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.

Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis.

More than 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease-modifying treatments for this disabling condition. Common polymorphic variants in ALDH1A2, which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. Both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo and identifies RAMBAs as potential disease-modifying drugs for OA.

A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb.

A locus for triphalangeal thumb, variably associated with pre-axial polydactyly, was previously identified in the zone of polarizing activity regulatory sequence (ZRS), a long range limb-specific enhancer of the Sonic Hedgehog (SHH) gene at human chromosome 7q36.3. Here, we demonstrate that a 295T>C variant in the human ZRS, previously thought to represent a neutral polymorphism, acts as a dominant allele with reduced penetrance. We found this variant in three independently ascertained probands from southern England with triphalangeal thumb, demonstrated significant linkage of the phenotype to the variant (LOD = 4.1), and identified a shared microsatellite haplotype around the ZRS, suggesting that the probands share a common ancestor. An individual homozygous for the 295C allele presented with isolated bilateral triphalangeal thumb resembling the heterozygous phenotype, suggesting that the variant is largely dominant to the wild-type allele. As a functional test of the pathogenicity of the 295C allele, we utilized a mutated ZRS construct to demonstrate that it can drive ectopic anterior expression of a reporter gene in the developing mouse forelimb. We conclude that the 295T>C variant is in fact pathogenic and, in southern England, appears to be the most common cause of triphalangeal thumb. Depending on the dispersal of the founding mutation, it may play a wider role in the aetiology of this disorder.

The Effect of Age on Outcome in Excision of Chronic Osteomyelitis with Free Muscle Flap Reconstruction.

Introduction: Curative surgical treatment of chronic osteomyelitis often requires free tissue transfer if there is significant soft tissue compromise. We investigated whether age influenced outcomes of curative osteomyelitis excision in those patients requiring free muscle flap soft tissue reconstruction. Methods: We assessed ninety-five consecutive patients treated with excision of chronic osteomyelitis, skeletal stabilisation/reconstruction and free muscle transfer between 2006 and 2012. We compared outcomes of those aged ≥60 years (n=23) with those <60 years old (n=72). Results: Groups were similar with regard to Cierny and Mader anatomic type and physiological host classification. Length of procedure and length of hospital stay were similar for both groups. There was a greater proportion of ASA grade III patients in the older cohort. Infection recurrence occurred in one of the older cohort (4.3%) and in seven patients in the younger cohort (9.9%) at a mean follow-up of 42 months (range 11-131 months), this was not statistically significant (p=0.27874). There were five free flap losses (6.9%) in the younger group and none in the older group. A greater proportion of patients from the younger cohort required further unplanned surgery (28%) compared to the older group (4.3%), which was statistically significant (p=0.01174). Seven patients (7.4%) had serious medical complications - five of whom were in the younger cohort, including one mortality. Conclusions: Both the young and old can enjoy satisfactory outcomes from surgical resection of chronic osteomyelitis with simultaneous orthoplastic reconstruction including free tissue transfer. Age alone should not be a barrier to potentially curative surgical treatment.

Retrospective audit of 957 consecutive 18F-FDG PET-CT scans compared to CT and MRI in 493 patients with different histological subtypes of bone and soft tissue sarcoma.

BACKGROUND: The use of 18F-FDG PET-CT (PET-CT) is widespread in many cancer types compared to sarcoma. We report a large retrospective audit of PET-CT in bone and soft tissue sarcoma with varied grade in a single multi-disciplinary centre. We also sought to answer three questions. Firstly, the correlation between sarcoma sub-type and grade with 18FDG SUVmax, secondly, the practical uses of PET-CT in the clinical setting of staging (during initial diagnosis), restaging (new baseline prior to definitive intervention) and treatment response. Finally, we also attempted to evaluate the potential additional benefit of PET-CT over concurrent conventional CT and MRI. METHODS: A total of 957 consecutive PET-CT scans were performed in a single supra-regional centre in 493 sarcoma patients (excluding GIST) between 2007 and 2014. We compared, PET-CT SUVmax values in relation to histology and FNCCC grading. We compared PET-CT findings relative to concurrent conventional imaging (MRI and CT) in staging, restaging and treatment responses. RESULTS: High-grade (II/III) bone and soft tissue sarcoma correlated with high SUVmax, especially undifferentiated pleomorphic sarcoma, leiomyosarcoma, translocation induced sarcomas (Ewing, synovial, alveolar rhabdomyosarcoma), de-differentiated liposarcoma and osteosarcoma. Lower SUVmax values were observed in sarcomas of low histological grade (grade I), and in rare subtypes of intermediate grade soft tissue sarcoma (e.g. alveolar soft part sarcoma and solitary fibrous tumour). SUVmax variation was noted in malignant peripheral nerve sheath tumours, compared to the histologically benign plexiform neurofibroma, whereas PET-CT could clearly differentiate low from high-grade chondrosarcoma. We identified added utility of PET-CT in addition to MRI and CT in high-grade sarcoma of bone and soft tissues. An estimated 21% overall potential benefit was observed for PET-CT over CT/MRI, and in particular, in 'upstaging' of high-grade disease (from M0 to M1) where an additional 12% of cases were deemed M1 following PET-CT. CONCLUSIONS: PET-CT in high-grade bone and soft tissue sarcoma can add significant benefit to routine CT/MRI staging. Further prospective and multi-centre evaluation of PET-CT is warranted to determine the actual predictive value and cost-effectiveness of PET-CT in directing clinical management of clinically complex and heterogeneous high-grade sarcomas.

Nonsense-mediated decay and the molecular pathogenesis of mutations in SALL1 and GLI3.

Mutations in SALL1 and GLI3 are responsible for human limb malformation syndromes. The molecular pathophysiology of these mutations is incompletely understood, and many conclusions have been drawn from studies performed in the mouse. We identified truncating mutations in SALL1 and GLI3 in patients with limb malformation and studied the contribution of nonsense-mediated decay (NMD) to the expression of mutant mRNA in patient-derived fibroblasts. Quantification of the relative proportions of mutant and wild-type alleles was performed by pyrosequencing. In SALL1, a mutant allele causing Townes-Brocks syndrome was unexpectedly resistant to NMD, whereas a different mutation causing a much milder phenotype was susceptible to NMD. In GLI3, all three mutant alleles tested were susceptible to NMD. This work provides novel insights into the molecular pathophysiology of SALL1 and GLI3 mutations, extends the phenotypic spectrum of SALL1 mutations, and provides an example of a human mutation which does not follow the usual accepted positional rules governing mammalian NMD. (c) 2007 Wiley-Liss, Inc.

Metastatic meningioma presenting as a malignant soft tissue tumour.

BACKGROUND: Extracranial metastasis of malignant meningioma to soft tissues is extremely rare and its clinical, radiological and pathological features are not well-characterised. CASE PRESENTATION: We report a case of a 58 year old man who presented with a mobile mass within the left trapezius muscle. The patient had previously undergone surgery for a right frontal lobe high grade anaplastic meningioma. Histology of the soft tissue lesion showed metastatic anaplastic meningioma with clumps of pleomorphic tumour cells which expressed epithelial membrane antigen, cytokeratin and P63 but were negative for other epithelial and mesenchymal markers. A PET-CT scan revealed additional metastatic lesions in the left pleura, liver and iliac bone. CONCLUSIONS: Metastatic malignant meningioma can very rarely present as a high grade pleomorphic malignant soft tissue tumour and needs to be distinguished from soft tissue sarcomas and metastatic carcinomas that express epithelial antigens.

Quality of Life and Surgical Outcomes After Soft-Tissue Reconstruction of Complex Oncologic Defects of the Spine and Sacrum.

BACKGROUND: Tumor-related spinal surgery has been revolutionized by recent advances in spinal stabilization, modern neuroimaging, and perioperative intensive medicine. This study examines clinical outcomes and factors associated with complications following reconstruction of complex oncologic defects of the spine and sacrum, in an attempt to increase preoperative recognition of high-risk patients with diminished wound-healing capacity and to optimize clinical outcomes in this cohort. METHODS: We performed a retrospective analysis of fifty-five consecutive patients who underwent soft-tissue reconstruction with or without osseous stabilization of defects following spinal or sacral tumor resection at a quaternary referral center over a twelve-year period. Surgical outcomes included the prevalence of postoperative complications and success of wound closure at the latest follow-up. Health-related quality-of-life outcomes were assessed using the EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire) and SF-36 (Short Form-36) questionnaires. RESULTS: The mean age of the cohort was 46.7 years (range, eighteen to seventy-one years), with a male preponderance (3:1). Soft-tissue reconstructions (n = 70 flaps) were performed in the fifty-five patients. Overall, 36.3% of patients had wound complications. There was a twofold higher wound complication rate after delayed (60%) compared with immediate (29%) reconstruction (p = 0.03). Patients undergoing delayed reconstruction reported significantly lower SF-36 and EORTC QLQ-C30 scores. CONCLUSIONS: Orthoplastic management of spinal tumors should involve a strategy for preoperative recognition of patients at risk of compromised wound-healing. Prophylactic soft-tissue reconstruction can achieve stable definitive wound closure and potentially avoid the need for secondary procedures in appropriately selected patients. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

A misdiagnosed burn: necrotising fasciitis in an elderly patient.

A 91-year-old man was admitted having been found unresponsive in his bed. He was previously well, but had sustained a laceration over the dorsum of his forearm after a recent fall. Initial appearances were innocuous, and suggestive of a superficial wound infection. A review of the wound by the plastic surgeons led to the diagnosis of a full-thickness burn, despite a lack of supporting evidence in the history. No clinician who had initially assessed the patient was involved in his ongoing care. Rapid clinical deterioration ensued, with sepsis and deteriorating mental state. Necrosis spread rapidly up his arm, and the diagnosis of necrotising fasciitis was made. The patient was urgently taken to theatre for circumferential excision of the necrotic tissue. He was subsequently managed on the intensive care unit where he made a promising initial recovery, but later died from pneumonia in the ward.

Local recurrence and assessment of sentinel lymph node biopsy in deep soft tissue leiomyosarcoma of the extremities.

BACKGROUND: Leiomyosarcoma of deep soft tissues of the extremities is a rare malignant tumour treated primarily by surgery. The incidence of local recurrence and lymph node metastasis is uncertain and it is not known whether a sentinel lymph node biopsy is indicated in these tumours. METHODS: A retrospective review of patients treated for extremity deep soft tissue leiomyosarcoma at our institution over a 10-year period was conducted. Patients developing local recurrence or lymph node metastasis were identified. The presence or absence of lymphatics in the primary tumours was assessed by immunohistochemical expression of LYVE-1 and podoplanin. RESULTS: 27 patients (mean age 62 years) were included in the study. 15 were female and 12 male. Lymph node metastasis was seen in only two cases (7%); intratumoural lymphatics were identified in the primary tumours of both these cases. Local recurrence occurred in 25.9% of cases despite complete excision and post-operative radiotherapy; the mean time to recurrence was 10.1 months. CONCLUSION: On the basis of this study, we do not advocate sentinel lymph node biopsy in this group of patients except in those cases in which intratumoural lymphatics can be demonstrated. Close follow up is important especially for high grade leiomyosarcomas, particularly in the first year, as these tumours have a high incidence of local recurrence.

A 10-year review of benign and malignant peripheral nerve sheath tumors in a single center: clinical and radiographic features can help to differentiate benign from malignant lesions.

BACKGROUND: Malignant peripheral nerve sheath tumors are rare, and their aggressive nature mandates treatment in specialist centers. In contrast, benign peripheral nerve sheath tumors are common and are treated by a variety of specialist surgeons, including plastic surgeons. The authors aimed to detect features in the clinical presentation of peripheral nerve sheath tumors that point toward a diagnosis of malignant peripheral nerve sheath tumor and therefore prompt referral to a specialist center. METHODS: All histologically diagnosed primary peripheral nerve sheath tumors from January of 1995 to December of 2004 were identified from histopathology records. Notes were reviewed and analyzed with regard to symptoms, signs, radiology, electrophysiology, surgery, and pathology. Statistical comparisons used Fisher's exact test and the Mann-Whitney test. RESULTS: During the study period, 32 cases of malignant peripheral nerve sheath tumor in 30 patients were treated. Factors in the clinical evaluation that significantly predicted the presence of malignant peripheral nerve sheath tumor included site, large size, depth in relation to the deep fascia, short duration of symptoms, and pain. Magnetic resonance imaging and computed tomography were sensitive and specific ways of confirming the clinical diagnosis. Interestingly, schwannomata were harder to distinguish from malignant peripheral nerve sheath tumors both clinically and radiologically. CONCLUSIONS: The authors have reviewed their institutional experience of peripheral nerve sheath tumors over a 10-year period. Their results will help to focus clinical and radiologic investigation of patients presenting with these tumors.

The Cook-Swartz venous Doppler probe for the post-operative monitoring of free tissue transfers in the United Kingdom: a preliminary report.

Accurate assessment of the perfusion of free tissue transfers has always been a challenge for surgeons undertaking microvascular reconstructive procedures. The complexities of flap microcirculation are often difficult to assess despite all the subjective and objective examination techniques available today, particularly when the free tissue transfer is buried, and not visible for monitoring. The Cook-Swartz venous Doppler system is a technique for monitoring venous flow in free tissue transfer consisting of an implantable, removable, 20 MHz ultrasonic probe around the venous pedicle and a battery operated portable monitor. We perceive it as a quick and easy to use system, which in our study was well received by both medical and nursing staff. It can be used in conjunction with other monitoring techniques and we found it of value following revascularisation, during inset and in post-operative monitoring of free flaps particularly when operating outside our base hospital. We believe our initial experiences, on 24 patients, with the device, supports the use of a Cook-Swartz probe as an adjunct to traditional clinical monitoring techniques. We have had no technical difficulties with its application, use and removal, so far and we plan to continue with its use when it becomes available outside of a clinical trial.