Background: Muscle attenuation (MA) and visceral adipose tissue (VAT) have not yet been included in the currently used alternative Fistula Risk Score (a-FRS). The aim of this study was to examine... Show moreBackground: Muscle attenuation (MA) and visceral adipose tissue (VAT) have not yet been included in the currently used alternative Fistula Risk Score (a-FRS). The aim of this study was to examine the added value of these parameters as predictors of clinically relevant postoperative pancreatic fistula (CR-POPF) in the a-FRS after pancreatoduodenectomy compared to Body Mass Index (BMI). Methods: A single center retrospective cohort study was performed in patients who underwent pancreatoduodenectomy between 2009 and 2018. The a-FRS model was reproduced, MA and VAT were both combined and separately added to the model instead of BMI using logistic regression analysis. Model discrimination was assessed by ROC-curves. Results: In total, 329 patients were included of which 55 (16.7%) developed CR-POPF. The a-FRS model showed an AUC of 0.74 (95%CI: 0.68-0.80). In this model, BMI was not significantly associated with CR-POPF (p = 0.16). The MA + VAT model showed an AUC of 0.81 (95%CI: 0.75-0.86). VAT was significantly associated with CR-POPF (per cm2, OR: 1.01; 95%CI: 1.00-1.01; p < 0.001). The AUC of the MA + VAT model differed significantly from the AUC of the a-FRS model (p = 0.001). Conclusion: Visceral adipose tissue is of added value in the a-FRS compared to BMI in predicting CRPOPF in patients undergoing pancreatoduodenectomy. Show less
Aziz, M.H.; Dongen, J.C. van; Saida, L.; Suker, M.; Vugt, J.L.A. van; Putten, Y. van; ... ; Eijck, C.J. van 2022
Background and Aims: Failing immune surveillance in pancreatic ductal adenocarcinoma (PDAC) is related to poor prognosis. PDAC is also characterized by its substantial alterations to patients' body... Show moreBackground and Aims: Failing immune surveillance in pancreatic ductal adenocarcinoma (PDAC) is related to poor prognosis. PDAC is also characterized by its substantial alterations to patients' body composition. Therefore, we investigated associations between the host systemic immune inflammation response and body composition in patients with resected PDAC. Methods: Patients who underwent a pancreatectomy for PDAC between 2004 and 2016 in two tertiary referral centers were included. Skeletal muscle mass quantity and muscle attenuation, as well as subcutaneous and visceral adipose tissue at the time of diagnosis, were determined by CT imaging measured transversely at the third lumbar vertebra level. Baseline clinicopathological characteristics, laboratory values including the systemic immune inflammation index (SIII), postoperative, and survival outcomes were collected. Results: A total of 415 patients were included, and low skeletal muscle mass quantity was found in 273 (65.7%) patients. Of the body composition indices, only low skeletal muscle mass quantity was independently associated with a high (>= 900) SIII (OR 7.37, 95% CI 2.31-23.5, p=0.001). The SIII was independently associated with disease-free survival (HR 1.86, 95% CI 1.12-3.04), and cancer-specific survival (HR 2.21, 95% CI 1.33-3.67). None of the body composition indices were associated with survival outcomes. Conclusion: This study showed a strong association between preoperative low skeletal muscle mass quantity and elevated host systemic immune inflammation in patients with resected PDAC. Understanding how systemic inflammation may contribute to changes in body composition or whether reversing these changes may affect the host systemic immune inflammation response could expose new therapeutic possibilities for improving patients' survival outcomes. Show less
Bot, D.; Droop, A.; Lucassen, C.J.; Veen, M.E. van; Vugt, J.L. van; Feshtali, S.S.; ... ; Hoek, B. van 2021
Background and aims: Malnutrition is highly prevalent in patients with end-stage liver disease (ESLD) and associated with impaired clinical outcome. Previous studies focused on one component of... Show moreBackground and aims: Malnutrition is highly prevalent in patients with end-stage liver disease (ESLD) and associated with impaired clinical outcome. Previous studies focused on one component of body composition and not in combination with nutritional intake, while both are components of the nutritional status. We aimed to evaluate the most important risk factors regarding body composition (muscle mass, muscle quality and fat mass) and nutritional intake (energy and protein intake) for waiting list mortality in patients with ESLD awaiting liver transplantation (LTx).Methods: Consecutive patients with ESLD listed for LTx between 2007 and 2014 were investigated. Muscle mass quantity (Skeletal Muscle Mass Index, SMI), and muscle quality (Muscle Attenuation, MA), and various body fat compartments were measured on computed tomography using SliceOmatic. Nutritional intake (e.g. energy and protein intake) was assessed. Multivariable stepwise forward Cox regression analysis was used for statistical analysis.Results: 261 Patients (mean age 54 years, 74.7% male) were included. Low SMI and MA were found to be statistically significant predictors of an increased risk for waiting list mortality in patients with ESLD, with a HR of 2.580 (95%CI 1.055-6.308) and HR of 9.124 (95%CI 2.871-28.970), respectively. No association between percentage adipose tissue, and protein and energy intake with waiting list mortality was found in this study.Conclusion: Both low muscle quantity and quality, and not nutritional intake, were independent risk factors for mortality in patients with ESLD. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. Show less
Christodoulou, E.; Rashid, M.; Pacini, C.; Droop, A.; Robertson, H.; Groningen, T. van; ... ; Doorn, R. van 2020
Targeting the MAPK signaling pathway has transformed the treatment of metastatic melanoma. CRISPR-Cas9 genetic screens provide a genome-wide approach to uncover novel genetic dependencies that... Show moreTargeting the MAPK signaling pathway has transformed the treatment of metastatic melanoma. CRISPR-Cas9 genetic screens provide a genome-wide approach to uncover novel genetic dependencies that might serve as therapeutic targets. Here, we analyzed recently reported CRISPR-Cas9 screens comparing data from 28 melanoma cell lines and 313 cell lines of other tumor types in order to identify fitness genes related to melanoma. We found an average of 1,494 fitness genes in each melanoma cell line. We identified 33 genes, inactivation of which specifically reduced the fitness of melanoma. This set of tumor type-specific genes includes established melanoma fitness genes as well as many genes that have not previously been associated with melanoma growth. Several genes encode proteins that can be targeted using available inhibitors. We verified that genetic inactivation of DUSP4 and PPP2R2A reduces the proliferation of melanoma cells. DUSP4 encodes an inhibitor of ERK, suggesting that further activation of MAPK signaling activity through its loss is selectively deleterious to melanoma cells. Collectively, these data present a resource of genetic dependencies in melanoma that may be explored as potential therapeutic targets. Show less
