Does anxiety influence outcome measurements in ankle replacement patients?

BACKGROUND: Total ankle arthroplasty (TAA) is increasingly used to treat end-stage ankle arthritis to restore ankle functional outcomes and alleviate pain. This treatment outcome may be influenced by pre-morbid patient anxiety. METHODS: Twenty-five Infinity TAA implants were prospectively followed post-operatively with a mean follow-up time of 34.18 months. Demographic, clinical, and functional outcomes were assessed. Analysis was performed on the effect of anxiety, reported by the HADS, on patient-perceived postoperative pain, functioning, and quality of life. RESULTS: Postoperative the PROMs and Range of Motion (ROM) improved significantly. Linear regression analysis and Pearson correlation showed a significant negative effect of anxiety on the postoperative patient-reported outcome measurements (EQ-5D-5L, VAS, and MOxFQ) at the end of follow-up. CONCLUSION: Good functional, clinical, and radiographic results were observed in this prospective cohort study. Anxiety had a negative influence on the outcome of the patient-reported outcome measurements (EQ-5D-5L and MOxFQ) postoperatively. LEVEL OF EVIDENCE: Level III, prospective cohort study.

Complications following total ankle arthroplasty: A systematic literature review and meta-analysis.

BACKGROUND: Total ankle arthroplasty (TAA) is increasingly used as a treatment for end-stage ankle arthropathy. However, TAA may be more sensitive to complications, failure and subsequent re-operations compared to ankle arthrodesis. The aim of this systematic review and meta-analysis is to generate an overview of complications of TAA surgery. METHODS: PubMed, EMBASE and the Cochrane library were searched between 2000 and 2020 to identify all papers reporting on complications in TAA surgery. Meta-analysis was conducted based on type of complication in TAA surgery. Pooled estimates of complications were calculated using a random effects model. Risk of bias and quality was assessed using the Cochrane risk of bias and ROBINS-I tools. The confidence in estimates was rated and described according to the recommendations of the GRADE working group. RESULTS: One hundred twenty-seven studies were included in this systematic review. All combined, they reported on 16.964 TAAs with an average follow-up of 47.99 ± 29.18 months. Complications with highest reported pooled incidence were intra-operative fracture 0.06 (95 %CI 0.04-0.08) (GRADE Very low) and impingement 0.06 (95 %CI 0.04-0.08) (GRADE low) respectively. CONCLUSION: Reported complication incidence of TAA surgery is still high and remains a significant clinical problem that can be severely hampering long-term clinical survival of the prosthesis. The results of this systematic review and meta-analysis can help guide surgeons in informing their patient about complication risks. Implementation of more stringent patient selection criteria might contribute to diminishing TAA complication rates.

Risk factors for total ankle arthroplasty failure: A Dutch Arthroplasty Register study.

BACKGROUND: Studies concerning total ankle arthroplasty could be influenced by several forms of bias. Independent national arthroplasty registries represent objective data on survival and patient reported outcomes. The aim of this study was to determine survival and identify risk factors for early failure in a nationwide series of total ankle arthroplasties from the Dutch Arthroplasty Register (LROI). PATIENTS AND METHODS: Data of 810 patients, who received 836 total ankle arthroplasties between 2014 and 2020 were obtained from the Dutch Arthroplasty Register (LROI) with a median follow-up of 38 months (range 1-84 months). Survival was expressed in Kaplan-Meier analysis and associated hazard ratios for implant failure were determined. Implant failure was defined as the need for revision surgery for any reason or (pan)arthrodesis. RESULTS: During follow-up, we recorded 39 failures (4.7%) resulting in a implant survival of 95.3% with a median follow-up of 38 months (range 1-84 months). Medial malleolus osteotomy (HR = 2.27), previous surgery (HR = 1.83), previous osteotomy (HR = 2.82) and previous ligament reconstruction (HR = 2.83) all showed potentially clinically meaningful associations with a higher incidence of implant failure, yet only previous OCD treatment (HR = 6.21), BMI (HR = 1.09) and age (HR = 0.71) were statistically significant. INTERPRETATION: Excellent short-term survival (95.3%) with a median follow-up of 38 months was reported for TAA patients from the Dutch Arthroplasty Register. Patients with a lower age, a higher BMI or who had a prior surgical OCD treatment before TAA surgery appear to have a higher risk for revision after short-term clinical follow-up. Thorough patient selection with emphasis on risk factors associated with early implant failure might be essential to improve TAA survivorship.

Gait analysis and functional outcome in patients after Lisfranc injury treatment.

INTRODUCTION: Lisfranc injuries involve any bony or ligamentous disruption of the tarsometatarsal joint. Outcome results after treatment are mainly evaluated using patient-reported outcome measures (PROM), physical examination and radiographic findings. Less is known about the kinematics during gait. METHODS: Nineteen patients (19 feet) treated for Lisfranc injury were recruited. Patients with conservative treatment and surgical treatment consisting of open reduction and internal fixation (ORIF) or primary arthrodesis were included. PROM, radiographic findings and gait analysis using the Oxford Foot Model (OFM) were analysed. Results were compared with twenty-one healthy subjects (31 feet). Multivariable logistic regression was used to determine factors influencing outcome. RESULTS: Patients treated for Lisfranc injury had a significantly lower walking speed than healthy subjects (P<0.001). There was a significant difference between the two groups regarding the range of motion (ROM) in the sagittal plane (flexion-extension) in the midfoot during the push-off phase (p<0.001). The ROM in the sagittal plane was significantly correlated with the AOFAS midfoot score (r2=0.56, p=0.012), FADI (r2=0.47, p=0.043) and the SF-36-physical impairment score (r2=0.60, p=0.007) but not with radiographic parameters for quality of reduction. In a multivariable analysis, the best explanatory factors were ROM in the sagittal plane during the push-off phase (ß=0.707, p=0.001), stability (ß=0.423, p=0.028) and BMI (ß=-0.727 p=<0.001). This prediction model explained 87% of patient satisfaction. CONCLUSIONS: This study showed that patients treated for Lisfranc injury had significantly lower walking speed and significantly lower flexion/extension in the midfoot than healthy subjects. The ROM in these patients was significantly correlated with PROM, but not with radiographic quality of reduction. Most important satisfaction predictors were BMI, ROM in the sagittal plane during the push-off phase and fracture stability.

Strategies to optimize the information provision for parents of children with developmental dysplasia of the hip.

Aims: The aim of this study was to identify the information topics that should be addressed according to the parents of children with developmental dysplasia of the hip (DDH) in the diagnostic and treatment phase during the first year of life. Second, we explored parental recommendations to further optimize the information provision in DDH care. Methods: A qualitative study with semi-structured interviews was conducted between September and December 2020. A purposive sample of parents of children aged younger than one year, who were treated for DDH with a Pavlik harness, were interviewed until data saturation was achieved. A total of 20 interviews with 22 parents were conducted. Interviews were audio recorded, transcribed verbatim, independently reviewed, and coded into categories and themes. Results: Interviews revealed four fundamental information topics that should be addressed in the different phases of the DDH healthcare trajectory: general information (screening phase), patient-specific information (diagnostic and treatment phase), practical information (treatment phase), and future perspectives (treatment and follow-up phase). To further optimize the information provision in DDH care, parents wished for more accessible and trustworthy general information prior to the first hospital visit to be better prepared for the diagnosis. Furthermore, parents wanted more personalized and visually supported information for a better understanding of the nature of the disease and the reason for treatment. Conclusion: This study offers novel insights to optimize the information provision in DDH care. The main finding is the shift in information need from general information in the screening phase to patient-specific information in the diagnostic and treatment phase of DDH. Parents prefer visually-supported information, provided in a timely fashion, and tailored to their child's situation. These recommendations potentially decrease parental anxiety, insecurity, confusion, and increase parental empowerment and treatment adherence throughout the diagnostic and treatment phase of DDH.

Parental experiences of children with developmental dysplasia of the hip: a qualitative study.

OBJECTIVE: The aim of this qualitative study was to explore the experiences of Dutch parents of children with developmental dysplasia of the hip (DDH), treated with a Pavlik harness, during the diagnostic and treatment process in the first year of life. DESIGN: A qualitative study by means of semistructured interviews was conducted between September and December 2020. Qualitative content analysis was applied to code, categorise and thematise data. SETTING: A large, tertiary referral centre for paediatric orthopaedics in the Netherlands. PARTICIPANTS: A purposive sample of parents of children aged younger than 1 year, who were treated for DDH with a Pavlik harness, were interviewed until data saturation was achieved. A total of 20 interviews with 22 parents were conducted. RESULTS: Five main themes emerged: (1) positive experiences with professionals and peers, (2) insufficient information, (3) treatment concerns, (4) difficulties parenting and (5) emotional burden. Most prominent features that resonated across the interviews which led to insecurity by parents were: insufficient pre-hospital information, unfiltered online information and the lack of overview of the patient journey. CONCLUSION: This study offers novel insights into parental experiences in DDH care. Parents were generally satisfied with DDH care provided by the hospital. The biggest challenges were to cope with (1) insufficient and unfiltered information, (2) the lack of patient journey overview and (3) practical problems and emotional doubts, which led to concerns during treatment. Future research and interventions should focus on optimising information provision and guidance with practical and emotional support for parents of children with DDH.

Evolving gene therapy approaches for osteosarcoma using viral vectors: review.

This review begins with an introduction to the malignant bone tumor, osteosarcoma [OS] and then moves to a discussion of the commonly used vectors for gene transfer. We first briefly highlight non-viral vectors including polymeric and liposomal delivery systems but concentrate predominantly on the 5 leading viral vectors used in cancer gene therapy, specifically retroviruses, adeno-associated viruses, herpes viruses and lentiviruses with the most detailed analysis reserved for adenoviruses. The 3 main strategies for gene therapy in osteosarcoma are next summarized. As part of this review, the several prodrug-converting enzymes utilized in OS suicide gene therapy are examined. The text then turns to a discussion of adenovirus-mediated gene transfer and the need for tumor targeting via transductional or transcriptional approaches. Because of practical problems with use of replication-incompetent viruses in achieving complete tumor kill in vivo, virotherapy utilizing replication competent viruses has come to the fore. This topic is, thus, next reviewed which allows for a natural transition to a discussion of armed therapeutic viruses many of which are conditionally replicating adenoviruses carrying transgenes with established anti-tumor efficacy. We recognize that several other issues have arisen which hamper progress in the field of cancer gene therapy. We, therefore, review viral-induced toxicity in the host and vector delivery issues which have been found to potentially influence safety. We end with a brief perspective including commenting on animal models used in examining delivery strategies for osteosarcoma gene therapy. The challenges remaining are touched upon most especially the need to deal with pulmonary metastatic disease from OS.

Expression of DNA topoisomerase IIalpha and topoisomerase IIbeta genes predicts survival and response to chemotherapy in patients with small cell lung cancer.

Drug resistance is a major problem in patients with small cell lung cancer; in fact, most die of resistant disease, despite an initial response. Several markers of drug resistance have been described in preclinical models, but the mechanism of drug resistance in lung cancer patients remains unknown. The objective of this study was to evaluate the role of the expression of a number of markers of drug resistance, proliferation, and apoptosis in relation to response to chemotherapy and survival in patients with small cell lung cancer. Tumor samples were derived from 93 previously untreated patients who were randomized in a Phase III study to receive cyclophosphamide, epirubicine, and etoposide or cyclophosphamide, epirubicine and vincristine alternating with carboplatin and etoposide. Paraffin-embedded samples, derived from the primary tumor site prior to chemotherapy, were analyzed by immunohistochemistry for expression of markers implicated in drug resistance [topoisomerase (topo) IIalpha, topo IIbeta, and multidrug resistance-associated protein], apoptosis (p53, p21, and bcl-2), or proliferation (Ki67). Response prediction was analyzed by chi2 test and logistic regression analysis; overall and disease-free survival curves were compared by log-rank test and Cox regression analysis. Shorter survival was observed in patients with extensive disease (P = 0.037) and poorer performance status (P = 0.028) and in patients whose tumors expressed high topo IIalpha levels (P = 0.01) and high Ki67 (P = 0.024). By multivariate analysis, the following factors were found to be predictive for worse survival: high expression levels of topo IIalpha, Ki67, and bcl-2; male sex; and extensive disease. High topo IIbeta expression was found to be predictive for lower overall and complete response rate. No relationship between apoptotic pathway markers or MRP and response to chemotherapy was observed. In conclusion, high expression of topo IIalpha was predictive of worse survival, and high expression of topo IIbeta was predictive of lower response rates. Furthermore, lower survival probability was observed in patients with bcl-2-positive tumors. Immunohistochemical assessment of these markers in diagnostic biopsies may give important prognostic information and may help selecting patients in the worse prognostic categories for new therapeutic strategies.

Molecular alterations as target for therapy in metastatic osteosarcoma: a review of literature.

Treating metastatic osteosarcoma (OS) remains a challenge in oncology. Current treatment strategies target the primary tumour rather than metastases and have a limited efficacy in the treatment of metastatic disease. Metastatic cells have specific features that render them less sensitive to therapy and targeting these features might enhance the efficacy of current treatment. A detailed study of the biological characteristics and behaviour of metastatic OS cells may provide a rational basis for innovative treatment strategies. The aim of this review is to give an overview of the biological changes in metastatic OS cells and the preclinical and clinical efforts targeting the different steps in OS metastases and how these contribute to designing a metastasis directed treatment for OS.

Different susceptibility of osteosarcoma cell lines and primary cells to treatment with oncolytic adenovirus and doxorubicin or cisplatin.

Despite improvements in treatment regimens for osteosarcoma (OS) patients, survival rate has not increased over the last two decades. New treatment modalities are therefore warranted. Preclinical results with conditionally replicative adenoviruses (CRAds) to treat OS are promising. One type of CRAd that was effective against OS cells is Ad5-Delta24RGD. In other types of cancer, CRAds have been shown to interact synergistically with chemotherapeutic agents. Chemotherapy for OS often includes doxorubicin and cisplatin. Therefore, we explored combination treatment of OS cell lines and primary OS cell cultures with Ad5-Delta24RGD and doxorubicin or cisplatin. On OS cell lines, combination treatment was additive to synergistic. Surprisingly, however, on seven of eight primary OS samples no such combination effects were observed. In contrast, in many cases chemotherapy even inhibited CRAd-mediated cell killing. The inhibitory effect of doxorubicin on Ad5-Delta24RGD in primary OS cells appeared to correlate with slow cell growth rate; reduced viral replication and absence of chemotherapy-induced G2 cell cycle arrest. Our results point to the possibility that, at least for OS, virotherapy and chemotherapy should best not be performed simultaneously. In general, our work underscores the importance of testing new genetic anticancer agents and treatment regimens on primary cancer specimens.

Gene-directed enzyme prodrug therapy with carboxylesterase enhances the anticancer efficacy of the conditionally replicating adenovirus AdDelta24.

Conditionally replicating adenoviruses (CRAds) selectively replicate in and thereby kill cancer cells. The CRAd AdDelta24 with pRb-binding-deficient E1A kills cancer cells efficiently. Arming CRAds with genes encoding prodrug-converting enzymes could allow for enhanced anticancer efficacy by the combined effects of oncolytic replication and local prodrug activation. Here, we investigated combination treatment of human colon cancer cell lines with AdDelta24-type CRAds and gene-directed enzyme prodrug therapy (GDEPT) using two different enzyme/prodrug systems, that is, thymidine kinase/ganciclovir (TK/GCV) and carboxylesterase (CE)/CPT-11. On all three cell lines tested, GDEPT with TK/GCV made CRAd treatment less efficacious. In contrast, expression of a secreted form of CE (sCE2) combined with CPT-11 treatment markedly enhanced the efficacy of AdDelta24 virotherapy. Based on this observation, we constructed an AdDelta24 variant expressing sCE2. In the absence of CPT-11, this new CRAd Ad5-Delta24.E3-sCE2 was similarly effective as its parent in killing human colon cancer cells. Low concentrations of CPT-11 inhibited Ad5-Delta24.E3-sCE2 propagation. Nevertheless, CPT-11 specifically augmented the cytotoxicity of Ad5-Delta24.E3-sCE2 against all three-colon cancer cell lines. Hence, the positive contribution of sCE2/CPT-11 GDEPT to colon cancer cytotoxicity outweighed its negative influence on CRAd propagation. Therefore, CRAd-sCE2/CPT-11 combination therapy appears useful for more effective treatment of colon cancer.

Epidermal growth factor receptor targeting enhances adenoviral vector based suicide gene therapy of osteosarcoma.

BACKGROUND: Despite improvements in the treatment of osteosarcoma (OS) there are still too many patients who cannot benefit from current treatment modalities. Therefore, new therapeutic approaches are warranted. Here we explore the efficacy of targeted adenoviral based suicide gene therapy. METHODS AND RESULTS: Immunohistochemistry and FACS analysis detected low or absent expression levels of the primary adenovirus receptor CAR on human primary OS and human OS cell lines. These results predict a low infection efficiency and thus a reduced therapeutic effect. Targeting the adenoviruses to another receptor highly expressed on OS could overcome this limitation. We found epidermal growth factor receptor (EGFR) to be widely expressed on primary OS. Immunohistochemistry on primary tumor samples and FACS analysis on primary short-term cultures and four OS cell lines showed that EGFR was consistently expressed. The recombinant bispecific single-chain antibody 425-s11 redirects adenoviral vectors towards the EGFR. Adenovirus transduction experiments in the presence or absence of 425-s11 showed significantly enhanced gene transfer with the targeted adenoviral vector compared with the native vector (OS cell lines 2.5 to 7.2 times enhanced gene transfer and OS primary short term cultures 1.7 to 10 times enhanced gene transfer). On this basis, targeted suicide gene therapy experiments with AdCMVHSV-TK in combination with ganciclovir were performed. These experiments demonstrated up to 3.5-fold enhanced kill of OS cell lines and primary short-term cultures by the EGFR targeted vector. CONCLUSIONS: Suicide gene therapy with adenovirus targeted towards EGFR may have favorable therapeutic characteristics for future gene therapy applications in OS.