Targeting the FAK-Src Complex in Desmoplastic Small Round Cell Tumors, Ewing Sarcoma, and RhabdomyosarcomaRead the full article
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Free Vascularized Fibula Salvage of Failed CPH in Pediatric Sarcoma Patients
Background. Due to extended life expectancy and recent improvements in surgical techniques, limb salvage has replaced amputation as the gold standard and is now performed in 90–95% of upper extremity malignancies. However, many of these salvage procedures are associated with significant postsurgical complications. In particular, the clavicula pro humero (CPH) procedure is associated with high rates of nonunion. We present our experience with upper extremity salvage using the free vascularized fibular flap (VFF) after failure or nonunion of the original CPH procedure in the pediatric population. Methods. Five patients under the age of 18 diagnosed with upper extremity sarcoma who underwent tumor resection with immediate CPH reconstruction complicated with nonunion, and subsequent revision with free VFF were included. Data on patient demographics, oncologic characteristics, surgical procedures, intraoperative details, postoperative complications, and time to graft union were recorded. Results. Five patients (average age = 8.4 years; range = 5–10 years at surgery date) underwent secondary limb salvage procedure with free VFF reconstruction following failed CPH reconstruction for proximal humeral osteosarcoma (n = 4) or Ewing sarcoma (n = 1). The mean follow-up was 3.7 years. Complications occurred in five patients (100%), with three patients requiring reoperation (60%). Four patients achieved graft union (average union time = 3.7 months) and successful limb reconstruction. Four patients were alive with no local recurrence of the disease. One patient did not achieve union and was lost to follow-up. Conclusion. Primary bone tumors in the pediatric population require wide surgical resection, and reconstruction often has high complication rates that can warrant further procedures. A free VFF is a viable option for upper extremity salvage after previously failed reconstructions because it provides vascularized tissue to a scarred tissue bed and allows for the replacement or augmentation of large bony defects.
Bone Metastases in Patients with Leiomyosarcoma: A Retrospective Analysis of Survival and Surgical Management
Background. Leiomyosarcomas (LMS) are malignancies with smooth muscle differentiation. Metastasis to the bone is not uncommon. The literature on the clinical course and management of such metastases is limited. Our study describes the clinical course of LMS to the bone, including survival rates, prognostic factors, and surgical management. Methods. We retrospectively reviewed 396 LMS patients presenting at an academic center between 1995 and 2020. We included LMS patients diagnosed with bone metastases and excluded patients with primary LMS of bone. We evaluated survival time with the Kaplan–Meier survival method and used Cox’s proportional hazards regression analysis to determine factors associated with survival. Results. Forty-five patients with LMS (11%) had bone metastases. The most common LMS subtypes with bone metastases were uterine (N = 18, 40%) and retroperitoneal (N = 15, 33%). Bone metastasis was not an independent predictor of mortality by Cox regression analysis (HR 1.0, 95% CI: 0.67–1.5). Patients more frequently metastasized to the axial (N = 29, 64%) than to the appendicular (N = 5, 11%) skeleton. Bone was the first site of metastasis in 13 patients (29%). Patients presented with bone metastases at a median of 32.7 months (IQR: 5.2, 62.6) after initial LMS diagnosis. Twelve patients (27%) sustained a pathologic fracture. Twenty (44%) required surgical management, with 30 surgeries total. Three (15%) had a failure of reconstructive constructs. The median overall survival time was 69.7 months (IQR: 43.2, 124.5). There were no associations between the LMS subtype and survival. Pathologic fracture was an independent predictor of mortality by Cox regression analysis (HR 5.4, 95% CI: 1.8–16). Conclusion. The majority of patients with metastatic LMS to bone survive greater than 5 years and frequently require surgical intervention. Extended survival in this patient population should inform fixation and implant choice. No anatomic subtype was associated with risk for bone metastases. Pathologic fracture was associated with worse survival.
Plexin-B2 and Semaphorins Do Not Drive Rhabdomyosarcoma Proliferation or Migration
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma for which subsets of patients have longstanding unmet clinical needs. For example, children with alveolar rhabdomyosarcoma and metastases at diagnosis will experience only 8% disease-free 5-year survival for nonlocalized unresectable recurrent disease. Hence, development of novel therapeutic strategies is urgently needed to improve outcomes. The Plexin-Semaphorin pathway is largely unexplored for sarcoma research. However, emerging interest in the Plexin-Semaphorin signaling axis in pediatric sarcomas has led to phase I cooperative group dose-finding clinical trials, now completed (NCT03320330). In this study, we specifically investigated the protein expression of transmembrane receptor Plexin-B2 and its cognate SEMA4C ligands in clinical RMS tumors and cell models. By RNA interferences, we assessed the role of Plexin-B2 in cell growth and cell migration ability in selected alveolar and embryonal RMS cell model systems. Our results affirmed expression of Plexin-B2 across human samples, while also dissecting expression of the different protein subunits of Plexin-B2 along with the assessment of preferred Semaphorin ligands of Plexin-B2. Plexin-B2 knockdown had positive or negative effects on cell growth, which varied by cell model system. Migration assayed after Plexin-B2 knockdown revealed selective cell line specific migration inhibition, which was independent of Plexin-B2 expression level. Overall, these findings are suggestive of context-specific and possibly patient-specific (stochastic) role of Plexin-B2 and SEMA4 ligands in RMS.
Time and Accuracy to Establish the Diagnosis of Soft Tissue Tumors: A Comparative Analysis from the Swiss Sarcoma Network
Soft tissue tumors are rare tumors, and their histological examination remains a challenge. The establishment of the correct initial histopathologic diagnosis is critical. However, due to the rarity of soft tissue and bone tumors and the inherent difficulty of their classification and diagnostics, discrepancies may occur in up to one third of cases. For these reasons, several studies recommend the involvement of experienced pathologists frequently performing sarcoma diagnostics. Until now, there is only scarce information about how long it takes to establish a correct sarcoma diagnosis. We thus analyzed all consecutive patients presented to the Swiss Sarcoma Network Tumor Board (SSN-MDT/SB) with a primary diagnosis of a soft tissue tumor over a 2-year period (01/2019 to 12/2020) based on a tumor biopsy. We then compared the final histopathological diagnosis of two comparable institutions with similar case load, but different workflows: (i) institution A, with an initial diagnosis performed by a local pathologist, and reviewed by a reference pathologist, and (ii) institution B, with the final diagnosis performed directly by a reference pathologist. In addition, we analyzed the time from biopsy to establishment of the diagnosis. A total of 347 cases were analyzed, 196 from institution A, and 149 from institution B. In 77.6% of the cases, the diagnosis from the local pathologist was concordant with the expert review. Minor discrepancies were found in 10.2% of the cases without any consecutive changes in treatment strategy. In the remaining 12.2% of the cases, there were major discrepancies which influenced the treatment strategy directly. Establishing the final report took significantly longer in institution A (4.7 working days) than in institution B (3.3 working days; ). Our results confirm the importance of a pathological second review by a reference pathologist. We recommend direct analysis by experts, as diagnoses can be made more accurately and quickly. Within the SSN, establishing the sarcoma diagnosis is overall accurate and quick but still can be improved.
Prognostic Significance of Bone Metastasis in Soft Tissue Sarcoma Patients Receiving Palliative Systemic Therapy: An Explorative, Retrospective Pooled Analysis of the EORTC-Soft Tissue and Bone Sarcoma Group (STBSG) Database
Background. Soft-tissue sarcomas (STS) constitute a rare group of heterogeneous mesenchymal tumours containing more than 100 histologic subtypes. Here, we investigate whether, and if so, to what extent, skeletal metastases affect the outcome of patients with advanced or metastatic disease. Materials and Methods. Selected patients participated in five clinical trials of EORTC-STBSG. Individuals were included if they started treatment with an active drug and had advanced/metastatic STS. The endpoints of interest were overall survival (OS) and progression-free survival (PFS). Univariate and multivariate pooled analyses (after correcting for 12 covariates) were employed with Kaplan–Meier and Cox regression to model the impact of bone metastasis at presentation per treatment line stratified by study. For the subset of patients with bone metastasis, the impact of another metastatic organ site was explored with multivariate Cox regression models. Results. 565 out of 1034 (54.6%) patients received first-line systemic treatment for locally advanced or metastatic disease. Bone metastases were present in 140 patients (77 first-line, 63 second-line or higher). The unadjusted difference in OS/PFS with or without bone metastasis was statistically significant only for first-line patients. For OS, the adjusted hazard ratios for bone metastasis presence were 1.33 (95%-CI: 0.99–1.78) and 1.11 (95%-CI: 0.81–1.52) for first-line/second-line or higher treated patients, respectively. Likewise, the adjusted hazard ratios for PFS were 1.31 (95%-CI: 1.00–1.73) and 1.07 (95%-CI: 0.80–1.43). Effects were not statistically significant, despite a trend in first-line patients for both endpoints. Subgroup analyses indicated bone and lymph node metastasis as the most detrimental combination for OS and bone and lung metastasis for PFS. Conclusions. Adult STS patients receiving palliative systemic therapy with bone metastasis carried an overall worse prognosis than STS patients without bone metastases. Skeletal metastasis was detrimental for both OS and PFS, independent of the treatment line. Findings may have implications for the management of these patients.
A Multidisciplinary Team Approach Is Highly Effective in the Management of Nondiagnostic Bone Tumour Biopsies: A 10-Year Retrospective Review at a Specialist Sarcoma Unit
Nondiagnostic (ND) biopsies are frequently encountered during the investigation of bone tumours and can lead to treatment delay. We performed a retrospective review of all ND bone tumour biopsies discussed at our regional MDT meeting between 2004 and 2014 with the aim of establishing the incidence of ND biopsies, identifying any factors that could predict the requirement for repeat biopsies, and evaluating the effectiveness of multidisciplinary team (MDT) decisions. We identified 98 ND out of 4949 biopsies. Diagnostic yield (DY) was 98%, 76%, and 40% for the first, second, and third successive biopsy, respectively. With an MDT approach utilising radiological and clinical information, the diagnostic success rate achieved was 99%, 85%, and 80% for the first, second, and third biopsies, respectively. Although a repeat biopsy was only performed in 34% of cases, there were no patients originally diagnosed with a benign lesion that re-presented with the same lesion subsequently being malignant throughout the study period. Malignant primary bone tumours () and malignant secondary tumours () were more likely to undergo repeat biopsy compared to benign and infective lesions. Upper limb () and lower limb () were more likely than pelvic and spinal tumours to undergo a repeat biopsy. Tumours of haematological origin frequently required multiple biopsies. Our study demonstrated that a specialist MDT approach leads to high diagnostic rates and is a safe and effective method of preventing unnecessary, repeat biopsies where the initial biopsy is ND.