Publications by authors named "Jorrit-Jan Verlaan"

101 Publications

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

Acta Biomater 2022 May 11. 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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http://dx.doi.org/10.1016/j.actbio.2022.05.007DOI Listing
May 2022

Comparison of and Toxicity of Bupivacaine in Musculoskeletal Applications.

Front Pain Res (Lausanne) 2021 20;2:723883. Epub 2021 Aug 20.

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

The recent societal debate on opioid use in treating postoperative pain has sparked the development of long-acting, opioid-free analgesic alternatives, often using the amino-amide local anesthetic bupivacaine as active pharmaceutical ingredient. A potential application is musculoskeletal surgeries, as these interventions rank amongst the most painful overall. Current literature showed that bupivacaine induced dose-dependent myo-, chondro-, and neurotoxicity, as well as delayed osteogenesis and disturbed wound healing . These observations did not translate to animal and clinical research, where toxic phenomena were seldom reported. An exception was bupivacaine-induced chondrotoxicity, which can mainly occur during continuous joint infusion. To decrease opioid consumption and provide sustained pain relief following musculoskeletal surgery, new strategies incorporating high concentrations of bupivacaine in drug delivery carriers are currently being developed. Local toxicity of these high concentrations is an area of further research. This review appraises relevant , animal and clinical studies on musculoskeletal local toxicity of bupivacaine.
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http://dx.doi.org/10.3389/fpain.2021.723883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8915669PMC
August 2021

Diffuse idiopathic skeletal hyperostosis of the cervical spine causing dysphagia and airway obstruction: an updated systematic review.

Spine J 2022 Mar 11. Epub 2022 Mar 11.

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

Background And Context: Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by growing ossifications of spinal entheses and tendons, which may cause trachea and esophagus compression when located anteriorly in the cervical spine.

Purpose: Our previous systematic review on the epidemiological and clinical knowledge of dysphagia and airway obstruction caused by cervical DISH was updated, with a focus on (surgical) treatment and outcomes.

Study Design: A systematic review of the literature was performed.

Methods: Publications in Medline and EMBASE from July 2010 to June 2021 were searched. Two investigators performed data extraction and study specific quality assessment.

Results: A total of 138 articles (112 case reports and 26 case series) were included, describing 419 patients with dysphagia and/or airway obstruction. The mean age of the patient group was 67.3 years (range: 35-91 years), and 85.4% was male. An evident increase of published cases was observed within the last decade. Surgical treatment was chosen for 66% of patients with the anterolateral approach most commonly used. The total complication rate after surgery was 22.1%, with 12.7% occurring within 1 month after intervention. Improvement of dysphagia was observed in 95.5% of operated patients. After a mean follow-up of 3.7 years (range: 0.4-9.0 years), dysphagia recurred in 12 surgically treated patients (4%), of which five patients had osteophyte regrowth.

Conclusions: The number of published cases of dysphagia in patients with DISH has doubled in the last decade compared to our previous review. Yet, randomized studies or guidelines on the treatment or prevention on recurrence are lacking. Surgical treatment is effective and has low (major) complication rates. Common trends established across the cases in our study may help improve our understanding and management of dysphagia and airway obstruction in cervical DISH.
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http://dx.doi.org/10.1016/j.spinee.2022.03.002DOI Listing
March 2022

Preoperative embolization in surgical treatment of spinal metastases originating from non-hypervascular primary tumors: a propensity score matched study using 495 patients.

Spine J 2022 Mar 6. Epub 2022 Mar 6.

Department of Orthopedic Surgery, Orthopedic Oncology Service, Massachusetts General Hospital - Harvard Medical School, 55 Fruit St., Boston, MA 02114, USA.

Background Context: Preoperative embolization (PE) reduces intraoperative blood loss during surgery for spinal metastases of hypervascular primary tumors such as thyroid and renal cell tumors. However, most spinal metastases originate from primary breast, prostate, and lung tumors and it remains unclear whether these and other spinal metastases benefit from PE.

Purpose: To assess the (1) efficacy of PE on the amount of intraoperative blood loss and safety in patients with spinal metastases originating from non-hypervascular primary tumors, and (2) secondary outcomes including perioperative allogeneic blood transfusion, anesthesia time, hospitalization, postoperative complication within 30 days, reoperation, 90-day mortality, and 1-year mortality.

Study Design: Retrospective propensity-score matched, case-control study at 2 academic tertiary medical centers.

Patient Sample: Patients 18 years of age or older undergoing surgery for spinal metastases originating from primary non-thyroid, non-renal cell, and non-hepatocellular tumors between January 1, 2002 and December 31, 2016 were included.

Outcome Measures: The primary outcomes were estimated amount of intraoperative blood loss and complications attributable to PE, such as neurologic injury, wound infection, thrombosis, or dissection. The secondary outcomes included perioperative allogeneic blood transfusion, anesthesia time, hospitalization, postoperative complication within 30 days, reoperation, 90-day mortality, and 1-year mortality.

Methods: In total, 495 patients were identified, of which 54 (11%) underwent PE. After propensity score matching on 21 variables, including primary tumor, number of spinal levels, and surgical treatment, 53 non-PE patients were matched to 53 PE patients. Matching was adequate measured by comparing the matched variables, testing the standardized mean differences (<0.25), and inspecting Kernel density plots. The degree of embolization was noted to be complete, until stasis, or successful in 43 (80%) patients.

Results: Intraoperative blood loss did not differ between both groups with a median blood loss in liters of 0.6 (IQR, 0.4-1.2) for non-PE patients and 0.9 (IQR, 0.6-1.2) for PE patients (p=.32). No complications occurred during embolization or the time between embolization and surgery. No differences were found in terms of the secondary outcomes.

Conclusions: Our data suggest that, although no complications occurred and the embolization procedure can be considered safe, patients with non-hypervascular spinal metastases might not benefit from PE. A larger, prospective study could confirm or refute these study findings and aid in elucidating a subset of spinal metastases that might benefit from PE.
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http://dx.doi.org/10.1016/j.spinee.2022.03.001DOI Listing
March 2022

A machine learning algorithm for predicting prolonged postoperative opioid prescription after lumbar disc herniation surgery. An external validation study using 1,316 patients from a Taiwanese cohort.

Spine J 2022 Feb 23. Epub 2022 Feb 23.

Department of Orthopaedic Surgery, National Taiwan University Hospital, Taiwan. Address: No. 7, Zhongshan S. Rd., Zhongzheng Dist., Taipei City 100225, Taiwan (R.O.C.). Electronic address:

Background Context: Preoperative prediction of prolonged postoperative opioid prescription helps identify patients for increased surveillance after surgery. The SORG machine learning model has been developed and successfully tested using 5,413 patients from the United States (US) to predict the risk of prolonged opioid prescription after surgery for lumbar disc herniation. However, external validation is an often-overlooked element in the process of incorporating prediction models in current clinical practice. This cannot be stressed enough in prediction models where medicolegal and cultural differences may play a major role.

Purpose: The authors aimed to investigate the generalizability of the US citizens prediction model SORG to a Taiwanese patient cohort.

Study Design: Retrospective study at a large academic medical center in Taiwan.

Patient Sample: Of 1,316 patients who were 20 years or older undergoing initial operative management for lumbar disc herniation between 2010 and 2018.

Outcome Measures: The primary outcome of interest was prolonged opioid prescription defined as continuing opioid prescription to at least 90 to 180 days after the first surgery for lumbar disc herniation at our institution.

Methods: Baseline characteristics were compared between the external validation cohort and the original developmental cohorts. Discrimination (area under the receiver operating characteristic curve and the area under the precision-recall curve), calibration, overall performance (Brier score), and decision curve analysis were used to assess the performance of the SORG ML algorithm in the validation cohort. This study had no funding source or conflict of interests.

Results: Overall, 1,316 patients were identified with sustained postoperative opioid prescription in 41 (3.1%) patients. The validation cohort differed from the development cohort on several variables including 93% of Taiwanese patients receiving NSAIDS preoperatively compared with 22% of US citizens patients, while 30% of Taiwanese patients received opioids versus 25% in the US. Despite these differences, the SORG prediction model retained good discrimination (area under the receiver operating characteristic curve of 0.76 and the area under the precision-recall curve of 0.33) and good overall performance (Brier score of 0.028 compared with null model Brier score of 0.030) while somewhat overestimating the chance of prolonged opioid use (calibration slope of 1.07 and calibration intercept of -0.87). Decision-curve analysis showed the SORG model was suitable for clinical use.

Conclusions: Despite differences at baseline and a very strict opioid policy, the SORG algorithm for prolonged opioid use after surgery for lumbar disc herniation has good discriminative abilities and good overall performance in a Han Chinese patient group in Taiwan. This freely available digital application can be used to identify high-risk patients and tailor prevention policies for these patients that may mitigate the long-term adverse consequence of opioid dependence: https://sorg-apps.shinyapps.io/lumbardiscopioid/.
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http://dx.doi.org/10.1016/j.spinee.2022.02.009DOI Listing
February 2022

Quality of Life After Stereotactic Body Radiation Therapy Versus Conventional Radiation Therapy in Patients With Bone Metastases.

Int J Radiat Oncol Biol Phys 2022 04 10;112(5):1203-1215. Epub 2022 Jan 10.

Division of Imaging and Cancer, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands. Electronic address:

Purpose: Painful bone metastases hamper quality of life (QoL). The aim of this prespecified secondary analysis of the PRESENT trial was to compare change in global QoL, physical functioning, emotional functioning, functional interference, and psychosocial aspects after conventional radiation therapy (cRT) versus stereotactic body RT (SBRT).

Methods And Materials: A total of 110 patients were enrolled in the phase 2 randomized controlled VERTICAL trial (NCT02364115) following the "trials within cohorts" design and randomized 1:1 to cRT or SBRT. Patient-reported global QoL, physical functioning, emotional functioning, functional interference, and psychosocial aspects were assessed by the European Organization for Research and Treatment of Cancer QoL Questionnaire (QLQ) Core 15 Palliative Care and QLQ Bone Metastases 22 modules. Changes in QoL domains over time were compared between patients treated with cRT and SBRT using intention-to-treat (ITT) and per-protocol (PP) linear mixed model analysis adjusting for baseline scores. Proportions of patients in the cRT versus SBRT arm reporting a clinically relevant change in QoL within 3 months were compared using a χ test.

Results: QoL scores had improved over time and were comparable between groups for all domains in both the ITT and PP analyses, except for functional interference and psychological aspects in the ITT. Functional interference scores had improved more after 12 weeks in the cRT arm than in the SBRT arm (25.5 vs 14.1 points, respectively; effect size [ES] = 0.49, P = .04). Psychosocial aspects scores had improved more after 8 weeks in the cRT arm than in the SBRT arm (12.2 vs 7.3; ES = 0.56, P = .04). No clinically relevant differences between groups at 12 weeks in terms of global QoL, physical functioning, emotional functioning, functional interference, and psychosocial aspects were observed.

Conclusions: Palliative RT improves QoL. Both SBRT and cRT have a comparable effect on patient-reported QoL outcomes in patients with painful bone metastases. Functional interference and psychological aspects scores improved more in patients treated with cRT versus patients offered SBRT.
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http://dx.doi.org/10.1016/j.ijrobp.2021.12.163DOI Listing
April 2022

Clinical Outcome Differences in the Treatment of Impending Versus Completed Pathological Long-Bone Fractures.

J Bone Joint Surg Am 2022 02;104(4):307-315

Orthopaedic Oncology Service, Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Background: The outcome differences following surgery for an impending versus a completed pathological fracture have not been clearly defined. The purpose of the present study was to assess differences in outcomes following the surgical treatment of impending versus completed pathological fractures in patients with long-bone metastases in terms of (1) 90-day and 1-year survival and (2) intraoperative blood loss, perioperative blood transfusion, anesthesia time, duration of hospitalization, 30-day postoperative systemic complications, and reoperations.

Methods: We retrospectively performed a matched cohort study utilizing a database of 1,064 patients who had undergone operative treatment for 462 impending and 602 completed metastatic long-bone fractures. After matching on 22 variables, including primary tumor, visceral metastases, and surgical treatment, 270 impending pathological fractures were matched to 270 completed pathological fractures. The primary outcome was assessed with the Cox proportional hazard model. The secondary outcomes were assessed with the McNemar test and the Wilcoxon signed-rank test.

Results: The 90-day survival rate did not differ between the groups (HR, 1.13 [95% CI, 0.81 to 1.56]; p = 0.48), but the 1-year survival rate was worse for completed pathological fractures (46% versus 38%) (HR, 1.28 [95% CI, 1.02 to 1.61]; p = 0.03). With regard to secondary outcomes, completed pathological fractures were associated with higher intraoperative estimated blood loss (p = 0.03), a higher rate of perioperative blood transfusions (p = 0.01), longer anesthesia time (p = 0.04), and more reoperations (OR, 2.50 [95% CI, 1.92 to 7.86]; p = 0.03); no differences were found in terms of the rate of 30-day postoperative complications or the duration of hospitalization.

Conclusions: Patients undergoing surgery for impending pathological fractures had lower 1-year mortality rates and better secondary outcomes as compared with patients undergoing surgery for completed pathological fractures when accounting for 22 covariates through propensity matching. Patients with an impending pathological fracture appear to benefit from prophylactic stabilization as stabilizing a completed pathological fracture seems to be associated with increased mortality, blood loss, rate of blood transfusions, duration of surgery, and reoperation risk.

Level Of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.21.00711DOI Listing
February 2022

Expectations of treatment outcomes in patients with spinal metastases; what do we tell our patients? A qualitative study.

BMC Cancer 2021 Nov 23;21(1):1263. Epub 2021 Nov 23.

Division of Imaging and Cancer, University Medical Center Utrecht, University of Utrecht, PO Box 85500, 3508, GA, Utrecht, the Netherlands.

Background: Realistic pre-treatment expectations are important and have been associated with post-treatment health related quality of life (HRQOL). Patient expectations are greatly influenced by physicians, as they are the primary resource for information. This study aimed to explore the communication practices of physicians regarding treatment outcomes for patients with spinal metastases, and physician experiences with patients' pre-treatment expectations.

Methods: An international qualitative study using semi-structured interviews with physicians routinely involved in treating metastatic spine disease (spine surgeons, radiation and medical oncologists, and rehabilitation specialists) was conducted. Physicians were interviewed about the content and extent of information they provide to patients with spinal metastases regarding treatment options, risks and treatment outcomes. Interviews were transcribed verbatim and analyzed using a thematic coding network.

Results: After 22 interviews data saturation occurred. The majority of the physicians indicated that they currently do not establish patients' pre-treatment expectations, despite acknowledging the importance of these expectations. Spine surgeons often believe that patient expectations are disproportionate. Physicians expressed they manage expectations by detailing the most common risks and providing a broad but nonspecific overview of treatment outcomes. While the palliative intent seems clear to the physicians, their perception is that the implications of a palliative treatment remains elusive to most patients.

Conclusion: This study highlights the current gap in patient-physician communication regarding expectations of treatment outcomes of patients with spinal metastases. These results warrant further research to improve communication practices and determine the effect of patient expectations on patient reported outcomes in this population.
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http://dx.doi.org/10.1186/s12885-021-08993-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8611925PMC
November 2021

Diffuse idiopathic skeletal hyperostosis is associated with incident stroke in patients with increased cardiovascular risk.

Rheumatology (Oxford) 2021 Nov 13. Epub 2021 Nov 13.

Department of Vascular Medicine, University Medical Center Utrecht and Utrecht University, the Netherlands, Utrecht.

Objectives: Earlier retrospective studies have suggested a relation between diffuse idiopathic skeletal hyperostosis [DISH] and cardiovascular disease, including myocardial infarction. The present study assessed the association between DISH and incidence of cardiovascular events and mortality in patients with high cardiovascular risk.

Methods: In this prospective cohort study, we included 4624 patients (mean age 58.4 years, 69.6% male) from the Second Manifestations of ARTerial disease cohort. The main end point was major cardiovascular events [MACE: stroke, myocardial infarction, and vascular death]. Secondary endpoints included all-cause mortality and separate vascular events. Cause specific proportional hazard models were used to evaluate the risk of DISH on all outcomes, and subdistribution hazard models were used to evaluate the effect of DISH on the cumulative incidence. All models were adjusted for age, sex, body mass index, blood pressure, diabetes, non-HDL cholesterol, packyears, renal function, and C-reactive protein.

Results: DISH was present in 435 (9.4%) patients. After a median follow-up of 8.7 (IQR 5.0-12.0) years, 864 patients had died and 728 patients developed a MACE event. DISH was associated with an increased cumulative incidence of ischaemic stroke.After adjustment in cause specific modelling, DISH remained significantly associated with ischaemic stroke (HR 1.55; 95%CI : 1.01-2.38), but not with MACE (HR 0.99; 95%CI : 0.79-1.24), myocardial infarction (HR 0.88; 95%CI : 0.59-1.31), vascular death (HR 0.94; 95%CI : 0.68-1.27), or all-cause mortality (HR 0.94; 95%CI : 0.77-1.16).

Conclusion: The presence of DISH is independently associated with an increased incidence and risk for ischaemic stroke, but not with MACE, myocardial infarction, vascular death, or all-cause mortality.
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http://dx.doi.org/10.1093/rheumatology/keab835DOI Listing
November 2021

The preoperative machine learning algorithm for extremity metastatic disease can predict 90-day and 1-year survival: An external validation study.

J Surg Oncol 2022 Feb 5;125(2):282-289. Epub 2021 Oct 5.

Department of Orthopaedics and Rehabilitation, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.

Background: The prediction of survival is valuable to optimize treatment of metastatic long-bone disease. The Skeletal Oncology Research Group (SORG) machine-learning (ML) algorithm has been previously developed and internally validated. The purpose of this study was to determine if the SORG ML algorithm accurately predicts 90-day and 1-year survival in an external metastatic long-bone disease patient cohort.

Methods: A retrospective review of 264 patients who underwent surgery for long-bone metastases between 2003 and 2019 was performed. Variables used in the stochastic gradient boosting SORG algorithm were age, sex, primary tumor type, visceral/brain metastases, systemic therapy, and 10 preoperative laboratory values. Model performance was calculated by discrimination, calibration, and overall performance.

Results: The SORG ML algorithms retained good discriminative ability (area under the cure [AUC]: 0.83; 95% confidence interval [CI]: 0.76-0.88 for 90-day mortality and AUC: 0.84; 95% CI: 0.79-0.88 for 1-year mortality), calibration, overall performance, and decision curve analysis.

Conclusion: The previously developed ML algorithms demonstrated good performance in the current study, thereby providing external validation. The models were incorporated into an accessible application (https://sorg-apps.shinyapps.io/extremitymetssurvival/) that may be freely utilized by clinicians in helping predict survival for individual patients and assist in informative decision-making discussion before operative management of long bone metastatic lesions.
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http://dx.doi.org/10.1002/jso.26708DOI Listing
February 2022

International Validation of the SORG Machine-learning Algorithm for Predicting the Survival of Patients with Extremity Metastases Undergoing Surgical Treatment.

Clin Orthop Relat Res 2022 02;480(2):367-378

Department of Orthopedic Surgery, National Taiwan University Hospital, Taipei City, Taiwan.

Background: The Skeletal Oncology Research Group machine-learning algorithms (SORG-MLAs) estimate 90-day and 1-year survival in patients with long-bone metastases undergoing surgical treatment and have demonstrated good discriminatory ability on internal validation. However, the performance of a prediction model could potentially vary by race or region, and the SORG-MLA must be externally validated in an Asian cohort. Furthermore, the authors of the original developmental study did not consider the Eastern Cooperative Oncology Group (ECOG) performance status, a survival prognosticator repeatedly validated in other studies, in their algorithms because of missing data.

Questions/purposes: (1) Is the SORG-MLA generalizable to Taiwanese patients for predicting 90-day and 1-year mortality? (2) Is the ECOG score an independent factor associated with 90-day and 1-year mortality while controlling for SORG-MLA predictions?

Methods: All 356 patients who underwent surgery for long-bone metastases between 2014 and 2019 at one tertiary care center in Taiwan were included. Ninety-eight percent (349 of 356) of patients were of Han Chinese descent. The median (range) patient age was 61 years (25 to 95), 52% (184 of 356) were women, and the median BMI was 23 kg/m2 (13 to 39 kg/m2). The most common primary tumors were lung cancer (33% [116 of 356]) and breast cancer (16% [58 of 356]). Fifty-five percent (195 of 356) of patients presented with a complete pathologic fracture. Intramedullary nailing was the most commonly performed type of surgery (59% [210 of 356]), followed by plate screw fixation (23% [81 of 356]) and endoprosthetic reconstruction (18% [65 of 356]). Six patients were lost to follow-up within 90 days; 30 were lost to follow-up within 1 year. Eighty-five percent (301 of 356) of patients were followed until death or for at least 2 years. Survival was 82% (287 of 350) at 90 days and 49% (159 of 326) at 1 year. The model's performance metrics included discrimination (concordance index [c-index]), calibration (intercept and slope), and Brier score. In general, a c-index of 0.5 indicates random guess and a c-index of 0.8 denotes excellent discrimination. Calibration refers to the agreement between the predicted outcomes and the actual outcomes, with a perfect calibration having an intercept of 0 and a slope of 1. The Brier score of a prediction model must be compared with and ideally should be smaller than the score of the null model. A decision curve analysis was then performed for the 90-day and 1-year prediction models to evaluate their net benefit across a range of different threshold probabilities. A multivariate logistic regression analysis was used to evaluate whether the ECOG score was an independent prognosticator while controlling for the SORG-MLA's predictions. We did not perform retraining/recalibration because we were not trying to update the SORG-MLA algorithm in this study.

Results: The SORG-MLA had good discriminatory ability at both timepoints, with a c-index of 0.80 (95% confidence interval 0.74 to 0.86) for 90-day survival prediction and a c-index of 0.84 (95% CI 0.80 to 0.89) for 1-year survival prediction. However, the calibration analysis showed that the SORG-MLAs tended to underestimate Taiwanese patients' survival (90-day survival prediction: calibration intercept 0.78 [95% CI 0.46 to 1.10], calibration slope 0.74 [95% CI 0.53 to 0.96]; 1-year survival prediction: calibration intercept 0.75 [95% CI 0.49 to 1.00], calibration slope 1.22 [95% CI 0.95 to 1.49]). The Brier score of the 90-day and 1-year SORG-MLA prediction models was lower than their respective null model (0.12 versus 0.16 for 90-day prediction; 0.16 versus 0.25 for 1-year prediction), indicating good overall performance of SORG-MLAs at these two timepoints. Decision curve analysis showed SORG-MLAs provided net benefits when threshold probabilities ranged from 0.40 to 0.95 for 90-day survival prediction and from 0.15 to 1.0 for 1-year prediction. The ECOG score was an independent factor associated with 90-day mortality (odds ratio 1.94 [95% CI 1.01 to 3.73]) but not 1-year mortality (OR 1.07 [95% CI 0.53 to 2.17]) after controlling for SORG-MLA predictions for 90-day and 1-year survival, respectively.

Conclusion: SORG-MLAs retained good discriminatory ability in Taiwanese patients with long-bone metastases, although their actual survival time was slightly underestimated. More international validation and incremental value studies that address factors such as the ECOG score are warranted to refine the algorithms, which can be freely accessed online at https://sorg-apps.shinyapps.io/extremitymetssurvival/.

Level Of Evidence: Level III, therapeutic study.
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http://dx.doi.org/10.1097/CORR.0000000000001969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8747677PMC
February 2022

Pseudohypoparathyroidism mimicking cervical diffuse idiopathic skeletal hyperostosis with dysphagia: A case report and literature review.

Bone Rep 2021 Dec 27;15:101111. Epub 2021 Jul 27.

Department of Vascular Medicine, University Medical Centre Utrecht, Utrecht, the Netherlands.

Dysphagia due to extensive ossification at anterior segments of the cervical spine is a rare occurrence and is usually attributable to diffuse idiopathic skeletal hyperostosis (DISH). We present the case of a 74-year-old female with dysphagia most likely due to ossification in pseudohypoparathyroidism type 1a (PHP1a). PHP1a is a rare, autosomal dominant disorder caused by mutations in the GNAS1 gene. Our patient had characteristic phenotype features of PHP1a, also known as Albright's hereditary osteodystrophy (AHO), which was diagnosed without genetic confirmation. She was conservatively treated with dietary measures and observation, and reported persisting symptoms of dysphagia at six-month follow-up. This is the first case to describe dysphagia in PHP1a with a similar presentation to DISH.
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http://dx.doi.org/10.1016/j.bonr.2021.101111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339251PMC
December 2021

Visceral Adipose Tissue and Different Measures of Adiposity in Different Severities of Diffuse Idiopathic Skeletal Hyperostosis.

J Pers Med 2021 Jul 15;11(7). Epub 2021 Jul 15.

Department of Radiology, University Medical Center Utrecht and Utrecht University, 3584 CX Utrecht, The Netherlands.

Background: Diffuse idiopathic skeletal hyperostosis (DISH) is associated with both obesity and type 2 diabetes. Our objective was to investigate the relation between DISH and visceral adipose tissue (VAT) in particular, as this would support a causal role of insulin resistance and low grade inflammation in the development of DISH.

Methods: In 4334 patients with manifest vascular disease, the relation between different adiposity measures and the presence of DISH was compared using -scores via standard deviation logistic regression analyses. Analyses were stratified by sex and adjusted for age, systolic blood pressure, diabetes, non-HDL cholesterol, smoking status, and renal function.

Results: DISH was present in 391 (9%) subjects. The presence of DISH was associated with markers of adiposity and had a strong relation with VAT in males (OR: 1.35; 95%CI: 1.20-1.54) and females (OR: 1.43; 95%CI: 1.06-1.93). In males with the most severe DISH (extensive ossification of seven or more vertebral bodies) the association between DISH and VAT was stronger (OR: 1.61; 95%CI: 1.31-1.98), while increased subcutaneous fat was negatively associated with DISH (OR: 0.65; 95%CI: 0.49-0.95). In females, increased subcutaneous fat was associated with the presence of DISH (OR: 1.43; 95%CI: 1.14-1.80).

Conclusion: Markers of adiposity, including VAT, are strongly associated with the presence of DISH. Subcutaneous adipose tissue thickness was negatively associated with more severe cases of DISH in males, while in females, increased subcutaneous adipose tissue was associated with the presence of DISH.
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http://dx.doi.org/10.3390/jpm11070663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305748PMC
July 2021

Wide range of applications for machine-learning prediction models in orthopedic surgical outcome: a systematic review.

Acta Orthop 2021 Oct 10;92(5):526-531. Epub 2021 Jun 10.

Department of Orthopedic Surgery, Orthopedic Oncology Service, Massachusetts General Hospital - Harvard Medical School, Boston, USA.

Background and purpose - Advancements in software and hardware have enabled the rise of clinical prediction models based on machine learning (ML) in orthopedic surgery. Given their growing popularity and their likely implementation in clinical practice we evaluated which outcomes these new models have focused on and what methodologies are being employed.Material and methods - We performed a systematic search in PubMed, Embase, and Cochrane Library for studies published up to June 18, 2020. Studies reporting on non-ML prediction models or non-orthopedic outcomes were excluded. After screening 7,138 studies, 59 studies reporting on 77 prediction models were included. We extracted data regarding outcome, study design, and reported performance metrics.Results - Of the 77 identified ML prediction models the most commonly reported outcome domain was medical management (17/77). Spinal surgery was the most commonly involved orthopedic subspecialty (28/77). The most frequently employed algorithm was neural networks (42/77). Median size of datasets was 5,507 (IQR 635-26,364). The median area under the curve (AUC) was 0.80 (IQR 0.73-0.86). Calibration was reported for 26 of the models and 14 provided decision-curve analysis.Interpretation - ML prediction models have been developed for a wide variety of topics in orthopedics. Topics regarding medical management were the most commonly studied. Heterogeneity between studies is based on study size, algorithm, and time-point of outcome. Calibration and decision-curve analysis were generally poorly reported.
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http://dx.doi.org/10.1080/17453674.2021.1932928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519550PMC
October 2021

Quality of Life Changes After Surgery for Metastatic Spinal Disease: A Systematic Review and Meta-analysis.

Clin Spine Surg 2022 02;35(1):38-48

Department of Orthopaedic Surgery, Academic Medical Center, University of Amsterdam, Amsterdam-Zuidoost.

Study Design: This was a systematic review and meta-analysis.

Objective: A systematic review and meta-analysis was conducted to assess the quality of life (QoL) after open surgery for spinal metastases, and how surgery affects physical, social/family, emotional, and functional well-being.

Summary Of Background Data: It remains questionable to what extent open surgery improves QoL for metastatic spinal disease, it would be interesting to quantify the magnitude and duration of QoL benefits-if any-after surgery for spinal metastases.

Materials And Methods: Included were studies measuring QoL before and after nonpercutaneous, open surgery for spinal metastases for various indications including pain, spinal cord compression, instability, or tumor control. A random-effect model assessed standardized mean differences (SMDs) of summary QoL scores between baseline and 1, 3, 6, or 9-12 months after surgery.

Results: The review yielded 10 studies for data extraction. The pooled QoL summary score improved from baseline to 1 month (SMD=1.09, P<0.001), to 3 months (SMD=1.28, P<0.001), to 6 months (SMD=1.21, P<0.001), and to 9-12 months (SMD=1.08, P=0.001). The surgery improved physical well-being during the first 3 months (SMD=0.94, P=0.022), improved emotional (SMD=1.19, P=0.004), and functional well-being (SMD=1.08, P=0.005) during the first 6 months, and only improved social/family well-being at month 6 (SMD=0.28, P=0.001).

Conclusions: The surgery improved QoL for patients with spinal metastases, and rapidly improved physical, emotional, and functional well-being; it had minimal effect on social/family well-being. However, choosing the optimal candidate for surgical intervention in the setting of spinal metastases remains paramount: otherwise postoperative morbidity and complications may outbalance the intended benefits of surgery. Future research should report clear definitions of selection criteria and surgical indication and provide stratified QoL results by indication and clinical characteristics such as primary tumor type, preoperative Karnofsky, and Bilsky scores to elucidate the optimal candidate for surgical intervention.
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http://dx.doi.org/10.1097/BSD.0000000000001213DOI Listing
February 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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http://dx.doi.org/10.1016/j.jpain.2021.04.006DOI Listing
November 2021

Availability and reporting quality of external validations of machine-learning prediction models with orthopedic surgical outcomes: a systematic review.

Acta Orthop 2021 Aug 18;92(4):385-393. Epub 2021 Apr 18.

Orthopedic Oncology Service, Massachusetts General Hospital, Harvard Medical School, Boston, USA;

Background and purpose - External validation of machine learning (ML) prediction models is an essential step before clinical application. We assessed the proportion, performance, and transparent reporting of externally validated ML prediction models in orthopedic surgery, using the Transparent Reporting for Individual Prognosis or Diagnosis (TRIPOD) guidelines.Material and methods - We performed a systematic search using synonyms for every orthopedic specialty, ML, and external validation. The proportion was determined by using 59 ML prediction models with only internal validation in orthopedic surgical outcome published up until June 18, 2020, previously identified by our group. Model performance was evaluated using discrimination, calibration, and decision-curve analysis. The TRIPOD guidelines assessed transparent reporting.Results - We included 18 studies externally validating 10 different ML prediction models of the 59 available ML models after screening 4,682 studies. All external validations identified in this review retained good discrimination. Other key performance measures were provided in only 3 studies, rendering overall performance evaluation difficult. The overall median TRIPOD completeness was 61% (IQR 43-89), with 6 items being reported in less than 4/18 of the studies.Interpretation - Most current predictive ML models are not externally validated. The 18 available external validation studies were characterized by incomplete reporting of performance measures, limiting a transparent examination of model performance. Further prospective studies are needed to validate or refute the myriad of predictive ML models in orthopedics while adhering to existing guidelines. This ensures clinicians can take full advantage of validated and clinically implementable ML decision tools.
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http://dx.doi.org/10.1080/17453674.2021.1910448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436968PMC
August 2021

Machine learning prediction models in orthopedic surgery: A systematic review in transparent reporting.

J Orthop Res 2022 Feb 29;40(2):475-483. Epub 2021 Mar 29.

Orthopedic Oncology Service, Department of Orthopedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Machine learning (ML) studies are becoming increasingly popular in orthopedics but lack a critically appraisal of their adherence to peer-reviewed guidelines. The objective of this review was to (1) evaluate quality and transparent reporting of ML prediction models in orthopedic surgery based on the transparent reporting of multivariable prediction models for individual prognosis or diagnosis (TRIPOD), and (2) assess risk of bias with the Prediction model Risk Of Bias ASsessment Tool. A systematic review was performed to identify all ML prediction studies published in orthopedic surgery through June 18th, 2020. After screening 7138 studies, 59 studies met the study criteria and were included. Two reviewers independently extracted data and discrepancies were resolved by discussion with at least two additional reviewers present. Across all studies, the overall median completeness for the TRIPOD checklist was 53% (interquartile range 47%-60%). The overall risk of bias was low in 44% (n = 26), high in 41% (n = 24), and unclear in 15% (n = 9). High overall risk of bias was driven by incomplete reporting of performance measures, inadequate handling of missing data, and use of small datasets with inadequate outcome numbers. Although the number of ML studies in orthopedic surgery is increasing rapidly, over 40% of the existing models are at high risk of bias. Furthermore, over half incompletely reported their methods and/or performance measures. Until these issues are adequately addressed to give patients and providers trust in ML models, a considerable gap remains between the development of ML prediction models and their implementation in orthopedic practice.
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http://dx.doi.org/10.1002/jor.25036DOI Listing
February 2022

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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http://dx.doi.org/10.1177/2192568220984789DOI Listing
January 2021

Diffuse Idiopathic Skeletal Hyperostosis (DISH) and a Possible Inflammatory Component.

Curr Rheumatol Rep 2021 01 26;23(1). Epub 2021 Jan 26.

Case Western Reserve University, Cleveland, OH, USA.

Purpose Of Review: Diffuse Idiopathic Skeletal Hyperostosis (DISH) is considered a metabolic condition, characterized by new bone formation affecting mainly at entheseal sites. Enthesitis and enthesopathies occur not only in the axial skeleton but also at some peripheral sites, and they resemble to some extent the enthesitis that is a cardinal feature in spondyloarthritis (SpA), which is an inflammatory disease.

Recent Findings: We review the possible non-metabolic mechanism such as inflammation that may also be involved at some stage and help promote new bone formation in DISH. We discuss supporting pathogenic mechanisms for a local inflammation at sites typically affected by this disease, and that is also supported by imaging studies that report some similarities between DISH and SpA. Local inflammation, either primary or secondary to metabolic derangements, may contribute to new bone formation in DISH. This new hypothesis is expected to stimulate further research in both the metabolic and inflammatory pathways in order to better understand the mechanisms that lead to new bone formation. This may lead to development of measures that will help in earlier detection and effective management before damage occurs.
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http://dx.doi.org/10.1007/s11926-020-00972-xDOI Listing
January 2021

Do Cohabitants Reliably Complete Questionnaires for Patients in a Terminal Cancer Stage when Assessing Quality of Life, Pain, Depression, and Anxiety?

Clin Orthop Relat Res 2021 Apr;479(4):792-801

O. Q. Groot, N. R. P. Pereira, M. E. R. Bongers, P. T. Ogink, E. T. Newman, K. A. Raskin, S. A. Lozano-Calderon, J. H. Schwab, Department of Orthopaedic Surgery, Orthopaedic Oncology Service, Massachusetts General Hospital - Harvard Medical School, Boston, MA, USA.

Background: Patients with bone metastases often are unable to complete quality of life (QoL) questionnaires, and cohabitants (such as spouses, domestic partners, offspring older than 18 years, or other people who live with the patient) could be a reliable alternative. However, the extent of reliability in this complicated patient population remains undefined, and the influence of the cohabitant's condition on their assessment of the patient's QoL is unknown.

Questions/purposes: (1) Do QoL scores, measured by the 5-level EuroQol-5D (EQ-5D-5L) version and the Patient-reported Outcomes Measurement Information System (PROMIS) version 1.0 in three domains (anxiety, pain interference, and depression), reported by patients differ markedly from scores as assessed by their cohabitants? (2) Do cohabitants' PROMIS-Depression scores correlate with differences in measured QoL results?

Methods: This cross-sectional study included patients and cohabitants older than 18 years of age. Patients included those with presence of histologically confirmed bone metastases (including lymphoma and multiple myeloma), and cohabitants must have been present at the clinic visit. Patients were eligible for inclusion in the study regardless of comorbidities, prognosis, prior surgery, or current treatment. Between June 1, 2016 and March 1, 2017 and between October 1, 2017 and February 26, 2018, all 96 eligible patients were approached, of whom 49% (47) met the selection criteria and were willing to participate. The included 47 patient-cohabitant pairs independently completed the EQ-5D-5L and the eight-item PROMIS for three domains (anxiety, pain, and depression) with respect to the patients' symptoms. The cohabitants also completed the four-item PROMIS-Depression survey with respect to their own symptoms.

Results: There were no clinically important differences between the scores of patients and their cohabitants for all questionnaires, and the agreement between patient and cohabitant scores was moderate to strong (Spearman correlation coefficients ranging from 0.52 to 0.72 on the four questionnaires; all p values < 0.05). However, despite the good agreement in QoL scores, an increased cohabitant's depression score was correlated with an overestimation of the patient's symptom burden for the anxiety and depression domains (weak Spearman correlation coefficient of 0.33 [95% confidence interval 0.08 to 0.58]; p = 0.01 and moderate Spearman correlation coefficient of 0.52 [95% CI 0.29 to 0.74]; p < 0.01, respectively).

Conclusion: The present findings support that cohabitants might be reliable raters of the QoL of patients with bone metastases. However, if a patient's cohabitant has depression, the cohabitant may overestimate a patient's symptoms in emotional domains such as anxiety and depression, warranting further research that includes cohabitants with and without depression to elucidate the effect of depression on the level of agreement. For now, clinicians may want to reconsider using the cohabitant's judgement if depression is suspected.

Clinical Relevance: These findings suggest that a cohabitant's impressions of a patient's quality of life are, in most instances, accurate; this is potentially helpful in situations where the patient cannot weigh in. Future studies should employ longitudinal designs to see how or whether our findings change over time and with disease progression, and how specific interventions-like different chemotherapeutic regimens or surgery-may factor in.
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http://dx.doi.org/10.1097/CORR.0000000000001525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083839PMC
April 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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http://dx.doi.org/10.1016/j.spinee.2020.10.031DOI Listing
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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http://dx.doi.org/10.1007/s00586-020-06599-xDOI Listing
December 2020

Does Artificial Intelligence Outperform Natural Intelligence in Interpreting Musculoskeletal Radiological Studies? A Systematic Review.

Clin Orthop Relat Res 2020 12;478(12):2751-2764

O. Q. Groot, M. E. R. Bongers, A. V. Karhade, J. H. Schwab, Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: Machine learning (ML) is a subdomain of artificial intelligence that enables computers to abstract patterns from data without explicit programming. A myriad of impactful ML applications already exists in orthopaedics ranging from predicting infections after surgery to diagnostic imaging. However, no systematic reviews that we know of have compared, in particular, the performance of ML models with that of clinicians in musculoskeletal imaging to provide an up-to-date summary regarding the extent of applying ML to imaging diagnoses. By doing so, this review delves into where current ML developments stand in aiding orthopaedists in assessing musculoskeletal images.

Questions/purposes: This systematic review aimed (1) to compare performance of ML models versus clinicians in detecting, differentiating, or classifying orthopaedic abnormalities on imaging by (A) accuracy, sensitivity, and specificity, (B) input features (for example, plain radiographs, MRI scans, ultrasound), (C) clinician specialties, and (2) to compare the performance of clinician-aided versus unaided ML models.

Methods: A systematic review was performed in PubMed, Embase, and the Cochrane Library for studies published up to October 1, 2019, using synonyms for machine learning and all potential orthopaedic specialties. We included all studies that compared ML models head-to-head against clinicians in the binary detection of abnormalities in musculoskeletal images. After screening 6531 studies, we ultimately included 12 studies. We conducted quality assessment using the Methodological Index for Non-randomized Studies (MINORS) checklist. All 12 studies were of comparable quality, and they all clearly included six of the eight critical appraisal items (study aim, input feature, ground truth, ML versus human comparison, performance metric, and ML model description). This justified summarizing the findings in a quantitative form by calculating the median absolute improvement of the ML models compared with clinicians for the following metrics of performance: accuracy, sensitivity, and specificity.

Results: ML models provided, in aggregate, only very slight improvements in diagnostic accuracy and sensitivity compared with clinicians working alone and were on par in specificity (3% (interquartile range [IQR] -2.0% to 7.5%), 0.06% (IQR -0.03 to 0.14), and 0.00 (IQR -0.048 to 0.048), respectively). Inputs used by the ML models were plain radiographs (n = 8), MRI scans (n = 3), and ultrasound examinations (n = 1). Overall, ML models outperformed clinicians more when interpreting plain radiographs than when interpreting MRIs (17 of 34 and 3 of 16 performance comparisons, respectively). Orthopaedists and radiologists performed similarly to ML models, while ML models mostly outperformed other clinicians (outperformance in 7 of 19, 7 of 23, and 6 of 10 performance comparisons, respectively). Two studies evaluated the performance of clinicians aided and unaided by ML models; both demonstrated considerable improvements in ML-aided clinician performance by reporting a 47% decrease of misinterpretation rate (95% confidence interval [CI] 37 to 54; p < 0.001) and a mean increase in specificity of 0.048 (95% CI 0.029 to 0.068; p < 0.001) in detecting abnormalities on musculoskeletal images.

Conclusions: At present, ML models have comparable performance to clinicians in assessing musculoskeletal images. ML models may enhance the performance of clinicians as a technical supplement rather than as a replacement for clinical intelligence. Future ML-related studies should emphasize how ML models can complement clinicians, instead of determining the overall superiority of one versus the other. This can be accomplished by improving transparent reporting, diminishing bias, determining the feasibility of implantation in the clinical setting, and appropriately tempering conclusions.

Level Of Evidence: Level III, diagnostic study.
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http://dx.doi.org/10.1097/CORR.0000000000001360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899420PMC
December 2020

Diffuse idiopathic skeletal hyperostosis: Etiology and clinical relevance.

Best Pract Res Clin Rheumatol 2020 06 23;34(3):101527. Epub 2020 May 23.

Department of Orthopedics, University Medical Center Utrecht, Postbus 85500, 3508 GA, Utrecht, the Netherlands.

Diffuse idiopathic skeletal hyperostosis (DISH) is a systemic bone-forming condition characterized by the presence of at least three bony bridges at the anterolateral spine. The aim of this review was to address the present state of pathophysiological knowledge, the clinical relevance, and diagnosis of DISH. The pathogenesis of DISH is currently unknown. The presence of DISH has been associated with older age, male sex, obesity, hypertension, atherosclerosis, and diabetes mellitus. Because the new bone forms mainly at entheseal sites, local fibroblasts, chondrocytes, collagen fibers, and calcified matrix are probably influenced by genetic, vascular, metabolic, and mechanical factors. Diagnosing the presence of DISH is of clinical importance, because the risk of a spinal fracture increases and associations with the metabolic syndrome, coronary and aortic disease, and respiratory effects are strong. Unravelling the pathogenesis of DISH can impact the field of regenerative medicine and bone tissue regeneration.
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http://dx.doi.org/10.1016/j.berh.2020.101527DOI Listing
June 2020

Imaging of diffuse idiopathic skeletal hyperostosis (DISH).

RMD Open 2020 02;6(1)

Rheumatology Unit, Department of Internal and Experimental Medicine, University of Messina, Messina, Italy.

Diffuse idiopathic skeletal hyperostosis (DISH) is a condition characterised by calcification and ossification of ligaments and entheses. The condition usually affects the axial skeleton, in particular, at the thoracic segment, though also other portions of the spine are often involved. DISH often involves also peripheral tendinous and/or entheseal sites either alone, or in association with the involvement of peripheral joints. At times, new bone formation involves the bone itself, but sometimes it involves joints not usually affected by osteoarthritis (OA) which result in bony enlargement of the epiphysis, joints space narrowing and a reduced range of motion. Because of the entheseal involvement, DISH can be mistaken for seronegative spondyloarthropathies or for a "simple" OA. Furthermore, other implications for the recognition of DISH include spinal fractures, difficult intubation and upper endoscopies, decreased response rates in DISH with concomitant spondyloarthritides, and increased likelihood to be affected by metabolic syndrome and cardiovascular diseases. This Atlas is intended to show the imaging finding in DISH in patients diagnosed with the condition by the Resnick classification criteria.
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http://dx.doi.org/10.1136/rmdopen-2019-001151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046956PMC
February 2020

An understanding of bone pain: A narrative review.

Bone 2020 05 13;134:115272. Epub 2020 Feb 13.

Department of Orthopedics, University Medical Centre Utrecht, Heidelberglaan 100, 3508 GA Utrecht, the Netherlands. Electronic address:

Skeletal pathologies are often accompanied by bone pain, which has negative effects on the quality of life and functional status of patients. Bone pain can be caused by a wide variety of injuries and diseases including (poorly healed) fractures, bone cancer, osteoarthritis and also iatrogenic by skeletal interventions. Orthopedic interventions are considered to be the most painful surgical procedures overall. Two major groups of medication currently used to attenuate bone pain are NSAIDs and opioids. However, these systemic drugs frequently introduce adverse events, emphasizing the need for alternative therapies that are directed at the pathophysiological mechanisms underlying bone pain. The periosteum, cortical bone and bone marrow are mainly innervated by sensory A-delta fibers and C-fibers. These fibers are mostly present in the periosteum rendering this structure most sensitive to nociceptive stimuli. A-delta fibers and C-fibers can be activated upon mechanical distortion, acidic environment and increased intramedullary pressure. After activation, these fibers can be sensitized by inflammatory mediators, phosphorylation of acid-sensing ion channels and cytokine receptors, or by upregulation of transcription factors. This can result in a change of pain perception such that normally non-noxious stimuli are now perceived as noxious. Pathological conditions in the bone can produce neurotrophic factors that bind to receptors on A-delta fibers and C-fibers. These fibers then start to sprout and increase the innervation density of the bone, making it more sensitive to nociceptive stimuli. In addition, repetitive painful stimuli cause neurochemical and electrophysiological alterations in afferent sensory neurons in the spinal cord, which leads to central sensitization, and can contribute to chronic bone pain. Understanding the pathophysiological mechanisms underlying bone pain in different skeletal injuries and diseases is important for the development of alternative, targeted pain treatments. These pain mechanism-based alternatives have the potential to improve the quality of life of patients suffering from bone pain without introducing undesirable systemic effects.
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http://dx.doi.org/10.1016/j.bone.2020.115272DOI Listing
May 2020

Clinical, radiological, and patient-reported outcomes 13 years after pedicle screw fixation with balloon-assisted endplate reduction and cement injection.

Eur Spine J 2020 04 8;29(4):914-921. Epub 2020 Feb 8.

Department of Orthopedics, University Medical Center Utrecht, Postbus 85500, 3508 GA, Utrecht, The Netherlands.

Purpose: In management of traumatic thoracolumbar burst fractures, short-segment pedicle screw fixation with balloon-assisted endplate reduction (BAER) and cement injection is a safe, feasible, and effective technique to maintain radiological alignment with minimum spinal segments involved. However, 20% of patients report daily discomfort despite good spinal alignment and fusion after this technique. This study provides clinical, radiological, and patient-reported outcomes after a minimum 13 years of follow-up.

Methods: Eighteen patients were invited at the outpatient clinic for clinical/radiological examinations. The cohort (originally 20 patients) was treated 13-14 years earlier with pedicle screw fixation, BAER, and cement injection for traumatic thoracolumbar burst fractures. Patient-reported outcome measures were obtained at time of examinations. Current data were compared with data obtained at 6 years of follow-up.

Results: Seventeen patients (median age 50; range 32-80) cooperated. No/minimal back pain was reported by 15 patients, and 12 patients returned to their previous heavy labor work. Median visual analog score of health (80%; 50-100%) was similar to results at 6 years (80%; 60-100% p = 0.259). An Oswestry Disability Index score of less than 20% (reflecting minimal disability) was reported by 14 patients, compared with 15 patients at 6 years of follow-up. No significant differences were found in wedge or Cobb angle between the time points. Intravertebral cement resorption was not observed.

Conclusion: Results from this study suggest that, 13 years after pedicle screw fixation with BAER and cement injection for traumatic thoracolumbar burst fractures, functional performance, pain and radiological outcomes of the current cohort were stable or had slightly improved. These slides can be retrieved under Electronic Supplementary Material.
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http://dx.doi.org/10.1007/s00586-020-06321-xDOI Listing
April 2020

How good are the outcomes of instrumented debulking operations for symptomatic spinal metastases and how long do they stand? A subgroup analysis in the global spine tumor study group database.

Acta Neurochir (Wien) 2020 04 17;162(4):943-950. Epub 2020 Jan 17.

Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, University College London, London, UK.

Background: The benefits of surgery for symptomatic spinal metastases have been demonstrated, largely based on series of patients undergoing debulking and instrumentation operations. However, as cancer treatments improve and overall survival lengths increase, the incidence of recurrent spinal cord compression after debulking may increase. The aim of the current paper is to document the postoperative evolution of neurological function, pain, and quality of life following debulking and instrumentation in the Global Spine Tumor Study Group (GSTSG) database.

Methods: The GSTSG database is a prospective multicenter data repository of consecutive patients that underwent surgery for a symptomatic spinal metastasis. For the present analysis, patients were selected from the database that underwent decompressive debulking surgery with instrumentation. Preoperative tumor type, Tomita and Tokuhashi scores, EQ-5D, Frankel, Karnofsky, and postoperative complications, survival, EQ-5D, Frankel, Karnofsky, and pain numeric rating scores (NRS) at 3, 6, 12, and 24 months were analyzed.

Results: A total of 914 patients underwent decompressive debulking surgery with instrumentation and had documented follow-up until death or until 2 years post surgery. Median preoperative Karnofsky performance index was 70. A total of 656 patients (71.8%) had visceral metastases and 490 (53.6%) had extraspinal bone metastases. Tomita scores were evenly distributed above (49.1%) and below or equal to 5 (50.9%), and Tokuhashi scores almost evenly distributed below or equal to 8 (46.3%) and above 8 (53.7%). Overall, 12-month survival after surgery was 56.3%. The surgery resulted in EQ-5D health status improvement and NRS pain reduction that was maintained throughout follow-up. Frankel scores improved at first follow-up in 25.0% of patients, but by 12 months neurological deterioration was observed in 18.8%.

Conclusion: We found that palliative debulking and instrumentation surgeries were performed throughout all Tomita and Tokuhashi categories. These surgeries reduced pain scores and improved quality of life up to 2 years after surgery. After initial improvement, a proportion of patients experienced neurological deterioration by 1 year, but the majority of patients remained stable.
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http://dx.doi.org/10.1007/s00701-019-04197-5DOI Listing
April 2020

Metastatic Spine Disease: Should Patients With Short Life Expectancy Be Denied Surgical Care? An International Retrospective Cohort Study.

Neurosurgery 2020 08;87(2):303-311

Division of Spine Surgery, Department of Orthopaedics, Vancouver General Hospital, University of British Columbia, Vancouver, Canada.

Background: Despite our inability to accurately predict survival in many cancer patients, a life expectancy of at least 3 mo is historically necessary to be considered for surgical treatment of spinal metastases.

Objective: To compare health-related quality of life (HRQOL) in patients surviving <3 mo after surgical treatment to patients surviving >3 mo to assess the validity of this inclusion criteria.

Methods: Patients who underwent surgery for spinal metastases between August 2013 and May 2017 were retrospectively identified from an international cohort study. HRQOL was evaluated using generic and disease-specific outcome tools at baseline and at 6 and 12 wk postsurgery. The primary outcome was the HRQOL at 6 wk post-treatment measured by the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ).

Results: A total of 253 patients were included: 40 patients died within the first 3 mo after surgery and 213 patients survived more than 3 mo. Patients surviving <3 mo after surgery presented with lower baseline performance status. Adjusted analyses for baseline performance status did not reveal a significant difference in HRQOL between both groups at 6 wk post-treatment. No significant difference in patient satisfaction at 6 wk with regard to their treatment could be detected between both groups.

Conclusion: When controlled for baseline performance status, quality of life 6 wk after surgery for spinal metastasis is independent of survival. To optimize improvement in HRQOL for this patient population, baseline performance status should take priority over expected survival in the surgical decision-making process.
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http://dx.doi.org/10.1093/neuros/nyz472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360875PMC
August 2020
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