ASPSCR1-TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma

Alveolar soft part sarcoma (ASPS) is a soft part malignancy affecting adolescents and young adults. ASPS is characterized by a highly integrated vascular network, and its high metastatic potential indicates the importance of ASPS’s prominent angiogenic activity. Here, we found that the expression of ASPSCR1-TFE3, the fusion transcription factor causatively associated with ASPS, is dispensable for in vitro tumor maintenance; however, it is required for in vivo tumor development via angiogenesis. ASPSCR1-TFE3 is frequently associated with super-enhancers (SEs) upon its DNA binding, and the loss of its expression induces SE-distribution dynamic modification related to genes belonging to the angiogenesis pathway. Using epigenomic CRISPR/dCas9 screening, we identified Pdgfb, Rab27a, Sytl2, and Vwf as critical targets associated with reduced enhancer activities due to the ASPSCR1-TFE3 loss. Upregulation of Rab27a and Sytl2 promotes angiogenic factor-trafficking to facilitate ASPS vascular network construction. ASPSCR1-TFE3 thus orchestrates higher ordered angiogenesis via modulating the SE activity.

A minimally invasive cerclage of the tibia in a modified Goetze technique: operative technique and first clinical results

Introduction In spiral fractures of the tibia, the stability of an osteosynthesis may be significantly increased by additive cerclages and, according to biomechanical studies, be brought into a state that allows immediate full weight bearing. As early as 1933, Goetze described a minimally invasive technique for classic steel cerclages. This technique was modified, so that it can be used for modern cable cerclages in a soft part saving way. Method After closed reduction, an 8 Fr redon drain is first inserted in a minimally invasive manner, strictly along the bone and placed around the tibia via 1 cm incisions on the anterolateral and dorsomedial tibial edges using a curette and a tissue protection sleeve. Via this drain, a 1.7 mm cable cerclage can be inserted. The fracture is then anatomically reduced while simultaneously tightening the cerclage. Subsequently, a nail or a minimally invasive plate osteosynthesis is executed using the standard technique. Using the hospital documentation system, data of patients that were treated with additional cerclages for tibial fractures between 01/01/2014 and 06/30/2020 were subjected to a retrospective analysis for postoperative complications (wound-healing problems, infections and neurovascular injury). Inclusion criteria were: operatively treated tibial fractures, at least one minimally invasive additive cerclage, and age of 18 years or older. Exclusion criteria were: periprosthetic or pathological fractures and the primary need of reconstructive plastic surgery. SPSS was used for statistical analysis. Results 96 tibial shaft spiral fractures were treated with a total of 113 additive cerclages. The foregoing resulted in 10 (10.4%) postoperative wound infections, 7 of which did not involve the cerclage. One lesion of the profundal peroneal nerve was detected, which largely declined after cerclage removal. In 3 cases, local irritation from the cerclage occurred and required removal of material. Conclusion In the described technique, cerclages may be inserted additively at the tibia in a minimally invasive manner and with a few complications, thus significantly increasing the stability of an osteosynthesis. How this ultimately affects fracture healing is the subject of an ongoing study.

Primary alveolar soft tissue sarcoma of the central nervous system. Case report

Background: Alveolar soft part sarcoma (ASPS) is a rare, slow-growing soft tissue tumor with uncertain etiology; it is considered among the least common sarcomas, representing 0.2-1% of these cases in large studies. These tumors usually appear during childhood or young patients, with predominance in females. Case description: We introduce the case of ASPS in a 62-year-old man, who presented with 7 months of progressive headache and diplopia. The brain MRI showed an infiltrative lesion in the anterior fossa that extended to the right orbital roof. The possibility of metastasis was ruled out. The patient underwent resection of the tumor with posteriorly good visual and neurologic recovery. Histologic characterization demonstrated homogeneous eosinophilic cells with a solid, vascularized pattern, cells with large and binucleated nucleoli, and vessels with endothelial and myoepithelial hyperplasia; numerous apoptotic bodies and mitosis figures were also present, but no necrosis. On immunohistochemistry, cells exhibited positive CD56, NSE in membrane form, and slight myogenin; vessels were strongly positive for myogenin, myoglobin, CD34, CD31, factor VIII, vimentin, and nestin as well as for HBM45, CD20, GFAP, and S-100; cytokeratin showed fine extracellular and intracellular filaments; GATA and TTF1 were negative. Some clear cells were observed to be positive for CD68. The piece was diagnosed as a non-meningeal alveolar sarcoma of the soft tissue with solid pattern. Discussion and Conclusion: This case corresponds to the second tumor of this kind presented at our institution, the first one reported, and perhaps, one of the oldest patients to develop it worldwide.

Activity of PD-1 Inhibitor Combined With Anti-Angiogenic Therapy in Advanced Sarcoma: A Single-Center Retrospective Analysis

Background: Immune checkpoint inhibitors (ICIs) are employed to treat various cancers, including soft tissue sarcomas (STSs), and less than 20% of patients benefit from this treatment. Vascular endothelial growth factor (VEGF) promotes the immunosuppressive tumor microenvironment and contributes to ICI-resistant therapy. Anti-VEGF receptor tyrosine-kinase inhibitors (TKIs) combined with ICIs have shown antitumor activity in patients with alveolar soft-part sarcoma (ASPS). However, they have not been extensively studied to treat other STS subtypes, such as leiomyosarcoma (LMS), dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), and angiosarcoma (AS).Methods: In this retrospective study, we collected data from 61 patients who were diagnosed with advanced STS based on imaging and histology, including LMS, DDLPS, and UPS. Among them, 41 patients were treated with ICIs combined with TKIs and 20 patients received ICI therapy. The endpoints of progression-free survival (PFS) and overall response rate (ORR) were analyzed in the two groups, and the overall response [partial response (PR), stable disease (SD), and progressive disease (PD)] of each patient was determined using RECIST 1.1 evaluation criteria.Results: In total, 61 STS patients had the following subtypes: LMS (n = 20), DDLPS (n = 17), UPS (n = 8), ASPS (n = 7), MFS (n = 7), and AS (n = 2). The median PFS (mPFS) was significantly prolonged after ICI treatment in combination with TKIs (11.74 months, 95% CI 4.41–14.00) compared to ICI treatment alone (6.81 months, 95% CI 5.43–NA) (HR 0.5464, p = 0.043). The 12-month PFS rates of patients who received ICI–TKI treatment were increased from 20.26% (95% CI 0.08–0.53) to 42.90% (95% CI 0.27–0.68). In the combination therapy group, 12 patients (30%) achieved PR, 25 patients (62.5%) achieved SD, and 3 patients (7.5%) achieved PD for 3 months or longer. In the non-TKI-combination group, 2 patients (9.5%) achieved PR, 14 patients (66.7%) achieved SD, and 5 patients (23.8%) achieved PD within 3 months. The ORRs in the two groups were 30.0% (ICI–TKI combination) and 9.5% (ICI only), respectively. A notable ORR was observed in the ICI–TKI combination group, especially for subtypes ASPS (66.7%), MFS (42.9%), and UPS (33.3%). The PD-L1 expression (n = 33) and tumor mutation burden (TMB, n = 27) were determined for each patient. However, our results showed no significant difference in PFS or response rates between the two groups.Conclusion: This study suggests that ICI–TKI treatment has antitumor activity in patients with STS, particularly the ASPS and MFS subtypes. Moreover, effective biomarkers to predict clinical outcomes are urgently needed after combination therapy in the STS subtypes.