scholarly journals Comparative oncology reveals DNMT3B as a therapeutic vulnerability in soft-tissue sarcoma

2021 ◽  
Author(s):  
Ashley M Fuller ◽  
Ann DeVine ◽  
Ileana Murazzi ◽  
Nicola J Mason ◽  
Kristy Weber ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Dna Methyltransferase ◽  
Epigenetic Modification ◽  
Companion Animals ◽  
Pleomorphic Sarcoma ◽  
Genome Wide ◽  
Exciting Opportunity ◽  
Tissue Specimens ◽  
Novel Therapeutic Strategies

Undifferentiated pleomorphic sarcoma (UPS), an aggressive subtype of soft-tissue sarcoma (STS), is exceedingly rare in humans and lacks effective, well-tolerated therapies. In contrast, STS are relatively common in canine companion animals; thus, incorporation of veterinary patients into studies of UPS offers an exciting opportunity to develop novel therapeutic strategies for this rare human disease. Genome-wide studies have demonstrated that UPS is characterized by aberrant patterns of DNA methylation. However, the mechanisms and impact of this epigenetic modification on UPS biology and clinical behavior are poorly understood. Leveraging cell lines and tissue specimens derived from human and canine patients, we discovered that the DNA methyltransferase DNMT3B is overexpressed in UPS relative to normal mesenchymal tissues and associated with a poor prognosis. Consistent with these findings, genetic DNMT3B depletion strongly inhibited UPS cell proliferation and tumor progression. However, existing hypomethylating agents, including the clinically approved drug 5-aza-2'-deoxycytidine and the DNMT3B-inhibiting tool compound nanaomycin A, were ineffective in UPS due to cellular uptake and toxicity issues. Thus, further development of DNMT3B-targeting strategies for these patients is critical.

scholarly journals Gemcitabine-Containing Chemotherapy for the Treatment of Metastatic Myxofibrosarcoma Refractory to Doxorubicin: A Case Series

2021 ◽  
Vol 28 (1) ◽  
pp. 813-817
Author(s):  
Arielle Elkrief ◽  
Suzanne Kazandjian ◽  
Thierry Alcindor
Keyword(s):  
Overall Survival ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Objective Response ◽  
Case Series ◽  
Progression Free Survival ◽  
Distant Metastases ◽  
First Line ◽  
Pleomorphic Sarcoma ◽  
Line Setting

Background: Myxofibrosarcoma is a type of soft-tissue sarcoma that is associated with high rates of local recurrence and distant metastases. The first-line treatment for metastatic soft-tissue sarcoma has conventionally been doxorubicin-based. Recent evidence suggests that myxofibrosarcoma may be molecularly similar to undifferentiated pleomorphic sarcoma (UPS), which is particularly sensitive to gemcitabine-based therapy. The goal of this study was to evaluate the activity of gemcitabine-containing regimens for the treatment of metastatic myxofibrosarcoma refractory to doxorubicin. Material and Methods: We retrospectively evaluated seven consecutive cases of metastatic myxofibrosarcoma at our institution treated with gemcitabine-based therapy in the second-line setting, after progression on doxorubicin. Baseline clinical and baseline characteristics were collected. Primary endpoints were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: After progression on first-line doxorubicin, a partial, or complete radiological response was observed in four of seven patients who received gemcitabine-based chemotherapy. With a median follow-up of 14 months, median progression-free and overall survival were 8.5 months and 11.4 months, respectively. Conclusions: Gemcitabine-based chemotherapy was associated with encouraging response rates in this cohort, similar to those seen in UPS. Both entities could be studied together for novel gemcitabine-based regimens.

scholarly journals Clinicopathological study of soft tissue sarcoma-retrospective study of tertiary cancer institute in eastern India

2020 ◽  
Vol 8 (11) ◽  
pp. 4075
Author(s):  
Kunhi Mohammed K. P. ◽  
Snehasis Pradhan ◽  
Supratim Bhattacharyya ◽  
Prafulla Kumar Das ◽  
Muhammed Navas N. K.
Keyword(s):  
Retrospective Study ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Malignant Tumors ◽  
Soft Tissue Sarcomas ◽  
The Body ◽  
Female Ratio ◽  
Pleomorphic Sarcoma ◽  
Frequent Variety ◽  
Male To Female

Background: Soft tissue sarcomas are a rare and heterogeneous group of malignant tumors of mesenchymal origin that comprise less than 1 percent of all adult malignancies. Although they occur anywhere in the body, they involve most commonly in extremities, trunk, retroperitoneum and head and neck. The aim of the study was to analyze clinical and histopathological features of various soft tissue sarcomas.Methods: This was a retrospective study, conducted in tertiary cancer centre in Odisha during the period 2015 to 2018. We collected clinical parameters like age, sex, site of swelling, any associated pain and biopsy reports and these variables were correlated with final histopathology reports.Results: A total of 107 patients were included in the study, with male to female ratio of 2:1(71 and 36) and average age of 43.45 years. All of them presented with a swelling. The lower extremities were the most common sites i.e. 44.62%. Pleomorphic sarcoma was the most frequent histologic variety comprising 43% and less frequent variety were angiosarcoma, and myxoid sarcoma.Conclusions: Soft tissue sarcoma are predominant in males and middle aged population are frequently affected. Most common affected site is lower extremity and pleomorphic sarcoma is the prominent histologic type.

The Use of Adjuvant or Neoadjuvant Chemotherapy in Extremity and Truncal Sarcoma

2018 ◽  
Author(s):  
Robert J Canter
Keyword(s):  
Soft Tissue ◽  
Neoadjuvant Chemotherapy ◽  
Soft Tissue Sarcoma ◽  
Synovial Sarcoma ◽  
Distant Recurrence ◽  
Curative Intent ◽  
Pleomorphic Sarcoma ◽  
Level I ◽  
Meta Analyses ◽  
The Impact

Although neoadjuvant chemotherapy has been an established component of multimodality cancer care for patients with pediatric sarcomas for the past 25 years, the role of adjuvant or neoadjuvant chemotherapy in the management of adult patients with soft tissue sarcoma (STS) amenable to treatment with curative intent remains controversial. Overall, meta-analyses have revealed modest improvements in survival outcomes with the use of adjuvant or neoadjuvant chemotherapy, but individual trials have demonstrated inconsistent results leading some to question the robustness and external validity of the results. A recent randomized trial using anthracycline- and ifosfamide-based chemotherapy has provided further positive evidence in support of neoadjuvant chemotherapy for adult STS patients, but concerns persist regarding the risks of chemotherapy-related toxicities and the generalizability of the findings. Given the substantial risk of distant recurrence and disease-specific death for adult STS patients with tumors greater than 10 cm, especially those with synovial sarcoma and myxoid or round liposarcoma histologies, these patients should be strongly considered for neoadjuvant chemotherapy as part of a combined modality approach. The impact of recent level I data on the broader implementation of adjuvant or neoadjuvant chemotherapy in adult STS remains to be seen.  This review contains 5 figures and 34 references Key Words: chemotherapy, limb salvage, myxoid/round cell liposarcoma, multimodality therapy, soft tissue sarcoma, surgery, survival, synovial sarcoma, undifferentiated pleomorphic sarcoma  

scholarly journals A Clinicopathological Analysis of Soft Tissue Sarcoma with Telangiectatic Changes

Sarcoma ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Hiroshi Kobayashi ◽  
Keisuke Ae ◽  
Taisuke Tanizawa ◽  
Tabu Gokita ◽  
Noriko Motoi ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Tumor Size ◽  
Epithelioid Sarcoma ◽  
Needle Aspiration ◽  
Nerve Sheath Tumor ◽  
Subsequent Recovery ◽  
Pleomorphic Sarcoma ◽  
History Of ◽  
Mri Characteristics

Background. Soft tissue sarcoma with a hemorrhagic component that cannot be easily diagnosed by needle biopsy is defined here as soft tissue sarcoma with telangiectatic changes (STST).Methods. We retrospectively reviewed clinicopathological data of STST from 14 out of 784 patients (prevalence: 1.8%) with soft tissue sarcoma.Results. Tumors were found mostly in the lower leg. Histological diagnoses were undifferentiated pleomorphic sarcoma (n=5), synovial sarcoma (n=5), epithelioid sarcoma (n=2), and malignant peripheral nerve sheath tumor and fibrosarcoma (n=1). No history of trauma to the tumor site was recorded in any patient. Needle aspiration transiently reduced the tumor volume, but subsequent recovery of tumor size was observed in all cases. Out of 14 patients, 9 presented with a painful mass. MRI characteristics included intratumoral nodules (64.3%). The local recurrence rate was 14.3%, and the 2-year event-free survival rate was poorer (50%) than that of most sarcomas.Conclusions. STST is unique in its clinicopathological presentation. Painful hematomas without a trauma history, intratumoral nodules within a large hemorrhagic component, and subsequent recovery of tumor size after aspiration are indicative of the presence of STST.

Cancer immunotherapy using trabectedin and nivolumab in advanced soft tissue sarcoma: A retrospective analysis.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 40-40 ◽  
Author(s):  
Erlinda Maria Gordon ◽  
Kamalesh Kumar Sankhala ◽  
Nathan Stumpf ◽  
Joshua Ravicz ◽  
Suzan Arasheben ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Retrospective Analysis ◽  
Progression Free Survival ◽  
Myxoid Liposarcoma ◽  
Synergistic Activity ◽  
Advanced Soft Tissue Sarcoma ◽  
Efficacy Analysis ◽  
Pleomorphic Sarcoma ◽  
Grade 3

40 Background: To restore innate tumor surveillance that is lost in cancer patients, a tumoricidal agent may have synergistic activity with an immune checkpoint inhibitor. Herein, we report on a retrospective analysis of our clinical experience using trabectedin, an alkylating agent, and nivolumab, a PD-1 inhibitor in advanced soft tissue sarcoma. Methods: Twenty previously treated STS patients received trabectedin (1.5 mg/m2 continuous intravenous infusion, CIV, for 24 hours) every 3 weeks, and nivolumab (3 mg/kg IV over 30 minutes) every 2 weeks. Safety/toxicity was analyzed using the NIH/NCI CTCAE v.4.03. Tumor responses were assessed by RECIST v1.1 and immune-related response criteria (irRECIST). Results: Histologic subtypes in 20 patients include undifferentiated pleomorphic sarcoma (UPS; n = 7), leiomyosarcoma (n = 5), synovial sarcoma (n = 2), myxoid liposarcoma (n = 4) and chondrosarcoma (n = 2). All patients had metastatic disease and a median of 4 lines of prior chemotherapy. Safety analysis (n = 20): Grade 3 treatment emergent adverse events include anemia (n = 2), fatigue (n = 1), decreased platelet count (n = 1), decreased granulocyte count (n = 1) and increased creatine kinase (n = 1). Efficacy analysis (n = 17): Seventeen patients were followed for at least 6 months and their results are reported here. There were 4 partial responses (UPS = 1, myxoid liposarcoma = 1, chondrosarcoma = 1, leiomyosarcoma = 1), 7 stable disease, and 6 progressive disease, with best overall response rate of 23.5%, median progression free survival (PFS) of > 11.6 months (range: 2.3- > 16.9 months), median overall survival (OS) of > 14.2 months (4.5- > 24.0 months), 6 month PFS rate of 64.7%, and 6 month OS rate of 94.1%. In a Phase 3 study, the median PFS was 4.2 months using trabectedin alone (Demetri et al., 2015). Conclusions: Taken together, the data suggest that paired administration of trabectedin and nivolumab is safe, and that this chemo-/immuno-therapy approach has synergistic activity.

scholarly journals Identification and characterization of the cytosine-5 DNA methyltransferase gene family in Salvia miltiorrhiza

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4461 ◽  
Author(s):  
Jiang Li ◽  
Caili Li ◽  
Shanfa Lu
Keyword(s):  
Dna Methylation ◽  
Salicylic Acid ◽  
Gene Family ◽  
Sequence Alignment ◽  
Dna Methyltransferase ◽  
Epigenetic Modification ◽  
Salvia Miltiorrhiza ◽  
Dna Methyltransferases ◽  
Genome Wide ◽  
Wide Range

Cytosine DNA methylation is highly conserved epigenetic modification involved in a wide range of biological processes in eukaryotes. It was established and maintained by cytosine-5 DNA methyltransferases (C5-MTases) in plants. Through genome-wide identification, eight putative SmC5-MTase genes were identified from the genome of Salvia miltiorrhiza, a well-known traditional Chinese medicine material and an emerging model medicinal plant. Based on conserved domains and phylogenetic analysis, eight SmC5-MTase genes were divided into four subfamilies, including MET, CMT, DRM and DNMT2. Genome-wide comparative analysis of the C5-MTase gene family in S. miltiorrhiza and Arabidopsis thaliana, including gene structure, sequence features, sequence alignment and conserved motifs, was carried out. The results showed conservation and divergence of the members of each subfamily in plants. The length of SmC5-MTase open reading frames ranges widely from 1,152 (SmDNMT2) to 5,034 bp (SmMET1). The intron number of SmC5-MTases varies between 7 (SmDRM1) and 20 (SmCMT1 and SmCMT2b). These features were similar to their counterparts from Arabidopsis. Sequence alignment and conserved motif analysis showed the existence of highly conserved and subfamily-specific motifs in the C5-MTases analyzed. Differential transcript abundance was detected for SmC5-MTases, implying genome-wide variance of DNA methylation in different organs and tissues. Transcriptome-wide analysis showed that the transcript levels of all SmC5-MTase genes was slightly changed under yeast extract and methyl jasmonate treatments. Six SmC5-MTases, including SmMET1, SmCMT1, SmCMT2a, SmCMT2b, SmCMT3 and SmDRM1, were salicylic acid-responsive, suggesting the involvement of SmC5-MTases in salicylic acid-dependent immunity. These results provide useful information for demonstrating the role of DNA methylation in bioactive compound biosynthesis and Dao-di herb formation in medicinal plants.

Pazopanib in soft tissue sarcoma: Experience from a U.K. expanded-access program.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e21516-e21516
Author(s):  
Anna Maria Frezza ◽  
Charlotte Benson ◽  
Aisha Miah ◽  
Mark David Linch ◽  
Rolyn Alvarado ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Abdominal Cavity ◽  
Healing Process ◽  
Angiogenesis Inhibitor ◽  
Median Number ◽  
Undifferentiated Sarcoma ◽  
Expanded Access ◽  
Pleomorphic Sarcoma

e21516 Background: Pazopanib has been recently proven to be a valuable treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma (STS). We present our expanded-access experience to assess the safety and efficacy in routine clinical practice. Methods: Twenty-two patients were treated at 3 UK Sarcoma Centres between December 2011 and September 2012. Response was assessed according to RECIST 1.1 criteria and treatment toxicity graded. Results: Patients had a median age of 50 years (range-21-83), female (54%), 19 (86%) were metastatic. Primary sites were limb (27%), abdominal cavity (46%) and trunk (27%). Median number of previous chemotherapy lines was 2 and all patients were angiogenesis inhibitor naïve. Eighteen patients (82%) started pazopanib at 800 mg daily, 4 (18%) at 600 mg due to borderline PS. The most common side effects included fatigue (G1/2: 59%; G3/4: 9%), hypertension (G1/2: 5%, G3/4: 23%), liver function abnormalities (G1/2: 14%, G3/4: 9%) and diarrhoea (G1/2: 18%). Nine patients (41%) required a dose reduction and four (18%) discontinued the drug due to toxicity. One patient with metastatic pleomorphic sarcoma underwent RFA of the largest lung lesions and was started on pazopanib two weeks later. Despite achieving a partial response, pazopanib was discontinued due to the development of lung cavitation at the site of a previous RFA. Twenty-one patients were available for response evaluation. There were 7 (33%) partial responses (2 synovial sarcoma, 2 undifferentiated sarcoma, 1 fibromyxoid sarcoma, 1 fibromatosis and a 1 retroperitoneal leiomyosarcoma), 5 (24%) stable disease and 9 (43%) progressive disease. Clinical benefit rate (PR+SD) was 56%. Follow-up data were available for 18 patients. At a median follow-up of 25 weeks (range: 9-49), 8 patients (44%) were still alive and 5 (28%) were progression free. Median TTP was 11 weeks (95% CI 5.6-16.3). Conclusions: Pazopanib is effective in the treatment of STS progressing despite standard chemotherapy and has a manageable toxicity profile. However, due to its anti-angiogenic effect, it can interfere with the healing process and its use should be carefully considered in patients undergoing invasive procedures.

The Use of Adjuvant or Neoadjuvant Chemotherapy in Extremity and Truncal Sarcoma

2018 ◽  
Author(s):  
Robert J Canter
Keyword(s):  
Soft Tissue ◽  
Neoadjuvant Chemotherapy ◽  
Soft Tissue Sarcoma ◽  
Synovial Sarcoma ◽  
Distant Recurrence ◽  
Curative Intent ◽  
Pleomorphic Sarcoma ◽  
Level I ◽  
Meta Analyses ◽  
The Impact

Although neoadjuvant chemotherapy has been an established component of multimodality cancer care for patients with pediatric sarcomas for the past 25 years, the role of adjuvant or neoadjuvant chemotherapy in the management of adult patients with soft tissue sarcoma (STS) amenable to treatment with curative intent remains controversial. Overall, meta-analyses have revealed modest improvements in survival outcomes with the use of adjuvant or neoadjuvant chemotherapy, but individual trials have demonstrated inconsistent results leading some to question the robustness and external validity of the results. A recent randomized trial using anthracycline- and ifosfamide-based chemotherapy has provided further positive evidence in support of neoadjuvant chemotherapy for adult STS patients, but concerns persist regarding the risks of chemotherapy-related toxicities and the generalizability of the findings. Given the substantial risk of distant recurrence and disease-specific death for adult STS patients with tumors greater than 10 cm, especially those with synovial sarcoma and myxoid or round liposarcoma histologies, these patients should be strongly considered for neoadjuvant chemotherapy as part of a combined modality approach. The impact of recent level I data on the broader implementation of adjuvant or neoadjuvant chemotherapy in adult STS remains to be seen.  This review contains 5 figures and 34 references Key Words: chemotherapy, limb salvage, myxoid/round cell liposarcoma, multimodality therapy, soft tissue sarcoma, surgery, survival, synovial sarcoma, undifferentiated pleomorphic sarcoma  

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