In contrast to bony metastases, soft tissue metastases from carcinoma are rare. We reviewed all referrals to our Sarcoma Unit over an eight-year period, and found an incidence of soft tissue metastases from carcinoma of 1.4%. The most common mode of presentation was a painless soft tissue lump in a patient with an occult primary. Lung and kidney were the most frequent primary sources. Overall, prognosis was poor, with a mean survival of 9.4 months. Renal tumours however had a much better prognosis that other types of tumours. Treatment should be individualised according to the underlying disease and the prognosis. Although much rarer than primary soft tissue sarcomas, soft tissue metastases from carcinoma should remain a differential diagnosis in any patient presenting with a suspicious soft tissue lump. Introduction: Carcinoma most commonly metastasises via the lymphatic system firstly to the regional lymph nodes and then into the general circulation. Dependent upon the primary site of tumour, metastases from carcinoma commonly occur to the lungs, liver and bone. Distant metastases to the soft tissues are rare. There are few published case series (. 1. ,. 2. ) – the majority of the literature containing only case reports. We report a series of 10 cases of soft tissue metastases from carcinoma, collected from retrospective review of the case notes of consecutive patients referred over a eight year period to our Sarcoma Unit with a soft tissue lump, suspicious of a sarcoma. Patients and Methods: We retrospectively reviewed the case notes of consecutive patients over a eight year period (April 1995 – April 2003) referred to our Unit with a soft tissue lump, suspicious of a sarcoma. All patients underwent magnetic resonance (MR) scanning, and then trucut or open biopsy of the lesion. Dependent on the histological and MR findings, patients then underwent computer tomography (CT) of the chest and ultrasound examination of the abdomen. Included in this series were all patients with a histologically proven, soft tissue (skeletal muscle or subcutaneous tissue) metastatic carcinomatous deposit. Demographic, diagnostic, clinical, radiological and treatment data was collected on all patients. Results: Of the 702 referrals to our Unit over the eight-year period with a soft tissue lump suspicious of a sarcoma, 10 cases proved to be soft tissue metastases from carcinomas (incidence 1.4%). Data for the 10 patients comprising the series is shown in Table 1. Eight of the patients were male, two were female. The mean age at presentation was 68 years (range 39–85 years). Two patients presented with a painful lump, and in the other eight patients the lump was asymptomatic. The involved sites included the thigh in four cases, the arm in three cases, the back, buttock and axilla one each.In nine cases, the soft tissue lump was the presenting symptom of an occult primary carcinoma, whilst in one case (Case 4); the patient had a history of previous excision of a hypernephroma. The sources of primary carcinoma were small cell carcinoma of the lung in 4 cases, renal clear cell carcinoma in 3 cases, large bowel adenocarcinoma in 1 case, prostate 1 case, and in 1 case the primary site was unknown. All but one patient (Case 6) underwent radiotherapy or chemotherapy or both. Case 6 presented with a soft tissue lump over the shoulder, which on biopsy was found to be metastatic adenocarcinoma of large bowel origin. CT scan of the head confirmed multiple brain metastases. He declined any treatment and died within 2 months of presentation. In total, nine of the ten patients have died of their disease. The mean duration from diagnosis of soft tissue metastasis to death was 9.4 months (range 2–31 months). The duration of survival was significantly better for metastatic carcinoma of the kidney (23 months) compared to the other carcinomas (7 months). Discussion: The most commonly reported primary carcinomas to result in soft tissue metastases are those of the lung, kidney and colon (. 1. –. 3. ), contrasting with those carcinomas which commonly metastasise to bone such as prostate, breast and thyroid which only very rarely metastasise to the soft tissues. Damron and Heiner (. 1. ) who reported the largest series to date however had no cases where the patients primary site of carcinoma was of renal or colon origin and suggested that these cases were over-represented in the literature. Our series differs from their findings, concurring instead with the other published literature. Histologically, the most common diagnosis is adenocarcinoma, though many have been reported (. 1. –. 3. ). Soft tissue metastases from carcinoma are rare, which again contrasts to bony metastases from carcinoma. Tolia and Whitmore (. 4. ) reviewed 586 patients with renal cell carcinoma, and whilst a quarter had evidence of distant metastases at presentation, no patient had soft tissue metastases. Chandler et al (. 5. ) reported on 726 patients who died following metastatic renal carcinoma; only 3 patients had soft tissue metastases, all of which were only found at autopsy. Our series, which reviewed all patients referred to our Unit over a eight year period with a soft tissue lump initially suspicious of a sarcoma, found an overall incidence of 1.4%. Damron and Heiner (. 1. ) reported that the most common mode of presentation was a painful soft tissue lump. In our series however, the majority were painless. Whilst for most, the lump is the first sign of an occult malignancy, renal cell carcinomas tend to be different, often presenting as a solitary soft tissue deposit a few months to up to 16 years after the initial diagnosis of renal cell carcinoma has been made (. 1. ,. 2. ). Our series agreed with these findings; only in 1 case (Case 4) was there evidence of previously documented carcinoma prior to presentation with the soft tissue lump. All patients in our series underwent pre-operative MR scans, the appearances of which were not diagnostic of metastases, though highly suggestive of malignancy. Subsequently patients underwent either Tru-cut or open biopsy which gave the definitive diagnosis. As part of the pre-operative work-up, all patients had a CT of the chest and abdominal ultrasound scanning. Rao et al (. 6. ) reported 5 cases of soft tissue metastases from primary sarcoma, concluding that metastases in these cases were seen as late events and survival was generally poor. In our series of soft tissue metastases from carcinoma, we also found that prognosis was poor (averaging 9.4 months), especially when the primary carcinoma was lung, though the prognosis, if the primary was renal carcinoma was less bleak. Conclusions: Although rare, soft tissue metastases from carcinoma should remain a differential diagnosis in any patient presenting with a suspicious soft tissue lump. Whilst the MR scan appearances were suggestive of malignancy, they were not diagnostic of metastases. Tru-cut or open biopsy was reliable in confirming the diagnosis of carcinoma and helpful in the detection of the possible origin of the primary. The most common primary sites were lung, kidney and bowel

Aims. Bone is a common site of metastatic disease. Skeletal complications include disabling pain and pathological fractures. Palliative surgery for incurable metastatic bone lesions aims to preserve quality of life and function by providing pain relief and stable mobility with fixation or replacement. Current literature has few treatment studies. We present a 5 year longitudinal cohort study of surgery for metastatic bone disease at our large teaching hospital reviewing our complication and mortality rates. Methods. Patients that underwent palliative surgery for metastatic bone lesions were identified from operative records. Demographics, clinical details and outcomes were recorded. Kaplan-Meier analysis was used to calculate survivorship. Results. 43 patients were treated for 44 bone metastases (34 IM Nails, 9 prosthetic replacements, 1 plate). The median age at primary diagnosis was 66 (33–92). Lung cancer was the most common primary. 56% presented with complete fractures and 44% with impending fractures (median Mirel score of 10). Pertrochanteric bone lesions were the most common (74%). Two out of 43 patients died within one day of surgery. 30 day mortality was 12% and 45% at 1 year. In those surviving the 30 day perioperative period, we report a complication rate of 14%. One patient had a dislocated prosthesis. Two patients had delayed or non union and two patients had failure of metalwork. No patient required re operation. Conclusion. Our series observed a 5% fixation failure rate and significant perioperative mortality. Whilst surgery may offer benefit in the non moribund patient with pathological fracture the decision to offer prophylactic surgery is more difficult in light of the high perioperative mortality seen in our study. Indeed, the patients in our study who died within 24 hours of surgery had prophylactic fixations. We conclude that surgical intervention must be carefully considered with realistic expectations of outcomes

Bone metastases radiographically appear as regions with high (i.e. blastic metastases) or low (i.e. lytic metastases) bone mineral density. The clinical assessment of metastatic features is based on computed tomography (CT) but it is still unclear if the actual size of the metastases can be accurately detected from the CT images and if the microstructure in regions surrounding the metastases is altered (Nägele et al., 2004, Calc Tiss Int). This study aims to evaluate (i) the capability of the CT in evaluating the metastases size and (ii) if metastases affect the bone microstructure around them. Ten spine segments consisted of a vertebra with lytic or mixed metastases and an adjacent control (radiologically healthy) were obtained through an ethically approved donation program. The specimens were scanned with a clinical CT (AquilionOne, Toshiba: slice thickness:1mm, in-plane resolution:0.45mm) to assess clinical metastatic features and a micro-CT (VivaCT80, Scanco, isotropic voxel size:0.039mm) to evaluate the detailed microstructure. The volume of the metastases was measured from both CT and micro-CT images (Palanca et al., 2021, Bone) and compared with a linear regression. The microstructural alteration around the metastases was evaluated in the volume of interest (VOI) defined in the micro-CT images as the volume of the vertebral body excluding the metastases. Three 3D microstructural parameters were calculated in the VOI (CTAn, Bruker SkyScan): Bone Volume Fraction (BV/TV), Trabecular Thickness (Tb.Th.), Trabecular Spacing (Tb.Sp.). Medians of each parameter were compared (Kruskal-Wallis, p=0.05). One specimen was excluded as it was not possible to define the size of the metastases in the CT scans. A strong correlation between the volume obtained from the CT and micro-CT images was found (R2=0.91, Slope=0.97, Intercept=2.55, RMSE=5.7%, MaxError=13.12%). The differences in BV/TV, Tb.Th. and Tb.Sp. among vertebrae with lytic and mixed metastases and control vertebrae were not statistically significant (p-value>0.6). Similar median values of BV/TV were found in vertebrae with lytic (13.2±2.4%) and mixed (12.8±9.8%) metastases, and in controls (13.0±10.1%). The median Tb.Th. was 176±18 ∓m, 179±43 ∓m and 167±91 ∓m in vertebrae with lytic and mixed metastases and control vertebrae, respectively. The median Tb. Sp. was 846±26 ∓m, 849±286 ∓m and 880±116 ∓m in vertebrae with lytic and mixed metastases and control vertebrae, respectively. In conclusion, the size of vertebral metastases can be accurately assess using CT images. The 3D microstructural parameters measured were comparable with those reported in the literature for healthy vertebrae (Nägele et al., 2004, Calc Tiss Int, Sone et al., 2004, Bone) and showed how the microstructure of the bone tissue surrounding the lesion is not altered by the metastases

Primary bone tumors are rare, complex and highly heterogeneous. Its diagnostic and treatment are a challenge for the multidisciplinary team. Developments on tumor biomarkers, immunohistochemistry, histology, molecular, bioinformatics, and genetics are fundamental for an early diagnosis and identification of prognostic factors. The personalized medicine allows an effective patient tailored treatment. The bone biopsy is essential for diagnosis. Treatment may include systemic therapy and local therapy. Frequently, a limb salvage surgery includes wide resection and reconstruction with endoprosthesis, biological or composites. The risk for local recurrence and distant metastases depends on the primary tumor and treatment response. Cancer patients are living longer and bone metastases are increasing. Bone is the third most frequently location for distant lesions. Bone metastases are associated to pain, pathological fractures, functional impairment, and neurological deficits. It impacts survival and patient quality of life. The treatment of metastatic disease is a challenge due to its complexity and heterogeneity, vascularization, reduced size and limited access. It requires a multidisciplinary treatment and depending on different factors it is palliative or curative-like treatment. For multiple bone metastases it is important to relief pain and increases function in order to provide the best quality of life and expect to prolong survival. Advances in nanotechnology, bioinformatics, and genomics, will increase biomarkers for early detection, prognosis, and targeted treatment effectiveness. We are taking the leap forward in precision medicine and personalized care

Decreasing the chance of local relapse or infection after surgical excision of bone metastases is a main goals in orthopedic oncology. Indeed, bone metastases have high incidence rate (up to 75%) and important cross-relations with infection and bone regeneration. Even in patients with advanced cancer, bone gaps resulting from tumor excision must be filled with bone substitutes. Functionalization of these substitutes with antitumor and antibacterial compounds could constitute a promising approach to overcome infection and tumor at one same time. Here, for the first time, we propose the use of nanostructured zinc-bone apatite coatings having antitumor and antimicrobial efficacy. The coatings are obtained by Ionized Jet Deposition from composite targets of zinc and bovine-derived bone apatite. Antibacterial and antibiofilm efficacy of the coatings is demonstrated in vitro against S. Aureus and E. Coli. Anti-tumor efficacy is investigated against MDA- MB-231 cells and biocompatibility is assessed on L929 and MSCs. A microfluidic based approach is used to select the optimal concentration of zinc to be used to obtain antitumor efficacy and avoid cytotoxicity, exploiting a custom gradient generator microfluidic device, specifically designed for the experiments. Then, coatings capable of releasing the desired amount of active compounds are manufactured. Films morphology, composition and ion-release are studies by FEG- SEM/EDS, XRD and ICP. Efficacy and biocompatibility of the coatings are verified by investigating MDA, MSCs and L929 viability and morphology by Alamar Blue, Live/Dead Assay and FEG-SEM at different timepoints. Statistical analysis is performed by SPSS/PC + Statistics TM 25.0 software, one-way ANOVA and post-hoc Sheffe? test. Data are reported as Mean ± standard Deviation at a significance level of p <0.05. Results and Discussion. Coatings have a nanostructured surface morphology and a composition mimicking the target. They permit sustained zinc release for over 14 days in medium. Thanks to these characteristics, they show high antibacterial ability (inhibition of bacteria viability and adhesion to substrate) against both the gram + and gram – strain. The gradient generator microfluidic device permits a fine selection of the concentration of zinc to be used, with many potential perspectives for the design of biomaterials. For the first time, we show that zinc and zinc-based coatings have a selective efficacy against MDA cells. Upon mixing with bone apatite, the efficacy is maintained and cytotoxicity is avoided. For the first time, new antibacterial metal-based films are proposed for addressing bone metastases and infection at one same time. At the same time, a new approach is proposed for the design of the coatings, based on a microfluidic approach. We demonstrated the efficacy of Zn against the MDA-MB-231 cells, characterized for their ability to form bone metastases in vivo, and the possibility to use nanostructured metallic coatings against bone tumors. At the same time, we show that the gradient-generator approach is promising for the design of antitumor biomaterials. Efficacy of Zn films must be verified in vivo, but the dual-efficacy coatings appear promising for orthopedic applications

Introduction. Patients (2.7M in EU) with positive cancer prognosis frequently develop metastases (≈1M) in their remaining lifetime. In 30-70% cases, metastases affect the spine, reducing the strength of the affected vertebrae. Fractures occur in ≈30% patients. Clinicians must choose between leaving the patient exposed to a high fracture risk (with dramatic consequences) and operating to stabilise the spine (exposing patients to unnecessary surgeries). Currently, surgeons rely on their sole experience. This often results in to under- or over-treatment. The standard-of-care are scoring systems (e.g. Spine Instability Neoplastic Score) based on medical images, with little consideration of the spine biomechanics, and of the structure of the vertebrae involved. Such scoring systems fail to provide clear indications in ≈60% patients. Method. The HEU-funded METASTRA project is implemented by biomechanicians, modellers, clinicians, experts in verification, validation, uncertainty quantification and certification from 15 partners across Europe. METASTRA aims to improve the stratification of patients with vertebral metastases evaluating their risk of fracture by developing dedicated reliable computational models based on Explainable Artificial Intelligence (AI) and on personalised Physiology-based biomechanical (VPH) models. Result. The METASTRA-AI model is expected to be able to stratify most patients with limited effort end cost, based on parameters extracted semi-automatically from the medical files and images. The cases which are not reliably stratified through the AI model, are examined through a more detailed and personalised biomechanical VPH model. These METASTRA numerical tools are trained through an unprecedentedly large multicentric retrospective study (2000 cases) and validated against biomechanical ex vivo experiments (120 specimens). Conclusion. The METASTRA decision support system is tested in a multicentric prospective observational study (200 patients). The METASTRA approach is expected to cut down the indeterminate diagnoses from the current 60% down to 20% of cases. METASTRA project funded by the European Union, HEU topic HLTH-2022-12-01, grant 101080135

Vertebral metastases are the most common type of malignant lesions of the spine. Although this tumour is still considered incurable and standard treatments are mainly palliative, the standard approach consists in surgical resection, which results in the formation of bone gaps. Hence, scaffolds, cements and/or implants are needed to fill the bone lacunae. Here, we propose a novel approach to address spinal metastases recurrence, based on the use of anti-tumour metallic-based nanostructured coatings. Moreover, for the first time, a gradient microfluidic approach is proposed for the screening of nanostructured coatings having anti-tumoral effect, to determine the optimal concentration of the metallic compound that permits selective toxicity towards tumoral cells. Coatings are based on Zinc as anti-tumour agent, which had been never explored before for treatment of bone metastases. The customized gradient generating microfluidic chip was designed by Autodesk Inventor and fabricated from a microstructured mould by using replica moulding technique. Microstructured mould were obtained by micro-milling technique. The chip is composed of a system of microfluidic channels generating a gradient of 6 concentrations of drug and a compartment with multiple arrays of cell culture chambers, one for each drug concentration. The device is suitable for dynamic cultures and in-chip biological assays. The formation of a gradient was validated using a methylene blue solution and the cell loading was successful. Preliminary biological data on 3D dynamic cultures of stromal cells (bone-marrow mesenchymal stem cells) and breast carcinoma cells (MDA-MB-231) were performed in a commercial microfluidic device. Results showed that Zn eluates had a selective cytotoxic effect for tumoral cells. Indeed, cell migration and cell replication of treated tumoral cells was inhibited. Moreover, the three-dimensionality of the model strongly affected the efficacy of Zn eluates, as 2D preliminary experiments showed a high cytotoxic effect of Zn also for stromal cells, thus confirming that traditional screening tests on 2D cultured cells usually lead to an overestimation of drug efficacy and toxicity. Based on preliminary data, the customized platform could be considered a major advancement in cancer drug screenings as it also allows the rapid and efficient screening of biomaterials having antitumor effect

Breast cancer is the most frequent malignancy in women with an estimation of 2.1 million new diagnoses in 2018. Even though primary tumours are usually efficiently removed by surgery, 20–40% of patients will develop metastases in distant organs. Bone is one of the most frequent site of metastases from advanced breast cancer, accounting from 55 to 58% of all metastases. Currently, none of the therapeutic strategies used to manage breast cancer bone metastasis are really curative. Tailoring a suitable model to study and evaluate the disease pathophysiology and novel advanced therapies is one of the major challenges that will predict more effectively and efficiently the clinical response. Preclinical traditional models have been largely used as they can provide standardization and simplicity, moreover, further advancements have been made with 3D cultures, by spheroids and artificial matrices, patient derived xenografts and microfluidics. Despite these models recapitulate numerous aspects of tumour complexity, they do not completely mimic the clinical native microenvironment. Thus, to fulfil this need, in our study we developed a new, advanced and alternative model of human breast cancer bone metastasis as potential biologic assay for cancer research. The study involved breast cancer bone metastasis samples obtained from three female patients undergoing wide spinal decompression and stabilization through a posterior approach. Samples were cultured in a TubeSpin Bioreactor on a rolling apparatus under hypoxic conditions at time 0 and for up to 40 days and evaluated for viability by the Alamar Blue test, gene expression profile, histology and immunohistochemistry. Results showed the maintenance and preservation, at time 0 and after 40 days of culture, of the tissue viability, biological activity, as well as molecular markers, i.e. several key genes involved in the complex interactions between the tumour cells and bone able to drive cancer progression, cancer aggressiveness and metastasis to bone. A good tis sue morphological and microarchitectural preservation with the presence of lacunar osteolysis, fragmented trabeculae locally surrounded by osteoclast cells and malignant cells and an intense infiltration by tumour cells in bone marrow compartment in all examined samples. Histomorphometrical data on the levels of bone resorption and bone apposition parameters remained constant between T0 and T40 for all analysed patients. Additionally, immunohistochemistry showed homogeneous expression and location of CDH1, CDH2, KRT8, KRT18, Ki67, CASP3, ESR1, CD8 and CD68 between T0 and T40, thus further confirming the invasive behaviour of breast cancer cells and indicating the maintaining of the metastatic microenvironment. The novel tissue culture, set-up in this study, has significant advantages in comparison to the pre-existent 3D models: the tumour environment is the same of the clinical scenario, including all cell types as well as the native extracellular matrix; it can be quickly set-up employing only small samples of breast cancer bone metastasis tissue in a simple, ethically correct and cost-effective manner; it bypasses and/or decreases the necessity to use more complex preclinical model, thus reducing the ethical burden following the guiding principles aimed at replacing/reducing/refining (3R) animal use and their suffering for scientific purposes; it can allow the study of the interactions within the breast cancer bone metastasis tissue over a relatively long period of up to 40 days, preserving the tumour morphology and architecture and allowing also the evaluation of different biological factors, parameters and activities. Therefore, the study provides for the first time the feasibility and rationale for the use of a human-derived advanced alternative model for cancer research and testing of drugs and innovative strategies, taking into account patient individual characteristics and specific tumour subtypes so predicting patient specific responses

Sarcomas generally metastasize to the lung, while extra-pulmonary metastases are rare. However, they may occur more frequently in certain histological sub-types. Bone metastases from bone and soft tissue sarcomas account for a significant number of extra-pulmonary disease. Resection of lung metastases is widely accepted as therapeutic option to improve the survival of oligometastatic patients but there is currently no literature supporting curative surgical management of sarcoma bone metastases. Most are treated on a case-by-case basis, following multidisciplinary tumour boards recommendations. One study reported some success in controlling bone metastases using radiofrequency ablation. Our goal was to assess the impact of curative resection of bone metastases from soft tissue and bone sarcomas on oncologic outcomes. Extensive review of literature was done to evaluate epidemiological and outcomes of bone metastases in sarcoma. We examined our prospective database for all cases of bone metastases from sarcoma treated with surgical resection between 1990 and 2016. Epidemiology, pathology, metastatic status upon diagnosis, type of secondary relapses and their treatments were recorded. Overall survival and disease-free survival were calculated and compared to literature. Thirty-five patients were included (18 men, 17 women) with a mean age of 46 years. Fifteen were soft tissue (STS) and 20 were bone (BS) sarcomas. Most STS were fibrosarcomas, leiomyosarcomas or UPS while chondrosarcomas and osteosarcomas were the most frequent BS. Nine (60%) STS were grade 3, 4 (27%) grade 2 and one grade 1 (3%). Eight (23%) were metastatic upon diagnosis (6 lungs, 3 bone). Treatment of the primary tumour included wide excision with reconstruction and (neo)-adjuvant therapies as required. Margins were negative in 32 cases and micro-positive in 3 cases. Amputation occurred in 6 (17%) cases. Primary lung metastases were treated by thoracotomy and primary bone metastases by wide excision. First relapse occurred in bone in 19 cases (54%), lungs and bone in 7 cases, 5 in lungs and 4 in soft-tissues. Lung metastases were treated by thoracotomy and chemotherapy in 3 cases, chemotherapy alone in the remaining cases. Bone metastases were treated by wide resection-reconstruction in 24 cases, extensive curettage in 4. Soft tissue relapses were re-excised in 4 patients. Two amputations were required. All margins were negative except for the 4 treated by curettage. Fourteen second relapses occurred in bone, 7 were radically-excised and 2 curetted. At last follow-up, 6 patients were alive (overall survival of 17%), with a mean survival of 57 months, a median overall survival of 42.5 months and a median disease-free survival (DFS) of 17 months. Overall survival was 17%, compared to an 11% 10-year survival previously reported in metastatic sarcomas. Median disease-free survival was better in this study, compared to 10 months in literature, so as median OS (42.5 months vs 15). Three patients were alive with no evidence of disease. DFS, OS and median survival seemed to be improved by bone metastases wide excision and even if several recurrences occur, curative surgery with adjuvant therapies should be considered

Bone turnover and microdamage are impacted by skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. This study aimed to establish an understanding of microdamage accumulation and load to failure in healthy and osteolytic vertebrae following cancer treatment (stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX)). Forty-two 6-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo) were studied; 22 were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Animals were randomly assigned to four groups: untreated (healthy=5, osteolytic=6), SBRT on day 14 (healthy=6, osteolytic=6), ZA on day 7 (healthy=4, osteolytic=5), and DTX on day 14 (healthy=5, osteolytic=5). Animals were euthanized on day 21. L1-L3 motion segments were compression loaded to failure and force-displacement data recorded. T13 vertebrae were stained with BaSO. 4. and µCT imaged (90kVp, 44uA, 4.9µm) to visualize microdamage location and volume. Damage volume fraction (DV/BV) was calculated as the ratio of BaSO. 4. to bone volume. Differences in mean load-to-failure were compared using three-way ANOVA (disease status, treatment, cells injected). Differences in mean DV/BV between treatment groups were compared using one-way ANOVA. Treatment had a significant effect on load-to-failure (p=0.004) with ZA strengthening the healthy and osteolytic vertebrae. Reduced strength post SBRT seen in the metastatic (but not the healthy) group may be explained by greater tumor involvement secondary to higher cell injection concentrations. Untreated metastatic samples had higher DV/BV (16.25±2.54%) compared to all treatment groups (p<0.05) suggesting a benefit of treatment to bone quality. Focal and systemic cancer treatments were shown to effect load-to-failure and microdamage accumulation in healthy and osteolytic vertebrae. Developing a better understanding of how treatments effect bone quality and mechanical stability is critical for effective management of patients with spinal metastases

En bloc resection for primary bone tumours and isolated metastasis are complex surgeries associated with a high rate of adverse events (AEs). The primary objective of this study was to explore the relationship between frailty/sarcopenia and major perioperative AEs following en bloc resection for primary bone tumours or isolated metastases of the spine. Secondary objectives were to report the prevalence and distribution of frailty and sarcopenia, and determine the relationship between these factors and length of stay (LOS), unplanned reoperation, and 1-year postoperative mortality in this population. This is a retrospective study of prospectively collected data from a single quaternary care referral center consisting of patients undergoing an elective en bloc resection for a primary bone tumour or an isolated spinal metastasis between January 1st, 2009 and February 28th, 2020. Frailty was calculated with the modified frailty index (mFI) and spine tumour frailty index (STFI). Sarcopenia, determined by the total psoas area (TPA) vertebral body (VB) ratio (TPA/VB), was measured at L3 and L4. Regression analysis produced ORs, IRRs, and HRs that quantified the association between frailty/sarcopenia and major perioperative AEs, LOS, unplanned reoperation and 1-year postoperative mortality. One hundred twelve patients met the inclusion criteria. Using the mFI, five patients (5%) were frail (mFI ³ 0.21), while the STFI identified 21 patients (19%) as frail (STFI ³ 2). The mean CT ratios were 1.45 (SD 0.05) and 1.81 (SD 0.06) at L3 and L4 respectively. Unadjusted analysis demonstrated that sarcopenia and frailty were not significant predictors of major perioperative AEs, LOS or unplanned reoperation. Sarcopenia defined by the CT L3 TPA/VB and CT L4 TPA/VB ratios significantly predicted 1-year mortality (HR of 0.32 per one unit increase, 95% CI 0.11-0.93, p=0.04 vs. HR of 0.28 per one unit increase, 95% CI 0.11-0.69, p=0.01) following unadjusted analysis. Frailty defined by an STFI score ≥ 2 predicted 1-year postoperative mortality (OR of 2.10, 95% CI 1.02-4.30, p=0.04). The mFI was not predictive of any clinical outcome in patients undergoing en bloc resection for primary bone tumours or isolated metastases of the spine. Sarcopenia defined by the CT L3 TPA/VB and L4 TPA/VB and frailty assessed with the STFI predicted 1-year postoperative mortality on univariate analysis but not major perioperative AEs, LOS or reoperation. Further investigation with a larger cohort is needed to identify the optimal measure for assessing frailty and sarcopenia in this spine population

One out of nine Canadian males would suffer prostate cancer (PC) during his lifetime. Life expectancy of males with PC has increased with modern therapy and 90% live >10 years. However, 20% of PC-affected males would develop incurable metastatic diseases. Bone metastases (BM) are present in ~80% of metastatic PC patients, and are the most severe complication of PC, generating severe pain, fractures, spinal cord compression, and death. Interestingly, PC-BMs are mostly osteoblastic. However, the structure of this newly formed bone and how it relates to pain and fracture are unknown. Due to androgen antagonist treatment, different PC phenotypes develop with differential dependency on androgen receptor (AR) signaling: androgen-dependent (AR+), double negative (AR-) and neuroendocrine. How these phenotypes are related to changes in bone structure has not been studied. Here we show a state-of-the-art structural characterization of PCBM and how PC phenotypes are associated to abnormal bone formation in PCBM. Cadaveric samples (n=14) obtained from metastases of PC in thoracic or lumbar vertebrae (mean age 74yo) were used to analyze bone structure. We used micro-computed tomography (mCT) to analyze the three-dimensional structure of the bone samples. After imaging, the samples were sectioned and one 3mm thick section was embedded in epoxy-resin, ground and polished. Scanning electron microscopy (SEM)/energy-dispersive X-ray spectroscopy (EDS) and quantitative backscattering electron (qBSE) imaging were used to determine mineral morphology and composition. Another section was used for histological analysis of the PC-affected bone. Collagen structure, fibril orientation and extracellular matrix composition were characterized using histochemistry. Additionally, we obtained biopsies of 3 PCBM patients undergoing emergency decompression surgery following vertebral fracture and used them for immunohistological characterization. By using mCT, we observed three dysmorphic bone patterns: osteolytic pattern with thinned trabecula of otherwise well-organized structures, osteoblastic pattern defined as accumulation of disorganized matrix deposited on pre-existing trabecula, and osteoblastic pattern with minimum residual trabecula and bone space dominated by accumulation of disorganized mineralized matrix. Comparing mCT data with patho/clinical parameters revealed a trend for higher bone density in males with larger PSA increase. Through histological sections, we observed that PC-affected bone, lacks collagen alignment structure, have a higher number of lacunae and increased amount of proteoglycans as decorin. Immunohistochemistry of biopsies revealed that PC-cells inside bone organize into two manners: i) glandular-like structures where cells maintain their polarization in the expression of prostate markers, ii) diffuse infiltrate that spreads along bone surfaces, with loss of cell polarity. These cells take direct contact with osteoblasts in the surface of trabecula. We define that PCBM are mostly composed by AR+ with some double negative cells. We did not observe neuroendocrine phenotype cells. PCBMs generate predominantly osteoblastic lesions that are characterized by high lacunar density, lack of collagen organization and elevated proteoglycan content. These structural changes are associated with the infiltration of PC cells that are mostly androgen-dependent but have lost their polarization and contact directly with osteoblasts, perhaps altering their function. These changes could be associated with lower mechanical properties that led to fracture and weakness of the PCBM affected bone

Introduction. Degenerative spondylosis (DS) represents a challenging condition to diagnose and treat. There are multiple modalities to investigate DS including X-ray, MRI and CT, but symptoms may not be equivocal to DS to support the clinical findings. The investigation of metastases commonly utilises SPECT/CT for identification of areas of increased osteoblastic activity to denote disease. The aim of the study was to analyse the prevalence of asymptomatic DS in a consecutive hospital cohort of oncology patients who had SPECT/CT for investigation of metastases. Methods. Oncology patients who underwent SPECT/CT at St. George's Hospital were analysed between 2015–2019. Exclusion criteria: back pain, inflammatory disorders, metastases, trauma, infection. Radiology reports were examined for DS and anatomical distribution of tracer uptake. Results. A total of 1182 patients had a Whole-Body SPECT CT used for the spinal analysis. After exclusions (age >80 [n=260], non-cancer [n=318], back pain [n=72]), 522 reports with cancer were utilised. Mean age was 65 (4–80). Age and distribution of DS are given in the table. Conclusion. The prevalence of radiological asymptomatic DS is prevalent in large proportions of patients without back pain, and its incidence increases with age. Approximately 60% of 60 year old and 70% of 70 years old patients have asymptomatic DS in the lumbosarcal region. We conclude that SPECT/CT will detect radiographic degenerative spondylosis in an asymptomatic hospital cohort and this prevalence increase with age. Therefore, this modality of imaging must be utilised with caution when investigating potential pain generators. For any figures or tables, please contact the authors directly

Mirels’ score predicts the likelihood of sustaining pathological fractures using pain, lesion site, size and morphology. The aim is to investigate its reproducibility, reliability and accuracy in upper limb bony metastases and validate its use in pathological fracture prediction. A retrospective cohort study of patients with upper limb metastases, referred to an Orthopaedic Trauma Centre (2013–18). Mirels’ was calculated in 32 patients; plain radiographs at presentation scored by 6 raters. Radiological aspects were scored twice by each rater, 2-weeks apart. Inter- and intra-observer reliability were calculated (Fleiss’ kappa test). Bland-Altman plots compared variances of individual score components &total Mirels’ score. Mirels’ score of ≥9 did not accurately predict lesions that would fracture (11% 5/46 vs 65.2% Mirels’ score ≤8, p<0.0001). Sensitivity was 14.3% &specificity was 72.7%. When Mirels’ cut-off was lowered to ≥7, patients were more likely to fracture (48% 22/46 versus 28% 13/46, p=0.045). Sensitivity rose to 62.9%, specificity fell to 54.6%. Kappa values for interobserver variability were 0.358 (fair, 0.288–0.429) for lesion size, 0.107 (poor, 0.02–0.193) for radiological appearance and 0.274 (fair, 0.229–0.318) for total Mirels’ score. Values for intraobserver variability were 0.716 (good, 95% CI 0.432–0.999) for lesion size, 0.427 (moderate, 95% CI 0.195–0.768) for radiological appearance and 0.580 (moderate, 0.395–0.765) for total Mirels’ score. We showed moderate to substantial agreement between &within raters using Mirels’ score on upper limb radiographs. Mirels’ has poor sensitivity &specificity predicting upper limb fractures - we recommend the cut-off score for prophylactic surgery should be lower than for lower limb lesions

Patients with cancer and bone metastases can have an increased risk of fracturing their femur. Treatment is based on the impending fracture risk: patients with a high fracture risk are considered for prophylactic surgery, whereas low fracture risk patients are treated conservatively with radiotherapy to decrease pain. Current clinical guidelines suggest to determine fracture risk based on axial cortical involvement of the lesion on conventional radiographs, but that appears to be difficult. Therefore, we developed a patient-specific finite element (FE) computer model that has shown to be able to predict fracture risk in an experimental setting and in patients. The goal of this study was to determine whether patient-specific finite element (FE) computer models are better at predicting fracture risk for femoral bone metastases compared to clinical assessments based on axial cortical involvement on conventional radiographs, as described in current clinical guidelines. 45 patients (50 affected femurs) affected with predominantly lytic bone metastases who were treated with palliative radiotherapy for pain were included. CT scans were made and patients were followed for six months to determine whether or not they fractured their femur. Non-linear isotropic FE models were created with the patient-specific geometry and bone density obtained from the CT scans. Subsequently, an axial load was simulated on the models mimicking stance. Failure loads normalized for bodyweight (BW) were calculated for each femur. High and low fracture risks were determined using a failure load of 7.5 × BW as a threshold. Experienced assessors measured axial cortical involvement on conventional radiographs. Following clinical guidelines, patients with lesions larger than 30 mm were identified as having a high fracture risk. FE predictions were compared to clinical assessments by means of diagnostic accuracy values (sensitivity, specificity and positive (PPV) and negative predictive values (NPV)). Seven femurs (14%) fractured during follow-up. Median time to fracture was 8 weeks. FE models were better at predicting fracture risk in comparison to clinical assessments based on axial cortical involvement (sensitivity 100% vs. 86%, specificity 74% vs. 42%, PPV 39% vs. 19%, and NPV 100% vs. 95%, for the FE computer model vs. axial cortical involvement, respectively). We concluded that patient-specific FE computer models improve fracture risk predictions of femoral bone metastases in advanced cancer patients compared to clinical assessments based on axial cortical involvement, which is currently used in clinical guidelines. Therefore, we are initiating a pilot for clinical implementation of the FE model

Spinal metastases are seen in 10–30% of cancer patients. Twenty percent of these metastases occur in the lumbo-sacral spine. Lumbo-sacral spine has different mechanical properties and encloses the cauda equina. Few studies took interest in this spinal segment. The objective of this study is to evaluate prognostic factors of lumbo-sacral spinal metastasis treated in our center. We retrospectively reviewed 376 patients who were operated in our center from 2010 to 2018. Eighty-nine patients presented lumbo-sacral metastases and thus were included. Data collected included age, smoking, tumor histology, American spinal injury association (ASIA) score, modified Tokuhashi score, modified Bauer score, ambulation status and adjuvant treatment. The mean population age was 60.9 years old (35–85). The tumor histology was predominantly lung (19 patients, 21.3%), breast (13 patients, 14.6%), kidney (11 patients, 12.4%) and prostate (9 patients 10.1%). Twenty-two patients (24.7%) were unable to walk preoperatively. Seventy-nine patients (88.8%) underwent a posterior open approach with corpectomy in 65 patients (73%). Eighteen patients regained ambulation post-operatively (81.8%). The mean survival was 24.03 months (CI95% 17,38–30,67, Range 0–90) and the median of survival was 9 months (CI95% 4.38–13.62). Better preoperative ASIA score had a significant favorable effect (p=0.03) on survival. Patients who regained their ability to walk had better survival (25.1 months (CI95% 18.2–32) VS 0.5 months (CI95% 0–1.1). Postoperative radiotherapy had a benefic effect on survival (p=0.019): Survival Increased from 10.5 months (CI95% 2.4–18.7) to 27.6 months (CI95% 19.5–35.8). The modified Tokuhashi and the modified Bauer scores underestimated the survival of the patients with lumbosacral metastases. Lumbosacral spinal metastases has better survival than expected by Tokuhashi and Bauer score. Surgical procedure have an important impact on survival and the ability to walk

Lung cancer is the most common cancer diagnosed, the leading cause of cancer-related deaths, and bone metastases occurs in 20–40% of lung cancer patients. They often present symptomatically with pain or skeletal related events (SREs), which are independently associated with decreased survival. Bone modifying agents (BMAs) such as Denosumab or bisphosphonates are routinely used, however no specific guidelines exist from the National Comprehensive Cancer Center or the European Society of Medical Oncologists. Perhaps preventing the formation of guidelines is the lack of a high-quality quantitative synthesis of randomized controlled trial (RCT) data to determine the optimal treatment for the patient important outcomes of 1) Overall survival (OS), 2) Time to SRE, 3) SRE incidence, and 4) Pain Resolution. The objective of this study was to perform the first systematic review and network meta-analysis (NMA) to assess the best BMA for treatment of metastatic lung cancer to bone. We conducted our study in accordance to the PRISMA protocol. We performed a librarian assisted search of MEDLINE, PubMed, EMBASE, and Cochrane Library and Chinese databases including CNKI and Wanfang Data. We included studies that are RCTs reporting outcomes specifically for lung cancer patients treated with a bisphosphonate or Denosumab. Screening, data extraction, risk of bias and GRADE were performed in duplicate. The NMA was performed using a Bayesian probability model with R. Results are reported as relative risks, odds ratios or mean differences, and the I2 value is reported for heterogeneity. We assessed all included articles for risk of bias and applied the novel GRADE framework for NMAs to rate the quality of evidence supporting each outcome. We included 132 RCTs comprising 11,161 patients with skeletal metastases from lung cancer. For OS, denosumab was ranked above zoledronic acid (ZA) and estimated to confer an average of 3.7 months (95%CI: −0.5 – 7.6) increased survival compared to untreated patients. For time to SRE, denosumab was ranked first with an average of 9.1 additional SRE-free months (95%CI: 4.0 – 14.0) compared to untreated patients, while ZA conferred an additional 4.8 SRE-free months (2.4 – 7.0). Patients treated with the combination of Ibandronate and systemic therapy were 2.3 times (95%CI: 1.7 – 3.2) more likely to obtain successful pain resolution, compared to untreated. Meta-regression showed no effect of heterogeneity length of follow-up or pain scales on the observed treatment effects. Heterogeneity in the network was considered moderate for overall survival and time to SRE, mild for SRE incidence, and low for pain resolution. While a generally high risk of bias was observed across studies, whether they were from Western or Chinese databases. The overall GRADE for the evidence underlying our results is High for Pain control and SRE incidence, and Moderate for OS and time to SRE. This study represents the most comprehensive synthesis of the best available evidence guiding pharmacological treatment of bone metastases from lung cancer. Denosumab is ranked above ZA for both overall survival and time to SRE, but both treatments are superior to no treatment. ZA was first among all bisphosphonates assessed for odds of reducing SRE incidence, while the combination of Ibandronate and radionuclide therapy was most effective at significantly reducing pain from metastases. Clinicians and policy makers may use this synthesis of all available RCT data as support for the use of a BMA in MBD for lung cancer

The aim was to analyze the efficacy of zoledronic acid (ZA) versus denosumab in the prevention of pathological fractures in patients with bone metastases from advanced cancers by evaluating all available randomized controlled trials (RCTs) on this subject. A systematic search of electronic databases (PubMed and MEDLINE) was performed to identify all published RCTs comparing zoledronic acid with denosumab in prevention of pathological fractures in bone metastases. Risk of bias of the studies was assessed. The primary outcomes evaluated were pathological fractures. Four RCTs (7320 patients) were included. Denosumab was superior to ZA in reducing the likelihood of pathological fractures, when all tumour types were combined (OR 0.86, 95% CI [0.74, 0.99], p = 0.04). Denosumab was not significantly favoured over ZA in endodermal origin (breast and prostate) (OR 0.85, 95% CI [0.68, 1.05], p = 0.13) and mesodermal origin tumours (solid tumours and MM) (OR 0.87, 95% CI [0.71, 1.06], p = 0.16). Denosumab significantly reduces the likelihood of pathological fractures in comparison to ZA in patients with bone metastases. When pathological fractures were grouped by tumour origin (endodermal or mesodermal), there was no significant difference between denosumab and ZA. Further long-term studies are needed to confirm the effectiveness of these treatment regimens

Infections are among the most diffused complications of the implantation of medical devices. In orthopedics, they pose severe societal and economic burden and interfere with the capability of the implants to integrate in the host bone, significantly increasing failure risk. Infection is particularly severe in the case of comorbidities and especially bone tumors, since oncologic patients are fragile, have higher infection rate and impaired osteoregenerative capabilities. For this reason, prevention of infection is to be preferred over treatment. This is even more important in the case of spine surgery, since spine is among the main site for tumor metastases and because incidence of post operative surgical-site infections is significant (up to 15-20%) and surgical options are limited by the need of avoiding damaging the spinal cord. Functionalization of the implant surfaces, so as to address infection and, possibly, co- adjuvate anti-tumor treatments, appears as a breakthrough innovation. Unmet clinical needs in infection and tumors is presented, with a specific focus on the spine, then, new perspectives are highlighted for their treatment

Patients with advanced cancer can develop bone metastases in the femur which are often painful and increase the risk of pathological fracture. Accurate segmentation of bone metastases is, amongst others, important to improve patient-specific computer models which calculate fracture risk, and for radiotherapy planning to determine exact radiation fields. Deep learning algorithms have shown to be promising to improve segmentation accuracy for metastatic lesions, but require reliable segmentations as training input. The aim of this study was to investigate the inter- and intra-operator reliability of manual segmentation of femoral metastatic lesions and to define a set of lesions which can serve as a training dataset for deep learning algorithms. F. CT-scans of 60 advanced cancer patients with a femur affected with bone metastases (20 osteolytic, 20 osteoblastic and 20 mixed) were used in this study. Two operators were trained by an experienced radiologist and then segmented the metastatic lesions in all femurs twice with a four-week time interval. 3D and 2D Dice coefficients (DCs) were calculated to quantify the inter- and intra-operator reliability of the segmentations. We defined a DC>0.7 as good reliability, in line with a statistical image segmentation study. Mean first and second inter-operator 3D-DCs were 0.54 (±0.28) and 0.50 (±0.32), respectively. Mean intra-operator I and II 3D-DCs were 0.56 (±0.28) and 0.71 (±0.23), respectively. Larger lesions (>60 cm. 3. ) scored higher DCs in comparison with smaller lesions. This study reveals that manual segmentation of metastatic lesions is challenging and that the current manual segmentation approach resulted in dissatisfying outcomes, particularly for lesions with small volumes. However, segmentation of larger lesions resulted in a good inter- and intra-operator reliability. In addition, we were able to select 521 slices with good segmentation reliability that can be used to create a training dataset for deep learning algorithms. By using deep learning algorithms, we aim for more accurate automated lesion segmentations which might be used in computer modelling and radiotherapy planning