Nanoparticle albumin-bound paclitaxel and PD-1 inhibitor (sintilimab) combination therapy for soft tissue sarcoma: a retrospective study

Background There is increasing evidence that combination therapy with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and programmed cell death protein 1 (PD-1) inhibitor is safe and efficacious in treating many types of malignant tumors. However, clinical data demonstrating the effect of this treatment combination for patients with metastatic soft tissue sarcoma (STS) are currently limited. Methods The clinical data of patients with metastatic STS who received nab-paclitaxel plus PD-1 inhibitor (sintilimab) therapy between January 2019 and February 2021 were retrospectively analyzed. The effectiveness and safety of the combined treatment were evaluated in terms of the median progression-free survival (PFS), estimated using the Kaplan–Meier method. The univariate Cox proportional hazards model was used to analyze the relationship between clinicopathological parameters and PFS. All statistical analyses were two-sided; P < 0.05 was considered statistically significant. Results A total of 28 patients treated with nab-paclitaxel plus sintilimab were enrolled in this study. The objective response rate was 25%, the disease control rate was 50%, and the median PFS was 2.25 months (95% CI = 1.8–3.0 months). The most common grade 1 or 2 adverse events (AEs) were alopecia (89.3%; 25/28), leukopenia (25.0%; 7/28), fatigue (21.4%; 6/28), anemia (21.4%; 6/28), and nausea (21.4%; 6/28). The most common grade 3 AEs were neutropenia (10.7%; 3/28) and peripheral neuropathy (10.7%; 3/28). No grade 4 AEs were observed. Among the present study cohort, patients with angiosarcoma (n = 5) had significantly longer PFS (P = 0.012) than patients with other pathological subtypes, including undifferentiated pleomorphic sarcoma (n = 7), epithelioid sarcoma (n = 5), fibrosarcoma (n = 4), synovial sarcoma (n = 3), leiomyosarcoma (n = 2), pleomorphic liposarcoma (n = 1), and rhabdomyosarcoma (n = 1); those who experienced three or more AEs had significantly longer median PFS than those who experienced less than three AEs (P = 0.018). Conclusion Nab-paclitaxel plus PD-1 inhibitor is a promising treatment regimen for advanced STS. Randomized controlled clinical trials are required to further demonstrate its efficacy and optimal application scenario.

Proximal-type epithelioid sarcoma in pubic region expressing L-type amino acid transporter 1: A case report

Proximal-type epithelioid sarcoma is an aggressive malignant soft-tissue neoplasm, a “proximal” variant of epithelioid sarcoma, resistant to multimodal therapy and involved in early tumor-related death. Pertinent treatments are, therefore, continually being explored. A 24-year-old woman with nonmetastatic proximal-type epithelioid sarcoma, originating subcutaneously on the right side of the vulva, underwent surgical resection; the lesion recurred, however, leading to death 3 months after the second surgery. Here described is a case of proximal-type epithelioid sarcoma expressing L-type amino acid transporter 1 (LAT1) that transports essential amino acids and p-borono-L-phenylalanine (BPA)—the chemical compound used in boron neutron capture therapy (BNCT)—and is highly expressed in many malignant tumors. Recently, LAT1 has drawn attention, and relevant treatments have been studied—LAT1 inhibitor and BNCT. LAT1 expression in proximal-type epithelioid sarcoma may lead to cogent treatments for the disease.

Primary Epithelioid Sarcoma Manifesting as a Fungating Scalp Mass - Imaging Features and Treatment Options. A Case Report and Literature Review

Primary epithelioid sarcoma is an extremely rare malignancy of the scalp. To date, less than a dozen such cases have been reported in the literature. The diagnosis often is a challenge to both radiologists and clinicians. This is largely attributed to the lack of literature on the imaging features of scalp epithelioid sarcoma. In this report, we highlight the role of multimodality imaging in the diagnosis of primary scalp epithelioid sarcoma and review the epidemiology, imaging, treatment options, and prognosis of these malignant scalp tumors. Displaying a multilobulated morphology, heterogeneous enhancement, and restricted diffusion on MRI, these tumors typically show central degeneration with hemorrhage, necrosis, and calcification. Wide surgical resection and adjuvant radiotherapy are the mainstays of treatment for localized scalp tumors. Nevertheless, the prognosis of patients with distant metastases at diagnosis is extremely poor compared to those with local or regional diseases.

Anal canal epithelioid sarcoma: Case report and literature review

Soft tissue tumors account for less than 0.1% of colon and rectum malignant neoplasms. Epithelioid sarcoma is a subtype of undifferentiated soft tissue neoplasia that makes up 1% of this category; it is characterized by a slow progression, commonly affecting young male adults, with little or no response to chemotherapy and radiotherapy, leaving surgical resection their main therapeutic option to reduce recurrence. We here present the case of a 71-year-old male patient admitted for major rectorrhagia after evacuations and anal pain. During physical examination, a posterior anal sphincter induration was noted, which extended to the puborectal muscle. Anoscopy was performed where a thrombosed hemorrhoidal bundle was detected adjacent to a mass. In the later biopsy with immunohistochemistry, a proximal ulcer type, histological grade three epithelioid sarcoma was diagnosed. Subsequently, traditional abdominal perineal resection with colostomy was performed, resulting in favorable postoperative evolution and discharge after six days of the procedure. Keywords: soft tissue tumors; epithelioid sarcoma.

EZH2-Mediated MHC Class II Silencing Drives Immune Evasion in AML with t(16;21) (FUS-ERG)

Acute myeloid leukemia (AML) patients with the prototypical FET-ETS fusion, FUS-ERG [t(16;21)(p11;q22)], have dismal outcomes. With median event-free survival (EFS) less than 9 months, and median overall survival (OS) under 13 months (Fig. 1A), pediatric AML (pAML) with FUS-ERG has even worse outcomes than its adult counterpart (median OS: 22 months). Stem cell transplant (SCT) does not improve outcomes in FUS-ERG AML, despite predicted neoantigen formation by the fusion protein. A targetable mechanism to restore immune response and graft-versus-leukemia effect could be of considerable therapeutic benefit. Here, using blast-corrected RNA sequencing data from over 1200 patients in Children's Oncology Group (COG) trials AAML0531 and AAML1031, we find that FUS-ERG AML is distinguished from other pAML subtypes by its high expression of EZH2, a histone lysine methyltransferase for which several small molecule inhibitors have already been approved in clinical trials. The immunophenotype of FUS-ERG AML at diagnosis resembles that of post-transplant relapse with epigenetic silencing of MHC class II. FUS-ERG AML patients, regardless of age group or morphology, downregulate transcripts for MHC class II molecules (HLA-DRA, HLA-DRB1, HLA-DRB5, HLA-DPA1, HLA-DPB1, HLA-DMA, HLA-DQA1, HLA-DQB1, HLA-DMB, HLA-DOA) and the master regulator of HLA expression, CIITA (Fig. 1B). Based on MHC class II expression, we find that FUS-ERG AML at diagnosis clusters with post-SCT-relapsed adult AML, and distinct from the same adult AMLs at diagnosis (Fig. 1C; DiPersio, NEJM 2018). The mechanism of FUS-ERG driven EZH2 expression has not been previously elucidated. Signaling through the MEK/ERK/ELK1 pathway drives elevated EZH2 in some tumors, but in contrast to other pAML subtypes, EZH2 expression in FUS-ERG AML does not correlate with MEK/ERK/ELK1 pathway activation (Fig. 1D). Up to 50% of prostate cancers are driven by the TMPRSS2-ERG fusion, where EZH2 expression is induced by MYC, via downregulation of inhibitory miRNAs and binding to the EZH2 promoter. ERG itself can directly activate MYC transcription by binding of the MYC P2 promoter, creating a positive feedback loop. Based on these similarities between TMPRSS2-ERG and FUS-ERG, we hypothesized that elevated EZH2 expression in FUS-ERG AML is due to MYC activity. Indeed, we observe a strong correlation between expression of MYC and EZH2 among all pAML subsets, with FUS-ERG patients exhibiting some of the highest expression levels for each (Pearson's R=0.68) (Fig. 1E). By contrast, HNRNPH1-ERG fusions and fusions pairing FUS with other partners (FUS-X) did not yield similarly high expression of MYC or EZH2. Thus, a neomorphic combination of features from both FUS and ERG appears to drive the severe phenotype associated with this fusion. To characterize the immune-evasive phenotype presented by FUS-ERG patients at diagnosis, we conducted gene set enrichment analyses (GSEA) on sets involved in immune response. Fig. 1F shows that FUS-ERG AML is depleted of transcripts involved in "antigen processing & presentation" (p-val: 0.043) and "T cell cytotoxicity" (p-val: 0.050), as compared to other pAML. Restoration of MHC class II by inhibition of EZH2 has been shown to combat leukemic relapse. Tazemetostat, a small molecule selective and S-adenosyl methionine (SAM) competitive inhibitor of EZH2, has been approved by the FDA for the treatment of epithelioid sarcoma and follicular lymphoma; clinical trials are underway in a number of other malignancies. Given the desperate need for novel therapeutic options in these high-risk patients, we believe targeted inhibition of EZH2 may provide clinical benefit. Further preclinical investigation is currently underway in the YNH-1 FUS-ERG model. Figure 1 Figure 1. Disclosures Shaw: T-Cell and/or Gene Therapy for Cancer: Patents & Royalties.

CHIR99021, trough GSK-3β Targeting, Reduces Epithelioid Sarcoma Cell Proliferation by Activating Mitotic Catastrophe and Autophagy

Epithelioid sarcoma (ES) is a rare disease representing <1% of soft tissue sarcomas. Current therapies are based on anthracycline alone or in combination with ifosfamide or other cytotoxic drugs. ES is still characterized by a poor prognosis with high rates of recurrence. Indeed, for years, ES survival rates have remained stagnant, suggesting that conventional treatments should be revised and improved. New therapeutic approaches are focused to target the key regulators of signaling pathways, the causative markers of tumor pathophysiology. To this end, we selected, among the drugs to which an ES cell line is highly sensitive, those that target signaling pathways known to be dysregulated in ES. In particular, we found a key role for GSK-3β, which results in up-regulation in tumor versus normal tissue samples and associated to poor prognosis in sarcoma patients. Following this evidence, we evaluated CHIR99021, a GSK-3 inhibitor, as a potential drug for use in ES therapy. Our data highlight that, in ES cells, CHIR99021 induces cell cycle arrest, mitotic catastrophe (MC) and autophagic response, resulting in reduced cell proliferation. Our results support the potential efficacy of CHIR99021 in ES treatment and encourage further preclinical and clinical studies.