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.
The spine is one of the most common sites of bony metastasis, with 80% of prostate, lung, and breast cancers metastasizing to the vertebrae resulting in significant morbidity. Current treatment modalities are systemic chemotherapy, such as Doxorubicin (Dox), administered after resection to prevent cancer recurrence, and systemic antiresorptive medication, such as Zolendronate (Zol), to prevent tumor-induced bone destruction. The large systemic doses required to elicit an adequate effect in the spine often leads to significant side-effects by both drugs, limiting their prolonged use and effectiveness. Recently published work by our lab has shown that biocompatible 3D-printed porous polymer scaffolds are an effective way of delivering Dox locally over a sustained period while inhibiting tumor growth in vitro. Our lab has also generated promising results regarding antitumor properties of Zol in vitro. We aim to develop 3D-printed scaffolds to deliver a combination of Zol and Dox that can potentially allow for a synergistic antitumor activity while preventing concurrent bone loss locally at the site of a tumor, avoiding long systemic exposure to these drugs and decreasing side effects in the clinical setting. The PORO Lay polymer filaments are 3D-printed into 5mm diameter disks, washed with deionized water and loaded with Dox or Zol in aqueous buffer over 7 days. Dox or Zol-containing supernatant was collected daily and the drug release was analyzed over time in a fluorescence plate reader. The polymer-drug (Dox or Zol) release was tested in vitro on prostate and lung cancer cell lines and on prostate- or lung-induced bone metastases cells. Alternatively, direct drug treatment was also carried out on the same cells in vitro. Following treatment, all cells were subject to proliferation assay (MTT and alamar blue), viability assay (LIVE/DEAD), migration assay (Boyden chamber) and invasion assay (3D gel matrix). 3D-printed scaffolds loaded with both Dox and Zol will also be tested on cells. We have established an effective dose (EC50) for prostate and lung cancer cell lines and bone metastases cells with direct treatment with Zol or Dox. We have titrated the drug loading of scaffolds to allow for a release amount of Dox at the EC50 dose over 7 days. In ongoing experiments, we are testing the release of Zol. We have shown Dox releasing scaffolds inhibit cancer cell growth in a 2D culture over 7 days using the above cellular assays and testing the scaffolds with Zol is currently being analyzed. 3D-printed porous polymers like the PORO Lay series of products offer a novel and versatile opportunity for delivery of drugs in future clinical settings. They can decrease systemic exposure of drugs while at the same time concentrating the drugs effect at the site of tumors and consequently inhibit tumor proliferation. Their ability to be loaded with multiple drugs can allow for achieving multiple goals while taking advantage of synergistic effects of different drugs. The ability to 3D-print these polymers can allow for production of custom implants that offer better structural support for bone growth.
The spine is a common site of metastasis. Complications include pathologic fracture, spinal cord compression, and neurological deficits. Vertebroplasty (VP) and Balloon Kyphoplasty (KP) are minimally invasive stabilization procedures used as a palliative treatment to improve mechanical stability, quality of life, and reduce pain. Photodynamic therapy (PDT) is a tumour-ablative modality that may complement mechanical stability afforded by VP/KP. This first-in-human study evaluates PDT safety when applied in conjunction with VP/KP. This dose escalation trial involved one light only control group and four light-drug doses (50,100,150,200J;n=6) delivered at 150mW from a 690nm diode laser by 800-micron optical fibers prior to KP/VP. Patients eligible for VP/KP in treating pathologic fracture or at-risk lesions at a single level were recruited. Exclusion criteria included spinal canal compromise or neurologic impairment. PDT is a two-step binary therapy of systemic drug followed by intravertebral light activation. Light was applied via bone trochar prior to cementation. This study used a benzoporphyrin derivative monoacid (BPD-MA), Verteporfin (VisudyneTm), as the photosensitizer drug in the therapy. Drug/light safety, neurologic safety, generic (SF-36), and disease-specific outcomes (VAS, EORTC-QLQ-BM22, EORTC-QLQ-C15-PAL) were recorded through six weeks. Phototoxicity and the side effects of the BPD-MA were also examined following PDT use. Thirty (10 male, 20 female) patients were treated (13 KP, 17 VP). The average age was 61 and significantly different between genders (Male 70yrs vs. Female 57yrs: p 0.05), and tumour status (lytic vs. mixed blastic/lytic: p>0.05). In most cases, fluence rates were similar throughout PDT treatment time, indicating a relatively stable treatment. Twelve (40%) of patients experienced complications during the study, none of which were attributed to PDT therapy. This included two kyphoplasty failures due to progression of disease, one case of shingles, one ankle fracture, one prominent suture, one case of constipation due to a lung lesion, one case of fatigue, and five patients experienced pain that was surgically related or preceded therapy. Vertebral PDT appears safe from pharmaceutical and neurologic perspectives. KP/VP failure rate is broadly in line with reported values and PDT did not compromise efficacy. The 50J group demonstrated an improved response. Ongoing study determining safe dose range and subsequent efficacy studies are necessary.
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.
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.
The management of skeletal metastases can be challenging for the orthopaedic surgeon. They represent a significant source of pain and disability for cancer patients, adding to the morbidity of their condition. Treatment is directed at the alleviation of symptoms and the restoration of function. Metastatic involvement of the proximal humerus can be especially debilitating, having the potential to cause severe pain which leads to loss of function, and may also be complicated by pathological fracture and hence attenuate upper limb function. We present a report of four cases where the use of reverse geometry proximal shoulder prostheses has provided excellent symptomatic relief and a pain free functional range of movement in metastatic proximal humerus disease. To demonstrate a novel, effective surgical strategy for the management of proximal humeral metastatic disease in elderly patients with concomitant poor rotator cuff function, a review of the medical records and radiographic imaging who underwent reverse geometry shoulder replacement for metastatic disease of the proximal humerus was performed. Two cases were secondary to breast cancer, the other two of unknown primary. All four patients were referred with severe shoulder pain significantly limiting range of movement, in one case pathological fracture was demonstrated. In all cases significant symptomatic relief was achieved in the post operative phase, signified by a marked reduction in analgesic requirements. Two patients were completely pain-free at follow up, whilst the remaining two used only minimal oral analgesia. Upper limb function was preserved in all cases, with demonstration of a satisfactory range of motion adequate for activities of daily living in all patients. No surgical complications were noted. The use of reverse geometry shoulder prostheses in proximal humeral metastases (either with or without an associated proximal humeral fracture) demonstrates a reliable and effective method of pain relief with excellent restoration of upper limb function. The unique implant geometry allows the patient to achieve a functional range of motion without reliance on the rotator cuff musculature, which is often defunct in elderly patient groups.
All patients referred to our unit with previously untreated metastatic renal cancer were included in this review. We investigated likely prognostic factors including age, sex, site, synchronous or metachronous metastasis, stage of the disease and the type of treatment received. From 1976 until 2004, a total of 198 patients were treated by our unit for renal metastases. 15 patients were excluded because they were referred after failure of previous treatment or only had advice. 96 patients were already known to have renal metastasis with their diagnosis having been made between 0.2 and 17 years from the diagnosis of primary cancer (mean 4 years). 33 patients presented to us with a pathological fracture and were found to have renal cancer. A total of 54 patients had multiple metastases and 129 had a solitary metastasis. The cumulative survival from the time of diagnosis of the bone metastasis is 70 percent at 1 year, 40% at 3 years and 18% at 5 years. In patients with a solitary metastasis, the overall survival was 74% at 1 year and 45% at 3 years, whereas in patients with multiple metastases it was 55% at 1 year and 22% at 3 years. (p=0.02) In patients with a solitary metastasis treated by excision of the metastasis, the survival at 1 year was 86% as compared to 38% for those that were treated with just a local procedure. Cox multivariate analysis shows that survival was better in those with solitary metachronus metastasis who underwent a radical procedure. We recommend a radical procedure for patients who present with a solitary renal metastasis, particularly those with a disease-free interval of more than one year.Conclusion
25% of patients with an unknown primary tumour present to the orthopaedic surgeon with skeletal metastases. The onus is on the orthopaedic surgeon to establish the diagnosis, not only to decrease the patient's anxiety but also because the median survival increases from 6–9 months to 23 months when the primary is identified and allows for specific cancer treatment. The diagnostic work up of an unknown primary includes a multitude of special investigations. Since PET/CT has high sensitivity and specificity for detecting the primary tumours, we asked the question: Can you diagnose the unknown primary in patients with skeletal metastases with a PET/CT? We included all PET/CT scans done in our institution between 2010 and 2013 for patients with malignancies known to metastasize to bone (melanoma, breast, lung, head and neck, GIT, other) and all scans done in patients with unknown primaries. After reviewing 686 PET/CT scans, 492 showed metastatic disease, with 78 of these having either spinal or skeletal metastases.Introduction:
Method:
To develop a low complexity highly-automated multimodal approach to segment vertebral structure and quantify mixed osteolytic/osteoblastic metastases in the rat spine using a combination of CT and MR imaging. We hypothesize that semi-automated multimodal analysis applied to 3D CT and MRI reconstructions will yield accurate and repeatable quantification of whole vertebrae affected by mixed metastases. Mixed spinal metastases were developed via intra-cardiac injection of canine Ace-1 luciferase transfected prostate cancer cells in a 3 week old rnu/rnu rat. Two sequential MR images of the L1-L3 vertebral motion segments were acquired using a 1H quadrature customized birdcage coil at 60 m isotropic voxel size followed by CT imaging at a 14m isotropic voxel size. The first MR image was T1 weighted to highlight the trabecular structure to ensure accurate registration with the CT image. The second MR image was T2 weighted to optimize differentiation between bone marrow and osteolytic tumour tissue. Samples were then processed for undecalcified histology and stained with Goldners Trichrome to identify mineralized bone and unmineralized new bone formation. All images were resampled to 34.9 m and manually aligned to a global axis. This was followed by an affine registration using a Quasi Newton optimizer and a Normalized Mutual Information metric to ensure accurate registration. The whole individual vertebrae and their trabecular centrums were then segmented from the CT images using an extended version of a previously developed atlas based registration algorithm. An intensity-based thresholding method was used to segment the regions corresponding to osteoblastic tumor predominantly attached to the outside of the cortical shell. The whole vertebral segmentation from the CT was warped around the T2 weighted MR to define the bone boundaries. An intensity-based thresholding approach was then applied to the T2 weighted MR segment the osteolytic tumor.Purpose
Method
Cement-induced thermal osteonecrosis is well documented, as is the potential for nerve injury from thermal energy. Cement is often used to augment fixation following excision of humeral metastases. Porcine femurs were used as a model. We sought to find out the maximum temperatures that would be reached in various parts of the bone during the cement setting process, to explore what negative effects this might have on neighbouring bone and nerve. A 12mm by 12mm window was cut from 12 porcine femoral shafts, and Palacos R+D cement injected into the defect. As cement set, bone surface temperature was measured using infra-red thermal imaging and thermocouples used to measure temperatures at the bone-cement interface, 5mm from the cement bolus, 10mm from cement bolus and an area running around the shaft replicating radial nerve. Bone surface temperature rose to a maximum of 34.0 C (on average), and 32.9 C in the ‘radial nerve’ thermocouple. Notably, in two bones there were fractures during specimen preparation, and maximum temperatures in these two areas exceeded 41 degrees C. Average maximum temperatures were 58.1 C, 36.5 C and 30.1 C at the bone cement interface, 5mm and 10mm from the cement bolus respectively.
70% of breast cancer patients develop metastatic bone deposits, predominantly spinal metasases. Adult Mesenchymal Stem Cells (MSCs) are multiprogenitor stem cells found within the bone marow which have the ability to self-renew and differentiate into multiple cell types. MSCs home specifically to tumour sites, highlighting their potential as delivery vehicles for therapeutic agents. However studies show they may also increase tumour metastatic potential. To investigate interactions between MSCs and breast cancer cells to further elucidate their role in the tumour microenvironment and hence understand factors involved in stimulating the formation of bone metastases.Background
Aim
70% of Breast Cancer patients develop metastatic bone deposits, predominantly spinal metasases. Adult Mesenchymal Stem Cells (MSCs) are multiprogenitor stem cells found within the bone marow which have the ability to self renew and differentiate into multiple cell types. MSCs home specifically to tumour sites, highlighting their potential as delivery vehicles for therapeutic agents. However studies show they may also increase tumour metastatic potential. The aim of this study was to investigate interactions between MSCs and breast cancer cells to further elucidate their role in the tumour microenvironment and hence understand factors involved in stimulating the formation of bone metastases.Background
Aims
Purpose:. To assess the outcomes of osteosarcoma cases managed between January 2006 & December 2010 in a tertiary centre. Methods:. A retrospective review of patient records. Results. Twenty eight consecutive cases of osteosarcoma managed over 5 years were reviewed retrospectively. 16 patients were male, and ages ranged from 11 to 69 years, with 20 patients in their 2nd decade. The distal femur was involved in 17 cases and the proximal tibia in 4. Histologically 13 cases were osteoblastic, 4 chondroblastic and the rest other forms of osteosarcoma. Tumour size varied from 6 to 35 cm, with only 6 less than 10 cm in size.
The management of pathological fractures due to Metastatic Bone Disease (MBD) and Primary Bone Tumours (PBTs) has implications for the Trauma service due to the extra pressures on staff, service delivery and budgets. We undertook an analysis of a cohort of patients presenting with MBD and PBTs. A retrospective chart review of all cases with MBD and PBTs admitted to a 40-bed Trauma Unit between 2005 and 2009 was conducted. The study looked at frequency, primary pathology, and site of pathology/fracture, time from primary diagnosis to referral, subsequent interventions and others. The results identified 34 patients, 21 females (62%) and 13 males (38%) (mean age: 64.6 years) with MBD or PBTs.
Objective. To evaluate functional and oncological outcomes following sacral resection. Methods. A retrospective review was conducted of 97 sacral tumours referred to tertiary referral spinal or oncology unit between 2004 and 2009. Results. The study included Chordoma 26;
