Intraoperative near-infrared fluorescence guided surgery using indocyanine green (ICG) may aid the surgical removal of benign bone and soft tissue tumours.

BACKGROUND: Benign bone and soft tissue tumours encompass a broad, heterogenous range of tumours with varying clinical characteristics. These are often managed surgically with either curettage or marginal excision, but unfortunately have high rates of local recurrence. Indocyanine green (ICG) is a fluorescent dye which can be used to identify solid malignancies intraoperatively but its use is not yet established in benign bone and soft tissue tumours. This study aims to assess whether these tumours fluoresce when administered with ICG pre-operatively and whether this helps surgeons to identify tumour intra-operatively. PATIENTS AND METHODS: Patients with locally aggressive benign bone and soft tissue tumours were administered with 25-75 mg of ICG preoperatively at the induction of anaesthesia. Fluorescence was imaged intraoperatively using the Stryker SPY-PHI camera. RESULTS: Of the 12 patients included, 11 tumours fluoresced. The surgeons felt the fluorescence guided the procedure in 7 out of the 11 cases which fluoresced. It was felt to be particularly useful in the curettage of bone tumours, in which curettage could be repeated until the absence of fluorescence on imaging. After 12 months, no patients had local recurrence of the tumour. There were no adverse events recorded in this study and surgeons found the technology acceptable. CONCLUSIONS: The use of ICG for fluorescence guided surgery is a promising technology to improve outcomes of surgery for benign bone and soft tissue tumours. Further, longer term, study with a control arm is needed to identify whether it results in a reduction in the local recurrence rate.

Fluorescence lifetime of injected indocyanine green as a universal marker of solid tumours in patients.

The surgical resection of solid tumours can be enhanced by fluorescence-guided imaging. However, variable tumour uptake and incomplete clearance of fluorescent dyes reduces the accuracy of distinguishing tumour from normal tissue via conventional fluorescence intensity-based imaging. Here we show that, after systemic injection of the near-infrared dye indocyanine green in patients with various types of solid tumour, the fluorescence lifetime (FLT) of tumour tissue is longer than the FLT of non-cancerous tissue. This tumour-specific shift in FLT can be used to distinguish tumours from normal tissue with an accuracy of over 97% across tumour types, and can be visualized at the cellular level using microscopy and in larger specimens through wide-field imaging. Unlike fluorescence intensity, which depends on imaging-system parameters, tissue depth and the amount of dye taken up by tumours, FLT is a photophysical property that is largely independent of these factors. FLT imaging with indocyanine green may improve the accuracy of cancer surgeries.

What Is the Significance of Indeterminate Pulmonary Nodules in High-Grade Soft Tissue Sarcomas? A Retrospective Cohort Study.

BACKGROUND: Sarcomas are rare, aggressive cancers which frequently metastasise to the lungs. Following diagnosis, patients typically undergo staging by means of a CT scan of their chest. This often identifies indeterminate pulmonary nodules (IPNs), but the significance of these in high-grade soft tissue sarcoma (STS) is unclear. Identifying whether these are benign or malignant is important for clinical decision making. This study analyses the clinical relevance of IPNs in high-grade STS. METHODS: All patients treated at our centre for high-grade soft tissue sarcoma between 2010 and 2020 were identified from a prospective database. CT scans and their reports were reviewed, and survival data were collected from patient records. RESULTS: 389 suitable patients were identified; 34.4% had IPNs on their CT staging scan and 20.1% progressed into lung metastases. Progression was more likely with IPNs ≥ 5 mm in diameter (p = 0.006), multiple IPNs (p = 0.013) or bilateral IPNs (p = 0.022), as well as in patients with primaries ≥ 5 cm (p = 0.014), grade 3 primaries (p = 0.009) or primaries arising deep to the fascia (p = 0.041). The median time to progression was 143 days. IPNs at diagnosis were associated with an increased risk of developing lung metastases and decreased OS in patients with grade 3 STS (p = 0.0019 and p = 0.0016, respectively); this was not observed in grade 2 patients. CONCLUSIONS: IPNs at diagnosis are associated with significantly worse OS in patients with grade 3 STS. It is crucial to consider the primary tumour as well as the IPNs when considering the risk of progression. Surveillance CT scans should be carried out within 6 months.

A Very Unusual Burn Complication: Bilateral Endogenous Bacterial Endophthalmitis.

Background: The authors report the rare, but potentially blinding, complication of bilateral endogenous bacterial endophthalmitis observed in a 35-year-old man during his admission to a regional burns center following a burn injury from an electronic cigarette device. This complication has been reported only twice in burn patients following extensive and life-threatening burn injuries. This patient underwent surgical debridement and split-thickness skin grafting of non-major burns as per standard of practice. In the postoperative period, the patient developed bilateral eye pain, redness, and photophobia, and was subsequently diagnosed with bilateral endogenous bacterial endophthalmitis secondary to a Staphylococcus aureus infection of the burn wound. After ophthalmology input and treatment with systemic and intravitreal antibiotics, he made a full recovery from both his burns and endophthalmitis. Conclusions: This report describes a rare, sight-threatening complication that arose from an infected burn wound in an otherwise healthy patient. It highlights the importance of prompt diagnosis and treatment to preserve vision and the need for burn surgeons to have a high level of awareness of this entity, even in the context of minor burns.

Synthesis and In Vivo Evaluation of a Site-specifically Labeled Radioimmunoconjugate for Dual-Modal (PET/NIRF) Imaging of MT1-MMP in Sarcomas.

Bone sarcomas are devastating primary bone cancers that mostly affect children, young adults, and the elderly. These aggressive tumors are associated with poor survival, and surgery remains the mainstay of treatment. Surgical planning is increasingly informed by positron emission tomography (PET), and tumor margin identification during surgery is aided by near-infrared fluorescence (NIRF) imaging, yet these investigations are confounded by probes that lack specificity for sarcoma biomarkers. We report the development of a dual-modal (PET/NIRF) immunoconjugate ([89Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW) that targets MT1-MMP, a matrix metalloproteinase overexpressed in high-grade sarcomas. [89Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW was synthesized via site-specific chemoenzymatic glycan modification, characterized, and isolated in high specific activity and radiochemical purity. Saturation binding and immunoreactivity assays indicated only minor perturbation of binding properties. A novel mouse model of dedifferentiated chondrosarcoma based on intrafemoral inoculation of HT1080 WT or KO cells (high and low MT1-MMP expression, respectively) was used to evaluate target binding and biodistribution. Fluorescence and Cerenkov luminescence images of [89Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW showed preferential uptake in HT1080 WT tumors. Ex vivo gamma counting revealed that uptake in MT1-MMP-positive tumors was significantly higher than that in control groups. Taken together, [89Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW is a promising dual-modal sarcoma imaging agent for pre-operative surgical planning and intraoperative surgical guidance.

Does the modified Glasgow Prognostic Score aid in the management of patients undergoing surgery for a soft-tissue sarcoma? : an international multicentre study.

AIMS: The modified Glasgow Prognostic Score (mGPS) uses preoperative CRP and albumin to calculate a score from 0 to 2 (2 being associated with poor outcomes). mGPS is validated in multiple carcinomas. To date, its use in soft-tissue sarcoma (STS) is limited, with only small cohorts reporting that increased mGPS scores correlates with decreased survival in STS patients. METHODS: This retrospective multicentre cohort study identified 493 STS patients using clinical databases from six collaborating hospitals in three countries. Centres performed a retrospective data collection for patient demographics, preoperative blood results (CRP and albumin levels and neutrophil, leucocyte, and platelets counts), and oncological outcomes (disease-free survival, local, or metastatic recurrence) with a minimum of two years' follow-up. RESULTS: We found that increased mGPS, tumour size, grade, neutrophil/lymphocyte ratio, and disease recurrence were associated with reduced survival. Importantly, mGPS was the best at stratifying prognosis and could be used in conjunction with tumour grade to sub-stratify patient survival. CONCLUSION: This study demonstrated that prognosis of localized STS strongly correlates with mGPS, as an increasing score is associated with a poorer outcome. We note that 203 patients (41%) with an STS have evidence of systemic inflammation. We recommend the mGPS and other biochemical blood indicators be introduced into the routine diagnostic assessment in STS patients to stratify patient prognosis. Its use will support clinical decision-making, especially when morbid treatment options such as amputation are being considered. Cite this article: Bone Joint J 2022;104-B(1):168-176.

Intraoperative Near-Infrared Fluorescence Guided Surgery Using Indocyanine Green (ICG) for the Resection of Sarcomas May Reduce the Positive Margin Rate: An Extended Case Series.

BACKGROUND: Sarcomas are rare, aggressive cancers which can occur in any region of the body. Surgery is usually the cornerstone of curative treatment, with negative surgical margins associated with decreased local recurrence and improved overall survival. Indocyanine green (ICG) is a fluorescent dye which accumulates in sarcoma tissue and can be imaged intraoperatively using handheld near-infrared (NIR) cameras, theoretically helping guide the surgeon's resection margins. METHODS: Patients operated on between 20 February 2019 and 20 October 2021 for intermediate to high grade sarcomas at our centres received either conventional surgery, or were administered ICG pre-operatively followed by intra-operative NIR fluorescence guidance during the procedure. Differences between the unexpected positive margin rates were compared. RESULTS: 115 suitable patients were identified, of which 39 received ICG + NIR fluorescence guided surgery, and 76 received conventional surgery. Of the patients given ICG, 37/39 tumours fluoresced, and surgeons felt the procedure was guided by the intra-operative images in 11 cases. Patients receiving ICG had a lower unexpected positive margin rate (5.1% vs. 25.0%, p = 0.01). CONCLUSIONS: The use of NIR fluorescence cameras in combination with ICG may reduce the unexpected positive margin rate for high grade sarcomas. A prospective, multi-centre randomised control trial is now needed to validate these results.

Co-localisation of intra-nuclear membrane type-1 matrix metalloproteinase and hypoxia inducible factor-2α in osteosarcoma and prostate carcinoma cells.

Increased membrane type-1 matrix metalloproteinase (MT1-MMP) expression in osteosarcoma is predictive of poor prognosis and directs bone metastasis in prostate carcinoma. MT1-MMP subcellular localisation varies with oxygen tension, and, therefore, the aim of the present study was to assess protein interactions between MT1-MMP and the hypoxia inducible factors (HIF-1α and HIF-2α). MT1-MMP protein expression was investigated across a panel of cancer cell lines, including a positive and negative control. The hypoxia-induced alteration in subcellular location of MT1-MMP, HIF-1α and HIF-2α in the U2OS osteosarcoma cell line was assessed using subcellular fractionation. A proximity ligation assay was utilised to assess protein to protein interactions in the osteosarcoma U2OS and prostate carcinoma PC3 cell lines. U2OS and PC3 cells exhibited a significantly increased intra-nuclear interaction between MT1-MMP and HIF-2α in response to hypoxia. The role of this warrants further investigation as it may unveil novel opportunities to target MT1-MMP, which is of particular significance for osteosarcoma since current treatment options are limited.

Surgical Advances in Osteosarcoma.

Osteosarcoma (OS) is the most common primary bone cancer in children and, unfortunately, is associated with poor survival rates. OS most commonly arises around the knee joint, and was traditionally treated with amputation until surgeons began to favour limb-preserving surgery in the 1990s. Whilst improving functional outcomes, this was not without problems, such as implant failure and limb length discrepancies. OS can also arise in areas such as the pelvis, spine, head, and neck, which creates additional technical difficulty given the anatomical complexity of the areas. We reviewed the literature and summarised the recent advances in OS surgery. Improvements have been made in many areas; developments in pre-operative imaging technology have allowed improved planning, whilst the ongoing development of intraoperative imaging techniques, such as fluorescent dyes, offer the possibility of improved surgical margins. Technological developments, such as computer navigation, patient specific instruments, and improved implant design similarly provide the opportunity to improve patient outcomes. Going forward, there are a number of promising avenues currently being pursued, such as targeted fluorescent dyes, robotics, and augmented reality, which bring the prospect of improving these outcomes further.

Intraoperative Near-infrared Fluorescence (NIR) Imaging With Indocyanine Green (ICG) Can Identify Bone and Soft Tissue Sarcomas Which May Provide Guidance for Oncological Resection.

BACKGROUND: Complete excision of sarcomas to maximize function without compromising the oncological outcome can be challenging. The aim of this study was to investigate the feasibility and potential drawbacks of near-infrared (NIR) fluorescence imaging with indocyanine green during resection of bone and soft tissue sarcomas. METHODS: Eleven patients with high-grade sarcomas were enrolled in the study. All patients received intravenous indocyanine green (75 mg) between 16 and 24 hours before the resection. Sarcomas were resected under NIR guidance and specimens were sent for routine histopathological analysis. RESULTS: Majority of treatment naive tumors demonstrated fluorescence. There were no adverse events from the indocyanine green administration. In 3 cases, the fluorescence was reported by the surgeon to have been of definite guidance leading to further tissue resection to improve the margin. CONCLUSION: This is the first report of NIR fluorescence guidance in the setting of open sarcoma surgery. The technique is acceptable to patients and surgeons and was able to guide resection. Multicenter studies are required to assess the utility of this technique in a large cohort of patients with regards to quantification of fluorescence, resection guidance, and longer follow-up period.