The NZ Standards of Service Provision for Sarcoma patients were developed by the NZ Sarcoma working group and published by the Ministry of Health (MOH) in 2013. Although not formally enacted by the MOH we aimed to determine the impact of these published standards and referral pathways on disease-specific survival of patients with soft-tissue sarcoma in NZ. The Middlemore Musculoskeletal Tumour Unit database was searched. Patients referred for treatment in our centre with a diagnosis of soft tissue sarcoma in the five-year period before (n=115) and after (n=155) were included. We excluded patients with bone sarcomas and retroperitoneal soft tissue sarcomas. The rate of referral after inappropriate treatment reduced after implementation of the Standards (24% vs 12%, p=0.010). The number of patients referred with tumours larger than 50mm decreased (74.8% vs 72.3%, p=0.021) and fewer had metastases at diagnosis (11.3% vs 3.2%, p=0.017). Mortality was lower in the group after introduction of the Standards (45% vs 30%, p=0.017). The estimated disease-specific survival curve between the two groups shows a trend towards increased survival in the post-standards group, although not reaching statistical significance. Local recurrence rate and metastasis rate after definitive treatment were similar between the two groups. Patients had a shorter duration of symptoms before referral in the post-Standards group although this was not statistically significant. Since implementation of the Standards, patients have been referred more promptly, with fewer inappropriate treatments. The time to mortality curve indicates a trend towards improved disease-specific survival. We conclude that the pathway for investigation and referral for this condition has become clearer, supporting the ongoing use of the Sarcoma Standards, and that these should be formally implemented by the MOH

Population-based studies from the United States have reported that sarcoma patients living in rural areas or belonging to lower socioeconomic classes experience worse overall survival; however, the evidence is not clear for universal healthcare systems where financial resources should theoretically not affect access to standard of care. The purpose of this study was to determine the survival outcomes of soft-tissue sarcoma (STS) patients treated in Ontario, Canada over 23 years and determine if the patient's geographic location or income quintile are associated with survival. We performed a population-based cohort study using linked administrative databases of patients diagnosed with STS between 1993 – 2015. The Kaplan-Meier method was used to estimate 2, 5, 10, 15 and 20-year survival stratified by age, stage and location of tumor. We estimated survival outcomes based on the patient's geographic location and income quintile. The Log-Rank test was used to detect significant differences between groups. If groups were significantly different, a Cox proportional hazards model was used to test for interaction effects with other patient variables. We identified 8,896 patients with biopsy-confirmed STS during the 23-year study period. Overall survival following STS diagnosis was 70% at 2 years, 59% at 5 years, 50% at 10 years, 43% at 15 years, and 38% at 20 years. Living in a rural location (p=0.0028) and belonging to the lowest income quintile (p<0.0001) were independently associated with lower overall survival following STS diagnosis. These findings were robust to tests of interaction with each other, age, gender, location of tumor and stage of disease. This population-based cohort study of 8,896 STS patients treated in Ontario, Canada over 23 years reveals that patients living in a rural area and belonging to the lowest income quintile are at risk for decreased survival following STS diagnosis. We extend previous STS survival reporting by providing 15 and 20-year survival outcomes stratified by age, stage, and tumor location

This study explored psychological functioning and coping styles in adult patients with localized and metastatic extremity soft-tissue sarcoma (STS) from diagnosis through survivorship in a single expert sarcoma center in Canada. Our analyses were driven by three main goals: 1) to develop a better understanding of the affective responses and coping mechanisms in patients who face this rare illness, 2) to identify areas of psychological functioning in which patients with STS experience most difficulties, and 3) to describe how these areas could be best addressed in clinical settings. This descriptive qualitative study is a part of a larger mixed-methods study on health related quality of life (HRQoL) in adult patients with soft-tissue sarcoma treated between 2003 and 2018. Purposive sampling based on demographic and disease variables from all patients within a prospective database was utilized to ensure a representative patient population. Three formats of data collection were conducted in French and English, 2 online focus groups (total n=12), 2 in-person focus groups (total n=12), as well as individual semi-structured interviews (n=4). Data was analyzed using inductive thematic networks approach using the qualitative software N-Vivo 12. Codes were generated by 2 independent qualitative experts that captured key concepts referring to psychological functioning and coping mechanisms. Basic themes were clustered into organizing themes, which were later merged into a global theme. Attention was paid to deviant cases, and within-group dynamics during focus group discussion analysis. Any discrepancies or inconsistencies in coding were resolved in a consensus meeting. The final sample size was determined when data saturation was reached, and no new themes emerged. Our analyses of psychological well-being and functioning revealed three main themes, mood, anxiety, and body image concerns. Feelings of depression and low mood were prominent, coinciding with physical symptoms and limitations especially during the phase of treatment and recovery. Women were more likely to report emotional volatility, while men tended to report more preoccupation. Loss of control and independence, anxiety related to illness recurrence, uncertainty about the future and facing one's mortality significantly impacted quality of life. Furthermore, while patients were more concerned with limb functionality, disfigurement and self-consciousness featured prominently in the narrative. Four adaptive coping styles were observed, positive reframing and optimism, finding a purpose, being proactive, and using humor. Among the maladaptive strategies, we noted passive acceptance, and avoidance and denial. Psychological well-being is an important domain in the HRQoL of adult patients with extremity STS. Physicians and medical workers should encourage adaptive coping mechanisms such as positive reframing and optimism. Patients endorsing higher levels of psychological distress and maladaptive coping styles should be monitored for their well-being and multidisciplinary strategies employed to optimize psychological function and HRQoL

Purpose. The optimal sequencing of radiotherapy (RT) with surgery in soft-tissue sarcomas (STS) remains undefined. We assessed the impact of RT sequencing on overall survival (OS), cause-specific survival (CSS), local failure, and distant failure. Methods. A retrospective analysis was conducted using the National Oncology Database, a proprietary database of aggregated tumour registries owned by Impac. (r). Medical Systems (Sunnyvale, CA). Eligible sites were soft tissues of the head/neck, thorax, abdomen, pelvis, extremities, trunk, and peritoneum. Only patients with known stage and grade were included. Prognostic factors were identified with multivariate analysis (MVA) using the Cox proportional hazards model. Survival was calculated using the Kaplan-Meier method, and compared for statistical significance (p< 0.05) using the log-rank test. Results. A total of 821 patients met the inclusion criteria. The median follow-up time for living patients was 62 months. The 5-year CSS was 69%. MVA identified the following independent predictors for CSS (p< 0.01): age, stage, grade, histology, surgery, RT sequence, and tumour size. CSS was significantly improved with pre-op RT versus post-op RT [hazard ratio (HR) 0.7, 95% confidence interval (CI) 0.51-0.94, p< 0.05], with a 5-year CSS of 81% and 73%, respectively (log-rank, p< 0.01). Pre-op RT improved CSS in patients with lower extremity tumours, leiomyosarcoma, and synovial sarcoma (p< 0.05). OS was not significantly improved with pre-op RT. Pre-op RT also resulted in significantly reduced local and distant relapse rates than post-op RT. Adverse prognostic factors were balanced between both groups. Conclusion. Pre-operative RT has a significant benefit in reducing cancer-specific mortality compared to post-operative RT in STS

Wide resection, with or without adjuvant therapy, is the mainstay of treatment for soft tissue sarcoma of the extremities. The surgical treatment of soft tissue sarcoma can portend a prolonged course of recovery from a functional perspective. However, data to inform the expected course of recovery following sarcoma surgery is lacking. The purpose of this study was to identify time to maximal functional improvement following sarcoma resection and to identify factors that delay the expected course of recovery.

A retrospective chart review was performed of all patients undergoing surgical treatment of a soft tissue sarcoma of the extremities between January 1st, 1985 and November 15, 2020 with a minimum of 1 follow up. The primary outcome measure was time to maximal functional improvement, defined as failure to demonstrate improvement on two consecutive follow up appointments, as defined by the functional outcome measures of Toronto Extremity Salvage Score (TESS) and Musculoskeletal Tumor Society (MSTS) Score or by achieving 90% of maximum outcome score.

We identified 1188 patients who underwent surgical resection of a soft tissue sarcoma of the extremities. Patients typically achieved a return to their baseline level of function by 1 year and achieved “maximal” functional recovery by 2 year's time postoperatively.

Patient and tumor factors that were associated with worse functional outcome scores and a delayed return to maximal functional improvement included older age (p=0.007), female sex (p-0.004), larger tumor size (p < 0 .001), deep tumor location (p < 0 .001), pelvic location (p < 0 .001), higher tumor grade (p < 0 .001). Treatment factors that were associated with worse functional outcome scores and a delayed return to maximal functional improvement included use of radiation therapy (p < 0 .001), perioperative complications (p < 0 .001), positive margin status (p < 0 .001) and return of disease, locally or systemically (p < 0 .001).

Most patients will recover their baseline function by 1 year and achieve “maximal” recovery by 2 years’ time following surgical resection for soft tissue sarcoma of the extremities. Several patient, tumor and treatment factors should be used to counsel patients as to a delayed course of recovery.

Myxofibrosarcoma (MFS) is the second most common subtype of soft tissue sarcoma (STS) and is associated with a high rate of local recurrence after resection. These tumours frequently present with peri-lesional edema, termed “tumour tails” on staging MRI scans [1]. Tumour tails(TT) may contain satellite neoplastic cells or can represent benign reactive edema. There are no clear radiological features to distinguish malignant from reactive peri-lesional edema which limits accurate surgical planning, resulting in either high rates of inadvertently positive resection margins and local recurrences or overly-aggressive resections which negatively impact function and increase morbidity [2]. The objective of this pilot study was to prospectively study a cohort of MFS patients with TTs in an attempt to identify radiological features that predict which type of edema is malignant and requires resection together with the main tumour mass.

Patients diagnosed with MFS on biopsy at an orthopaedic oncology referral centre between January 1-December 31 2018 who also had TTs on staging MRI scans were prospectively recruited for the study. Tumours were treated with wide surgical excision, including the TTs, and (neo)adjuvant radiotherapy as per institutional protocol. Staging MRI scans were reviewed in a blinded fashion by two musculoskeletal radiologists to distinguish malignant from reactive TTs. The main tumour mass underwent standard histological evaluation while the regions encompassing the TTs were photographed and sectioned into grids. Each tissue section was examined histologically for the presence of satellite neoplastic cells based on morphological criteria. Radiological and histological findings were compared.

Six patients met the inclusion criteria and underwent analysis. All tumours were located in the extremities and were deep to fascia. Mean age at presentation was 67 years (range 51 – 85), with a male:female ratio of 4:2. All patients received radiotherapy (50 Gy), either pre- (n=4) or post-operatively (n=2) based on multidisciplinary tumor board discussion or enrolment in a prospective clinical trial. Radiologically, TTs were labelled as malignant in four patients (66.7%) and as benign TTs in two others. The tails were recognised to be malignant due to the differing signal characteristics to reactive edema on mixed MRI sequences. The radiological evaluation correlated exactly with histological analysis, as satellite neoplastic cells were identified microscopically in the same four cases in which the TTs were designated to be malignant by MRI (specificity&sensitivity=100%). Surgical resection margins were microscopically positive in 50% of cases in the TTs themselves, and 75% of cases in which TTs were designated as malignant on staging MRI.

“The malignant nature of peri-lesional edema in MFS, also known as the TT, was accurately predicted in this small pilot study based on specific radiological features which correlated exactly with histologic identification of isolated tumor cells. These findings validate development of a larger prospective study to recruit additional patients with tumor tails beyond just MFS, in order to more robustly study the correlation between the MRI appearance and histological distribution of satellite sarcoma cells in peri-lesional edema in STS. We are already recruiting to this expanded radiological-histological investigation including evaluation of additional novel MRI sequences.

Soft tissue sarcomas (STS) are rare, aggressive malignancies derived from connective tissues such as muscle and fat. Undifferentiated pleomorphic sarcoma (UPS) is one of the most common STS in adults. UPS is an aggressive, highly metastatic sarcoma, and is resistant to chemotherapy. New therapies for UPS are desperately needed. STS have an immune desert tumour immune microenvironment (TIME), characterized by a paucity of tumour infiltrating lymphocytes and subsequent resistance to immunotherapies such as immune checkpoint inhibitors. Strategies capable of creating an immune-rich, inflamed TIME may improve immunotherapy efficacies for sarcoma. Activation of the STING (stimulator of interferon genes) receptor can induce potent innate and adaptive immune responses within immunogenic solid tumours. However, this approach has never been attempted in immune-inert sarcomas.

Purpose: To determine the therapeutic anti-tumour effects of STING activation in UPS tumours.

We have developed an inducible, immune-competent mouse model of UPS. We evaluated intra-tumoural injection of the murine STING receptor agonist, DMXAA, into UPS-bearing immune-competent mice. DMXAA was injected into palpable UPS tumours of the hindlimb. Tumour volume and bioluminescence imaging was recorded bi-weekly. DMXAA treated UPS tumours were also evaluated for necrosis and immune infiltration at defined time points.

UPS tumours developed necrosis and lymphocytic infiltration 72 hours after DMXAA treatment. A single intra-tumoural dose of DMXAA into UPS tumours resulted in durable cure in 50% of mice. All survivors rejected a re-challenge of the UPS tumours in both the contralateral hindlimb and lung, suggesting adaptive immunity. The therapeutic effects of DMXAA were mitigated in lymphocyte deficient Rag2 knockout mice.

STING therapy is a promising immunotherapeutic opportunity for immune-inert sarcomas. Our data warrants further preclinical investigations in other sarcoma models and in combination with other immune-based therapies.

For soft tissue sarcoma patients receiving preoperative radiation therapy, wound complications are common and potentially devastating; they may result in multiple subsequent surgeries and significant patient morbidity. The purpose of this study was to assess the feasibility of intraoperative indocyanine green fluorescent angiography (ICGA) as a predictor of wound complications in resections of irradiated soft tissue sarcoma of the extremities.

A consecutive series of patients of patients with soft tissue sarcoma of the extremities or pelvis who received neoadjuvant radiation and a subsequent radical resection received intraoperative ICGA with the SPY PHI device (Stryker Inc, Kalamazoo MI) at the time of closure. Three fellowship trained Orthopaedic Oncologic Surgeons were asked to prospectively predict likelihood of wound complications based on fluorescence. Retrospective analysis of fluorescence signal along multiple points of the wound length was performed and quantified. The primary endpoint was wound complication, defined as delayed wound healing or wound dehiscence, within 3 months of surgery. An a priori power analysis demonstrated that 5 patients were necessary to achieve statistical significance. Univariate and multivariate statistical analyses were performed to identify predictors of wound complications.

14 patients were consecutively imaged. The diagnosis was undifferentiated pleomorphic sarcoma in 9 (64.3%) of patients; 11 (78.6%) tumors were high grade. There were 6 patients with wound complications classified as “aseptic” in 5 cases and secondary to hematoma in 1 case. Using the ICGA, blinded surgeons correctly predicted wound complications in 75% of cases. In the area of wound complication, the mean % of maximal signal for wound complications was 49% during the inflow phase and 48% during the peak phase. The mean % maximal signal for peri-incisional tissue without wound complications was 77% during the inflow phase and 83% during the peak phase (p=0.003 and p<0.001). During the inflow phase, a mean ratio of normal of 0.62 maximized the area under the curve (AUC=0.90) for predicting wound complications with a sensitivity of 100% and specificity of 77.4%. During the peak phase, a mean ratio of normal of 0.55 maximized the area under the curve (AUC=0.95) for predicting wound complications with a sensitivity of 88.9% and a specificity 100%.

Intraoperative use of indocyanine green fluorescent angiography may help to predict wound complications in patients undergoing resection of preoperatively irradiated soft tissue sarcomas of the extremities and pelvis. Future studies are necessary to validate this technology in a prospective manner and to determine if interventions can be instituted to prevent predicted wound complications.

Major wound complication risk factors following soft tissue sarcoma resection.

Wound-healing complications represent an important source of morbidity in patients treated surgically for soft tissue sarcomas (STS). The purpose of this study was to determine which factors are predictive of major wound complication rates following STS resection, including tumour site, size, grade, and depth, as well as radiotherapy and chemotherapy.

We reviewed 256 cases of STS treated surgically between 2000 and 2011. The primary outcome was occurrence of major wound complications post STS resection.

Major wound complications were more likely to occur post STS resection with larger tumour diameters (p = 0.001), high grade tumours (p = 0.04), location in the proximal lower extremity (p = 0.01), and use of preoperative radiotherapy (p = 0.01). Tumours located in the adductor compartment were at highest risk of complications. We did not demonstrate a significant difference in complications rates based on method of closure. Diabetes, smoking, obesity, tumour diameter, tumour location in the proximal lower extremity, and preoperative radiotherapy were independent predictors on multivariate analysis.

There are multiple predictors for major wound complications post STS resection. A more aggressive resection of irradiated soft tissues, combined with primary reconstruction, should be considered in cases with multiple risk factors.

The patient's subjective experience of disease is an increasing focus in health care delivery. Health-related quality of life (HRQoL) is defined as a “functional effect of a medical condition and its consequent treatment”; it is both self-reported and multi-dimensional. While functional outcome is well researched among the soft tissue sarcoma (STS) population, few studies have focused on HRQoL, which gives a broader understanding of the psychological, somatic, social and physical toll of cancer and its treatment from the patient's viewpoint. The biologic and anatomic heterogeneity of sarcomas are considerable, just as the treatments are diverse, we surmise that the indicators of patient HRQoL differ and are not captured in existing generic HRQoL tools for cancer. The study objectives were to explore the domains of HRQoL and functioning in adult patients diagnosed with extremity STS from the patient's perspective from active care through survivorship through qualitative inquiry, so as to form the basis for the development of a patient-derived, sarcoma-specific, preference based HRQoL tool.

Study design is a sequential exploratory mixed methods study of patient experience in localized or metastatic adult extremity STS (2007 and 2017). The study was conducted at a high-volume sarcoma centre. Qualitative descriptive design was grounded in an integrated knowledge translation approach and aimed at identifying HRQoL domains through in-person and electronic focus groups, and individual semi-structured interviews in both English and French (N=28). The interview guide topics were selected based on existing knowledge about PROs and HRQoL life, including (a) impact of diagnosis on employment or acquisition of academic/vocational skills; (b) physical and psychological functioning; (c) symptom burden; (d) treatment preferences; (e) knowledge of and use of existing resources; (f) impact on family time and resources; and (g) overall experience. Data was analyzed using inductive thematic networks approach using the qualitative software N-Vivo 12. Codes were generated by 2 independent qualitative experts capturing key concepts of HRQoL that is impacted by STS. Basic themes were clustered into organizing themes, and merged into global domains. Attention was paid to deviant cases and within-group dynamics during focus group discussion analysis. Discrepancies or inconsistencies in coding were resolved in consensus meetings. Final sample size was determined when data saturation was reached and no new themes emerged. Qualitative reduction of identified items to reach a consensus framework was facilitated by a moderator during multi-disciplinary panel meetings comprised of sarcoma experts, patient partners, allied health staff and other stakeholders.

Twenty-nine patients with biopsy-proven localized or metastatic STS of the extremity participated (69% lower extremity STS; mean age 56 years, 25% with local recurrence, 21% metastatic, 18% amputation). Inductive thematic network analysis revealed five function-related domains HRQoL for patients with STS. The functional domains were mapped to the Wilson & Cleary Model and experience domains were mapped to the Picker Institute's Through Patient's Eyes model.

This is a critical step toward developing disease specific outcome measures. Patient-centered research is crucial to understanding the impact of surgery, adjuvant therapy and the associated complications for patients with extremity STS, and thereby improving the quality of care provision. This study offers a unique perspective on what domains and sub domains are most impactful on HRQoL and provides the basis for our on-going development of a disease-specific, preference-based HRQoL measure.

High grade sarcoma present a systemic metastatic progression in approximaly 50% of cases. The effectiveness of palliative chemotherapy as a treatment of systemic metastases is still controversed. The main objectif of this study is to assess disease progression and survival of patients diagnosed with metastatic soft tissue sarcomas treated with palliative chemotherapy, analyse chemotherapy treatment patterns and response to different lines of treatment.

Retrospective chart review of 75 patients treated with palliative chemotherapy for metastatic soft tissue sarcomas between 2003 and 2013 at Maisonneuve-Rosemont Hospital. Data for control group of 40 patients with metastatic soft tissue sarcomas not treated with chemotherapy was collected retrospectively. Collected data include demographic data, overall survival, time free survival, type of chemotherapy treatment, surgical treatment and adverse reaction to palliative chemotherapy. Overall survival was analysed with Kaplan-Meier test. Categorial variable were compared with Log-Rank test.

Seventy-five patients (37% female; mean age 50.4 years) received minimally one line of chemotherapy for their metastatic sarcomas. The regimens most commonly used in first-line were doxorubicin (48%) and doxorubicin combined with ifosfamide (21.3%). Favorable response was achieved by 38.7% in first-line and 27.9% in second-line therapy. Median overall survival with chemotherapy treatments was more than two times overall survival without treatments. Median overall survival was 19 months with chemotherapy treatments and 7 months without chemotherapy (p<0.0001). There was no statistically significant difference between survivals for treated and untreated patients with chemotherapy when analysed in term of the histological subtype, age and monotherapy versus combined treatment. Event-free survival was statistically longer during the first year for the group of patients treated with combined chemotherapy (p=0.0125).

Results have shown a significantly improved overall survival in all histological groups, resulting in an OS of 19 vs 7 months for the chemotherpy and non chemotherapy group respectively. Nevertheless, patients with favorable response to chemotherapy have poor outcomes. Additional treatment options are needed.

Wound complications are common in patients with soft tissue sarcomas (STS) treated with surgical excision. Limited data is available on predictive factors for wound complications beyond the relationship to neo-adjuvant or adjuvant radiotherapy. Likewise, the association between blood transfusion, patient comorbidities and post-operative outcomes is not well described. In the present study we identified the predictive factors for blood transfusion and wound complications in patients undergoing surgical resection of soft tissue sarcoma from a national cohort.

The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was used to identify patients who underwent surgical resection of a STS from 2005 to 2013. Primary malignant soft tissue neoplasms were identified using the following ICD-9 codes: 171.2, 171.3 and 171.6. Patients treated with both wide excision and amputation were identified using the current procedural terminology (CPT) codes. Prolonged operative time was defined as greater than 90th percentile of time required per procedure. A multivariable logistic regression model was used to identify associations between patient factors and post-operative wound complications (superficial and deep surgical site infections (SSI), and wound dehiscence). A similar regression model sought to identify prognostic factors for blood transfusion and associations with post-operative outcomes.

A total of 788 patients met our inclusion criteria. Of theses, 64.2% had tumours in the lower limb, 23.1% patients had tumours in the upper limb, and 12.7% patients had pelvic tumours. Six hundred and forty patients (81.2%) underwent surgical excision; 148 (18.8%) patients had an amputation. Multivariable logistic regression modeling identified American Society of Anaesthesiologist (ASA) class 3 and 4 (OR=2.3, P=0.03; OR=8.3, P=0.001, respectively), amputation (OR=14.0, P<0.001) and prolonged operative time (OR=4.6, P<0.001) as significant predictors of blood transfusion. Radiotherapy (OR=2.6, P=0.01) and amputation (OR=2.6, P=0.01) were identified as predictors of superficial SSI, whereas ASA class 4 (OR=6.2, P=0.03), prolonged operative time (OR=3.9, P=0.012) and return to the operating room (OR=10.5, P<0.001) were associated with deep SSI. Male gender (OR=1.8, P=0.03), diabetes (OR=2.3, P=0.03), ASA class 3 (OR=2.4, P=0.003), amputation (OR=3.8, P<0.001) and steroids (OR=4.5, P=0.03) were identified as predictors for wound dehiscence and open SSI.

A national cohort demonstrates that male gender, diabetes, chronic steroid use, higher ASA score and radiotherapy are associated with an increased incidence of wound complications. One in twenty-three patients undergoing resection of an STS will require a blood transfusion, and this risk is correlated with amputation, prolonged operative time and increased ASA score. Strategies to decrease the risk of blood transfusion and wound complication should be considered for these patient groups.

The poor prognosis of patients with soft-tissue sarcoma as not changed in the past several decades, highlighting the necessity for new therapeutic approaches. T-cell based immunotherapies are a promising alternative to traditional cancer treatments due to their ability to target only malignant cells, leaving benign cells unharmed. The development of successful immunotherapy requires the identification and characterization of targetable immunogenic tumor antigens. Cancer-testis antigens (CTA) are a group of highly immunogenic tumor-associated proteins that have emerged as potential targets for CD8+ T-cell recognition. In addition to identifying a targetable antigen, it is crucial to understand the tumor immune microenvironment. The level of immune infiltration and mechanisms of immune suppression within the tumor play important roles in the outcome of immunotherapy. The goal of this study is to identify targetable immunogenic antigens for T-cell based immunotherapy and to characterize the tumor immune microenvironment in human dedifferentiated liposarcoma (DDLS) by Nanostring and IHC. To assess the complexity of the human DDLS tumor immune microenvironment and to identify target antigens we used the nCounter NanoString platform to generate a gene expression profile for hundreds of genes from RNA obtained from 29 DDLS and 10 control fat FFPE samples. To classify inflammatory status of DDLS tumors, we performed hierarchical clustering based on expression levels of selected tumor inflammatory signature genes (CCL5, CD27, CD274, CD276, CD8A, CMKLR1, CXCL9, CXCR6, HLA-DQA1, HLA-E, IDO1, LAG3, PDCDILG2, PSMB10, STAT1, TIGIT). To confirm protein expression and distribution of identified antigens, we performed immunohistochemistry on human tissue micro-arrays encompassing DDLPS tumor tissues and matched normal control tissue from 63 patients. IHC for the cancer testis antigens PBK, SPA17, MAGE-A3, NY-ESO-1 and SSX2 was performed, and the staining results were scored by two authors based on maximal staining intensity on a scale of zero to three (absent=0, weak=1, moderate=2, or strong=3) and the percentage of tumor cells that stained. Hierarchical clustering of DDLS tumors based on expression of tumor inflammation signature genes revealed two distinct groups, consisting of 15 inflamed tumor and 14 non-inflamed tumors, demonstrating tumor heterogeneity within the DDLS sarcoma subtype. All antigens were found to be expressed in DDLS at an mRNA level. SPA17 was expressed at the highest levels in DDLS, however, this antigen was expressed at high levels in normal fat. Notably, antigens PBK and TTK had the largest fold change increase in expression in DDLS compared to normal fat controls. Immunohistochemical analysis of selected antigens revealed that PBK was found to be expressed in 96% (52/54) of DDLS samples at high levels. Other antigens were absent or expressed at low levels in DDLS; MAGEA3 in 15.87% (10/63) NY-ESO-1 in 6.35% (4/62) and SSX2 in 12.7% (8/63) and SPA17 in 5.5% (3/54). This data shows considerable inter-tumoral heterogeneity of inflammation, which should be taken into consideration when designing an immunotherapy for DDLS. To date, these results show promising expression of PBK antigen in DDLS, which may be used as a target in the future development of an immunotherapy for sarcoma

The poor prognosis of patients with advanced bone and soft-tissue sarcoma has highlighted the necessity for new therapeutic approaches. T-cell based immunotherapies are a promising alternative to traditional cancer treatments due to their ability to target only malignant cells, leaving benign cells unharmed. The development of successful immunotherapy requires the identification of targetable immunogenic tumor antigens. Cancer-testis antigens (CTA) are a group of highly immunogenic tumor-associated proteins that have emerged as potential targets for CD8+ T-cell recognition. The goal of this study is to screen for CTA expression, HLA expression, and tumor T-cell infiltration in human dedifferentiated liposarcoma (DDLPS) and osteosarcoma (OS) to establish their immune profile and to identify targetable immunogenic antigens for T-cell based immunotherapy. Human tissue micro-arrays composed of 78 cores of OS and 50 cores of DDLPS were obtained, along with matched control tissues from the same patients. IHC for the cancer testis antigens NY-ESO-1, MAGE-A3, and SSX2, was performed, and the staining results were scored by two authors based on maximal staining intensity on a scale of zero to three (absent=0, weak=1, moderate=2, or strong=3) and the percentage of tumor cells that stained. IHC for CD8 and CD3 was also performed, and T-cell tumor infiltration was defined as either brisk, nonbrisk, or absent, as described in melanoma literature. Concurrently, evaluation of 38 human DDLPS specimens and 10 healthy human fat specimens by the Nanostring nCounter platform is underway for identification of novel antigen targets and to establish the immune profile of DDLPS. Immunohistochemical analysis of CTA expression showed considerable inter- and intra-tumoral heterogeneity. DDLPS showed relatively low expression of all CTAs tested, with only 22% of samples exhibiting MAGE-A3 and one sample each (3.1%) showing expression of SSX2 and NY-ESO-1 in low percentages of tumor cells. By contrast, in osteosarcoma, 74% of samples expressed MAGE-A3 and 68% expressed SSX, both with >80% of positive cases showing moderate to high expression. NY-ESO-1 was expressed in 41% of OS samples, predominantly at low levels. Brisk infiltration of CD8+ T cells was observed in over 70% of both sarcoma types tested. Furthermore, all sarcoma samples tested were positive for HLA expression. To date, these results show promising expression of CTAs MAGE-A3 and SSX in OS, which may be used as targets in the future development of an immunotherapy for sarcoma. DDLPS shows relatively low expression, highlighting the need for more exploratory study with NanoString. The data generated throughout this project will provide insight into the immune profile of DDLPS

The rate of fracture and subsequent nonunion after radiation therapy for soft-tissue sarcomas and bone tumors has been demonstrated to quite high. There is a paucity of data describing the optimal treatment for these nonunions. Free vascularized fibular grafts (FVFG) have been used successfully in the treatment of large segmental bone defects in the axial and appendicular skeleton, however, their efficacy with respect to treatment of radiated nonunions remains unclear. The purpose of the study was to assess the 1) union rate, 2) clinical outcomes, and 3) complications following FVFG for radiation-induced femoral fracture nonunions. We identified 24 patients who underwent FVFG for the treatment of radiation-induced femoral fracture nonunion between 1991 and 2015. Medical records were reviewed in order to determine oncologic diagnosis, total preoperative radiation dose, type of surgical treatment for the nonunion, clinical outcomes, and postoperative complications. There were 11 males and 13 females, with a mean age of 59 years (range, 29 – 78) and a mean follow-up duration of 61 months (range, 10 – 183 months). Three patients had a history of diabetes mellitus and three were current tobacco users at the time of FVFG. No patient was receiving chemotherapy during recovery from FVFG. Oncologic diagnoses included unspecified soft tissue sarcomas (n = 5), undifferentiated pleomorphic sarcoma (UPS) (n = 3), myxofibrosarcoma (n = 3), liposarcoma (n = 2), Ewing's sarcoma (n = 2), lymphoma (n = 2), hemangiopericytoma, leiomyosarcoma, multiple myeloma, myxoid chondrosarcoma, myxoid liposarcoma, neurofibrosarcoma, and renal cell carcinoma. Mean total radiation dose was 56.3 Gy (range, 39 – 72.5), given at a mean of 10.2 years prior to FVFG. The average FVFG length was 16.4 cm. In addition to FVFG, 13 patients underwent simultaneous autogenous iliac crest bone grafting, nine had other cancellous autografting, one received cancellous allograft, and three were treated with synthetic graft products. The FVFG was fixed as an onlay graft using lag screws in all cases, additional fixation was obtained with an intramedullary nail (n = 19), dynamic compression plate (n = 2), blade plate (n = 2), or lateral locking plate (n = 1). Nineteen (79%) fractures went on to union at a mean of 13.1 months (range, 4.8 – 28.1 months). Musculoskeletal Tumor Society scores improved from eight preoperatively to 22 at latest follow-up (p < 0.0001). Among the five fractures that failed to unite, two were converted to proximal femoral replacements (PFR), two remained stable pseudarthroses, and one was converted to a total hip arthroplasty. A 6th case did unite initially, however, subsequent failure lead to PFR. Seven patients (29%) required a second operative grafting. There were five additional complications including three infections, one wound dehiscence, and one screw fracture. No patient required amputation. Free vascularized fibular grafts are a reliable treatment option for radiation-induced pathologic femoral fracture nonunions, providing a union rate of 79%. Surgeons should remain cognizant, however, of the elevated rate of infectious complications and need for additional operative grafting procedures

This is quite an innovative study that should lead to a multicentre validation trial. We have developed an FDG-PET/MRI texture-based model for the prediction of lung metastases (LM) in newly diagnosed patients with soft-tissue sarcomas (STSs) using retrospective analysis. In this work, we assess the model performance using a new prospective STS cohort. We also investigate whether incorporating hypoxia and perfusion biomarkers derived from FMISO-PET and DCE-MRI scans can further enhance the predictive power of the model. A total of 66 patients with histologically confirmed STSs were used in this study and divided into two groups: a retrospective cohort of 51 patients (19 LM) used for training the model, and a prospective cohort of 15 patients (two patients with LM, one patient with bone metastases and suspicious lung nodules) for testing the model. In the training phase, a model of four texture features characterising tumour sub-region size and intensity heterogeneities was developed for LM prediction from pre-treatment FDG-PET and MRI scans (T1-weighted, T2-weighted with fat saturation) of the retrospective cohort, using imbalance-adjusted bootstrap statistical resampling and logistic regression multivariable modeling. In the testing phase, this multivariable model was applied to predict the distant metastasis status of the prospective cohort. The predictive power of the obtained model response was assessed using the area under the receiver-operating characteristic curve (AUC). In the exploratory phase of the study, we extracted two heterogeneity metrics from the prospective cohort: the area under the intensity-volume histogram of pre-treatment DCE-MRI volume transfer constant parametric maps and FMISO-PET hypoxia maps (AU-IVH-Ktrans, AU-IVH-FMISO). The impact of the addition of these two individual metrics to the texture-based model response obtained in the testing phase was first investigated using Spearman's correlation (rs), and lastly using logistic regression and leave-one-out cross-validation (LOO-CV) to account for overfitting bias. First, the texture-based model reached an AUC of 0.94, a sensitivity of 1, a specificity of 0.83 and an accuracy of 0.87 when tested in the prospective cohort. In the exploratory phase, the addition of AU-IVH-FMISO did not improve predictive power, yielding a correlation of rs = −0.42 (p = 0.12) with lung metastases, and a relative change in validation AUC of 0% in comparison with the texture-based model response alone in LOO-CV experiments. In contrast, the addition of AU-IVH-Ktrans improved predictive power, yielding a correlation of rs = −0.54 (p = 0.04) with lung metastases, and a change in validation AUC of +10%. Our results demonstrate that texture-based models extracted from pre-treatment FDG-PET and MRI anatomical scans could be successfully used to predict distant metastases in STS cancer. Our results also suggest that the addition of perfusion heterogeneity metrics may contribute to improving model prediction performance

We reviewed 234 benign solitary schwannomas treated between 1984 and 2004. The mean age of the patients was 45.2 years (11 to 82). There were 170 tumours (73%) in the upper limb, of which 94 (40%) arose from the brachial plexus or other nerves within the posterior triangle of the neck. Six (2.6%) were located within muscle or bone. Four patients (1.7%) presented with tetraparesis due to an intraspinal extension.

There were 198 primary referrals (19 of whom had a needle biopsy in the referring unit) and in these patients the tumour was excised. After having surgery or an open biopsy at another hospital, a further 36 patients were seen because of increased neurological deficit, pain or incomplete excision. In these, a nerve repair was performed in 18 and treatment for pain or paralysis was offered to another 14.

A tender mass was found in 194 (98%) of the primary referrals. A Tinel-like sign was recorded in 155 (81%). Persistent spontaneous pain occurred in 60 (31%) of the 194 with tender mass, impairment of cutaneous sensibility in 39 (20%), and muscle weakness in 24 (12%).

After apparently adequate excision, two tumours recurred. No case of malignant transformation was seen.