement was observed in 50% of evaluations and was lower at baseline than follow-up (36% vs. 60%, p < 0.001). Among surgeons in general, votes for resectable CRLM at baseline and follow-up ranged between 0–12% and 27–62%, and for permanently unresectable CRLM between 3–40% and 6–47%, respectively. Surgeons proposed different local treatment plans in 77% of patients. The most pronounced intersurgeon differences concerned the advice to proceed with hemihepatectomy versus parenchymal-preserving approaches. Eighty-four percent of patients judged by the panel as having resectable CRLM indeed received local treatment. Local surgeons followed the technical plan proposed by the panel in 40% of patients. Conclusion Considerable variability exists among expert liver surgeons in assessing resectability and local treatment planning of initially unresectable CRLM. This stresses the value of panel-based decisions, and the need for consensus guidelines on resectability criteria and technical approach to prevent unwarranted variability in clinical practice.

Introduction: In 2017, the Southampton guideline stated that minimally invasive liver resections (MILR) should considered standard practice for minor liver resections. This study aimed to assess recent implementation rates of minor MILR, factors associated with performing MILR, hospital variation, and outcomes in patients with colorectal liver metastases (CRLM). Methods: This population-based study included all patients who underwent minor liver resection for CRLM in the Netherlands between 2014 and 2021. Factors associated with MILR and nationwide hospital variation were assessed using multilevel multivariable logistic regression. Propensity-score matching (PSM) was applied to compare outcomes between minor MILR and minor open liver resections. Overall survival (OS) was assessed with Kaplan–Meier analysis on patients operated until 2018. Results: Of 4,488 patients included, 1,695 (37.8%) underwent MILR. PSM resulted in 1,338 patients in each group. Implementation of MILR increased to 51.2% in 2021. Factors associated with not performing MILR included treatment with preoperative chemotherapy (aOR 0.61 CI:0.50–0.75, p < 0.001), treatment in a tertiary referral hospital (aOR 0.57 CI:0.50–0.67, p < 0.001), and larger diameter and number of CRLM. Significant hospital variation was observed in use of MILR (7.5% to 93.0%). After case-mix correction, six hospitals performed fewer, and six hospitals performed more MILRs than expected. In the PSM cohort, MILR was associated with a decrease in blood loss (aOR 0.99 CI:0.99–0.99, p < 0.01), cardiac complications (aOR 0.29, CI:0.10–0.70, p = 0.009), IC admissions (aOR 0.66, CI:0.50–0.89, p = 0.005), and shorter hospital stay (aOR CI:0.94–0.99, p < 0.01). Five-year OS rates for MILR and OLR were 53.7% versus 48.6%, p = 0.21. Conclusion: Although uptake of MILR is increasing in the Netherlands, significant hospital variation remains. MILR benefits short-term outcomes, while overall survival is comparable to open liver surgery. Graphical abstract: [Figure not available: see fulltext.].

Introduction Aging of the worldwide population has been observed, and postoperative outcomes could be worse in elderly patients. This nationwide study assessed trends in number of surgical resections in octogenarians regarding various major surgical procedures and associated postoperative outcomes. Methods All patients who underwent surgery between 2014 and 2018 were included from Dutch nationwide quality registries regarding esophageal, stomach, pancreas, colorectal liver metastases, colorectal cancer, lung cancer and abdominal aortic aneurysms (AAA). For each quality registry, the number of patients who were 80 years or older (octogenarians) was calculated per year. Postoperative outcomes were length of stay (LOS), 30 day major morbidity and 30 day mortality between octogenarians and younger patients. Results No increase in absolute number and proportion of octogenarians that underwent surgery was observed. Median LOS was higher in octogenarians who underwent surgery for colorectal cancer, colorectal liver metastases, lung cancer, pancreatic disease and esophageal cancer. 30 day major morbidity was higher in octogenarians who underwent surgery for colon cancer, esophageal cancer and elective AAA-repair. 30 day mortality was higher in octogenarians who underwent surgery for colorectal cancer, lung cancer, stomach cancer, pancreatic disease, esophageal cancer and elective AAA-repair. Median LOS decreased between 2014 and 2018 in octogenarians who underwent surgery for stomach cancer and colorectal cancer. 30 day major morbidity decreased between 2014 and 2018 in octogenarians who underwent surgery for colon cancer. No trends were observed in octogenarians regarding 30 day mortality between 2014 and 2018. Conclusion No increase over time in absolute number and proportion of octogenarians that underwent major surgery was observed in the Netherlands. Postoperative outcomes were worse in octogenarians.

Item does not contain fulltext 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.

Background and Objectives: A dynamic prediction model for patients with soft tissue sarcoma of the extremities was previously developed to predict updated overall survival probabilities throughout patient follow‐up. This study updates and externally validates the dynamic model. Methods: Data from 3826 patients with high‐grade extremity soft tissue sarcoma, treated surgically with curative intent were used to update the dynamic PERsonalised SARcoma Care (PERSARC) model. Patients were added to the model development cohort and grade was included in the model. External validation was performed with data from 1111 patients treated at a single tertiary center. Results: Calibration plots show good model calibration. Dynamic C‐indices suggest that the model can discriminate between high‐ and low‐risk patients. The dynamic C‐indices at 0, 1, 2, 3, 4, and 5 years after surgery were equal to 0.697, 0.790, 0.822, 0.818, 0.812, and 0.827, respectively. Conclusion: Results from the external validation show that the dynamic PERSARC model is reliable in predicting the probability of surviving an additional 5 years from a specific prediction time point during follow‐up. The model combines patient‐, treatment‐specific and time‐dependent variables such as local recurrence and distant metastasis to provide accurate survival predictions throughout follow‐up and is available through the PERSARC app.

Additional file 1. Handbook histopathological features CRC – HGP.

Additional file 2. Supplementary File 2. Uni- and multivariable Cox regression analysis for overall survival.

Patients with constitutional mismatch repair deficiency syndrome(CMMRD) usually develop multiple tumors at a young age. Chemotherapywas previously shown to be less effective in these tumors. Recent reportssuggest immunotherapeutic treatment in CMMRD-associated tumors. Here,we present a CMMRD patient, successfully treated with immunotherapyfor metastasized colorectal cancer (CRC). A young adolescent male wasdiagnosed with T2N2M1 cecum carcinoma with liver metastases. Hereceived four initial doses of nivolumab (3 mg/kg) with ipilimumab (1 ml/kg) every three weeks, followed by 41 doses of nivolumab alone every twoweeks. A complete response was achieved; also pathological assessmentof removed liver metastases was indicative of a complete response. Atthe time of writing, 14 months after end of treatment, the CRC had notrecurred. Immunotherapeutic treatment resulted in a complete response ofthe primary CRC and metastases. Immunotherapy as first line treatmentshould be strongly considered in treatment of CMMRD-associated CRCs

Purpose: This multicenter cohort study aimed to identify clinicopathologic and treatment-related factors associated with the development of distant metastasis (DM) and with overall survival (OS) after DM diagnosis in patients with malignant peripheral nerve sheath tumors (MPNST). Methods: All patients diagnosed with primary MPNST from 1988 to 2019 who were surgically treated for the primary tumor were included. Multivariable Cox regression analyses were performed to identify factors associated with DM and OS after DM diagnosis. Results: A total of 383 patients were included in this analysis, of which 150 developed metastatic disease. No differences in clinicopathologic characteristics and clinical outcome were found between patients with synchronous and metachronous DM. Neurofibromatosis type 1 (NF1), high grade, tumor size, triton and R2 resections were independent risk factors for the development of DM. NF1 and more than two metastasis sites were independently associated with worse OS after DM diagnosis. Metastasectomy, chemotherapy and the metastatic site category ‘other’ were associated with prolonged survival after DM diagnosis. Conclusions: This analysis provides important insights into clinicopathologic and treatment factors associated with outcomes in metastatic MPNST. Moreover, NF1-status is associated with a higher risk of DM, it is also independently associated with worse survival in metastatic MPNST.

Background The histopathological growth patterns (HGPs) are a prognostic and predictive biomarker in colorectal cancer liver metastasis (CRLM). This study evaluates the relationship between the HGP and primary colorectal cancer (CRC) histopathology. Methods A total of 183 treatment-naive patients with resected CRC and CRLM were included. Thirteen CRC histopathology markers were determined and compared between the desmoplastic and non-desmoplastic HGP; tumour sidedness, pT&pN stage, tumour grade, tumour deposits, perineural- (lympho-)vascular- and extramural venous invasion, peritumoural budding, stroma type, CRC growth pattern, Crohn’s-like lymphoid reaction, and tumour-infiltrating lymphocyte (TIL) density. Logistic regression analysis was performed using both CRC and CRLM characteristics. Results Unfavourable CRC histopathology was more frequent in non-desmoplastic CRLM for all markers evaluated, and significantly so for a lower TIL density, absent Crohn’s-like lymphoid reaction, and a “non-mature” stroma (all p p Conclusions The results of this study associates primary CRC histopathology with the HGP of corresponding liver metastases.

Background: The Dutch Hepato Biliary Audit (DHBA) was initiated in 2013 to assess the national quality of liver surgery. This study aimed to describe the initiation and implementation of this audit along with an overview of the results and future perspectives.Methods: Registry of patients undergoing liver surgery for all primary and secondary liver tumors in the DHBA is mandatory. Weekly, benchmarked information on process and outcome measures is reported to surgical teams. In this study, the first results of patients with colorectal liver metastases were presented, including results of data verification.Results: Between 2014 and 2017, 6241 procedures were registered, including 4261 (68%) resections for colorectal liver metastases. For minor- and major liver resections for colorectal liver metastases, the median [interquartile range] hospital stay was 6 [4-8] and 8 [6-12] days, respectively. A postoperative complicated course (complication leading to >14 days of hospital stay, reintervention or death) occurred in 26% and 43% and the 30-day/in-hospital mortality was 1% and 4%, respectively. The completeness of data was 97%. In 3.6% of patients, a complicated postoperative course was erroneously omitted.Conclusion: Nationwide implementation of the DHBA has been successful. This was the first step in creating a complete evaluation of the quality of liver surgery.

Additional file 1: Figure S1. The compatibility of different blood collection tubes with MeD-seq analysis. Percentages of A. LpnPI filtered reads and B. duplicate reads are shown for EDTA and CellSave tubes obtained during the same blood draw from 3 patients. For each sample, 10 ng cfDNA and maximal cfDNA input in 8 µl (> 10 ng) was analysed, in which the maximal amount was kept equal between EDTA and CellSave per patient.

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Additional file 4: Figure S4. MeD-seq results for published biomarkers on cfDNA from HBDs and paired tissue, pre-operative and post-operative cfDNA from CRLM patients. Sequenced MeD-seq reads shown for BCAT1, IKZF1, SEPT9, B4GALT1, MAP3K14-AS1, and SHOX2 from pre-operative cfDNA (red) and post-operative cfDNA (orange) of CRLM-patients and cfDNA samples of HBDs (black). Results are visualized in Integrative Genomics Viewer (IGV) v.2.9.4.

Additional file 3: Figure S3. Leukocyte-specific markers in HBDs. A heat map of a subset of leukocyte-specific methylation markers described by Accomando et al. (17) shows consistent methylation patterns across the included healthy blood donors. Only regions showing at least 1 read in 9 HBD samples are included.

Additional file 5: Figure S5. Correlation between MeD-seq and qMSP for previously identified markers for CRLM. Scatterplots showing the Pearson correlations between MeD-seq and qMSP results for A. EYA4, B. GRIA4, C. MSC, and D. ITGA4.

Additional file 2: Figure S2. Observed correlations between biological replicates compared to HBDs. Boxplots show significant higher Pearson’s r between biological replicates per patient (n = 4), in white, compared to the Pearson’s r between these samples and unrelated HBD samples (n = 9), in grey (Mann–Whitney U, p = 0.015 for M4, p = 0.004 for M10, and p

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This thesis aims to validate and establish the histopathological growth patterns of colorectal cancer liver metastasis as a relevant biomarker, and to evaluate immunity and genetics as potential underlying biological mechanisms.

With the introduction of new therapeutic options for patients with melanoma, a new era has begun.This thesis addresses the current developments and challenges in optimizing the treatment of patients with cutaneous melanoma.

The objective of this thesis was to develop clinical trials on hepatic arterial infusion pump (HAIP) chemotherapy in patients with resectable colorectal liver metastases (CRLM), and to study factors that are associated with prognosis and prediction in CRLM patients. The results of this thesis will be evaluated in three parts. Part I focused on the outcomes of perioperative HAIP and systemic chemotherapy in patients with resectable CRLM. In Part II results off a phase II safety and feasibility study on HAIP chemotherapy in the Netherlands were discussed. Additionally, a trial protocol of a multicenter phase III randomized controlled trial (RCT) was presented. This trial is currently running in the Netherlands and was designed to investigate the efficacy of HAIP chemotherapy after resection compared to resection only in patients with CRLM confined to the liver and a low clinical risk score (CRS). Part III focused on the prognostic and predictive value of clinical and pathological factors after resection of CRLM. In addition, models that predict individual patient outcome were evaluated.

Within the two parts of this thesis, detection, treatment and prognostication of colorectal cancer recurrences were studied. The overarching targets of this thesis were to individualize follow-up and treatment strategies (Part I), and to evaluate histopathological growth patterns as a novel risk factor for colorectal liver metastases (Part II).

The current thesis describes several efforts to evaluate HGPs in terms of clinical applicability in patients undergoing surgical treatment of CRLM