Osteohematology: To be or Notch to be.

Osteohematology is an emerging research field that studies the crosstalk between hematopoietic and bone stromal cells, to elucidate the mechanisms of hematological and skeletal malignancies and diseases. The Notch is an evolutionary conserved developmental signaling pathway, with critical roles in embryonic development by controlling cell proliferation and differentiation. However, the Notch pathway is also critically involved in cancer initiation and progression, such as osteosarcoma, leukemia, and multiple myeloma. The Notch-mediated malignant cells dysregulate bone and bone marrow cells in the tumour microenvironment, resulting in disorders ranging from osteoporosis to bone marrow dysfunction. To date, the complex interplay of Notch signaling molecules in hematopoietic and bone stromal cells is still poorly understood. In this mini-review, we summarize the crosstalk between cells in bone and bone marrow and their influence under the Notch signaling pathway in physiological conditions and in tumour microenvironment.

Will virtual multidisciplinary team meetings become the norm for musculoskeletal oncology care following the COVID-19 pandemic? - experience from a tertiary sarcoma centre.

BACKGROUND: Like with all cancers, multidisciplinary team (MDT) meetings are the norm in bone and soft tissue tumour (BST) management too. Problem in attendance of specialists due to geographical location is the one of the key barriers to effective functioning of MDTs. To overcome this problem, virtual MDTs involving videoconferencing or telemedicine have been proposed, but however this has been seldom used and tested. The COVID-19 pandemic forced the implementation of virtual MDTs in the Oxford sarcoma service in order to maintain normal service provision. We conducted a survey among the participants to evaluate its efficacy. METHODS: An online questionnaire comprising of 24 questions organised into 4 sections was circulated among all participants of the MDT after completion of 8 virtual MDTs. Opinions were sought comparing virtual MDTs to the conventional face-to-face MDTs on various aspects. A total of 36 responses were received and were evaluated. RESULTS: 72.8% were satisfied with the depth of discussion in virtual MDTs and 83.3% felt that the decision-making in diagnosis had not changed following the switch from face-to-face MDTs. About 86% reported to have all essential patient data was available to make decisions and 88.9% were satisfied with the time for discussion of patient issues over virtual platform. Three-fourths of the participants were satisfied (36.1% - highly satisfied; 38.9% - moderately satisfied) with virtual MDTs and 55.6% of them were happy to attend MDTs only by the virtual platform in the future. Regarding future, 77.8% of the participants opined that virtual MDTs would be the future of cancer care and an overwhelming majority (91.7%) felt that the present exercise would serve as a precursor to global MDTs involving specialists from abroad in the future. CONCLUSION: Our study shows that the forced switch to virtual MDTs in sarcoma care following the unprecedented COVID-19 pandemic to be a viable and effective alternative to conventional face-to-face MDTs. With effective and efficient software in place, virtual MDTs would also facilitate in forming extended MDTs in seeking opinions on complex cases from specialists abroad and can expand cancer care globally.

What Proportion of Patients with Bone and Soft Tissue Tumors Contracted Coronavirus-19 and Died From Surgical Procedures During the Initial Period of the COVID-19 Pandemic? Results From the Multicenter British Orthopaedic Oncology Society Observational Study.

BACKGROUND: Delivering uninterrupted cancer treatment to patients with musculoskeletal tumors has been essential during the rapidly evolving coronavirus 2019 (COVID-19) pandemic, as delays in management can be detrimental. Currently, the risk of contracting COVID-19 in hospitals when admitted for surgery and the susceptibility due to adjuvant therapies and associated mortality due to COVID-19 is unknown, but knowledge of these potential risks would help treating clinicians provide appropriate cancer care. QUESTIONS/PURPOSES: (1) What is the risk of hospital-acquired COVID-19 in patients with musculoskeletal tumors admitted for surgery during the initial period of the pandemic? (2) What is the associated mortality in patients with musculoskeletal tumors who have contracted COVID-19? (3) Are patients with musculoskeletal tumors who have had neoadjuvant therapy (chemotherapy or radiation) preoperatively at an increased risk of contracting COVID-19? (4) Is a higher American Society of Anesthesiologists (ASA) grade in patients with musculoskeletal tumors associated with an increased risk of contracting COVID-19 when admitted to the hospital for surgery? METHODS: This retrospective, observational study analyzed patients with musculoskeletal tumors who underwent surgery in one of eight specialist centers in the United Kingdom, which included the five designated cancer centers in England, one specialist soft tissue sarcoma center, and two centers from Scotland between March 12, 2020 and May 20, 2020. A total of 347 patients were included, with a median (range) age of 53 years (10 to 94); 60% (207 of 347) were men, and the median ASA grade was II (I to IV). These patients had a median hospital stay of 8 days (0 to 53). Eighteen percent (61 of 347) of patients had received neoadjuvant therapy (8% [27] chemotherapy, 8% [28] radiation, 2% [6] chemotherapy and radiation) preoperatively. The decision to undergo surgery was made in adherence with United Kingdom National Health Service and national orthopaedic oncology guidelines, but specific data with regard to the number of patients within each category are not known. Fifty-nine percent (204 of 347) were negative in PCR testing done 48 hours before the surgical procedure; the remaining 41% (143 of 347) were treated before preoperative PCR testing was made mandatory, but these patients were asymptomatic. All patients were followed for 30 days postoperatively, and none were lost to follow-up during that period. The primary outcome of the study was contracting COVID-19 in the hospital after admission. The secondary outcome was associated mortality after contracting COVID-19 within 30 days of the surgical procedure. In addition, we assessed whether there is any association between ASA grade or neoadjuvant treatment and the chances of contracting COVID-19 in the hospital. Electronic patient record system and simple descriptive statistics were used to analyze both outcomes. RESULTS: Four percent (12 of 347) of patients contracted COVID-19 in the hospital, and 1% (4 of 347) of patients died because of COVID-19-related complications. Patients with musculoskeletal tumors who contracted COVID-19 had increased mortality compared with patients who were asymptomatic or tested negative (odds ratio 55.33 [95% CI 10.60 to 289.01]; p < 0.001).With the numbers we had, we could not show that adjuvant therapy had any association with contracting COVID-19 while in the hospital (OR 0.94 [95% CI 0.20 to 4.38]; p = 0.93). Increased ASA grade was associated with an increased likelihood of contracting COVID-19 (OR 58 [95% CI 5 to 626]; p < 0.001). CONCLUSION: Our results show that surgeons must be mindful and inform patients that those with musculoskeletal tumors are at risk of contracting COVID-19 while admitted to the hospital and some may succumb to it. Hospital administrators and governmental agencies should be aware that operations on patients with lower ASA grade appear to have lower risk and should consider restructuring service delivery to ensure that procedures are performed in designated COVID-19-restricted sites. These measures may reduce the likelihood of patients contracting the virus in the hospital, although we cannot confirm a benefit from this study. Future studies should seek to identify factors influencing these outcomes and also compare surgical complications in those patients with and without COVID-19. LEVEL OF EVIDENCE: Level III, therapeutic study.

Service delivery during the COVID-19 pandemic: Experience from The Oxford Bone Tumour and Soft Tissue Sarcoma service.

The COVID-19 (Coronavirus disease 2019) pandemic has caused an unprecedented strain on healthcare systems across the globe. Apart from being a major hurdle to delivery of basic healthcare services, this may be associated with potential harm for cancer patients. Usually being immunocompromised, cancer patients are at a higher risk of contracting the disease and with hospitals being a potential source of the infection, an urgent need to reorganise the structure of delivery of cancer care is essential. Cancer departments must balance patient care whilst also minimising transmission among patients and healthcare professionals. The Oxford Sarcoma Service was re-structured based on the guidelines issued by the National Health Service (NHS) and the British Orthopaedic Oncology Society (BOOS) to deliver unhindered care to patients. Prioritising patients who needed urgent surgery, weighing the risk-benefit ratio while delivering adjuvant treatments and conducting regular virtual multi-disciplinary team (MDT) meetings combined with personal protection equipment (PPE) usage by all involved healthcare workers were salient features in terms of ensuring the delivery of effective care during the COVID-19 pandemic. Our new model of modus operandi during this global crisis was effective in delivering high standard of care to patients and might serve as a guide to similar units managing bone and soft tissue tumours.

Patient safety associated with the surgical treatment of bone and soft tissue tumours during the COVID-19 pandemic-results from an observational study at the Oxford Sarcoma Service.

PURPOSE: Deferring cancer surgery can have profound adverse effects including patient mortality. During the COVID-19 pandemic, departmental reorganisation and adherence to evolving guidelines enabled provision of uninterrupted surgical care to patients with bone and soft tissue tumours (BST) in need of surgery. We reviewed the outcomes of surgeries on BST during the first two months of the pandemic at one of the tertiary BST centres in the UK. MATERIALS AND METHODS: Between 12 March 2020 and 12 May 2020, 56 patients of a median age of 57 years (18-87) underwent surgery across two sites: index hospital (n = 27) and COVID-free facility (n = 29). Twenty-five (44.6%) patients were above the age of 60 years and 20 (35.7%) patients were in ASA III and ASA IV category. The decision to offer surgery was made in adherence with the guidelines issued by the NHS, BOOS and BSG. RESULTS: At a minimum follow-up of 30 days post-surgery, 54 (96.4%) patients were recovering well. Thirteen patients (23.2%) had post-operative complications which included four (7.1%) patients developing pulmonary embolism. The majority of complications (12/13 = 92.7%) occurred in ASA III and IV category patients. Four (7.1%) patients contracted COVID-19, of which three required escalation of care due to pulmonary complications and two (3.6%) died. Patients < 60 years of age had significantly less complications than those > 60 years (p < 0.001). Patients operated on in the COVID-free facility had fewer complications compared with those operated on at the index hospital (p < 0.027). CONCLUSION: In spite of the favourable results in majority of our patients, our study shows that patients with sarcoma operated at the height of the pandemic are at a risk of contracting COVID-19 and also having associated with mortality. The use of a COVID-free facility, surgery in patients < 60 60 years and in ASA I & II category are associated with better outcomes. If a second wave occurs, a serious consideration should be given to ways of minimising the risk of contracting COVID-19 in these vulnerable patients either by using COVID-free facilities or delaying treatment until peak of infection has passed.

Clinical Outcome of Massive Endoprostheses Used for Managing Periprosthetic Joint Infections of the Hip and Knee.

BACKGROUND: Endoprosthetic replacement (EPR) is an option for management of massive bone loss resulting from infection around failed lower limb implants. The aim of this study is to determine the mid-term outcome of EPRs performed in the treatment of periprosthetic joint infection (PJI) and infected failed osteosyntheses around the hip and knee joint and identify factors that influence it. METHODS: We retrospectively reviewed all hip and knee EPRs performed between 2007 and 2014 for the management of chronic infection following complex arthroplasty or fracture fixation. Data recorded included indication for EPR, number of previous surgeries, comorbidities, and organism identified. Outcome measures included PJI eradication rate, complications, implant survival, mortality, and functional outcome (Oxford Hip or Knee Score). RESULTS: Sixty-nine EPRs (29 knees and 40 hips) were performed with a mean age of 68 years (43-92). Polymicrobial growth was detected in 36% of cases, followed by coagulase-negative staphylococci (28%) and Staphylococcus aureus (10%). Recurrence of infection occurred in 19 patients (28%): 5 were treated with irrigation and debridement, 5 with revision, 1 with above-knee amputation, and 8 remain on long-term antibiotics. PJI eradication was achieved in 50 patients (72%); the chance of PJI eradication was greater in hips (83%) than in knees (59%) (P = .038). The 5-year implant survivorship was 81% (95% confidence interval 74-88). The mean Oxford Hip Score and Oxford Knee Score were 22 (4-39) and 21 (6-43), respectively. CONCLUSION: This study supports the use of EPRs for eradication of PJI in complex, multiply revised cases. We describe PJI eradication rate of 72% with acceptable functional outcome.

Giant cell tumour of the distal radius/ulna: response to pre-operative treatment with short-term denosumab.

BACKGROUND: Treatment of giant cell tumour of bone (GCTB) of the distal radius/ulna poses a surgical challenge, as complex reconstructive surgery may be required. This study evaluates the clinical, radiological and pathological findings in five cases of GCTB of the distal forearm where a 3 month course of denosumab was given prior to surgery. METHODS: Patients with biopsy proven distal forearm GCTB, treated for 3 months with denosumab, followed by salvage surgery (curettage and cementation) were included. Wrist pain and function were assessed using the modified Mayo Wrist Score (MMWS). Plain radiographs, MRI and PET/CT were performed pre-treatment and 2 months after initiation of denosumab therapy. Histological comparison was made between the original biopsy and surgical curettage specimens. RESULTS: Five patients with an average age of 25 years were included in the study. Improvement in wrist pain and function was seen in all patients with the average MMWS increasing from 30 pre-treatment to 85 at 3 months. Plain radiographs demonstrated marginal sclerosis in all cases with reconstitution of cortical and subarticular bone by 2 months; internal matrix sclerosis and osseous consolidation was more variable. Increased tumour heterogeneity and low signal were observed on T2-weighted MR images. PET/CT revealed a decrease in average SUV from 14.8 pre-treatment to 4.7 at 2 months. Histology showed disappearance of osteoclasts and increased fibro-osseous tissue. Denosumab treatment has the potential to facilitate salvage surgery, thus avoiding bone resection and graft reconstruction. A good outcome was achieved apart from local recurrence in one case. Follow up ranged from 17 to 54 months. CONCLUSION: Distal forearm GCTB responds clinically, radiologically and histologically to a short course of pre-operative denosumab therapy, which has the potential to facilitate salvage surgery.

Metal wear-induced pseudotumour following an endoprosthetic knee replacement for Ewing sarcoma.

Pseudotumours are well recognised as a complication of metal-on-metal hip arthroplasties and are thought to develop on the basis of an innate and adaptive immune response to cobalt-chrome (Co-Cr) wear particles. We report a case of a large pseudotumour that developed following a knee endoprosthetic replacement (EPR) undertaken for Ewing sarcoma. The lesion contained necrotic and degenerate connective tissue in which there were numerous scattered metal wear-containing macrophages, eosinophil polymorphs, lymphocytes, plasma cells and aseptic lymphocyte-dominated vascular-associated lesion-like lymphoid aggregates. Metal ion levels were elevated. No evidence of infection or tumour was noted and it was concluded that the lesion was most likely an inflammatory pseudotumour developing on the basis of an innate and adaptive immune response to components of Co-Cr metal wear derived from the knee EPR.

Surgical treatment of recurrent proximal tibio-fibular joint ganglion cysts.

BACKGROUND: Complex symptomatic ganglion cysts arising from the proximal tibio-fibular joint (PTJ) are not an uncommon presentation in specialist knee clinics and can be managed by aspiration or excision. There is, however, a high rate of recurrence and often there is progressive involvement of the common peroneal nerve (CPN) and its branches, and permanent nerve damage may result. METHODS: This study is a review of the outcome of recalcitrant and recurrent cyst disease with CPN involvement treated by proximal fibulectomy. Nine patients with clinical and radiological diagnosis of a ganglion cyst involving the proximal tibio-fibular joint were treated by proximal fibulectomy. Average age was 47.2years (19 to 75). Patients were followed up clinically and radiologically. Medical notes were reviewed to assess clinical/pathological characteristics, surgical outcome, recurrence rate and the symptoms of instability and nerve function. RESULTS: None of the patients were lost to follow-up. After an average follow-up of 83months (15 to 150), none of the patients had clinical or radiological evidence of recurrence. All patients were pain-free and had a complete resolution of nerve symptoms and no evidence of CPN injury. None of the patients complained of localised pain or knee instability and there were no wound healing problems. CONCLUSIONS: MRI now confirms TFJ-ganglion cysts to be more common than previously recognised. Where there is refractory disease with progressive nerve symptoms and evidence of nerve sheath involvement, joint excision by proximal fibulectomy gives a satisfactory functional result in controlling disease and preventing further nerve damage. LEVEL OF EVIDENCE: IV.

No difference in survivorship after unicompartmental knee arthroplasty with or without an intact anterior cruciate ligament.

PURPOSE: Anterior cruciate ligament deficiency (ACLD) has been considered a contraindication for Oxford unicompartmental knee arthroplasty (UKA) because of the reported higher incidence of failure when implanted in ACLD knees. However, given the potential advantages of UKA over total knee arthroplasty (TKA), we have performed UKA in a limited number of patients with ACL deficiency and end-stage medial compartment osteoarthritis (OA) over the past 11 years. The primary aim of this study was to establish the clinical outcome of this cohort; the secondary aim was to compare both clinical and radiographic data with a matched cohort of ACL-intact (ACLI) patients who have undergone UKA for anteromedial OA. METHODS: This retrospective observational study describes the clinical and radiological outcome in 46 medial Oxford UKAs implanted in 42 consecutive patients with ACL deficiency and concomitant symptomatic medial compartment OA at mean follow-up of 5 years. It also compares the outcomes with a matched cohort of UKA patients with an intact ACL (ACLI group). RESULTS: At the time of last follow-up, there was no significant difference in clinical results or survivorship between the two groups in this study. CONCLUSION: The successful short-term results of the ACLD group suggest ACL deficiency may not always be a contraindication to Oxford UKA as previously thought. Until long-term data is available, however, we maintain our recommendation that ACLD be considered a contraindication.

The imaging spectrum of peri-articular inflammatory masses following metal-on-metal hip resurfacing.

INTRODUCTION: Resurfacing metal-on-metal hip arthroplasty is increasing in popularity, especially in younger patients. To date, studies indicate that the procedure is associated with a good outcome in the medium-term. Formation of a peri-articuar mass is a rarely reported complication. In this study we analyse the imaging findings in patients with resurfacing implants presenting to our institution with peri-articular masses identified on cross sectional imaging. MATERIALS AND METHODS: All patients with documented peri-articular masses following resurfacing arthroplasty were included. The available imaging related to the masses was reviewed and the findings documented along with the patient's demographics. RESULTS: There were 10 patients (13 joints). All patients were female. Patients presented with periprosthetic anterior or posterolateral solid and cystic masses. The anterior masses involved psoas muscle and were predominately solid. The posterolateral masses were predominately cystic. In the three cases with bilateral arthroplasties, masses were detected in both hips. Histology in six cases showed features compatible with a type IV hypersensitivity reaction. CONCLUSIONS: The preponderance of females, the bilateral nature of the masses and the histological features suggest that peri-articular masses following resurfacing arthroplasty is due to the metal hypersensitivity.

Oncogenic hypophosphataemic osteomalacia: biomarker roles of fibroblast growth factor 23, 1,25-dihydroxyvitamin D3 and lymphatic vessel endothelial hyaluronan receptor 1.

Oncogenic osteomalacia (OOM) is characterised by tumour production of fibroblast growth factor 23 (FGF23) that results in hypophosphataemia and renal phosphate wasting, reduced 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) synthesis and osteomalacia. Here, we demonstrate the roles of serum FGF23 and 1,25(OH)2D3, together with the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), as biomarkers for OOM. A previously well 52-year-old man presented with a 2-year history of generalised musculoskeletal pain and proximal myopathy. He had hypophosphataemia, elevated serum alkaline phosphatase activity, low serum 1,25(OH)2D3 and a reduced tubular maximum of phosphate/glomerular filtration rate. These findings indicated a diagnosis of OOM, but magnetic resonance imaging (MRI) and octreotide scintigraphy did not identify any tumours. Treatment with oral phosphate and calcitriol resolved the symptoms and biochemical abnormalities within 6 months. Four years later, he relapsed whilst on treatment with oral phosphate and calcitriol. Serum FGF23 concentration was elevated and MRI identified a 2 cm tumour within Hoffa's fat pad of the left knee. Removal of the tumour resulted in a complete resolution of symptoms and normalisation of the serum biochemical abnormalities including serum FGF23. Histology demonstrated a phosphaturic mesenchymal tumour, mixed connective tissue variant (PMTMCT), which revealed immunostaining with anti-LYVE-1 antibody and hence the presence of lymphatic vessels. Serum FGF23 and 1,25(OH)2D3 were found to be reliable biomarkers for OOM. In addition, the demonstration of lymphatics in the PMTMCT helps to distinguish this tumour from most typical benign haemangiomas.

Oxford medial unicompartmental arthroplasty for focal spontaneous osteonecrosis of the knee.

BACKGROUND: Spontaneous osteonecrosis of the knee (SONK) is a distinct clinical condition occurring in patients without any associated risk factors. There is controversy as to the best method of treatment, and the available literature would suggest that patients with SONK have a worse outcome than those with primary osteoarthrosis when arthroplasty is performed. We assessed the outcome of medial unicompartmental knee arthroplasty (UKA) using the Oxford prosthesis for end-stage focal spontaneous osteonecrosis of the knee (SONK; Ahlbäck grades III and IV). PATIENTS AND METHODS: We assessed 29 knees (27 patients) with spontaneous osteonecrosis of the knee using the Oxford Knee Score. 26 knees had osteonecrosis of the medial femoral condyle and 3 had osteonecrosis of the medial tibial plateau. All had been operated on using the Oxford Medial Unicompartmental Knee Arthroplasty (UKA). This group was compared to a similar group (28 knees, 26 patients) who had undergone the same arthroplasty, but because of primary osteoarthrosis. Patients were matched for age, sex and time since operation. The mean length of follow-up was 5 (1-13) years. RESULTS: There were no implant failures in either group, but there was 1 death (from unrelated causes) 9 months after arthroplasty in the group with osteonecrosis. The mean Oxford Knee Score in the group with osteonecrosis was 38, and it was 40 in the group with osteoarthrosis. INTERPRETATION: Use of the Oxford Medial UKA for spontaneous focal osteonecrosis of the knee is reliable in the short to medium term, and gives results similar to those obtained when it is used for patients with primary osteoarthrosis.