Inne H M Borel Rinkes

University Medical Center Utrecht, Utrecht, Utrecht, Netherlands

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Publications (278)896.03 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Previous studies have shown that 5-14% of patients undergoing pancreatoduodenectomy for suspected malignancy ultimately are diagnosed with benign disease. A "pancreatic mass" on computed tomography (CT) is considered to be the strongest predictor of malignancy, but studies describing its diagnostic value are lacking. The aim of this study was to determine the diagnostic value of a pancreatic mass on CT in patients with presumed pancreatic cancer, as well as the interobserver agreement among radiologists and the additional value of reassessment by expert-radiologists. Reassessment of preoperative CT scans was performed within a previously described multicenter retrospective cohort study in 344 patients undergoing pancreatoduodenectomy for suspected malignancy (2003-2010). Preoperative CT scans were reassessed by 2 experienced abdominal radiologists separately and subsequently in a consensus meeting, after defining a pancreatic mass as "a measurable space occupying soft tissue density, except for an enlarged papilla or focal steatosis". CT scans of 86 patients with benign and 258 patients with (pre)malignant disease were reassessed. In 66% of patients a pancreatic mass was reported in the original CT report, versus 48% and 50% on reassessment by the 2 expert radiologists separately and 44% in consensus (P < .001 vs original report). Interobserver agreement between the original CT report and expert consensus was fair (kappa = 0.32, 95% confidence interval 0.23-0.42). Among both expert-radiologists agreement was moderate (kappa = 0.47, 95% confidence interval 0.38-0.56), with disagreement on the presence of a pancreatic mass in 29% of cases. The specificity for malignancy of pancreatic masses identified in expert consensus was twice as high compared with the original CT report (87% vs 42%, respectively). Positive predictive value increased to 98% after expert consensus, but negative predictive value was low (12%). Clinicians need to be aware of potential considerable disagreement among radiologists about the presence of a pancreatic mass. The specificity for malignancy doubled by expert radiologist reassessment when a uniform definition of "pancreatic mass" was used. Copyright © 2015 Elsevier Inc. All rights reserved.
    Surgery 04/2015; DOI:10.1016/j.surg.2015.03.008 · 3.11 Impact Factor
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    ABSTRACT: Chemotherapy treatment of metastatic colon cancer ultimately fails due to development of drug resistance. Identification of chemotherapy-induced changes in tumor biology may provide insight into drug resistance mechanisms. We studied gene expression differences between groups of liver metastases that were exposed to pre-operative chemotherapy or not. Multiple patient-derived colonosphere cultures were used to assess how chemotherapy alters energy metabolism by measuring mitochondrial biomass, oxygen consumption and lactate production. Genetically manipulated colonosphere-initiated tumors were used to assess how altered energy metabolism affects chemotherapy efficacy. Gene ontology and pathway enrichment analysis revealed significant upregulation of genes involved in oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis in metastases that were exposed to chemotherapy. This suggested chemotherapy induces a shift in tumor metabolism from glycolysis towards OXPHOS. Indeed, chemo-treatment of patient-derived colonosphere cultures resulted in an increase of mitochondrial biomass, increased expression of respiratory chain enzymes and higher rates of oxygen consumption. This was mediated by the histone deacetylase sirtuin-1 (SIRT1) and its substrate, the transcriptional co-activator PGC1α. Knockdown of SIRT1 or PGC1α prevented chemotherapy-induced OXPHOS and significantly sensitized patient-derived colonospheres, as well as tumor xenografts to chemotherapy. Chemotherapy of colorectal tumors induces a SIRT1/PGC1α-dependent increase in OXPHOS that promotes tumor survival during treatment. This phenomenon is also observed in chemotherapy-exposed resected liver metastases, strongly suggesting that chemotherapy induces long-lasting changes in tumor metabolism that potentially interfere with drug efficacy. In conclusion, we propose a novel mechanism of chemotherapy resistance that may be clinically relevant and therapeutically exploitable. Copyright © 2015, American Association for Cancer Research.
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    ABSTRACT: Novel spheroid-type tumor cell cultures directly isolated from patients’ tumors preserve tumor characteristics better than traditionally grown cell lines. However, such cultures are not generally used for high-throughput toxicity drug screens. In addition, the assays that are commonly used to assess drug-induced toxicity in such screens usually measure a proxy for cell viability such as mitochondrial activity or ATP-content per culture well, rather than actual cell death. This generates considerable assay-dependent differences in the measured toxicity values. To address this problem we developed a robust method that documents drug-induced toxicity on a per-cell, rather than on a per-well basis. The method involves automated drug dispensing followed by paired image- and FACS-based analysis of cell death and cell cycle changes. We show that the two methods generate toxicity data in 96-well format which are highly concordant. By contrast, the concordance of these methods with frequently used well-based assays was generally poor. The reported method can be implemented on standard automated microscopes and provides a low-cost approach for accurate and reproducible high-throughput toxicity screens in spheroid type cell cultures. Furthermore, the high versatility of both the imaging and FACS platforms allows straightforward adaptation of the high-throughput experimental setup to include fluorescence-based measurement of additional cell biological parameters.
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    ABSTRACT: Only a minority of thyroid nodules is malignant; nevertheless, many invasive diagnostic procedures are performed to distinguish between benign and malignant nodules. Qualitative ultrasound elastography is a non-invasive technique to evaluate thyroid nodules.
    European Journal of Radiology 01/2015; 84(4). DOI:10.1016/j.ejrad.2015.01.003 · 2.16 Impact Factor
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    ABSTRACT: Background Perioperative epirubicin, cisplatin, and capecitabine (ECC) chemotherapy was evaluated in patients who underwent esophageal resection for adenocarcinoma of the esophagus or gastroesophageal junction (GEJ). Methods A cohort of 93 consecutive patients was analyzed. The median follow-up period was 60 months. Source data verification of adverse events was performed by two independent observers. Results All three planned preoperative chemotherapy cycles were administered to 65 patients (69.9 %). Only 27 % of the patients completed both pre- and postoperative chemotherapy. The reasons for not receiving postoperative adjuvant chemotherapy could be separated in two main problems: toxicity of the preoperative chemotherapy and postoperative problems involving difficulty in recovery and postoperative complications. Finally, 25 patients (27 %), completed three preoperative and three postoperative cycles. Grades 3 and 4 nonhematologic adverse events of preoperative chemotherapy mainly consisted of thromboembolic events (16.2 %) and cardiac complications (7.5 %). A history of cardiac and vascular disease was independently associated with discontinuation of preoperative chemotherapy and the occurrence of grade 3 or higher adverse events. Surgery was performed for 94 % of all the patients who started with ECC chemotherapy. A radical resection (R0) was achieved in 93 % of the patients. A complete pathologic response was observed in 8 % of the patients. During a median follow-up period of 60 months, the median disease-free survival time was 28 months, and the median overall survival time was 36 months. The 3-year overall survival rate was 50 %, and the 5-year overall survival rate was 42 %. Conclusion For patients with adenocarcinoma of the esophagus or GEJ, six cycles of ECC-based perioperative chemotherapy is associated with a relatively high number of adverse events. Although this toxicity did not affect the esophageal resectability rate, this regimen should be used with caution in this patient population.
    Annals of Surgical Oncology 01/2015; 22(5). DOI:10.1245/s10434-014-4120-9 · 3.94 Impact Factor
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    ABSTRACT: Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model of murine pancreatic system to discover characteristics of this deadly malignancy.
    Cell 12/2014; DOI:10.1016/j.cell.2014.12.021 · 33.12 Impact Factor
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    ABSTRACT: Computed tomography (CT) is the most widely used method to assess resectability of pancreatic and peri-ampullary cancer. One of the contra-indications for curative resection is the presence of extra-regional lymph node metastases. This meta-analysis investigates the accuracy of CT in assessing extra-regional lymph node metastases in pancreatic and peri-ampullary cancer. We systematically reviewed the literature according to the PRISMA guidelines. Studies reporting on CT assessment of extra-regional lymph nodes in patients undergoing pancreatoduodenectomy were included. Data on baseline characteristics, CT-investigations and histopathological outcomes were extracted. Diagnostic accuracy, positive predictive value (PPV), negative predictive value (NPV), sensitivity and specificity were calculated for individual studies and pooled data. After screening, 4 cohort studies reporting on CT-findings and histopathological outcome in 157 patients with pancreatic or peri-ampullary cancer were included. Overall, diagnostic accuracy, specificity and NPV varied from 63 to 81, 80-100% and 67-90% respectively. However, PPV and sensitivity ranged from 0 to 100% and 0-38%. Pooled sensitivity, specificity, PPV and NPV were 25%, 86%, 28% and 84% respectively. CT has a low diagnostic accuracy in assessing extra-regional lymph node metastases in pancreatic and peri-ampullary cancer. Therefore, suspicion of extra-regional lymph node metastases on CT alone should not be considered a contra-indication for exploration. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Surgical Oncology 10/2014; 23(4):229-235. DOI:10.1016/j.suronc.2014.10.005 · 2.37 Impact Factor
  • A.H.W. Schiphorst, A. Pronk, I.H.M. Borel Rinkes, M.E. Hamaker
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    ABSTRACT: AimMost colorectal cancer patients are elderly, but there are few data on the optimal surgical treatment for this age group and most studies are observational. We have reviewed the characteristics of randomised trials reporting laparoscopic surgery for colorectal cancer to determine the degree to which the elderly are represented.MethodA search was conducted of the NIH clinical trial registry and the ISRCTN register for randomized trials on laparoscopic surgery for colorectal cancer. Trial characteristics and end points were extracted from the registry website and supplemented by published results where available.ResultsOf 52 trial protocols the majority did not state any restrictions regarding cardiac (40 [77%]) or pulmonary function (41 [79%]). More than half (30 [58%]) had no restrictions regarding ASA-score. Twenty three (44%) trials excluded the elderly either simply on age or by comorbidity or organ function. When an upper age limit was set, half of the studies had no restriction regarding organ function, indicating that chronologic age rather than physical condition was taken as the reason for exclusion. In 45 (86%) of the trials the average age of participants was less than 70years, and no details of concurrent disease were given.Conclusion Participation of the elderly in trials of laparoscopic surgery for colorectal cancer is very limited. This should be remedied in future trials if adequate information on the majority of patients with colorectal cancer is to be obtained.This article is protected by copyright. All rights reserved.
    Colorectal Disease 10/2014; DOI:10.1111/codi.12806 · 2.02 Impact Factor
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    ABSTRACT: Colorectal tumorigenesis is accompanied by the generation of oxidative stress, but how this controls tumor development is poorly understood. Here, we studied how the H2O2-reducing enzyme glutathione peroxidase 2 (GPx2) regulates H2O2 stress and differentiation in patient-derived 'colonosphere' cultures. GPx2 silencing caused accumulation of radical oxygen species, sensitization to H2O2-induced apoptosis and strongly reduced clone- and metastasis-forming capacity. Neutralization of radical oxygen species restored clonogenic capacity. Surprisingly, GPx2-suppressed cells also lacked differentiation potential and formed slow-growing undifferentiated tumors. GPx2 overexpression stimulated multi-lineage differentiation, proliferation and tumor growth without reducing tumor-initiating capacity. Finally, GPx2 expression was inversely correlated with H2O2-stress signatures in human colon tumor cohorts, but positively with differentiation and proliferation. Moreover, high GPx2 expression was associated with early tumor recurrence, particularly in the recently identified aggressive subtype of human colon cancer. We conclude that H2O2 neutralization by GPx2 is essential for maintaining clonogenic and metastatic capacity but also for the generation of differentiated proliferating tumor mass. The results reveal an unexpected redox-controlled link between tumor mass formation and metastatic capacity.
    Cancer Research 09/2014; 74(22). DOI:10.1158/0008-5472.CAN-14-1645 · 9.28 Impact Factor
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    ABSTRACT: Carcinoid tumors are the most common malignant lesions arising from Appendix and are mostly found incidentally during surgery for appendicitis. Perforation of Appendix occurs in 10-20 % of cases with appendicitis. Currently, no guidelines exist for the treatment of perforated carcinoids of Appendix.
    Annals of Surgical Oncology 09/2014; DOI:10.1245/s10434-014-4023-9 · 3.94 Impact Factor
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    ABSTRACT: Treatment of oncologic disease has improved significantly in the last decades and in the future a vast majority of cancer types will continue to increase worldwide. As a result, many patients are confronted with primary liver cancers or metastatic liver disease. Surgery in liver malignancies has steeply improved and curative resections are applicable in wider settings, leading to a prolonged survival. Simultaneously, radiofrequency ablation (RFA) and liver transplantation (LTx) have been applied more commonly in oncologic settings with improving results. To minimize adverse events in treatments of liver malignancies, locoregional minimal invasive treatments have made their appearance in this field, in which radioembolization (RE) has shown promising results in recent years with few adverse events and high response rates. We discuss several other applications of RE for oncologic patients, other than its use in the palliative setting, whether or not combined with other treatments. This review is focused on the role of RE in acquiring patient eligibility for radical treatments, like surgery, RFA, and LTx. Inducing significant tumor reduction can downstage patients for resection or, through attaining stable disease, patients can stay on the LTx waiting list. Hereby, RE could make a difference between curative of palliative intent in oncologic patient management. Prior to surgery, the future remnant liver volume might be inadequate in some patients. In these patients, forming an adequate liver reserve through RE leads to prolonged survival without risking post-operative liver failure and minimizing tumor progression while inducing hypertrophy. In order to optimize results, developments in procedures surrounding RE are equally important. Predicting the remaining liver function after radical treatment and finding the right balance between maximum tumor irradiation and minimizing the chance of inducing radiation-related complications are still challenges.
    Frontiers in Oncology 07/2014; 4:199. DOI:10.3389/fonc.2014.00199
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    ABSTRACT: Preoperative differentiation between malignant and benign pancreatic tumors can be difficult. Consequently, a proportion of patients undergoing pancreatoduodenectomy for suspected malignancy will ultimately have benign disease. The aim of this study was to compare preoperative clinical and diagnostic characteristics of patients with unexpected benign disease after pancreatoduodenectomy with those of patients with confirmed (pre)malignant disease. We performed a multicenter retrospective cohort study in 1,629 consecutive patients undergoing pancreatoduodenectomy for suspected malignancy between 2003 and 2010 in 11 Dutch centers. Preoperative characteristics were compared in a benign:malignant ratio of 1:3. Malignant cases were selected from the entire cohort by using a random number list. A multivariable logistic regression prediction model was constructed to predict benign disease. Of 107 patients (6.6 %) with unexpected benign disease after pancreatoduodenectomy, 86 fulfilled the inclusion criteria and were compared with 258 patients with (pre)malignant disease. Patients with benign disease presented more often with pain (56 vs. 38 %; P = 0.004), but less frequently with jaundice (60 vs. 80 %; P < 0.01), a pancreatic mass (13 vs. 54 %, P < 0.001), or a double duct sign on computed tomography (21 vs. 47 %; P < 0.001). In a prediction model using these parameters, only 19 % of patients with benign disease were correctly predicted, and 1.4 % of patients with malignant disease were missed. Nearly 7 % of patients undergoing pancreatoduodenectomy for suspected malignancy were ultimately diagnosed with benign disease. Although some preoperative clinical and imaging characteristics might indicate absence of malignancy, their discriminatory value is insufficient for clinical use.
    Pancreatology 05/2014; 13(3):S11. DOI:10.1016/j.pan.2013.04.030 · 2.50 Impact Factor
  • Cancer 04/2014; 120(7). DOI:10.1002/cncr.28526 · 4.90 Impact Factor
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    ABSTRACT: Rapid advances in evidence-based treatment schedules are a hallmark of modern oncology. In rare neoplastic diseases, however, clinical expertise is hard to build and evidence based on randomized trials almost impossible to collect. Gorham disease is a rare form of lymphatic proliferation accompanied by osteolysis, which usually occurs in young adults. Despite the fact that the clinical course of Gorham disease is often devastating and occasionally fatal, insights into its biological background are sparse and standardized treatment unavailable. Interestingly, recent knowledge on the mechanisms of lymphangiogenesis may help elucidate the pathophysiology of Gorham disease and lead to novel treatment targets. Here, we discuss our current understanding of Gorham disease, discuss established and emerging therapeutic strategies, and attempt to frame a treatment rationale. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 03/2014; 61(3). DOI:10.1002/pbc.24832 · 2.56 Impact Factor
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    ABSTRACT: /st>Transthoracic oesophagectomy requires prolonged one-lung ventilation causing systemic and local inflammatory responses. Application of continuous positive airway pressure (CPAP) to the collapsed lung potentially reduces pulmonary damage, hypoxia, and consequent inflammation. This randomized controlled trial studied the influence of CPAP applied to the collapsed right lung during thoracoscopic oesophagectomy on local and systemic inflammatory response. /st>Broncho-alveolar lavage fluid (BALF) from the right collapsed and left ventilated lung and serum samples were obtained during surgery from 30 patients undergoing thoracolaparoscopic oesophagectomy for cancer who were randomized for one-lung ventilation with or without CPAP applied to the collapsed right lung. Concentrations of cytokines and chemokines, in BALF and serum, were determined with Luminex. /st>Patients from the control (no CPAP) group had significantly increased concentrations of interleukin (IL)-1α, IL-1β, IL-10, tumour necrosis factor-alpha, macrophage inflammatory protein (MIP)-1α, pulmonary and activation-regulated chemokine (PARC), and IL-8 in the collapsed (right) lung when compared with patients from the CPAP group (P<0.05). The ventilated (left) lung of the control group showed increased concentrations of monocyte chemoattractant protein (MCP)-1 and MIP-1α (P<0.05). Serum concentrations of cytokines and chemokines increased during surgery, but did not differ between the control and CPAP groups. /st>A significantly lower local immune response was observed during one-lung ventilation when CPAP was applied to the collapsed lung. The findings suggest a beneficial effect of CPAP on the collapsed lung during oesophagectomy with one-lung ventilation.
    BJA British Journal of Anaesthesia 02/2014; 112(5). DOI:10.1093/bja/aet476 · 4.35 Impact Factor
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    ABSTRACT: Resection of colorectal liver metastases (CRLM) is often hindered by their location close to the major hepatic vessels. So far, radiofrequency ablation for perivascular tumours was thought to be ineffective and unsafe due to either the heat sink effect or vascular thrombosis. The aim of this study was to examine whether RFA using multipolar probes could be a safe and effective option for CRLM adjacent to major hepatic vessels. Patients were treated with multipolar RFA during an open procedure using 3 simultaneously placed electrodes. In 52 consecutive patients with CRLM, 144 tumours were ablated with RFA. In 16 out of 52 (31%) patients, metastases were abutting major hepatic vessels. We examined whether perivascular location was a risk factor for local tumour progression. The relation between perivascular location and time to local tumour progression and recurrence free survival was assessed using cox-regression analysis. All patients were followed for at least 3 years after RFA unless they deceased before this time. Local tumour progression following RFA occurred in 17 out of 144 tumours (12%), of which 4 out of 21 were perivascular tumours. Tumour size was the only risk factor for local tumour progression in this study. Proximity to large vessels was neither a risk factor for local local tumour progression, nor for time to local tumour progression or recurrence free survival. This study indicates that patients with CRLM abutting any of the large hepatic vessels can be safe and effectively treated with RFA when using a multipolar system.
    The surgeon: journal of the Royal Colleges of Surgeons of Edinburgh and Ireland 01/2014; 13(2). DOI:10.1016/j.surge.2013.11.013 · 2.21 Impact Factor
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    ABSTRACT: To assess the impact of first recurrence location on survival following surgery of colorectal liver metastases. A total of 265 consecutive patients with colorectal liver metastases undergoing liver surgery (2000-2011) were categorized according to first site of tumor recurrence. Time to recurrence (TTR) and overall survival (OS) were determined. Uni- and multivariate analysis were performed to identify factors associated with TTR and OS. Median TTR was 1.16 years following liver resection, and 0.56 years following radiofrequency ablation (RFA). Intrahepatic recurrence following liver resection resulted in a significantly shorter median TTR compared to extrahepatic recurrence. Intrapulmonary recurrence was associated with superior survival compared to other recurrence locations. Such patterns were not observed in the RFA-treated group. Multivariate analysis identified the type of surgical treatment and extra-hepatic first-site recurrence (other than lung) as independent predictors for OS. Pre-operative chemotherapy and simultaneous intrahepatic and extrahepatic recurrence were independent predictors for both TTR and OS. Patients with intrahepatic recurrence following liver resection have a significantly shorter TTR and OS when compared to patients developing extrahepatic recurrence. Pulmonary recurrence following resection is associated with longer survival. Simultaneous intra- and extrahepatic recurrence is an independent prognostic factor for TTR and OS.
    Journal of Gastrointestinal Surgery 01/2014; 18(5). DOI:10.1007/s11605-014-2461-0 · 2.39 Impact Factor
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    ABSTRACT: Background Resection of colorectal liver metastases (CRLM) is often hindered by their location close to the major hepatic vessels. So far, radiofrequency ablation for perivascular tumours was thought to be ineffective and unsafe due to either the heat sink effect or vascular thrombosis. The aim of this study was to examine whether RFA using multipolar probes could be a safe and effective option for CRLM adjacent to major hepatic vessels. Methods Patients were treated with multipolar RFA during an open procedure using 3 simultaneously placed electrodes. In 52 consecutive patients with CRLM, 144 tumours were ablated with RFA. In 16 out of 52 (31%) patients, metastases were abutting major hepatic vessels. We examined whether perivascular location was a risk factor for local tumour progression. The relation between perivascular location and time to local tumour progression and recurrence free survival was assessed using cox-regression analysis. Results All patients were followed for at least 3 years after RFA unless they deceased before this time. Local tumour progression following RFA occurred in 17 out of 144 tumours (12%), of which 4 out of 21 were perivascular tumours. Tumour size was the only risk factor for local tumour progression in this study. Proximity to large vessels was neither a risk factor for local local tumour progression, nor for time to local tumour progression or recurrence free survival. Discussion This study indicates that patients with CRLM abutting any of the large hepatic vessels can be safe and effectively treated with RFA when using a multipolar system.
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    ABSTRACT: The aim of this study was to evaluate whether a change in the routine feeding strategy applied after pancreatoduodenectomy (PD) from nasojejunal tube (NJT) feeding to early oral feeding improved clinical outcomes. An observational cohort study was performed in 102 consecutive patients undergoing PD. In period 1 (n = 51, historical controls), the routine postoperative feeding strategy was NJT feeding. This was changed to a protocol of early oral feeding with on-demand NJT feeding in period 2 (n = 51, consecutive prospective cohort). The primary outcome was time to resumption of adequate oral intake. The baseline characteristics of study subjects in both periods were comparable. In period 1, 98% (n = 50) of patients received NJT feeding, whereas in period 2, 53% (n = 27) of patients did so [for delayed gastric empting (DGE) (n = 20) or preoperative malnutrition (n = 7)]. The time to resumption of adequate oral intake significantly decreased from 12 days in period 1 to 9 days in period 2 (P = 0.015), and the length of hospital stay shortened from 18 days in period 1 to 13 days in period 2 (P = 0.015). Overall, there were no differences in the incidences of complications of Clavien-Dindo Grade III or higher, DGE, pancreatic fistula, postoperative haemorrhage and mortality between the two periods. The introduction of an early oral feeding strategy after PD reduced the time to resumption of adequate oral intake and length of hospital stay without negatively impacting postoperative morbidity.
    HPB 12/2013; 16(7). DOI:10.1111/hpb.12197 · 2.05 Impact Factor
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    ABSTRACT: To assess the contribution of hypoxia and bone marrow-derived cells to aggressive outgrowth of micrometastases after liver surgery. Liver surgery generates a microenvironment that fosters aggressive tumor recurrence. These areas are characterized by chronic hypoxia and influx of bone marrow-derived cells. The contribution of hematopoietic cell types was studied in mice lacking specific components of the immune system and in irradiated mice lacking all bone marrow-derived cells. Tumor cells were derived from colorectal cancer patients and from a metastatic tumor cell line. Hypoxia-induced changes in stem cell and differentiation marker expression, clone-forming potential, and metastatic capacity were assessed. The effect of vascular clamping on cancer stem cell (CSC) characteristics was performed in mice bearing patient-derived liver metastases. Immune cells and bone marrow-derived cells were not required for aggressive outgrowth of micrometastases in livers treated with surgery. Rather, hypoxia was sufficient to promote invasion and accelerate metastatic outgrowth. This was associated with a rapid loss of differentiation markers and increased expression of CSC markers and clone-forming capacity. Likewise, metastases residing in ischemia-reperfusion-injured liver lobes acquired CSC characteristics. Despite their renowned general resistance to chemotherapy, clone-forming CSCs were readily killed by the hypoxia-activated prodrug tirapazamine. Surgery-generated hypoxia in the liver causes rapid dedifferentiation of tumor cells into immature CSCs with high clone- and metastasis-forming capacity. The results help explain the phenomenon of aggressive local tumor recurrence after liver surgery and offer a potential strategy to kill aggressive CSCs by hypoxia-activated prodrugs.
    Annals of surgery 11/2013; DOI:10.1097/SLA.0b013e318295c160 · 7.19 Impact Factor

Publication Stats

4k Citations
896.03 Total Impact Points

Institutions

  • 1997–2015
    • University Medical Center Utrecht
      • • Department of Surgery
      • • Department of Radiology
      Utrecht, Utrecht, Netherlands
    • Red Cross
      Washington, Washington, D.C., United States
  • 2013
    • Hubrecht Institute
      Utrecht, Utrecht, Netherlands
  • 2012
    • University of Malaya
      • Department of Surgery
      Kuala Lumpur, Kuala Lumpur, Malaysia
  • 2000–2008
    • Utrecht University
      Utrecht, Utrecht, Netherlands
  • 1997–2006
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1995–2006
    • Leiden University Medical Centre
      • • Department of Molecular Cell Biology
      • • Department of Surgery
      Leyden, South Holland, Netherlands
  • 2002
    • Diakonessen Hospital Utrecht
      Utrecht, Utrecht, Netherlands
  • 1997–1999
    • Erasmus MC
      • • Department of Oncological Surgery
      • • Department of Radiology
      Rotterdam, South Holland, Netherlands
  • 1991–1999
    • Erasmus Universiteit Rotterdam
      • Department of Surgery
      Rotterdam, South Holland, Netherlands
  • 1990
    • Het Oogziekenhuis Rotterdam
      Rotterdam, South Holland, Netherlands