Publications by authors named "Floris R van Tol"

10 Publications

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Robust gelatin hydrogels for local sustained release of bupivacaine following spinal surgery.

Acta Biomater 2022 07 11;146:145-158. Epub 2022 May 11.

Department of Orthopaedics, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, the Netherlands; Regenerative Medicine Utrecht, Utrecht University, Uppsalalaan 8, 3584CT Utrecht, the Netherlands; SentryX B.V., Woudenbergseweg 41, 3711 AA Austerlitz, the Netherlands. Electronic address:

Adequate treatment of pain arising from spinal surgery is a major clinical challenge. Opioids are the mainstay of current treatment methods, but the frequency and severity of their side effects display a clear need for opioid-free analgesia. Local anesthetics have been encapsulated into sustained-release drug delivery systems to provide postoperative pain relief. However, these formulations are limited by rapid diffusion out of the surgical site. To overcome this limitation, we synthesized ring-shaped hydrogels incorporating bupivacaine, designed to be co-implanted with pedicle screws during spinal surgery. Hydrogels were prepared by riboflavin-mediated crosslinking of gelatin functionalized with tyramine moieties. Additionally, oxidized β-cyclodextrin was introduced into the hydrogel formulation to form dynamic bonds with tyramine functionalities, which enables self-healing behavior and resistance to shear. Feasibility of hydrogel implantation combined with pedicle screws was qualitatively assessed in cadaveric sheep as a model for instrumented spinal surgery. The in-situ crystallization of bupivacaine within the hydrogel matrix provided a moderate burst decrease and sustained release that exceeded 72 hours in vitro. The use of bupivacaine crystals decreased drug-induced cytotoxicity in vitro compared to bupivacaine HCl. Thus, the presented robust hydrogel formulation provides promising properties to enable the stationary release of non-opioid analgesics following spinal surgery. STATEMENT OF SIGNIFICANCE: Currently, postoperative pain following spinal surgery is mainly treated with opioids. However, the use of opioids is associated with several side effects including addiction. Here we developed robust and cytocompatible gelatin hydrogels, prepared via riboflavin-mediated photocrosslinking, that can withstand orthopedic implantation. The implantability was confirmed in cadaveric instrumented spinal surgery. Further, hydrogels were loaded with bupivacaine crystals to provide sustained release beyond 72 hours in vitro. The use of crystallized bupivacaine decreased cytotoxicity compared to bupivacaine HCl. The present formulation can aid in enabling opioid-free analgesia following instrumented spinal surgery.
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July 2022

Sensory Innervation of Human Bone: An Immunohistochemical Study to Further Understand Bone Pain.

J Pain 2021 11 5;22(11):1385-1395. Epub 2021 May 5.

Department of Orthopedic Surgery, University Medical Center Utrecht, The Netherlands; SentryX B.V., Woudenbergseweg 41, Austerlitz, The Netherlands.

Skeletal diseases and their surgical treatment induce severe pain. The innervation density of bone potentially explains the severe pain reported. Animal studies concluded that sensory myelinated A∂-fibers and unmyelinated C-fibers are mainly responsible for conducting bone pain, and that the innervation density of these nerve fibers was highest in periosteum. However, literature regarding sensory innervation of human bone is scarce. This observational study aimed to quantify sensory nerve fiber density in periosteum, cortical bone, and bone marrow of axial and appendicular human bones using immunohistochemistry and confocal microscopy. Multivariate Poisson regression analysis demonstrated that the total number of sensory and sympathetic nerve fibers was highest in periosteum, followed by bone marrow, and cortical bone for all bones studied. Bone from thoracic vertebral bodies contained most sensory nerve fibers, followed by the upper extremity, lower extremity, and parietal neurocranium. The number of nerve fibers declined with age and did not differ between male and female specimens. Sensory nerve fibers were organized as a branched network throughout the periosteum. The current results provide an explanation for the severe pain accompanying skeletal disease, fracture, or surgery. Further, the results could provide more insight into mechanisms that generate and maintain skeletal pain and might aid in developing new treatment strategies. PERSPECTIVE: This article presents the innervation of human bone and assesses the effect of age, gender, bone compartment and type of bone on innervation density. The presented data provide an explanation for the severity of bone pain arising from skeletal diseases and their surgical treatment.
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November 2021

Time to Surgical Treatment for Metastatic Spinal Disease: Identification of Delay Intervals.

Global Spine J 2021 Feb 18:2192568221994787. Epub 2021 Feb 18.

Department of Orthopedic Surgery, University Medical Center Utrecht, The Netherlands.

Study Design: Retrospective cohort study.

Objectives: Minimizing delays in referral, diagnosis and treatment of patients with symptomatic spinal metastases is important for optimal treatment outcomes. The primary objective of this study was to investigate several forms of delay from the onset of symptoms until surgical treatment of spinal metastases for patients with and without a known preexisting known malignancy.

Methods: All patients receiving surgical treatment for spinal metastases in a single tertiary spine center were identified. Referral patterns were reconstructed and the total delay was divided into 4 categories: patient delay (onset of symptoms until medical consultation), diagnostic delay (medical consultation until diagnosis), referral delay (diagnosis until referral to spine surgeon) and treatment delay (referral spine to surgeon until treatment). These intervals were compared between patients with and without a known preexisting malignancy.

Results: The median total delay was 99 days, patient delay 19 days, diagnostic delay 21,5 days, referral delay 7 days, treatment delay 8 days and diagnosis and treatment delay combined 18,5 days. No difference in total delay was observed between patients with and without a known preexisting malignancy. Total delay was not significantly associated with patient age, sex, oncological history, tumor prognosis and spinal level of the tumor.

Conclusions: Patients with symptomatic spinal metastases experience considerable delays, even after metastatic spinal disease has been diagnosed, regardless of a preexisting malignancy. By identifying and eliminating the causes of these delays, diagnosis, referral and treatment may be expedited leading to improved patient outcome.
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February 2021

Costs Associated With Timely and Delayed Surgical Treatment of Spinal Metastases.

Global Spine J 2021 Jan 29:2192568220984789. Epub 2021 Jan 29.

Department of Orthopedics, 569621University Medical Center Utrecht, the Netherlands.

Study Design: Retrospective cohort study.

Objectives: Symptoms caused by spinal metastases are often difficult to distinguish from symptoms caused by non-malignant spinal disease, complicating timely diagnosis, referral and treatment. The ensuing delays may promote the risk of neurological deficits or severe mechanical instability and consequent emergency surgery, leading to poorer prognosis. Presumably, treatment delay may subsequently lead to more health-care consumption and therefore increased average costs of treatment.

Methods: All patients surgically treated for spinal metastases were included in the current study. Based on the presence of alarming symptoms and urgency of the required intervention, patients were categorized as having received timely or delayed treatment. Pre-surgical, in-hospital, aftercare and total costs were analyzed and compared between the 2 groups.

Results: In total, 299 patients were included, of which 205 underwent timely and 94 delayed treatment. There was no significant difference in pre-surigcal costs (€3.229,13 in the timely treated group €2.528,70 in the delayed treatment group, p = 0.849). The in-hospital costs (€16.738,49 €13.108,81, p < 0.001) and the aftercare costs (€13.950,37 . 3.981,93, p < 0.001) were significantly higher for delayed treatment timely treatment, respectively. The total costs were €33.741,71 for delayed treatment and €20.318,52 for timely treatment (p < 0.001).

Conclusions: The total costs for timely treated patients with spinal metastases are significantly lower compared with patients receiving delayed treatment. Investing in the optimization of referral patterns may therefore reduce the overall pretreatment delay and subsequently increase patient outcome, leading to better clinical outcomes at lower costs.
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January 2021

Postoperative adverse events secondary to iatrogenic vascular injury during anterior lumbar spinal surgery.

Spine J 2021 05 3;21(5):795-802. Epub 2020 Nov 3.

Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.

Background: Anterior lumbar spine surgery (ALSS) requires mobilization of the great vessels, resulting in a high risk of iatrogenic vascular injury (VI). It remains unclear whether VI is associated with increased risk of postoperative complications and other related adverse outcomes.

Purpose: The purpose of this study was to (1) assess the incidence of postoperative complications attributable to VI during ALSS, and (2) outcomes secondary to VI such as procedural blood loss, transfusion of blood products, length of stay (LOS), and in hospital mortality.

Study Design: Retrospective propensity-score matched, case-control study at 2 academic and 3 community medical centers, PATIENT SAMPLE: Patients 18 years of age or older, undergoing ALSS between January 1st, 2000 and July 31st, 2019 were included in this analysis.

Outcome Measures: The primary outcome was the incidence of postoperative complications attributable to VI, such as venous thromboembolism, compartment syndrome, transfusion reaction, limb ischemia, and reoperations. The secondary outcomes included estimated operative blood loss (milliliter), transfused blood products, LOS (days), and in-hospital mortality.

Methods: In total, 1,035 patients were identified, of which 75 (7.2%) had a VI. For comparative analyses, the 75 VI patients were paired with 75 comparable non-VI patients by propensity-score matching. The adequacy of the matching was assessed by testing the standardized mean differences (SMD) between VI and non-VI group (>0.25 SMD).

Results: Two patients (2.7%) had VI-related postoperative complications in the studied period, which consisted of two deep venous thromboembolisms (DVTs) occurring on day 3 and 7 postoperatively. Both DVTs were located in the distal left common iliac vein (CIV). The VI these patients suffered were to the distal inferior vena cava and the left CIV, respectively. Both patients did not develop additional complications in consequence of their DVTs, however, did require systemic anticoagulation and placement of an inferior vena cava filter. There was no statistical difference with the non-VI group where no instances (0%) of postoperative complications were reported (p=.157). No differences were found in LOS or in hospital mortality between the two groups (p=.157 and p=.999, respectively). Intraoperative blood loss and blood transfusion were both found to be higher in the VI group in comparison to the non-VI group (650 mL, interquartile range [IQR] 300-1400 vs. 150 mL, IQR 50-425, p≤.001; 0 units, IQR 0-3 vs. 0 units, IQR 0-1, p=.012, respectively).

Conclusion: This study found a low number of serious postoperative complications related to VI in ALSS. In addition, these complications were not significantly different between the VI and matched non-VI ALSS cohort. Although not significant, the found DVT incidence of 2.7% after VI in ALSS warrants vigilance and preventive measures during the postoperative course of these patients.
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May 2021

The importance of timely treatment for quality of life and survival in patients with symptomatic spinal metastases.

Eur Spine J 2020 12 18;29(12):3170-3178. Epub 2020 Sep 18.

Department of Orthopedic Surgery, University Medical Center Utrecht, P.O. Box 85500 (G05.228), 3508 GA, Utrecht, The Netherlands.

Purpose: A major challenge in metastatic spinal disease is timely identification of patients. Left untreated, spinal metastases may lead to gross mechanical instability and/or neurological deficits, often requiring extensive invasive surgical treatment. The aim of this cohort study was to assess the correlation between delayed treatment of patients with spinal metastases and functional performance, quality of life and survival.

Methods: All patients surgically treated for metastatic spinal disease at a tertiary care facility were included for analysis. Patients who underwent elective surgery were considered as timely treated, whereas patients requiring emergency surgery were considered to be treated in a delayed fashion. EQ-5D scores, KPS scores and mortality rates were compared between the two groups.

Results: A total of 317 patients (215 timely treated, 102 delayed) had survivorship data available and 202 patients (147 timely treated, 55 delayed) had clinical data available. Multivariate analyses showed delayed treatment was associated with lower EQ-5D and KPS scores and higher mortality rates, independent of confounders such as baseline EQ-5D/KPS scores, neurological status, tumor prognosis and patient age.

Conclusions: The results from the present study show delayed treatment of patients with symptomatic spinal metastases has both direct and indirect adverse consequences for functional performance status, quality of life and survival. Optimization of referral pattern may accelerate the time to surgical treatment, potentially leading to better quality of life and survival.
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December 2020

Malnutrition in patients who underwent surgery for spinal metastases.

Ann Transl Med 2019 May;7(10):213

Department of Orthopaedic Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Malnutrition is common among cancer patients and has been associated with increased morbidity and mortality. The primary objective of this study was to evaluate the nutritional status of patients who underwent surgical treatment for spinal metastases. In addition, the association between nutritional status and length of stay, health related quality of life (HRQOL), the occurrence of adverse events and survival was investigated.

Methods: A single center prospective observational cohort study including patients with spinal metastases who underwent surgical treatment was performed. Demographic, diagnostic, treatment, and HRQOL (SOSGOQ2.0 and EQ-5D-3L) data were prospectively collected at baseline and 12 weeks post-treatment. Nutritional status was evaluated with the Patient-Generated Subjective Global Assessment (PG-SGA).

Results: A total of 39 patients were included. Malnutrition as determined by the PG-SGA was present in 36 (92%) of the patients, of whom 32 (82%) were moderately malnourished and 4 (10%) were severely malnourished. Malnourishment was associated with lower baseline SOSGOQ2.0 total scores, SOSGOQ2.0 physical function, mental health and social functioning scores, EQ-5D total scores and EQ-5D mobility scores. No association between malnutrition and survival could be determined.

Conclusions: The prevalence of malnutrition among surgically treated patients with spinal metastases is high. Malnutrition demonstrated to be associated with lower baseline HRQOL scores. Future larger studies are needed to further investigate the prognostic significance of malnutrition.
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May 2019

Delayed presentation to a spine surgeon is the strongest predictor of poor postoperative outcome in patients surgically treated for symptomatic spinal metastases.

Spine J 2019 09 18;19(9):1540-1547. Epub 2019 Apr 18.

Department of Orthopedic Surgery, University Medical Center Utrecht, the Netherlands.

Background Context: Symptoms associated with spinal metastases are often nonspecific and resemble noncancer-related symptoms. Therefore, patients with spinal metastases are at risk for delayed referral and treatment. Delayed presentation of symptomatic spinal metastases may lead to the development of neurological deficits, often followed by emergency surgery.

Purpose: The aim of this cohort study was to analyze the effect of delayed referral and treatment of spinal metastases on clinical outcome.

Methods: We included all patients surgically treated for spinal metastases at our tertiary care center. Based on the (in)ability to undergo elective surgery, patients were identified as timely treated or delayed. Patient- and tumor-characteristics, surgical variables, and postoperative variables such as complication rate, the ability to return home and length of hospital stay were recorded and compared between the two groups.

Results: Based on the urgency of treatment at admission, 206 patients were identified as timely treated and 98 as delayed. At baseline, the two groups did not differ significantly except for the extent of neurological symptoms. Timely treated patients underwent less invasive procedures (52.9% vs 13.3% percutaneous pedicle screw fixations), had less median blood loss (200cc vs 450cc), shorter median admission time (7 vs 13 days), lower complication rate (26.2% vs 48.0%) and higher chances of being discharged home immediately (82.6% vs 41.1%) compared with delayed patients. Using multivariate regression models these correlations remained present independent of tumor prognosis, preoperative mobility, and American Society of Anesthesiologists-score.

Conclusions: The delayed presentation of patients with spinal metastases to a spinal surgeon is strongly and independently associated with worse surgical and postoperative outcome parameters. Improvements in referral patterns could potentially lead to more scheduled care, negating the detrimental effects of delay.
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September 2019

The Occurrence of Meniscal and Chondral Injury in Two-Stage Revision Anterior Cruciate Ligament Reconstruction: A Consecutive Case Series.

J Knee Surg 2020 Mar 18;33(3):223-227. Epub 2019 Jan 18.

Focus Clinic Orthopedic Surgery, Haaglanden Medical Center, Den Haag, Zuid-Holland, The Netherlands.

Two-stage revision anterior cruciate ligament (ACL) reconstruction is an effective way to revise suboptimal tunnel-placement allowing for proper graft fixation. However, prolonged increased laxity of the knee may increase the risk of meniscal or chondral injury. It was hypothesized that no additional meniscal or chondral lesions occur in between the two stages of the two-stage revision ACL reconstruction. In this retrospective study, 42 patients undergoing a two-stage revision ACL reconstruction were included. Surgical notes for both stages were screened for meniscal and chondral status, interventions to any concurrent injury, surgery dates, along with basic patient characteristics. In 4 of the 42 patients, a new meniscal tear occurred in between the two stages, of which three required partial meniscectomy during the second stage of the ACL revision. One patient experienced a new small degenerative tear that did not require intervention. Two out of the four menisci that were repaired during the first stage had failed and required partial meniscectomy. No significant difference was found in the time between the two stages with respect to the occurrence of meniscal tears. No significant differences in chondral status were found. In conclusion, approximately 10% of patients developed a new meniscal tear and no difference in macroscopic chondral injury was observed between the first and second stages.
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March 2020

Which implant should we use for primary total hip replacement? A systematic review and meta-analysis.

J Bone Joint Surg Am 2014 Dec;96 Suppl 1:79-97

Department of Orthopaedic Surgery, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, Leiden, the Netherlands. E-mail address for J.C. Keurentjes:

Background: Many total hip implants are currently available on the market worldwide. We aimed to estimate the probability of revision surgery at ten years for each individual total hip implant and to compare these estimates with the National Institute for Health and Care Excellence (NICE) benchmark.

Methods: We performed a meta-analysis of cohort studies. The methodological quality was assessed with use of the Assessment of Quality in Lower Limb Arthroplasty (AQUILA) checklist. We searched PubMed, Embase, Web of Science, and the Cochrane Library. Additionally, national joint registries that were full members of the International Society of Arthroplasty Registers (ISAR) were hand searched. Studies in which the authors reported the survival probability for either the acetabular or the femoral component of primary total hip replacements with use of revision for any reason or for aseptic loosening at ten years as the end point, with at least 100 implants at baseline, and in which at least 60% of the patients had primary osteoarthritis were eligible for inclusion.

Results: The search strategy revealed 5513 papers describing survival probabilities for thirty-four types of acetabular components and thirty-two types of femoral components. Eight types of acetabular cups and fifteen types of femoral stems performed better than the NICE benchmark.

Conclusions: We recommend that surgeons performing a primary total hip replacement use an implant that outperforms the NICE benchmarks.
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December 2014