High-grade Sarcoma Research Articles

Prospective Trial of Neutrophil/Lymphocyte Ratio and Other Blood Counts as Biomarkers of Survival among Patients with High-Grade Soft Tissue Sarcomas Treated with Pegylated Liposomal Doxorubicin and Ifosfamide.

Simple SummaryPrevious studies have reported an association between the ratio of neutrophils to lymphocytes circulating in blood and outcomes in patients with cancer. This study examined the association between lymphocyte and neutrophil counts and survival in a prospective trial of preoperative chemotherapy for high-grade soft-tissue sarcomas. A statistically significant association between overall survival was observed with the neutrophil/lymphocyte ratio. Our results suggest that a balance between the lymphocyte count and the number of circulating myeloid cells that might suppress lymphocyte function may be predictive of survival in patients with soft-tissue sarcomas. Future research should examine the role of lymphocyte-myeloid cell balance in sarcoma biology.Several studies have reported an association between levels of circulating blood cells, in particular the neutrophil to lymphocyte ratio (absolute neutrophil count (ANC)/absolute lymphocyte count (ALC)) and outcomes in patients with cancer. In the current study, the association between lymphocyte, neutrophil, monocyte, and platelet counts and survival was examined in a prospective trial of preoperative pegylated-liposomal doxorubicin and ifosfamide for high-grade soft-tissue sarcomas. A statistically significant association between overall survival, but not progression free-survival, was observed with the ANC/ALC ratio at a cutoff value of ≥2 and a statistically significant trend using a cutoff of ≥5. Our results suggest that a balance between the lymphocyte count and the number of circulating myeloid cells that can suppress lymphocyte function may be predictive of survival in patients with soft-tissue sarcomas. Future research should therefore examine the role of lymphocyte-myeloid cell balance in sarcoma biology.

Novel ATXN1/ATXN1L::NUTM2A fusions identified in aggressive infant sarcomas with gene expression and methylation patterns similar to CIC-rearranged sarcoma

CIC-rearranged sarcomas are newly defined undifferentiated soft tissue tumors with CIC-associated fusions, and dismal prognosis. CIC fusions activate PEA3 family genes, ETV1/4/5, leading to tumorigenesis and progression. We report two high-grade CNS sarcomas of unclear histological diagnosis and one disseminated tumor of unknown origin with novel fusions and similar gene-expression/methylation patterns without CIC rearrangement. All three patients were infants with aggressive diseases, and two experienced rapid disease deterioration and death. Whole-transcriptome sequencing identified an ATXN1-NUTM2A fusion in the two CNS tumors and an ATXN1L-NUTM2A fusion in case 3. ETV1/4/5 and WT1 overexpression were observed in all three cases. Methylation analyses predicted CIC-rearranged sarcoma for all cases. Retrospective IHC staining on case 2 demonstrated ETV4 and WT1 overexpression. ATXN1 and ATXN1L interact with CIC forming a transcription repressor complex. We propose that ATXN1/ATXN1L-associated fusions disrupt their interaction with CIC and decrease the transcription repressor complex, leading to downstream PEA3 family gene overexpression. These three cases with novel ATXN1/ATXN1L-associated fusions and features of CIC-rearranged sarcomas may further expand the scope of “CIC-rearranged” sarcomas to include non-CIC rearrangements. Additional cases are needed to demonstrate if ATXN1/ATXN1L-NUTM2A fusions are associated with younger age and more aggressive diseases.

An Unusual Benign Uterine Stromal Spindle Cell Tumor Harboring JAZF1::BCORL1.

Uterine mesenchymal lesions demonstrate various underlying genomic alterations involving MED12 , JAZF1 , YWHAE , BCOR , and ALK genes, among others. Recent publications describe a subset of high-grade endometrial stromal sarcoma lesions harboring BCORL1 gene aberrations including JAZF1::BCORL1 . Herein, we present an unusual benign endomyometrial spindle cell lesion that defies classificatory efforts by demonstrating mixed histomorphologic and immunohistochemical features of endometrial stromal nodule, leiomyoma, and uterine inflammatory myofibroblastic tumor while harboring a JAZF1::BCORL1 . The lesion was found in a 43-yr-old woman with pelvic pain and heavy menses as a 5.5cm well-circumscribed ulcerated mass fungating from the cervical os. Microscopic examination revealed a polypoid, well-circumscribed, moderately cellular endomyometrial tumor composed by bland spindle cells haphazardly disposed within a slightly edematous stroma enriched by a delicate network of thin-walled vessels that were occasionally encircled by the tumor cells. Unequivocal evidence of tongue-like growth pattern into the myometrium, tumor-type necrosis or increased mitotic activity was not identified after sampling the entire lesion. The lesion showed patchy immunoreactivity for both smooth muscle actin-alpha and desmin while negative for CD10, HMB45, ALK (D5F3), and BCOR. An Archer FusionPlex panel assay demonstrated a fusion involving both exons 4 from the JAZF1 and BCORL1 genes. The JAZF1::BCORL1 has not, to the best of our knowledge, been previously reported in a benign/low-grade mesenchymal uterine lesion.

Analyzing BMP2, FGFR, and TGF Beta Expressions in High-Grade Osteosarcoma Untreated and Treated Autografts Using Proteomic Analysis.

In the last few decades, biological reconstruction techniques have improved greatly for treating high-grade osteosarcoma patients. To conserve the limb, and its function the affected tumor-bearing bones have been treated using liquid nitrogen and irradiation processes that enable the removal of entire tumors from the bone, and these treated autografts can be reconstructed for the patients. Here, we focus on the expressions of the growth factor family proteins from the untreated and treated autografts that play a crucial role in bone union, remodeling, and regeneration. In this proteomic study, we identify several important cytoskeletal, transcriptional, and growth factor family proteins that showed substantially low levels in untreated autografts. Interestingly, these protein expressions were elevated after treating the tumor-bearing bones using liquid nitrogen and irradiation. Therefore, from our preliminary findings, we chose to determine the expressions of BMP2, TGF-Beta, and FGFR proteins by the target proteomics approach. Using a newly recruited validation set, we successfully validate the expressions of the selected proteins. Furthermore, the increased growth factor protein expression after treatment with liquid nitrogen may contribute to bone regeneration healing, assist in faster recovery, and reduce local recurrence and metastatic spread in high-grade sarcoma patients.

Transanal Resection of Anorectal Leiomyosarcoma

Anorectal leiomyosarcoma (AL) is a rare and aggressive malignancy. Although the optimal treatment of AL is unknown, surgical resection with negative margins is the mainstay of management. We describe the case of a 72-year-old woman with metastatic rectal leiomyosarcoma, who initially presented with blood per rectum and worsening constipation. She was found to have a 7 × 7.3 cm mass prolapsing through the anal canal into the perineum without extraluminal extension or pathologic lymph nodes on MRI, with pathology consistent with sarcomatoid carcinoma. Transanal R0 resection was performed. Pathology showed a 6 cm high grade sarcoma consistent with leiomyosarcoma and negative margins. Two years post-resection, the patient was found to have a metastatic flank lesion, for which she underwent surgery. If accessible transanally, radical resection of AL is a valuable approach to treatment. Evidence regarding the best adjuvant treatment strategy is lacking and should be evaluated on a case-by-case basis. Number of similar cases published: 27 articles published with 51 cases of anorectal sarcoma based on a review published in 2019.

A Cryoprotectant-Gel Composite Designed to Preserve Articular Cartilage during Frozen Osteoarticular Autograft Reconstruction for Malignant Bone Tumors: An Animal-Based Study.

ObjectiveWe designed a highly adhesive cryoprotectant-gel composite (CGC), based on regular liquid-form cryoprotectant base (CB), aiming to protect cartilage tissue during frozen osteoarticular autograft reconstruction for high-grade sarcoma around the joint. This study aimed to evaluate its effectiveness in rat and porcine distal femur models.DesignFresh articular cartilage samples harvested from distal rat and porcine femurs were divided into 4 test groups: untreated control group, liquid nitrogen (LN) freezing group, LN freezing group pretreated with CB (CB group), and LN freezing group pretreated with CGC (CGC group). Microscopic and macroscopic evaluation of cartilage condition, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay, and apoptotic protein analysis of chondrocytes were performed to confirm our results.ResultsIn the rat model, CGC could prevent articular cartilage from roughness and preserve more proteoglycans when compared with the LN freezing and CB groups. Western blot analysis showed CGC could prevent cartilage from LN-induced apoptosis supported by caspase-3/8 apoptotic signaling cascade. Macroscopically, we observed CGC could reduce both articular clefting and loss of articular luminance after freezing in the porcine model. In both models, CGC could reduce articular chondrocytes from degeneration. Fewer TUNEL-positive apoptotic and more viable chondrocytes in cartilage tissue were observed in the CGC group in our animal models.ConclusionOur study proved that CGC could effectively prevent cartilage surface and chondrocytes from cryoinjury after LN freezing. Freezing articular cartilage surrounded with high concentration of CGC can be a better alternative to preserve articular cartilage during limb salvage surgery for malignant bone tumor.

Association of Vascular Endothelial Growth Factor (VEGF) and Mammalian Target of Rapamycin (mTOR) with Radiotherapy Response in High-Grade Sarcomas

Background: Sarcoma is a rare malignant aggressive tumor originating from mesenchymal elements. High-grade sarcoma has a poor prognosis. The mortality rate of high-grade sarcomas is 50–75%. Radiotherapy is needed in high-grade sarcoma. Radioresistance in the high-grade sarcoma is still common. Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) are molecular markers that play a role in radioresistance. This study aimed to analyze the association of VEGF and mTOR with radiotherapy response in high-grade sarcoma. Method: This study was an analytic observational study with a cross-sectional design. The minimum samples based on Lameshow’s formula included 40 selected paraffin-embedded tissue blocks from biopsy high-grade sarcoma, consisting of 20 samples of radioresistance and 20 samples of radiosensitive. Immunohistochemistry staining for VEGF and mTOR were performed on all samples. Statistical analysis used the Chi-Square test. The significance of the data was obtained when p-value <0.05.Result: High immunoexpression of VEGF (OR = 17, p < 0.05) and mTOR in high-grade sarcoma showed a significant association with radiotherapy response (OR = 16, p < 0.05). The stepwise logistic regression analysis revealed that both VEGF and mTOR immunoexpression influenced radiotherapy response simultaneously. Conclusion: In this study, which used a minimum sample, it can be concluded that the higher VEGF and mTOR immunoexpression showed the higher radioresistance in high-grade sarcoma.

A Case Report on Carcinosarcoma of the Pancreas with a Concise Literature Review

Carcinosarcoma is a rare neoplasm that most commonly affects the uterus. In the pancreas, fewer than thirty cases are reported worldwide. We present a 47-year-old female with epigastric pain, and jaundice. Histopathology revealed a pancreatic head mass showing a biphasic tumor composed of seventy percent Pancreatic Ductal Adenocarcinoma, and thirty percent High Grade Sarcoma with immunohistochemistry using Pancytokeratin, Vimentin, Desmin, S-100, Smooth Muscle Actin, CD34, and Ki-67.

Pleuropulmonary blastoma (PPB) and other DICER1-associated high-grade malignancies are morphologically, genetically and epigenetically related – A comparative study of 4 PPBs and 6 sarcomas

DICER1-related tumors occur hereditary or sporadically, with high-grade malignancies sharing clinicopathological and (epi)genetic features. We compared 4 pleuropulmonary blastomas (PPBs) and 6 sarcomas by mutation analysis, whole transcriptome sequencing and methylation profiling.9/10 patients were female. PPB patients were 0–4 years. 3/4 were alive; 2 without disease. One patient died of metastatic disease (median follow-up, 16 months). Sarcoma patients were 16–56 years. Locations included: uterine cervix/corpus (3/1), soft tissue back/shoulder (1) and paravertebral (1). 5/6 patients were alive; 2 developed metastases: intracranial (1) and lung and kidney (1) (median follow-up, 17 months). The deceased patient previously had a PPB and a Sertoli-Leydig cell tumor.Histologically, tumors showed atypical primitive-looking cells with incomplete rhabdomyoblastic differentiation and cartilage (n = 5). Immunohistochemistry demonstrated desmin- (n = 9/10), myogenin- (n = 6/10) and keratin positivity (n = 1/1).Eight cases harbored biallelic DICER1 mutations with confirmed germline mutations in 4 cases. Two cases showed a monoallelic mutation.By RNA expression- and methylation profiling, distinct clustering of our cases was seen demonstrating a close relationship on (epi)genetic level and similarities to embryonal rhabdomyosarcoma.In conclusion, this study shows overlapping morphological, immunohistochemical and (epi)genetic features of PPBs and DICER1-associated high-grade sarcomas, arguing that these neoplasms form a spectrum with a broad clinicopathological range.

Limb-sparing surgery with latissimus dorsi flap reconstruction in extremity soft tissue sarcoma: Case series.

Introduction and importanceFunction-preserving and Limb-sparing surgery are now the accepted gold standard of care for Extremity Soft Tissue Sarcoma (ESTS) with the goal of surgery for STS of extremities to obtain local tumor control and minimal morbidity. Limb-sparing surgery with post-operative radiotherapy for STS results in high survival rates and local control. Adjuvant radio chemotherapy might improve distant and local recurrence in high-risk patients. Hence, we aim to present how to achieve local tumor control and minimal morbidity for high grade ESTS by conducting limb-sparing surgery combined with appropriate reconstruction and radio chemotherapy.Case presentationWe present 2 cases with high grade sarcoma that underwent limb-sparing surgery with Latissimus Dorsi (LD) flap reconstructions. Wide excisions were completed with limb-sparing surgeries for both cases with free surgical margins and LD flap reconstructions. There was no post-operative complication. Follow up examination revealed normal function of the arm. The first patient was still in remission after 2-years follow up. The second patient got pulmonary metastasis after complete resection and adjuvant radiotherapy.Clinical discussionLimb-sparing surgery with LD flap reconstruction is able to remove the tumor completely with negative margin for the primary objective. Secondary objectives are minimizing the morbidity, maximizing postoperative body functions, as well as achieving the best cosmetic value are also achieved. LD flap is commonly easy to harvest and able to give large tissue coverage for reconstruction after surgery.ConclusionLimb sparing surgery followed by soft-tissue reconstruction and radio chemotherapy are suitable for increasing oncologic outcome, tumor control, and limb preservation. However, inhibitions towards local recurrence and distant metastases were not guaranteed.

CIC-DUX4 sarcomas.

CIC-DUX4 sarcoma (CDS) is a high-grade undifferentiated round cells sarcoma that belongs to the undifferentiated round cell sarcomas family. It represents less than one percent of sarcomas, defining a rarest among rare malignancies. It affects young adults, displaying soft tissue mass. Considered very aggressive, a high proportion of cases display an advanced disease with lung metastasis at diagnosis. Here we discuss recent progress in molecular characterization of CDS, the main tracks of CDS biology and the current and future prospects of therapeutic approaches. CDS is characterized by a specific oncogenic translocation CIC::DUX4 that induce ETV4 overexpression. Patients with CDS show an aggressive clinical course and have a significantly unfavorable outcome compared to Ewing sarcoma. As of today, there is a lack of consensus on whether they should be treated with an Ewing-like approach, as currently done by most sites, or regarded as high-grade soft tissue sarcoma (STS). Anyway, when feasible, combination regimens including anthracycline and alkylating agents should be favored and patients should not benefit from a therapeutic de-escalation. Overall, registration within clinical trials and prospective registries is recommended. Overall, CDS showed a poor prognosis regardless of the patterns of treatment that warrant biological studies to better understand the disease.

Malignant Transformation of Giant Cell Tumor of Bone and the Association with Denosumab Treatment: A Radiology and Pathology Perspective.

Objective Malignancy in giant cell tumor of bone (mGCTB) is categorized as primary (concomitantly with conventional GCTB) or secondary (after radiotherapy or other treatment). Denosumab therapy has been suggested to play a role in the etiology of secondary mGCTB. In this case series from a tertiary referral sarcoma center, we aimed to find distinctive features for malignant transformation in GCTB on different imaging modalities. Furthermore, we assessed the duration of denosumab treatment and lag time to the development of malignancy. Methods From a histopathology database search, 6 patients were pathologically confirmed as having initial conventional GCTB and subsequently with secondary mGCTB. Results At the time of mGCTB diagnosis, 2 cases were treated with denosumab only, 2 with denosumab and surgery, 1 with multiple curettages and radiotherapy, and 1 with surgery only. In the 4 denosumab treated patients, the mean lag time to malignant transformation was 7 months (range 2–11 months). Imaging findings suspicious of malignant transformation related to denosumab therapy are the absence of fibro-osseous matrix formation and absent neocortex formation on CT, and stable or even increased size of the soft tissue component. Conclusion In 4 patients treated with denosumab, secondary mGCTB occurred within the first year after initiation of treatment. Radiotherapy-associated mGCTB has a longer lag time than denosumab-associated mGCTB. Close clinical and imaging follow-up during the first months of denosumab therapy is key, as mGCTB tends to have rapid aggressive behavior, similar to other high-grade sarcomas. Nonresponders should be (re) evaluated for their primary diagnosis of conventional GCTB.

Primary chondroblastic osteosarcoma with glandular areas - An extremely rare case of divergent differentiation

Malignant bone tumors with epithelial differentiation are extremely rare. A primary carcinosarcoma arising in bone is characterised by the presence of both epithelial and mesenchymal differentiation. Herein we report an extremely rare case of primary chondroblastic osteosarcoma with true divergent glandular differentiation in a twenty-nine year old female. Microscopic sections reveal a high-grade chondroblastic osteogenic sarcoma with definite areas showing neoplastic osteoid formation and nests, cords and acinar (glandular) structures with cytokeratin positivity suggesting definitive epithelial glandular differentiation. Our case illustrates the ability of osteosarcomas to show epithelial differentiation characterized both by cytokeratin expression and differentiation to adenocarcinomatous cells displaying distinct glandular differentiation

Abstract 1268: Early proliferative response via [18]FLT-PET/CT and serum TK1 activity are predictive biomarkers for synergistic effect of sequential cell cycle targeted therapy in sarcoma

Abstract Introduction: Sarcomas are rare, aggressive tumors that make up a higher percentage of overall cancer mortality in children and young adults. Primary management of sarcoma patients includes surgical resection with adjuvant or neoadjuvant radiation/chemotherapy. Even with aggressive multimodal treatment regimens, patients with high-grade sarcomas experience suboptimal prognosis and advanced disease is almost universally fatal. Innovative biomarker driven targeted therapies are in urgent need to improve survival in these patients. Discoveries in molecular and genetic basis of sarcoma have revealed new targets that deserve consideration. Inactivation of retinoblastoma (Rb) pathway, which causes unabated cell proliferation, through overexpression of cyclin D1 and/or CDK4/6 has been detected in the majority of sarcomas even when wild-type Rb protein is expressed. Hence, inhibition of cell cycle progression through reactivation of the tumor suppressor function of Rb by inhibiting CDK4/6 activity poses a potential avenue for new therapeutic options. Methods: A panel of 4 sarcoma cell lines and 4 patient derived xenograft (PDX) models were used: 2 with an intact Rb pathway (Rb+ve, p16-ve) and 2 with an altered Rb pathway (Rb low/-ve, p16+ve). CDK4/6 inhibitor, abemaciclib, was used to reactivate the Rb pathway followed by treatment with gemcitabine or WEE1-kinase-inhibitor, to target the enriched S and G2/M phase cells post-abemaciclib removal. 18F-FLT PET imaging and serum thymidine kinase 1 (TK1) were used to monitor changes in cell proliferation and treatment response in both in vitro and in vivo. Changes in cell cycle biomarkers in response to treatment were also interrogated. Results: Rb+ve sarcoma cell lines were sensitive to the anti-proliferative activity of abemaciclib leading to their reversible G1 arrest, while Rb null cells did not arrest in any phase of cell cycle in response to CDK4/6 inhibition. Following abemciclib removal, Rb+ve models (but not Rb-ve) showed significant increase in 18F-FLT biotracer uptake concomitant with elevated serum TK1 and enrichment of cells in S phase. The enrichment of cells in S phase maximized therapeutic efficacy of S-phase or G2/M targeting agents leading to synergistic cell killing in Rb+ve cell lines and PDX models. Conclusion: Our study presents an innovative treatment strategy inhibiting the Rb pathway followed by S or G2/M pathway sequentially resulting in synergistic cell killing in those cells/tumors with wild-type Rb. We also incorporate real-time PET imaging and serum TK1 as non-invasive indicators of response to the treatment strategy. The study with PDX models also identified biomarkers of cell proliferation to be used in conjunction with PET imaging to provide the pre-clinical rationale to translate our findings into clinical trials for this aggressive disease. Citation Format: Tuyen Duong Nguyen, Marc A. Pina, Yan Wang, Cansu Karakas, Tuyen N. Bui, Osama Mawlawi, Alexander J. Lazar, Davis R. Ingram, Peter J. Hougton, Kelly K. Hunt, Khandan Keyomarsi. Early proliferative response via [18]FLT-PET/CT and serum TK1 activity are predictive biomarkers for synergistic effect of sequential cell cycle targeted therapy in sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1268.

Neoadjuvant Radiation in High-Grade Soft-Tissue Sarcomas: Histopathologic Features and Response Evaluation.

In this study, we sought to determine the prognostic value of both the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) score and the histologic parameters viable tumor, coagulative necrosis, hyalinization/fibrosis, and infarction in patients (n=64) with localized, nonmetastatic high-grade soft-tissue sarcomas after preoperative radiomonotherapy. A standardized macroscopic workup for pretreated surgical specimen including evaluation of a whole section of high-grade soft tissue sarcomas in the largest diameter, was used. Association with overall survival and disease-free survival was assessed. Limb salvage could be accomplished in 98.4% of patients. Overall, 90.6% tumors had negative resection margins. The median postoperative tumor diameter was 9 cm. Undifferentiated pleomorphic sarcoma (42.2%) and myxofibrosarcoma (17.2%) were the most common diagnoses. In all, 9.4% of patients had local recurrence despite clear resection margins, and 50% had distant metastases. Morphologic mapping suggests an overall heterogenous intratumoral response to radiotherapy, with significant differences among histologic subtypes. Complete regression (0% vital tumor cells) was not seen. Categorizing the results according to the proposed EORTC-STBSG 5-tier response score, <1% viable tumor cells were seen in 3.1%, ≥1% to <10% viable tumor cells in 20.4%, ≥10% to <50% viable tumor cells in 35.9% and ≥50% viable tumor cells in 40.6% of cases. Mean values for viable tumor cells were 40% (range: 1% to 100%), coagulative necrosis 5% (0% to 60%), hyalinization/fibrosis 25% (0% to 90%) and infarction 15% (0% to 79%). Hyalinization/fibrosis was a significant independent prognostic factor for overall survival (hazard ratio=4.4; P =0.047), while the other histologic parameters including the EORTC-STBSG score were not prognostic.

OTHR-41. Amplification of the PLAG family genes – PLAGL1 and PLAGL2 – is a key feature of a novel embryonal CNS tumor type

Pediatric central nervous system (CNS) tumors differ substantially from their adult counterparts, are marked by considerable molecular and clinical heterogeneity, and diagnosis through histopathology alone can be challenging. Using DNA methylation-based CNS tumor classification in combination with copy number and RNAseq analysis, we identify a rare, novel pediatric CNS tumor type (n=32) which is characterized by focal high-level amplification and consecutive overexpression of one of the PLAG family genes – PLAGL1 or PLAGL2. It is epigenetically divergent from other known tumor types such as high-grade gliomas, medulloblastomas, embryonal tumors, or CNS sarcomas. The wide range of original histopathologic diagnosis rendered attests to their polyphenotypic nature in terms of morphology. We suggest that these tumors may arise from early to intermediate neural progenitor cells with some neuronal commitment. Using ChIPseq data, we show that both PLAGL1 and PLAGL2 act as transcription factors for: i) the oncogenic kinase RET, a potential drug target, that was overexpressed in our cohort; ii) components of the Wnt/β-Catenin pathway; iii) a set of imprinted genes, reported to regulate the imprinted gene network in mouse models, that was deregulated in the PLAGL-amplified tumors. Consequently, a 250-gene expression PLAGL-signature indicated dysregulation of imprinting control and differentiation/development as a prominent feature. We report differences regarding age and sex distribution between PLAGL1- and PLAGL2-amplified tumors and shed light on differences in clinical behavior and outcomes between these subtypes in male and female patients. PLAGL1-amplified tumors were more prevalent in school-age children and teenagers, while PLAGL2-amplified cases occurred in very young patients. Kaplan-Meier analysis showed a trend towards a more favorable outcome in patients with PLAGL1-amplified tumors and in female patients. Survival rates remained constant after 5 years with a five-/ten-year overall survival of 75% for PLAGL1, 24% for PLAGL2, 18% for male patients, and 88% for female patients.

ETMR-03. Intra- and extra-cranial BCOR-ITD tumours are separate entities within the BCOR-rearranged family

BCOR-ITD tumours form an emerging family of aggressive entities with an internal tandem duplication (ITD) in the last exon of the BCOR gene. The family includes cerebral tumours, termed central nervous system BCOR-ITD (CNS BCOR-ITD), and sarcomatous types described in the kidney as clear cell sarcoma of the kidney (CCSK), in the endometrium as high-grade endometrial stromal sarcoma (HG-ESS), in bone, and in soft tissue as undifferentiated round cell sarcoma (URCS) or primitive myxoid mesenchymal tumour of infancy (PMMTI). Based on a series of 33 retrospective cases, including 10 CNS BCOR-ITD and 23 BCOR-ITD sarcomas, we interrogated the homogeneity of the entity regarding clinical, radiological and histopathological findings, and molecular signatures. Whole transcriptomic sequencing and DNA methylation profiling were used for unsupervised clustering. Histopathological review revealed marked differences between CNS BCOR-ITD and BCOR-ITD sarcomas. These two groups were consistently segregated by unsupervised clustering of expression (n=22) and DNA methylation (n=21) data. Proximity between the two groups may result from common somatic changes within key pathways directly related to the novel activity of the ITD itself. Conversely, comparison of gene signatures with single-cell RNAseq atlases suggests that the distinction between BCOR-ITD sarcomas and CNS BCOR-ITD may result from differences in cells of origin.

Secondary Malignancy in Giant Cell Tumor: A Single-Center Study.

Giant cell tumor of bone (GCTB) undergoes a sarcomatous transformation. Secondary malignancy in giant cell tumor (MGCT) is associated with radiotherapy and has a dismal prognosis. We reviewed medical records to investigate the clinicopathological characteristics and prognosis of MGCT patients. The enrollment criterion was high-grade spindle-cell sarcoma, which developed at the site of prior GCTB treatment. Twelve patients were analyzed: six females and six males. The median age was 42.5 years. Benign recurrence occurred in five GCTB patients not treated with radiotherapy. No pulmonary implants were observed. The median latency to the malignant transformation was 63 months. Nine patients were AJCC stage IIB, and three were stage IVA. The median follow-up period after malignant transformation was 62.5 months. Five patients developed local recurrence, and six had distant metastasis. Five-year overall recurrence and metastasis-free survival rates were 61.9%, 66.7%, and 58.3%, respectively. Initial metastasis was a predictive factor for overall survival. Benign local recurrence of GCTB was also a negative factor for metastasis-free survival of MGCT patients. Differences in overall survival according to benign recurrence also showed a tendency toward significance. In our series, secondary MGCT did not occur after radiotherapy. The prognosis was better than previous findings. Benign recurrence of GCTB could reflect the prognosis of MGCT.

Phase Ib study of selinexor and eribulin combination in advanced solid tumors and triple-negative breast cancer.

3108 Background: Selinexor (KPT-330) is potent inhibitor of Exportin-1. In vitro, Selinexor was found to be synergistic with eribulin in triple negative breast cancer (TNBC) cell lines and enhanced antitumor activity of eribulin in TNBC patient-derived xenografts (PMID 28810913). Methods: We conducted a phase Ib trial in combination of selinexor and eribulin using 3 + 3 design in dose escalation for patients with advanced solid tumors and in TNBC in dose expansion cohort. Eribulin could be discontinued after combination for 6 cycles at physician discretion. Primary objectives: Safety, Recommended Phase 2 Dose (RP2D). Secondary Objectives: Objective Response Rate (ORR), Duration of Response (DOR), Disease Control Rate (DCR), Overall Survival (OS) and Progression Free Survival (PFS). Results: 31 patients, TNBC (n = 19), sarcoma (n = 8), others (n = 4) enrolled in dose escalation (n = 10) and dose expansion phases (n = 21). Median prior therapies:4 (1–6). Study initiated selinexor at 60mg twice weekly and eribulin 1.4mg/m2 on Day1, Day8 every 3 weeks which led to 1 Dose Limiting Toxicity (DLT) and hence, selinexor 80mg once weekly and eribulin 1mg/m2 was elected as RP2D due to efficacy and tolerability. As of 01/15/2022, of 29 patients (94%) who have discontinued treatment, 24 (77%) were due to progressive disease, 3 (10%) withdrew consent and 2 (6%) due to toxicities (G1 pneumonitis; G3 neutropenia) while 2 (6%) remain on trial. All 31 patients had at least one treatment emergent adverse event (TEAE) while most prevalent TEAEs (all grades) were leukopenia (77%), nausea (71%), anemia and neutropenia (68%) and fatigue (48%). The most common G3/4 TEAE were leukopenia (26%) and neutropenia (29%). 2 DLTs occurred; 1 in first dose level (DL); 1 in second DL dosed at selinexor 80 mg once weekly due to G3 neutropenia. ORR for all was 10% while DCR (SD+PR+CR) &gt; 6 months seen in 3 (15%) TNBC and 2 (20%) sarcoma patients. The median OS and PFS for all were 12.3 (7.3, 27.3) months and 2.3 (1.6, 4.1) months. In dose escalation cohort, ORR was 10% where one patient (3%) with vaginal SCC had confirmed PR (-44%) for 2.1 months. Five patients (62.5%) with sarcoma had stable disease (SD). One patient with high grade sarcoma has SD for 68 months and remains on selinexor after 4 months of eribulin and selinexor. In TNBC dose expansion (n = 19), ORR was 10.5% with 2 confirmed PRs and median duration of response (DOR) of 10.8 months. One patient who has remained on treatment for 18 months, and after receiving 8 months of eribulin and selinexor, remains on selinexor with 100% target regression and an indeterminate brain lesion. Conclusions: Selinexor with eribulin is safe with manageable toxicity profile and modest overall clinical efficacy. Durable responses and disease control were observed with metastatic TNBC. Further study is needed to examine the determinants of response to this combination. Clinical trial information: NCT02419495.

TTI-621-03: A phase I/II study of TTI-621 in combination with doxorubicin in patients with unresectable or metastatic high-grade leiomyosarcoma (LMS).

TPS11593 Background: Doxorubicin is a standard of care agent for patients with advanced soft tissue sarcoma, with a response rate of around 15%, progression-free survival of 5-7 months and cumulative cardiac toxicity that limits its use. TTI-621 is a recombinant soluble fusion protein that combines the N-terminal portion of human SIRPα (the binding domain for CD47) with the Fc region of human IgG1, generating a decoy receptor for CD47 on the surface of tumor cells that both over-rides CD47-mediated inhibition of phagocytosis and provides a pro-phagocytic stimulation. Many solid tumors express high levels of CD47 which is associated with poor prognosis, thought to be the result of CD47-mediated inhibition of macrophage phagocytosis and escape of immune-mediated clearance. Interruption of the CD47-SIRPα signaling pathway using monoclonal antibodies to CD47 has shown anti-tumor activity in animal models and in some early clinical trials. The combination of doxorubicin with CD47-targeted antibodies results in enhanced anti-tumor activity and increased macrophage-mediated cell killing in animal models and macrophage-mediated phagocytosis of cancer cell lines in vitro, suggesting that combining TTI-621 with doxorubicin might be more effective than doxorubicin alone in tumor types that express CD47 and have high numbers of macrophages, such as LMS. Thus, a Phase 1/2 study was initiated to evaluate this combination in patients with advanced soft tissue sarcoma, including LMS. Methods: TTI-621-03 is a Phase 1/2, open-label study of TTI-621 in combination with doxorubicin in patients with anthracycline-naïve disease. The Phase 1 dose escalation evaluates doses of TTI-621 (0.2 to 2.0 mg/kg) in combination with doxorubicin at 75 mg/m2 in patients with high-grade soft tissue sarcomas. Expansion cohorts will evaluate TTI-621 (0.2 and 2.0 mg/kg) with doxorubicin in patients with LMS, with pathology confirmed at a central laboratory. The primary goals of this study are evaluation of safety of TTI-621 administered in combination with standard-of-care doxorubicin and to further evaluate clinical activity (ORR, PFS, OS), safety, PK and patient-reported quality of life in the LMS subpopulation. The dose escalation portion of the study has been completed without DLT. Enrollment to the expansion portion of the study is underway. Clinical trial information: NCT04996004.