Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas.

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.

GLI1 Coamplification in Well-Differentiated/Dedifferentiated Liposarcomas: Clinicopathologic and Molecular Analysis of 92 Cases.

GLI1(12q13.3) amplification is identified in a subset of mesenchymal neoplasms with a distinct nested round cell/epithelioid phenotype. MDM2 and CDK4 genes are situated along the oncogenic 12q13-15 segment, amplification of which defines well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). The 12q amplicon can occasionally include GLI1, a gene in close proximity to CDK4. We hereby describe the first cohort of GLI1/MDM2/CDK4 coamplified WD/DDLPS. The departmental database was queried retrospectively for all cases of WD/DDLPS having undergone next-generation (MSK-IMPACT) sequencing with confirmed MDM2, CDK4, and GLI1 coamplification. Clinicopathologic data was obtained from a review of the medical chart and available histologic material. Four hundred eighty-six WD/DDLPS cases underwent DNA sequencing, 92 (19%) of which harbored amplification of the GLI1 locus in addition to that of MDM2 and CDK4. These included primary tumors (n = 60), local recurrences (n = 29), and metastases (n = 3). Primary tumors were most frequently retroperitoneal (47/60, 78%), mediastinal (4/60, 7%), and paratesticular (3/60, 5%). Average age was 63 years, with a male:female ratio of 3:2. The cohort was comprised of DDLPS (86/92 [93%], 6 of which were WDLPS with early dedifferentiation) and WDLPS without any longitudinal evidence of dedifferentiation (6/92, 7%). One-fifth (13/86, 17%) of DDLPS cases showed no evidence of a well-differentiated component in any of the primary, recurrent, or metastatic specimens. Dedifferentiated areas mostly showed high-grade undifferentiated pleomorphic sarcoma-like (26/86,30%) and high-grade myxofibrosarcoma-like (13/86,16%) morphologies. A disproportionately increased incidence of meningothelial whorls with/without osseous metaplasia was observed as the predominant pattern in 16/86 (19%) cases, and GLI1-altered morphology as described was identified in a total of 10/86 (12%) tumors. JUN (1p32.1), also implicated in the pathogenesis of WD/DDLPS, was coamplified with all 3 of MDM2, CDK4, and GLI1 in 7/91 (8%) cases. Additional loci along chromosomal arms 1p and 6q, including TNFAIP3, LATS1, and ESR1, were also amplified in a subset of cases. In this large-scale cohort of GLI1 coamplified WD/DDLPS, we elucidate uniquely recurrent features including meningothelial whorl-like and GLI-altered morphology in dedifferentiated areas. Assessment of tumor location (retroperitoneal or mediastinal), identification of a well-differentiated liposarcoma component, and coamplification of other spatially discrete genomic segments (1p and 6q) might aid in distinction from tumors with true driver GLI1 alterations.

Atypical Spindle Cell/Pleomorphic Lipomatous Tumor With Sarcomatous Transformation: Clinicopathologic and Molecular Analysis of 4 Cases.

Atypical spindle cell/pleomorphic lipomatous tumor (ASPLT) is a recently described adipocytic tumor predominantly affecting the subcutaneous soft tissues of adults. Previous studies have shown that ASPLT follows a benign clinical course with a 4% to 12% local recurrence rate and no risk of dedifferentiation. Herein, we describe the clinicopathologic and molecular findings of 4 cases of ASPLT showing unequivocal sarcomatous transformation. Three patients were male and one was female, aged 65, 70, 74, and 78 years. Two cases presented as mass-forming lesions, while 1 case was incidentally discovered. The tumors measured 30, 55, 80, and 110 mm and occurred in the chest wall (n = 2) or arm (n = 2); all were subcutaneous. Microscopically, they showed a biphasic appearance comprising a low-grade ASPLT component and a high-grade sarcomatous component. The low-grade components showed features in the spectrum of either atypical pleomorphic lipomatous tumor (n = 2) or atypical spindle cell lipomatous tumor (n = 2). The high-grade components displayed leiomyosarcoma-like (n = 2), pleomorphic liposarcoma-like (n = 1) or undifferentiated sarcoma-like (n = 1) morphology. On immunohistochemistry, tumors were negative for MDM2 and showed loss of RB1 expression. In addition, the leiomyosarcoma-like areas seen in 2 cases were positive for smooth muscle actin and H-caldesmon. Single-nucleotide polymorphism array, performed in 3 cases, showed deletions of TP53, RB1, and flanking genes in both components. In contrast, the sarcomatous components showed more complex genomic profiles with rare segmental gains and recurrent loss of PTEN (n = 3), ATM (n = 2), and CDKN2A/B (n = 2) among other genes. Whole exome sequencing identified a TP53 variant in one case and an ATRX variant in another, each occurring in both tumor components. Limited clinical follow-up showed no recurrence or metastasis after 1 to 13 months (median, 7.5 months) postsurgical excision. Altogether, our data support that ASPLT can rarely develop sarcomatous transformation and offer insights into the molecular mechanisms underlying this event.

Preclinical 3D model screening reveals digoxin as an effective therapy for a rare and aggressive type of endometrial cancer.

OBJECTIVE: Dedifferentiated endometrial carcinoma (DDEC) characterized by SWItch/Sucrose Non-Fermentable (SWI/SNF) complex inactivation is a highly aggressive type of endometrial cancer without effective systemic therapy options. Its uncommon nature and aggressive disease trajectory pose significant challenges for therapeutic progress. To address this obstacle, we focused on developing preclinical models tailored to this tumor type and established patient tumor-derived three-dimensional (3D) spheroid models of DDEC. METHODS: High-throughput drug repurposing screens were performed on in vitro 3D spheroid models of DDEC cell lines (SMARCA4-inactivated DDEC-1 and ARID1A/ARID1B co-inactivated DDEC-2). The dose-response relationships of the identified candidate drugs were evaluated in vitro, followed by in vivo evaluation using xenograft models of DDEC-1 and DDEC-2. RESULTS: Drug screen in 3D models identified multiple cardiac glycosides including digoxin and digitoxin as candidate drugs in both DDEC-1 and DDEC-2. Subsequent in vitro dose-response analyses confirmed the inhibitory activity of digoxin and digitoxin with both drugs showing lower IC50 in DDEC cells compared to non-DDEC endometrial cancer cells. In in vivo xenograft models, digoxin significantly suppressed the growth of DDEC tumors at clinically relevant serum concentrations. CONCLUSION: Using biologically precise preclinical models of DDEC derived from patient tumor samples, our study identified digoxin as an effective drug in suppressing DDEC tumor growth. These findings provide compelling preclinical evidence for the use of digoxin as systemic therapy for SWI/SNF-inactivated DDEC, which may also be applicable to other SWI/SNF-inactivated tumor types.

Redifferentiation of genetically modified dedifferentiated chondrocytes in a microcavitary hydrogel.

OBJECTIVES: We genetically modified dedifferentiated chondrocytes (DCs) using lentiviral vectors and adenoviral vectors encoding TGF-ß3 (referred to as transgenic groups below) and encapsulated these DCs in the microcavitary hydrogel and investigated the combinational effect on redifferentiation of the genetically manipulated DCs. RESULTS: The Cell Counting Kit-8 data indicated that both transgenic groups exhibited significantly higher cell viability in the first week but inferior cell viability in the subsequent timepoints compared with those of the control group. Real-time polymerase chain reaction and western blot analysis results demonstrated that both transgenic groups had a better effect on redifferentiation to some extent, as evidenced by higher expression levels of chondrogenic genes, suggesting the validity of combination with transgenic DCs and the microcavitary hydrogel on redifferentiation. Although transgenic DCs with adenoviral vectors presented a superior extent of redifferentiation, they also expressed greater levels of the hypertrophic gene type X collagen. It is still worth further exploring how to deliver TGF-ß3 more efficiently and optimizing the appropriate parameters, including concentration and duration. CONCLUSIONS: The results demonstrated the better redifferentiation effect of DCs with the combinational use of transgenic TGF-ß3 and a microcavitary alginate hydrogel and implied that DCs would be alternative seed cells for cartilage tissue engineering due to their easily achieved sufficient cell amounts through multiple passages and great potential to redifferentiate to produce cartilaginous extracellular matrix.

Immune characteristics of dedifferentiated retroperitoneal liposarcomas and the reliability of regional samples in evaluating their tumor immune microenvironments.

BACKGROUND: Tumor immunotherapy is a new treatment breakthrough for retroperitoneal liposarcoma (RPLS), which is highly invasive and has few effective treatment options other than tumor resection. However, the heterogeneity of the tumor immune microenvironment (TIME) leads to missed clinical diagnosis and inappropriate treatment. Therefore, it is crucial to evaluate whether the TIME of a certain part of the tumor reliably represents the whole tumor, particularly for very large tumors, such as RPLS. METHODS: We conducted a prospective study to evaluate the TIME in different regions of dedifferentiated RPLS (DDRPLS) by detecting the expressions of markers such as CD4+, CD8+, Foxp3+, CD20+, CD68+, LAMP3+, PD-1+ tumor-infiltrating lymphocytes (TILs), and PD-L1 in tumors and corresponding paratumor tissues via immunohistochemistry and RNA sequencing. RESULTS: In DDRPLS, very few TILs were observed. Differentially expressed genes were significantly enriched in cell part and cell functions, as well as the metabolic pathway and PI3K-Akt signaling pathway. In addition, for most tumors (70-80%), the TIME was similar in different tumor regions. CONCLUSIONS: For most tumors (70-80%), the TIME in any region of the tumor reliably represents the whole tumor. DDRPLS may regulate cell functions by modulating the metabolic and PI3K-Akt signaling pathways to promote its malignant behavior.

Dedifferentiated Schwann cells promote perineural invasion mediated by the PACAP paracrine signalling in cervical cancer.

Perineural invasion (PNI) has emerged as a key pathological feature and be considered as a poor prognostic factor in cervical cancer. However, the underlying molecular mechanisms are largely unknown. Here, PNI status of 269 cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) samples were quantified by using whole-slide diagnostic images obtained from The Cancer Genome Atlas. Integrated analyses revealed that PNI was an indicative marker of poorer disease-free survival for CESC patients. Among the differentially expressed genes, ADCYAP1 were identified. Clinical specimens supported that high expression of PACAP (encoded by ADCYAP1) contributed to PNI in CESC. Mechanistically, PACAP, secreted from cervical cancer cells, reversed myelin differentiation of Schwann cells (SCs). Then, dedifferentiated SCs promoted PNI by producing chemokine FGF17 and by degrading extracellular matrix through secretion of Cathepsin S and MMP-12. In conclusion, this study identified PACAP was associated with PNI in cervical cancer and suggested that tumour-derived PACAP reversed myelin differentiation of SCs to aid PNI.

Prognostic Significance of Percentage and Size of Dedifferentiation in Dedifferentiated Chondrosarcoma.

Dedifferentiated chondrosarcoma is rare, aggressive, and microscopically bimorphic. How pathologic features such as the amounts of dedifferentiation affect prognosis remains unclear. We evaluated the percentages and sizes of dedifferentiation in a consecutive institutional series of dedifferentiated chondrosarcomas from 1999 to 2021. The statistical analysis included cox proportional hazard models and log-rank tests. Of the 67 patients (26 women, 41 men; age, 39 to >89 [median 61] years; 2 with Ollier disease), 58 presented de novo; 9 were identified with conventional chondrosarcomas 0.6-13.2 years (median, 5.5 years) prior. Pathologic fracture and distant metastases were noted in 27 and 7 patients at presentation. The tumors involved the femur (n = 27), pelvis (n = 22), humerus (n = 7), tibia (n = 4), scapula/ribs (n = 4), spine (n = 2), and clivus (n = 1). In the 56 resections, the tumors ranged in size from 3.5 to 46.0 cm (median, 11.5 cm) and contained 1%-99.5% (median, 70%) dedifferentiated components that ranged in size from 0.6 to 24.0 cm (median, 7.3 cm). No correlation was noted between total size and percentage of dedifferentiation. The dedifferentiated components were typically fibrosarcomatous or osteosarcomatous, whereas the associated cartilaginous components were predominantly grade 1-2, rarely enchondromas or grade 3. The entire cohort's median overall survival and progression-free survival were 11.8 and 5.4 months, respectively. In the resected cohort, although the total size was not prognostic, the percentage of dedifferentiation ≥20% and size of dedifferentiation >3.0 cm each predicted worse overall survival (9.9 vs 72.5 months; HR, 3.76; 95% CI, 1.27-11.14; P = .02; 8.7 vs 58.9 months; HR, 3.03; 95% CI, 1.21-7.57; P = .02, respectively) and progression-free survival (5.3 vs 62.1 months; HR, 3.05; 95% CI, 1.13-8.28; P = .03; 5.3 vs 56.6 months; HR, 2.50; 95% CI, 1.06-5.88; P = .04, respectively). In conclusion, both the percentages and sizes of dedifferentiation were better prognostic predictors than total tumor sizes in dedifferentiated chondrosarcomas, highlighting the utility of their pathologic evaluations.

Undifferentiated and Dedifferentiated Metastatic Melanomas Masquerading as Soft Tissue Sarcomas: Mutational Signature Analysis and Immunotherapy Response.

The distinction between undifferentiated melanoma (UM) or dedifferentiated melanoma (DM) from undifferentiated or unclassifiable sarcoma can be difficult and requires the careful correlation of clinical, pathologic, and genomic findings. In this study, we examined the utility of mutational signatures to identify patients with UM/DM with particular attention as to whether this distinction matters for treatment because the survival of patients with metastatic melanoma has dramatically improved with immunologic therapy, whereas durable responses are less frequent in sarcomas. We identified 19 cases of UM/DM that were initially reported as unclassified or undifferentiated malignant neoplasm or sarcoma and submitted for targeted next-generation sequencing analysis. These cases were confirmed as UM/DM by harboring melanoma driver mutations, UV signature, and high tumor mutation burden. One case of DM showed melanoma in situ. Meanwhile, 18 cases represented metastatic UM/DM. Eleven patients had a prior history of melanoma. Thirteen of 19 (68%) of the tumors were immunohistochemically completely negative for 4 melanocytic markers (S100, SOX10, HMB45, and MELAN-A). All cases harbored a dominant UV signature. Frequent driver mutations involved BRAF (26%), NRAS (32%), and NF1 (42%). In contrast, the control cohort of undifferentiated pleomorphic sarcomas (UPS) of deep soft tissue exhibited a dominant aging signature in 46.6% (7/15) without evidence of UV signature. The median tumor mutation burden for DM/UM vs UPS was 31.5 vs 7.0 mutations/Mb (P < .001). A favorable response to immune checkpoint inhibitor therapy was observed in 66.6% (12/18) of patients with UM/DM. Eight patients exhibited a complete response and were alive with no evidence of disease at the last follow-up (median 45.5 months). Our findings support the usefulness of the UV signature in discriminating DM/UM vs UPS. Furthermore, we present evidence suggesting that patients with DM/UM and UV signatures can benefit from immune checkpoint inhibitor therapy.

Loss of H3K27 trimethylation in a distinct group of de-differentiated chordoma of the skull base.

De-differentiated chordoma is defined as a high-grade sarcoma lacking notochordal differentiation, which arises in association with conventional chordoma. The mechanism underlying de-differentiation remains unclear. We immunohistochemically investigated trimethylation at lysine 27 of histone 3 (H3K27me3) in nine de-differentiated chordomas. The tumours occurred at the skull base (n = 5) or the sacrum (n = 4) in four men and five women with a median age of 50 years. De-differentiation occurred de novo in four cases and at recurrence/metastasis in five cases. Five tumours retained H3K27me3, whereas four showed complete loss of H3K27me3 only in the de-differentiated component, while the conventional chordoma component retained H3K27me3. All the H3K27me3-negative tumours showed co-loss of dimethylation at H3K27 (H3K27me2), consistent with inactivation of polycomb repressive complex 2. Two genetically analysed H3K27me3-negative tumours harboured EED homozygous deletions. All four H3K27me3-negative de-differentiated chordomas affected the skull base of young or middle-aged women. Unlike dense proliferation of highly pleomorphic spindle or epithelioid cells in the H3K27me3-positive de-differentiated chordomas, all H3K27me3-negative tumours displayed swirling fascicles of relatively uniform spindle cells with alternating cellularity and perivascular accentuation, resembling malignant peripheral nerve sheath tumour (MPNST). Rhabdomyoblastic differentiation was present in one H3K27me3-negative tumour. We identified a novel group of de-differentiated chordomas in the skull base that lost H3K27me3/me2 only in the de-differentiated component, which was associated with EED homozygous deletion and MPNST-like histology. Our data suggest a distinct 'polycomb-type' de-differentiation pathway in chordoma, similar to a recently described de-differentiated chondrosarcoma with H3K27me3 loss.

Genomic profiling of dedifferentiated endometrial carcinomas arising in the background of high-grade carcinoma: a targeted next-generation sequencing study.

AIMS: Our understanding of dedifferentiated endometrial carcinoma (DEC), a rare and aggressive malignancy, mainly reflects undifferentiated carcinomas (UC) arising in the setting of low-grade endometrial cancer (DEC-LG). However, cases of UC arising in the setting of high-grade EC (DEC-HG) have been noted in the literature. Our knowledge of the genomics of DEC-HG is limited. To characterise the molecular landscape of DEC-HC, targeted genomic sequencing and immunohistochemical analysis was carried out on seven DEC-HG and four DEC-LG. METHODS AND RESULTS: DEC-HG and DEC-LG, including undifferentiated and differentiated components, both showed a similar frequency and spectrum of mutations. ARID1A mutations were identified in 6/7 (86%) DEC-HG and 4/4 (100%) DEC-LG, while SMARCA4 mutations were present in 4/7 (57%) DEC-HG and in 1/4 (25%) DEC-LG. Concurrent SMARCA4/BRG1 protein loss by immunohistochemistry was observed in 3/4 and 1/1 SMARCA4 mutated DEC-HG and DEC-LG, respectively. Neither genomic alterations nor protein loss in SMARCB1/INI1 were observed in any of our cases. TP53 mutations were detected in 4/7 (57%) DEC-HG and in 2/4 (50%) DEC-LG, while mutation-pattern p53 immunohistochemistry expression was observed in 2/7 (29%) DEC-HG and none of the DEC-LG. MLH1 mutations were observed in 1/7 (14%) DEC-HG and 1/4 (25%) DEC-LG. MSH2 and MSH6 mutations were each detected in 1/7 (14%) DEC-HG, but neither was associated with corresponding loss of protein expression. CONCLUSION: The findings support expanding the definition of DEC to include DEC-HG, a previously under-recognised phenomenon with genomic similarities to DEC-LG.

Cambial meristematic cell culture: a sustainable technology toward in vitro specialized metabolites production.

Cambial meristematic cells (CMCs) culture has received a fair share of scientific and industrial attention among the trending topics of plant cell culture, especially their potential toward secondary metabolites production. However, the conventional plant cell culture is often not commercially feasible because of difficulties associated with culture dedifferentiated cells. Several reports have been published to culture CMCs and bypass the dedifferentiation process in plant cell culture. Numerous mitochondria, multiple vacuoles, genetic stability, self-renewal, higher biomass, and stable metabolites accumulation are the characteristics features of CMCs compared with dedifferentiated cells (DDCs) culture. The CMCs culture has a broader application to produce large-scale natural compounds for: pharmaceuticals, food, and cosmetic industries. Cutting-edge progress in plant cellular and molecular biology has allowed unprecedented insights into cambial stem cell culture and its fundamental processes. Therefore, regarding sustainability and natural compound production, cambial cell culture ranks among the most vital biotechnological interventions for industrial and economic perspectives. This review highlights the recent advances in plant stem cell culture and understands the cambial cells induction and culture mechanisms that affect the growth and natural compounds production.

Establishment and validation of preclinical models of SMARCA4-inactivated and ARID1A/ARID1B co-inactivated dedifferentiated endometrial carcinoma.

OBJECTIVE: Dedifferentiated endometrial cancer (DDEC) is an uncommon and clinically highly aggressive subtype of endometrial cancer characterized by genomic inactivation of SWItch/Sucrose Non-Fermentable (SWI/SNF) complex protein. It responds poorly to conventional systemic treatment and its rapidly progressive clinical course limits the therapeutic windows to trial additional lines of therapies. This underscores a pressing need for biologically accurate preclinical tumor models to accelerate therapeutic development. METHODS: DDEC tumor from surgical samples were implanted into immunocompromised mice for patient-derived xenograft (PDX) and cell line development. The histologic, immunophenotypic, genetic and epigenetic features of the patient tumors and the established PDX models were characterized. The SMARCA4-deficienct DDEC model was evaluated for its sensitivity toward a KDM6A/B inhibitor (GSK-J4) that was previously reported to be effective therapy for other SMARCA4-deficient cancer types. RESULTS: All three DDEC models exhibited rapid growth in vitro and in vivo, with two PDX models showing spontaneous development of metastases in vivo. The PDX tumors maintained the same undifferentiated histology and immunophenotype, and exhibited identical genomic and methylation profiles as seen in the respective parental tumors, including a mismatch repair (MMR)-deficient DDEC with genomic inactivation of SMARCA4, and two MMR-deficient DDECs with genomic inactivation of both ARID1A and ARID1B. Although the SMARCA4-deficient cell line showed low micromolecular sensitivity to GSK-J4, no significant tumor growth inhibition was observed in the corresponding PDX model. CONCLUSIONS: These established patient tumor-derived models accurately depict DDEC and represent valuable preclinical tools to gain therapeutic insights into this aggressive tumor type.

The NIH pediatric/young adult chordoma clinic and natural history study: Making advances in a very rare tumor.

BACKGROUND: Chordomas are rare tumors arising from the skull base and spine, with approximately 20 pediatric chordoma cases in the Unitedn States per year. The natural history and optimal treatment of pediatric chordomas, especially poorly differentiated and dedifferentiated subtypes, is incompletely understood. Herein, we present findings from our first National Cancer Institute (NCI) chordoma clinic and a retrospective analysis of published cases of pediatric poorly differentiated chordomas (PDC) and dedifferentiated chordomas (DC). METHODS: Patients less than 40 years old with chordoma were enrolled on the NCI Natural History and Biospecimens Acquisitions Study for Children and Adults with Rare Solid Tumors protocol (NCT03739827). Chordoma experts reviewed patient records, evaluated patients, and provided treatment recommendations. Patient-reported outcomes, biospecimens, and volumetric tumor analyses were collected. A literature review for pediatric PDC and DC was conducted. RESULTS: Twelve patients (median age: 14 years) attended the clinic, including four patients with active disease and three patients with PDC responsive to systemic therapy. Consensus treatment, management, and recommendations were provided to patients. Literature review returned 45 pediatric cases of PDC or DC with variable treatments and outcomes. CONCLUSIONS: A multidisciplinary expert clinic was feasible and successful in improving understanding of pediatric chordoma. While multimodal approaches have all been employed, treatment for PDC has been inconsistent and a recommended standardized treatment approach has not been defined. Centralized efforts, inclusive of specialized chordoma-focused clinics, natural history studies, and prospective analyses will help in the standardization of care for this challenging disease.

Dedifferentiated Chondrosarcoma: Diagnostic Controversies and Emerging Therapeutic Targets.

PURPOSE OF REVIEW: The pathogenesis of dedifferentiated chondrosarcoma is controversial, and no genetic abnormality has consistently been identified in the disease. Focusing on the diagnostic challenges encountered in dedifferentiated chondrosarcoma, the following review aims at summarizing the tumor's active neoplastic pathways while highlighting therapeutic modalities that could potentially be explored to enhance patient survivorship. RECENT FINDINGS: Owing to the challenging examination of small needle biopsy sampling as well as the disease's overlapping morphological and immunohistochemical features with other bone and soft-tissue sarcomas, the diagnosis of dedifferentiated chondrosarcoma can be problematic. While combined doxorubicin- and cisplatin-based regimens remain the first-line systemic chemotherapy in the disease, ~50% of tumors carry EXT1/2 or IDH1/2 mutations, advancing EXT or IDH inhibitors as potential alternative therapies, respectively. Despite systemic chemotherapy, dedifferentiated chondrosarcoma remains an aggressive tumor with dismal prognosis and limited survival. A multidisciplinary collaboration across multiple cancer centers is warranted to yield an accurate diagnosis, understand the disease's underlying pathogenesis, develop adequate treatment, and improve patient survivorship.

Brightline-1: phase II/III trial of the MDM2-p53 antagonist BI 907828 versus doxorubicin in patients with advanced DDLPS.

Dedifferentiated liposarcoma (DDLPS) is a rare, aggressive liposarcoma associated with poor prognosis. First-line treatment for advanced/metastatic DDLPS is systemic chemotherapy, but efficacy is poor and toxicities substantial. Most DDLPS tumors have amplification of the MDM2 gene, which encodes a negative regulator of the p53 suppressor protein. BI 907828 is a highly potent, oral MDM2-p53 antagonist that inhibits the interaction between p53 and MDM2, thereby restoring p53 activity. BI 907828 has shown promising activity in preclinical studies and in a phase Ia/Ib study in patients with solid tumors, particularly those with DDLPS. This manuscript describes the rationale and design of an ongoing multicenter, randomized, phase II/III trial (Brightline-1; NCT05218499) evaluating BI 907828 versus doxorubicin as first-line treatment for advanced DDLPS.

Dedifferentiated liposarcoma (DDLPS) is a rare, fast-growing cancer that begins in fat cells. Patients with DDLPS that cannot be removed surgically or has spread to other areas of the body are usually treated with chemotherapy at first, but this typically stops working only 2­4 months after the start of treatment and has a lot of side effects. The drug BI 907828 works differently to chemotherapy by specifically targeting a gene called MDM2. This gene is abnormally increased in most DDLPS tumors and causes cancer by shutting down one of the pathways that the body uses to kill cancerous cells. BI 907828 restores this pathway, leading to the targeted destruction of tumor cells. Results from initial studies show that BI 907828 is able to slow the growth of DDLPS, and is now being investigated further, in a study called Brightline-1. Brightline-1, which is currently underway, is comparing BI 907828 with the chemotherapy drug doxorubicin for the initial treatment of DDLPS that is inoperable or has spread to other areas of the body. Clinical Trial Registration: NCT05218499 (ClinicalTrials.gov).

Mechanical signals induces reprogramming of mature adipocytes through the YAP/TAZ-binding motif.

Tissue engineering technology will be the main approach to tissue regeneration in the future and are promising for the treatment of large-area burns and refractory wounds. Dedifferentiated fat cells (DFAT) derived from mature adipocytes (MAs) as a seed cell have great potential in cell therapy and tissue engineering for the treatment of a variety of clinical diseases because of their wider availability, stronger proliferation ability, multidirectional redifferentiation potential, higher cell purity, lower heterogeneity, and greater biosafety profile. However, the triggering mechanism for MAs reprogramming in vitro is unclear. In this study, MAs were successfully induced to dedifferentiate into DFAT in a short time in vitro using an "improved ceiling culture method". Flow cytometry, adipogenic, and osteogenic differentiation experiments verified that DFAT cells present the biological characteristics of stem cells. In addition, changing the stiffness of the extracellular matrix can inhibit the dedifferentiation of MAs to DFAT, and increase the expression of Yes-associated protein/transcriptional co-activator with the PDZ-binding motif (YAP/TAZ), nuclear translocation, and the expression of reprogramming transcription factors. In conclusion, extracellular matrix stiffness can induce MAs to dedifferentiate into DFAT in vitro, and can directly transmit mechanical force signals to the nucleus via YAP/TAZ binding to trigger the expression of stem cell-related reprogramming factors.

Characterization of cell line with dedifferentiated GIST-like features established from cecal GIST of familial GIST model mice.

Approximately 40 families with multiple gastrointestinal stromal tumors (GISTs) and germline c-kit gene mutations have been reported. Three knock-in mouse models have been generated, and all the models showed a cecal GIST. In the present study, we established a cell line derived from cecal GIST in a familial GIST model mouse with KIT-Asp818Tyr. Since the established cells showed spindle-shaped morphology with atypical nuclei, and since immunohistochemistry revealed that they were positive for α-SMA but negative for KIT, CD34 and desmin, the phenotypes of the cells were reminiscent of dedifferentiated GIST-like ones but not the usual GIST-like ones. Gene expression analysis showed that the cell line, designated as DeGISTL1 cell, did not express c-kit gene apparently, but highly expressed HSP90 families and glutaminase 1. Pathway analysis of the cells revealed that metabolic pathway might promote their survival and growth. Pimitespib, a heat shock protein 90α/ß inhibitor, and Telaglenastat, a selective glutaminase 1 inhibitor, inhibited proliferation of DeGISTL1 cells and the combination of these showed an additive effect. DeGISTL1 cells might be a good model of dedifferentiated GISTs, and combination of Pimitespib and Telaglenastat could be a possible candidate for treatment strategy for them.

Recurrent metastatic retroperitoneal dedifferentiated liposarcoma: a case report and literature review.

BACKGROUND: Retroperitoneal liposarcoma (RPLPS), a rare tumor, is often treated using surgical procedures as the first choice for treatment. However, there is no consensus on the scope of surgical resection. In addition, the treatment outcomes of conventional radiotherapy and chemotherapy have not been satisfactory, particularly for specific types of LPS, such as dedifferentiated LPS. In this case study, we present a brief review of other cases of RPLPS, highlighting the selection of surgical scope for RPLPS and related adjuvant treatment for advanced RPLPS. CASE PRESENTATION: A case study is reported regarding an extremely rare recurrent and metastatic retroperitoneal dedifferentiated LPS. The primary RPLPS tumor, with a diameter of 20 cm and a weight of 2.5 kg, occupied the whole left abdomen and adhered to the left kidney. A surgical tumor resection combined with a left nephrectomy is performed. During the 6th -month postoperative follow-up examination, we observed the local recurrence of the tumor in the operation area, in addition to multiple metastatic tumors in both lungs. Further, the prescribed 3-month targeted treatment with anlotinib significantly reduced the size of the metastatic pulmonary tumors. However, the recurrent retroperitoneal tumors showed no significant change in size. Eventually, we observed no substantial evidence of tumor progression, with the patient's condition under control. CONCLUSION: The case demonstrated that the postoperative recurrence of widespread RPLPS required R0 resection to cure the disease, considering targeted therapy for advanced RPLPS control.

The many faces of Atypical fibroxanthoma.

Atypical fibroxanthoma (AFX) is an uncommon, primary dermal neoplasm of uncertain histogenesis, typically originating in the sun-damage skin of the head and neck of the elderly. Since first description in 1958, ∼3000 cases have been reported in the literature. However, the disease is underreported as the neoplasm is considered a standard diagnosis in the last decades. On the other hand, many earlier reports likely have included non-AFX mimics or aggressive pleomorphic dermal sarcomas. In contrast to its alarming high-grade histology, AFX behaves indolently with rare recurrences/ metastatic rate of <2%. The overall 10- and 20-year disease-specific survival rates are ∼ 100% and 98%, respectively. Histologically, AFX displays undifferentiated pleomorphic spindle cell morphology akin to undifferentiated pleomorphic sarcoma (UPS), a feature that was the basis of the abandoned historical terminology "MFH of skin". However, in contrast to other undifferentiated sarcomatoid neoplasms, AFX is notorious for its highly variable histology with a plethora of patterns, underlining a wide differential diagnosis. Notably, spindle cell, keloid-like, pleomorphic, epithelioid, rhabdoid, clear cell, foamy cell, granular cell, bizarre cell, pseudoangiomatous, inflammatory, osteoclast-rich, and many others have been recognized with varying frequencies. Immunohistochemically, AFX is characterized by nonspecific profile with block-type expression of CD10 and aberrant p53 pattern and lack of pankeratin and other lineage-specific epithelial, mesenchymal, melanocytic and hematolymphoid markers. Sarcomatoid melanoma, spindle cell carcinoma and cutaneous anaplastic large cell lymphoma are major considerations. Distinction of AFX from pleomorphic dermal sarcoma (PDS) is arbitrary and is based on presence of ≥ 1 of four unfavorable histological features: more than minimal subcutaneous involvement, coagulative necrosis, lymphovascular invasion and perineurial invasion.