Emerging innovations and advancements in the treatment of extremity and truncal soft tissue sarcomas.

In this special edition update on soft tissue sarcomas (STS), we cover classifications, emerging technologies, prognostic tools, radiation schemas, and treatment disparities in extremity and truncal STS. We discuss the importance of enhancing local control and reducing complications, including the role of innovative imaging, surgical guidance, and hypofractionated radiation. We review advancements in systemic and immunotherapeutic treatments and introduce disparities seen in this vulnerable population that must be considered to improve overall patient care.

What are the indications and survivorship of tumor endoprosthetic reconstructions for patients with extremity metastatic bone disease?

BACKGROUND AND OBJECTIVES: Given advances in therapies, endoprosthetic reconstruction (EPR) in metastatic bone disease (MBD) may be increasingly indicated. The objectives were to review the indications, and implant and patient survivorship in patients undergoing EPR for MBD. METHODS: A review of patients undergoing EPR for extremity MBD between 1992 and 2022 at two centers was performed. Surgical data, implant survival, patient survival, and implant failure modes were examined. RESULTS: One hundred fifteen patients were included with a median follow-up of 14.9 months (95% confidence interval [CI]: 9.2-19.3) and survival of 19.4 months (95% CI: 13.6-26.1). The most common diagnosis was renal cell carcinoma (34/115, 29.6%) and the most common location was proximal femur (43/115, 37.4%). Indications included: actualized fracture (58/115, 50.4%), impending fracture (30/115, 26.1%), and failed fixation (27/115, 23.5%). Implant failure was uncommon (10/115, 8.7%). Patients undergoing EPR for failed fixation were more likely to have renal or lung cancer (p = 0.006). CONCLUSIONS: EPRs were performed most frequently for renal cell carcinoma and in patients with a relatively favorable survival. EPR was indicated for failed previous fixation in 23.5% of cases, emphasizing the importance of predictive survival modeling. EPR can be a reliable and durable surgical option for patients with MBD.

Does surgical technique influence the burden of lung metastases in patients with pathologic long bone fractures?

BACKGROUND: The aims of this study are to (1) determine whether fixation of metastatic long bone fractures with an intramedullary nail (IMN) influences the incidence of lung metastasis in comparison to arthroplasty or ORIF (Arthro/ORIF); and (2) assess this relationship in primary tumor types; and (3) to assess survival implications of lung metastasis after surgery. METHODS: Retrospective cohort study investigating 184 patients (107 IMN, and 77 Arthro/ORIF) surgically treated for metastatic long bone fractures. Patients were required to have a single surgically treated impending or established pathologic fracture of a long bone, pre-operative lung imaging (lung radiograph or computed tomography) and post-operative lung imaging within 6 months of surgery. Primary cancer types included were breast (n = 70), lung (n = 43), prostate (n = 34), renal cell (n = 37). Statistical analyses were conducted using two-tailed Fisher's exact tests, and Kaplan-Meier survival analyses. RESULTS: Patients treated with IMN and Arthro/ORIF developed new or progressive lung metastases following surgery at an incidence of 34 and 26%, respectively. Surgical method did not significantly influence lung metastasis (p = 0.33). Furthermore, an analysis of primary cancer subgroups did not yield any differences between IMN vs Arthro/ORIF. Median survival for the entire cohort was 11 months and 1-year overall survival was 42.7% (95% CI: 35.4-49.8). Regardless of fixation method, the presence of new or progressive lung metastatic disease at follow up imaging study was found to have a negative impact on patient survival (p < 0.001). CONCLUSIONS: In this study, development or progression of metastatic lung disease was not affected by long bone stabilization strategy. IM manipulation of metastatic long bone fractures therefore may not result in a clinically relevant increase in metastatic lung burden. The results of this study also suggest that lung metastasis within 6 months of surgery for metastatic long bone lesions is negatively associated with patient survival. LEVEL OF EVIDENCE: III, therapeutic study.

Venous thromboembolism rates in patients with bone and soft tissue sarcoma of the extremities following surgical resection: A systematic review.

BACKGROUND: Patients undergoing an orthopedic surgery for bone or soft tissue sarcoma are at increased venous thromboembolism (VTE) risk. Unfortunately, there is a lack of thromboprophylaxis guidelines in this population. The purpose of this systematic review was to determine the soft tissue and bone sarcoma VTE rate and to explore the thromboprophylaxis regimens used. METHODS: The databases MEDLINE, EMBASE, and CENTRAL were queried using keywords related to VTE and long bone malignancy requiring surgical intervention to 2020. Included studied reported VTE rate in patients with surgically managed extremity sarcoma. Descriptive statistics and weighted mean totals were calculated. RESULTS: A total of 2082 studies were screened and 23 studies were included. The overall VTE rate was 2.9%, with a rate of 3.7% and 1.4% in patients with bone and soft tissue sarcomas, respectively. Low-molecular-weight heparin was the most commonly used chemoprophylaxis. CONCLUSIONS: There is a high VTE rate following sarcoma surgery. The VTE rate is higher in bone sarcoma surgery, which may be attributed to differences in surgery and postoperative recovery. There was no consensus on the duration or type of thromboprophylaxis used. Future research is needed to determine the most effective thromboprophylaxis regimen in patients with sarcoma and whether individualized thromboprophylaxis is required.

Thromboembolic complications after surgical fixation of bone metastases: A systematic review.

BACKGROUND: Patients undergoing a major orthopedic surgery for metastatic bone disease (MBD) are at high risk of developing venous thromboembolic (VTE) complications. Despite concerns, there is no consensus on the most effective strategy to prevent VTE in these patients. The purpose of this systematic review was to determine the VTE rate following the surgical management of MBD. METHODS: The databases MEDLINE, EMBASE, and CENTRAL were searched using keywords related to VTE and MBD requiring surgical management. Included studies reported VTE rates in patients with surgically managed MBD. Descriptive statistics and weighted mean totals were calculated. RESULTS: In total, 2082 abstracts were screened, and 29 studies were included. The overall VTE rate was 4.7%. Patients receiving surgery for impending pathologic fracture had a higher rate of VTE (5.6%) compared to patients with acute pathologic fractures (4.2%). Low-molecular-weight heparin was the most used chemoprophylaxis. CONCLUSIONS: Relative to other cancer and orthopedic patients, the VTE rate is extremely high in patients with MBD. The discordant recommendations of thromboprophylaxis, and absence of research in this distinct and more granular surgical oncology subgroup, underpins the challenges associated with developing guidelines to lessen the VTE risks in the MBD patient population.

Communication in surgical decision-making while managing metastatic bone disease: matching patient expectations with surgical goals.

BACKGROUND: There is a paucity of research examining how surgical decision-making for metastatic bone disease (MBD) can be optimized to improve quality of life (QOL) and functional outcomes, while accurately aligning with patient goals and expectations. The objective of this study was to survey and interview patients with MBD and support persons (PS), physicians, and allied health care providers (HCP) with the goal of identifying (1) important surgical issues related to MBD management, (2) discordance in perioperative expectations, and (3) perceived measures of success in the surgical management of MBD. METHODS: Utilizing a custom survey developed by HCP and patients with MBD, participants were asked to (1) identify important issues related to MBD management, (2) rank perceived measures of success, and (3) answer open-ended questions pertaining to the management of MBD. RESULTS: From the survey, increased life expectancy, minimizing disease progression, removal of local tumour, timely surgery after diagnosis, increased length of hospitalization, and physiotherapy access were all identified as significant discordant goals between PS and physicians/HCP. Conversely, there was an agreement between physicians and HCP who considered improved QOL and functional outcomes as most important goals. Structured homogenous-group workshops identified the need for (1) improved discussions of prognosis, surgical options, expectations, timelines, and resources, (2) the use of a care team "quarterback", and (3) an increased use of multi-disciplinary treatment planning. CONCLUSIONS: We feel this data highlights the importance of improved communication and coordination in treating patients with MBD. Further research evaluating how surgical techniques influence survival and disease progression in MBD is highly relevant and important to patients.

Is Use of BMP-2 Associated with Tumor Growth and Osteoblastic Differentiation in Murine Models of Osteosarcoma?

BACKGROUND: The putative benefit of rhBMP-2 is in the setting of limb reconstruction using structural allografts, whether it be allograft-prosthetic composites, osteoarticular allografts, or intercalary segmental grafts. There are also potential advantages in augmenting osseointegration of uncemented endoprosthetics and in reducing infection. Recombinant human BMP-2 might mitigate nonunion in structural allograft augmented osteosarcoma limb salvage surgery; however, its use is limited because of concerns about the prooncogenic effects of the agent. QUESTIONS/PURPOSES: (1) To assess if BMP-2 signaling influences osteosarcoma cell line growth. (2) To characterize degree of osteosarcoma cell line osteoblastic differentiation in response to BMP-2. (3) To assess if BMP-2 signaling has a consistent effect on local or systemic tumor burden in various orthotopic murine models of osteosarcoma. METHODS: In this study, 143b, SaOS-2 and DLM8-M1 osteosarcoma cell lines were transfected with BMP-2 cDNA controlled by a constitutive promoter (experimental) or an empty vector (control) using a PiggyBac transposon system. Cellular proliferation was assessed using a quantitative MTT colorimetric assay. Osteoblastic differentiation was compared between control and experimental cell lines using quantitative real-time polymerase chain reaction of the osteoblastic markers connective tissue growth factor, Runx-2, Osterix, alkaline phosphatase and osteocalcin. Experimental and control cell lines were injected into the proximal tibia of either NOD-SCID (143b and SaOS-2 xenograft model), or C3H (DLM8-M1 syngeneic model) mice. Local tumor burden was quantitatively assessed using tumor volume caliper measurements and bioluminescence, and qualitatively assessed using post-mortem ex vivo microCT. Lung metastasis was qualitatively assessed by the presence of bioluminescence, and incidence was confirmed using histology. rhBMP-2 soaked absorbable collagen sponges (experimental) and sterile-H2O soaked absorbable collagen sponges (control) were implanted adjacent to 143b proximal tibial cell line injections to compare the effects of exogenous BMP-2 application with endogenous upregulation. RESULTS: Constitutive expression of BMP-2 increased the in vitro proliferation of 143b cells (absorbance values 1.2 ± 0.1 versus 0.89 ± 0.1, mean difference 0.36 [95% CI 0.12 to 0.6]; p = 0.01), but had no effect on SaOS-2 and DLM8-M1 cell proliferation. In response to constitutive BMP-2 expression, 143b cells had no differences in osteoblastic differentiation, while DLM8-M1 cells downregulated the early marker connective tissue growth factor (mean ΔCt 0.2 ± 0.1 versus 0.6 ± 0.1; p = 0.002) and upregulated the early-mid range marker Runx-2 (mean ΔCt -0.8 ± 0.1 versus -1.1 ± 0.1; p = 0.002), and SaOS-2 cells upregulated the mid-range marker Osterix (mean ΔCt -2.1 ± 0.6 versus -3.9 ± 0.6; p = 0.002). Constitutive expression of BMP-2 resulted in greater 143b and DLM8-M1 local tumor volume (143b: 307.2 ± 106.8 mm versus 1316 ± 387.4 mm, mean difference 1009 mm [95% CI 674.5 to 1343]; p < 0.001, DLM8-M1 week four: 0 mm versus 326.1 ± 72.8 mm, mean difference 326.1 mm [95% CI 121.2 to 531]; p = 0.009), but modestly reduced local tumor growth in SaOS-2 (9.5 x 10 ± 8.3x10 photons/s versus 9.3 x 10 ± 1.5 x 10 photons/s, mean difference 8.6 x 10 photons/s [95% CI 5.1 x 10 to 1.2 x 10]; p < 0.001). Application of exogenous rhBMP-2 also increased 143b local tumor volume (495 ± 91.9 mm versus 1335 ± 102.7 mm, mean difference 840.3 mm [95% CI 671.7 to 1009]; p < 0.001). Incidence of lung metastases was not different between experimental or control groups for all experimental conditions. CONCLUSIONS: As demonstrated by others, ectopic BMP-2 signaling has unpredictable effects on local tumor proliferation in murine models of osteosarcoma and does not consistently result in osteosarcoma cell line differentiation. Further investigations into other methods of safe bone and soft tissue healing augmentation and the use of differentiation therapies is warranted. CLINICAL RELEVANCE: Our results indicate that BMP-2 has the potential to stimulate the growth of osteosarcoma cells that are poorly responsive to BMP-2 mediated osteoblastic differentiation. As this differentiation potential is unpredictable in the clinical setting, BMP-2 may promote the growth of microscopic residual tumor burden after resection. Our study provides further support for the recommendation to avoid the use of BMP-2 after limb-salvage surgery in patients with osteosarcoma.

A scoping review on the surgical management of metastatic bone disease of the extremities.

BACKGROUND: Management of metastatic bone disease of the extremities (MBD-E) is challenging, and surgical directions pose significant implications for overall patient morbidity and mortality. Recent literature reviews on the surgical management of MBD-E present a paucity of high-level evidence and global inconsistencies in study design. In order to steer productive research, a scoping review was performed to map and assess critical knowledge gaps. METHODS: The Arksey and O'Malley framework for scoping studies was followed. A comprehensive literature search identified a large body of literature pertaining to the surgical management of MBD-E. Study data and meta-data was extracted and presented using descriptive analytics and a thematic framework. Literature gaps were identified and analyzed. RESULTS: Three hundred eighty five studies from 1969 to 2017 were included. Studies were categorized into 11 separate themes, with the majority (63%) falling into the "surgical fixation strategies" theme, followed by "complications" at 7% and "prognosis and survival" at 6.2%. Less than 3% of studies were categorized in "patient related outcomes" or "epidemiology" themes. 89% of studies were retrospective and only 6 studies were of level 1 or 2 evidence. We identified a temporal increase in publication by decade, and all studies published on interventional radiology techniques or economic analyses were published after 2007 or 2009, respectively. 64.9% of studies were published in Europe and 20.3% were published in North America. Average patient age was 62 (± 5.2 years), and breast was the most common primary tumour (28%), followed by lung (17%) and kidney (15%). In terms of surgical location, 75% of operations involved the femur, followed by the humerus at 22% and tibia at 3%. CONCLUSIONS: We present a descriptive overview of the current published literature on the surgical management of MBD-E. Critical knowledge gaps have been identified through the development of a thematic framework. Consolidation of literary gaps must involve bolstered efforts towards patient and family-engaged research initiatives and assessment of patient-related surgical outcomes. Multi-disciplinary engagement in developing prospective research will also help guide evidence-based personalized practice for these patients. By building on existing comprehensive patient databases and registries, knowledge on survival and prognostic parameters can be greatly improved.

Outcomes of Modified Harrington Reconstructions for Nonprimary Periacetabular Tumors: An Effective and Inexpensive Technique.

BACKGROUND: Metastatic disease to the acetabulum presents a difficult technical and philosophical challenge: complicated surgeries in patients with often short life expectancies force us to examine both the outcome and cost of these operations. Therefore, we studied the durability of a cement-screw rebar reconstruction technique and risk factors for failure, and we compare the results to other reconstruction options. METHODS: This is a retrospective review of 52 acetabular reconstructions in 50 patients for nonprimary disease using a retrograde screw-rebar-cement all-polyethylene technique. Mean age was 57 years (range 25-81 years). Twenty-four lesions were classified as Harrington class II; 28 were Harrington class III. Mean follow-up was 17.7 months (range 1-92 months). Outcomes included patient survival, prosthesis survival, and complications. RESULTS: Forty-eight of 50 (96 %) patients ambulated after surgery. Five of 52 (9.6 %) of prostheses failed, three from loosening due to tumor progression, one from aseptic loosening, and one from soft tissue instability (dislocation). The three cases of tumor progression failure occurred in patients with massive preoperative ischial tumor burden. Mean surgical time was 198 min, and hospital stay was 5.2 days. DISCUSSION: The screw-cement-rebar all-polyethylene cup reconstruction technique is a comparatively successful and inexpensive reconstruction option for treating nonprimary oncologic disease in the acetabulum. All cases of loosening occurred beyond the median patient survival. Surgeons should be wary of massive ischial tumor burden in patients with projected longevity, as it may be associated with implant failure. Surgical time and hospital stay are consistent with historical data for alternative implants, and implant cost is lower.

Tumoral TP53 and/or CDKN2A alterations are not reliable prognostic biomarkers in patients with localized Ewing sarcoma: a report from the Children's Oncology Group.

BACKGROUND: A growing collection of retrospective studies have suggested that TP53 mutations and/or CDKN2A deletions have prognostic significance in Ewing sarcoma. We sought to evaluate these variables in patients with localized disease treated prospectively on a single Children's Oncology Group protocol. PROCEDURE: Of the 568 patients enrolled on Children's Oncology Group protocol AEWS0031 (NCT00006734), 112 had tumor specimens of sufficient quality and quantity to allow for analysis of TP53 mutations status by DNA sequencing, and CDKN2A deletion by dual color fluorescent in situ hybridization. RESULTS: Eight of 93 cases (8.6%) were found to have TP53 point mutations and 12 of 107 cases (11.2%) demonstrated homozygous CDKN2A deletion. Two cases were found to have an alteration in both genes. There was no significant difference in event-free survival of patients with TP53 mutations and/or CDKN2A deletions compared to patients with normal TP53/CDKN2A gene status, as demonstrated by log rank test (p = 0.58). CONCLUSIONS: Although previous retrospective studies suggest their significance, TP53 mutation and/or CDKN2A deletion are not reliable prognostic biomarkers in localized Ewing sarcoma.

What are the 5-year survivorship outcomes of compressive endoprosthetic osseointegration fixation of the femur?

BACKGROUND: Aseptic complications such as stress shielding leading to bone loss are major problems associated with revision of cemented and uncemented long-stem tumor endoprostheses. Endoprosthetic reconstruction using compressive osseointegration fixation is a relatively new limb salvage technology designed to enhance osseointegration, prevent stress shielding, and provide fixation for short end-segments. QUESTIONS/PURPOSES: (1) What is the survivorship of this technique at minimum 5-year followup? (2) Were patient factors (age, sex, body mass index), oncological factors, or anatomic locations associated with implant failure? (3) Were there any prosthesis-related variables associated with failure? METHODS: A single-center, retrospective review of patients with a minimum 5-year followup (mean, 8 years; range, 5-12 years) treated with an osseointegration compressive device for endoprosthetic fixation of proximal and distal femoral limb salvage reconstructions was performed. We have previously published the implant survivorship of this patient cohort with a minimum 2-year followup and are now reporting on the 5-year survivorship data. From 2002 to 2008, we performed 22 such procedures in 22 patients. Four patients died of their disease within 5 years of surgery and all surviving patients (n = 18) had complete followup data at a minimum of 5 years. General indications for this device during that time were pediatric and adult patients requiring primary endoprosthetic reconstructions of the proximal or distal femur for benign and malignant bone lesions. The primary outcome was reoperations for mechanical (aseptic) failures. Secondary outcomes included implant removal for nonmechanical failures and any patient-, oncological-, or implant-related variables associated with implant removal. RESULTS: At a minimum of 5 years followup, overall mechanical (aseptic) implant survivorship was 16 of 18. Survivorship for all modes of failure (oncological failure, infection, arthrofibrosis, and mechanical failure) was 12 of 18. All mechanical failures occurred early, within the first 30 months. We identified no patient-, oncological-, or implant-related features predictive of failure. CONCLUSIONS: Our intermediate-term experience with compressive osseointegration fixation for endoprosthetic limb reconstructions demonstrates with longer clinical followup, no additional mechanical failures were observed as compared with our early analysis. Our experience with this fixation at a minimum of 5-years followup adds to a very limited but increasing body of literature demonstrating that after a transient period of increased risk for implant failures, survivorship stabilizes. Assessment of this fixation strategy beyond 10 years of clinical followup is needed. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Molecular characterization of bone tumors and implications for treatment and prognosis.

Neoplastic transformation is a consequence of maladaptive alterations in the cellular processes normally involved in cell growth, proliferation, differentiation, and survival. Despite the relative infrequent nature of skeletal neoplasms, current understanding of the pathobiology underlying these conditions is becoming increasingly characterized. This article highlights some of the established molecular abnormalities identified in various benign and malignant skeletal neoplasms and how they pertain to tumor biology, diagnosis, and prognosis. Most of the commonly accepted cellular aberrancies in skeletal neoplasms pertain to mutations, copy number changes, and/or chromosomal rearrangements. However, it is becoming increasingly understood that the complexity of tumorigenic pathways necessary for neoplastic growth are manipulated by numerous overlapping alterations in the genetic code and are further influenced by higher-order molecular programs, such as pretranscriptional and posttranscriptional regulation and chromatin reorganization. Over time, identification and quantification of these increasingly recognized neoplastic processes will gradually translate into valuable clinical applications, enhancing the current diagnostic and prognostic capabilities.

Rotationplasty: Beauty is in the Eye of the Beholder.

Rotationplasty is an alternative reconstructive strategy after sarcoma resection that often gets overlooked due to concerns about cosmesis. "Rotating" a distal segment 180 degrees and fixing it to a proximal segment leaves a highly-functional, durable reconstruction that functionally compares favorably to other limb-salvage techniques. Cosmetic outcomes have no discernible impact of the emotional and social functioning of cancer survivors following rotationplasty. This chapter discusses techniques of rotationplasty, as well as its oncologic, functional and emotional outcomes.

Effectiveness of immune checkpoint inhibitor therapy on bone metastases in non-small-cell lung cancer.

Background: Bone metastases (BoMs) are prevalent in patients with metastatic non-small-cell lung cancer (NSCLC) however, there are limited data detailing how BoMs respond to immune checkpoint inhibitors (ICIs). The purpose of this study was to compare the imaging response to ICIs of BoMs against visceral metastases and to evaluate the effect of BoMs on survival. Materials and methods: A retrospective, multicentre cohort study was conducted in patients with NSCLC treated with nivolumab or pembrolizumab in Alberta, Canada from 2015 to 2020. The primary endpoint was the real-world organ specific progression free survival (osPFS) of bone versus visceral metastases. Visceral metastases were categorized as adrenal, brain, liver, lung, lymph node, or other intra-abdominal lesions. The secondary outcome was overall survival (OS) amongst patients with and without BoMs. Results: A total of 573 patients were included of which all patients had visceral metastases and 243 patients (42.4%) had BoMs. High PD-L1 expression was identified in 268 patients (46.8%). No significant difference in osPFS was observed between bone, liver, and intra-abdominal metastases (p=0.20 and p=0.76, respectively), with all showing shorter osPFS than other disease sites. There was no difference in the osPFS of extra-thoracic sites of disease in patients with high PD-L1 expression. There was significant discordance between visceral disease response and bone disease response to ICI (p=0.047). The presence of BoMs was an independent poor prognostic factor for OS (HR 1.26, 95%CI: 1.05-1.53, p=0.01). Conclusion: Metastatic bone, liver, and intra-abdominal lesions demonstrated inferior clinical responses to ICI relative to other sites of disease. Additionally, the presence of bone and liver metastases were independent poor prognostic factors for overall survival. This real-world data suggests that BoMs respond poorly to ICI and may require treatment adjuncts for disease control.

Posttraumatic elbow contractures: targeting neuroinflammatory fibrogenic mechanisms.

Posttraumatic elbow stiffness remains a common and challenging clinical problem. In the setting of a congruent articular surface, the joint capsule is regarded as the major motion-limiting anatomic structure. The affected joint capsule is characterized by irreversible biomechanical and biochemical fibrogenic changes strikingly similar to those observed in many other fibroproliferative human conditions. Studies in humans and preclinical animal models are providing emergent evidence that neuroinflammatory mechanisms are critical upstream events in the pathogenesis of posttraumatic connective tissue fibrogenesis. Maladaptive recruitment and activation of mast cell infiltrates coupled with the aberrant expression of growth factors such as transforming growth factor-beta, nerve growth factor, and neuropeptides such as substance P are common observations in posttraumatic joint contractures and many other fibroproliferative disorders. Blockade of these factors is providing promising evidence that if treatment is timed correctly, the fibrogenic process can be interrupted or impeded. This review serves to highlight opportunities derived from these recent discoveries across many aberrant fibrogenic disorders as we strive to develop novel, targeted antifibrotic prevention and treatment strategies for posttraumatic elbow stiffness.

The mast cell stabilizer ketotifen reduces joint capsule fibrosis in a rabbit model of post-traumatic joint contractures.

OBJECTIVES: Using a rabbit model of post-traumatic joint contractures, we investigated whether treatment with a mast cell stabilizer after joint injury would lessen the molecular manifestations of joint capsule fibrosis. METHODS: Surgical joint injury was used to create stable post-traumatic contractures of the knee in skeletally mature New Zealand white rabbits. Four groups of animals were studied: a non-operated control group (n = 8), an operated contracture group (n = 13) and two operated groups treated with the mast cell stabilizer, ketotifen, at doses of 0.5 mg/kg (n = 9) and 1.0 mg/kg (n = 9) twice daily. Joint capsule fibrosis was assessed by quantifying the mRNA and protein levels of α-SMA, tryptase, TGF-ß1, collagen I and collagen III. Significance was tested using an ANOVA analysis of variance. RESULTS: The protein and mRNA levels of α-SMA, TGF-ß1, tryptase and collagen I and III were significantly elevated in the operated contracture group compared to control (p < 0.01). In both ketotifen-treated groups, protein and mRNA levels of α-SMA, TGF-ß1 and collagen I were significantly reduced compared to the operated contracture group (p < 0.01). CONCLUSIONS: These data suggest an inflammatory pathway mediated by mast cell activation is involved in joint capsule fibrosis after traumatic injury.

Extra-abdominal desmoid tumors associated with familial adenomatous polyposis.

Extra-abdominal desmoid tumors are a significant cause of morbidity in patients with familial adenomatous polyposis syndrome. Understanding of the basic biology and natural history of these tumors has increased substantially over the past decade. Accordingly, medical and surgical management of desmoid tumors has also evolved. This paper analyzes recent evidence pertaining to the epidemiology, molecular biology, histopathology, screening, and treatment of extra-abdominal desmoid tumors associated with familial adenomatous polyposis syndrome.

Heightened Procoagulation after Post-Operative Thromboprophylaxis Completion in Patients with Metastatic Bone Disease from Primary Colorectal Cancer.

BACKGROUND: Platelets play a role in venous thromboembolism (VTE) and in mediating colorectal cancer (CRC) progression. Still, platelets' role in hypercoagulability after surgical intervention for metastatic bone disease (MBD) is ill-defined. METHODS: In this quantitative observational study, we utilized a high-resolution imaging approach to temporally examine platelet procoagulant membrane dynamics (PMD) in four patients with MBD from primary CRC (CRC/MBD), before and after surgical intervention, over a 6-month period. We coupled this investigation with thrombelastography, quantitative plasma shotgun proteomics, and biochemical analysis. RESULTS: The plasma of CRC/MBD patients was enriched in ADAM1a, ADAMTS7, and physiological ligands for platelet glycoprotein-VI/spleen tyrosine kinase (GPVI/Syk) activation. Thromboprophylaxis attenuated procoagulation upon its initial prescription (post-operative day one, POD1); however, all patients experienced rebound procoagulation between POD3 and POD14, which was associated with Syk activation (Y525/Y526) in all patients, and a VTE event in two patients. Plasma levels of DNA-histone complexes increased steadily after surgery and remained elevated throughout the study period. Additionally, we increasingly sighted both homotypic and heterotypic platelet microaggregates after surgery in CRC/MBD patients, but not in healthy control participants' plasma. CONCLUSIONS: Our data elucidates the cell biology of a prothrombo-inflammatory state caused by disease and vascular injury, and recalcitrant to thromboprophylaxis. New mechanistic insights into hypercoagulability in CRC/MBD patients may identify novel drug targets for effective thromboprophylaxis type and duration after orthopaedic surgery.

Intratumoral STING activation causes durable immunogenic tumor eradication in the KP soft tissue sarcoma model.

Introduction: Soft tissue sarcomas (STS) are highly metastatic, connective-tissue lineage solid cancers. Immunologically, sarcomas are frequently characterized by a paucity of tumor infiltrating lymphocytes and an immune suppressive microenvironment. Activation of the STING pathway can induce potent immune-driven anti-tumor responses within immunogenic solid tumors; however, this strategy has not been evaluated in immunologically cold sarcomas. Herein, we assessed the therapeutic response of intratumoral STING activation in an immunologically cold murine model of undifferentiated pleomorphic sarcoma (UPS). Materials and Results: A single intratumoral injection of the murine STING agonist, DMXAA resulted in durable cure in up to 60% of UPS-bearing mice. In mice with synchronous lung metastases, STING activation within hindlimb tumors resulted in 50% cure in both anatomic sites. Surviving mice all rejected UPS re-challenge in the hindlimb and lung. Therapeutic efficacy of STING was inhibited by lymphocyte deficiency but unaffected by macrophage deficiency. Immune phenotyping demonstrated enrichment of lymphocytic responses in tumors at multiple timepoints following treatment. Immune checkpoint blockade enhanced survival following STING activation. Discussion: These data suggest intratumoral activation of the STING pathway elicits local and systemic anti-tumor immune responses in a lymphocyte poor sarcoma model and deserves further evaluation as an adjunctive local and systemic treatment for sarcomas.