scholarly journals Optimal Clinical Management and the Molecular Biology of Angiosarcomas

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3321
Author(s):  
Tom Wei-Wu Chen ◽  
Jessica Burns ◽  
Robin L. Jones ◽  
Paul H. Huang
Keyword(s):  
Clinical Management ◽  
Standard Treatment ◽  
Checkpoint Inhibitors ◽  
Soft Tissue Sarcomas ◽  
Phase 3 ◽  
Molecular Alterations ◽  
Molecular Features ◽  
Different Origins ◽  
Chronic Lymphedema ◽  
Secondary Angiosarcoma

Angiosarcomas comprise less than 3% of all soft tissue sarcomas but have a poor prognosis. Most angiosarcomas occur without obvious risk factors but secondary angiosarcoma could arise after radiotherapy or chronic lymphedema. Surgery remains the standard treatment for localized angiosarcoma but neoadjuvant systemic treatment may improve the curability. For advanced angiosarcoma, anthracyclines and taxanes are the main chemotherapy options. Anti-angiogenic agents have a substantial role but the failure of a randomized phase 3 trial of pazopanib with or without an anti-endoglin antibody brings a challenge to future trials in angiosarcomas. Immune checkpoint inhibitors as single agents or in combination with oncolytic virus may play an important role but the optimal duration remains to be investigated. We also report the current understanding of the molecular pathways involved in angiosarcoma pathogenesis including MYC amplification, activation of angiogenic pathways and different molecular alterations that are associated with angiosarcomas of different aetiology. The success of the patient-partnered Angiosarcoma Project (ASCProject) has provided not only detailed insights into the molecular features of angiosarcomas of different origins but also offers a template for future fruitful collaborations between patients, physicians, and researchers. Lastly, we provide our perspective of future developments in optimizing the clinical management of angiosarcomas.

scholarly journals Immunotherapy Strategies for Gastrointestinal Stromal Tumor

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3525
Author(s):  
Junaid Arshad ◽  
Philippos A. Costa ◽  
Priscila Barreto-Coelho ◽  
Brianna Nicole Valdes ◽  
Jonathan C. Trent
Keyword(s):  
Monoclonal Antibodies ◽  
Soft Tissue ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Soft Tissue Sarcomas ◽  
Standard Of Care ◽  
Current Standard ◽  
Molecular Alterations

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal soft tissue sarcoma of the gastrointestinal tract. The management of locally advanced or metastatic unresectable GIST involves detecting KIT, PDGFR, or other molecular alterations targeted by imatinib and other tyrosine kinase inhibitors. The role of immunotherapy in soft tissue sarcomas is growing fast due to multiple clinical and pre-clinical studies with no current standard of care. The potential therapies include cytokine-based therapy, immune checkpoint inhibitors, anti-KIT monoclonal antibodies, bi-specific monoclonal antibodies, and cell-based therapies. Here we provide a comprehensive review of the immunotherapeutic strategies for GIST.

RNAseq and DNA whole-exome sequence analysis reveal novel response signatures to IO treatment in muscle invasive bladder cancer (MIBC) patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4558-4558
Author(s):  
Gregory Mayhew ◽  
Yoichiro Shibata ◽  
Joshua M Uronis ◽  
Michele C Hayward ◽  
Tracy L Rose ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Clinical History ◽  
Rapid Progression ◽  
Ecog Performance Status ◽  
Molecular Alterations ◽  
Molecular Features ◽  
Panel Testing ◽  
Platinum Based Chemotherapy

4558 Background: Objective: To examine in a cohort of anti-PD-(L)1 immune checkpoint inhibitors (ICP) treated urothelial cancer patients a strategy combining treatment outcomes with molecular alterations, pathways, and immune/tumor microenvironment features to determine potential responder and rapid-progression signatures. Methods: De-identified clinical history and treatment outcomes were collected on 109 MIBC patients treated with ICP agents. Archived FFPE samples from these patients were obtained and processed for mRNAseq, exome-seq, tumor mutation burden (TMB), microsatellite instability (MSI) and mutation panel testing. Comprehensive tumor/immune profiling is being analyzed in the context of ICP treatments and RECIST 1.1 outcomes. A 60 gene MIBC 4-typer expression subtyper and other response associated predictors are used to stratify and identify positive/negative ICP response indicators. Results: 109 patients were identified (median age 75, 64% male, 78% white, 17% black). 74% of patients had received prior platinum-based chemotherapy, and 12% had received 2 or more prior lines of therapy. At initiation of ICP, 28% of patients had hemoglobin < 10, 30% had liver metastases, and 59% had ECOG performance status > 0. Mutation analysis of the first 66 patients showed TP53 (n = 34, 52%), FGFR (n = 17, 26%), CDKN2A (n = 13, 20%) and RB1 (n = 12, 18%) as the top alterations. No patients (0/8) with known pathogenic mutations in FGFR3 (S249C and TACC3-fusion) responded to ICP. Of patients with T2 staging prior to ICP (37/66), overall survival was markedly shorter (2.7 years) in those possessing FGFR3 mutations (n = 6/37) compared to that for FGFR3 WT patients (5.7 years, n = 31/37; p = 0.045). Further analyses of molecular features relative to treatment outcomes are ongoing to characterize response signatures. Conclusions: Our preliminary cohort of patients with pathogenic FGFR3 alterations showed 0% favorable response to ICP. We are expanding on this observation with further comprehensive molecular analyses and retrospective treatments/outcomes data. We anticipate identifying expression signatures that reflect ICP patient responder/non-responder signatures that may aid in future therapy decisions.

Radiation-Associated Angiosarcoma of the Breast: Clinical and Pathologic Features

2016 ◽  
Vol 140 (5) ◽  
pp. 477-481 ◽  
Author(s):  
Saira Shah ◽  
Marilin Rosa
Keyword(s):  
Standard Treatment ◽  
Early Stage ◽  
Soft Tissue Sarcomas ◽  
Breast Cancer Patients ◽  
Breast Parenchyma ◽  
Pathologic Features ◽  
Angiosarcoma Of The Breast ◽  
Secondary Form ◽  
Secondary Angiosarcoma ◽  
Primary Form

Breast angiosarcoma is an unusual malignancy accounting for approximately 1% of soft tissue sarcomas. It can occur as a primary form without a known precursor or as a secondary form associated with radiotherapy. Adjuvant radiotherapy has a significant role in preventing local recurrence in women treated with conservation therapy for early stage breast carcinoma or multicentric tumors. Postradiation angiosarcoma usually affects the dermis of the breast within the radiation field and may occasionally develop in the breast parenchyma. Compared with the latency of other radiation-associated sarcomas, the latency for breast radiation-associated angiosarcoma is relatively short with a median of 6 years. The risk of developing secondary angiosarcoma does not outweigh the benefit of treatment; therefore, radiation therapy continues to be a mainstay modality in the treatment of breast cancer patients. Early detection is essential because angiosarcomas are associated with a poor prognosis. Wide surgical resection is the standard treatment for these tumors.

Predictive and prognostic biomarkers with therapeutic targets in colorectal cancer: A 2021 update on current development, evidence, and recommendation

2021 ◽  
pp. 107815522110055
Author(s):  
Clement Chung
Keyword(s):  
Checkpoint Inhibitors ◽  
Therapeutic Targets ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Tumor Location ◽  
Prognostic Biomarkers ◽  
Her2 Gene ◽  
Braf Mutations ◽  
Therapeutic Implications ◽  
Molecular Alterations

Although therapeutically actionable molecular alterations are widely distributed across many cancer types, only a handful of them show evidence of clinical utility and are recommended for routine clinical practice in the management of cancers of colon and rectum (CRC). This 2021 update aims to provide a succinct summary on the use of prognostic and/or predictive biomarkers (expanded RAS, BRAF, microsatellite-high [MSI-H] or deficient mismatch repair [dMMR], neurotrophic tyrosine receptor kinase [ NTRK] fusion genes, and human epidermal growth factor receptor type II [ HER2] gene amplification) associated with CRC. Therapeutic implications of each relevant predictive or prognostic biomarker for patients with CRC are described, along with discussion on new developments on (1) biomarker-driven therapies such as testing of BRAF, MLH1 promoter methylation and MMR germline genes in differentiating sporadic CRC or hereditary conditions such as Lynch syndrome; (2) first-line use of immune checkpoint inhibitors in metastatic CRC; (3) risk stratification and therapy selection based on primary tumor location (left-sided vs. right-sided colon cancer); (3) atypical BRAF mutations; (4) use of EGFR directed therapy in the perioperative oligometastatic disease setting; (5) re-challenge of EGFR directed therapy and (6) personalizing therapy of fluoropyrimidine and irinotecan based on new evidence in pharmacogenomic testing. Data are collected and analyzed from available systematic reviews and meta-analyses of treatments with known therapeutic targets in CRC, which may be associated with predictive and/or prognostic biomarkers. Discussions are presented in an application-based format, with goal to empower pharmacists or other clinicians to gain awareness and understanding in biomarker-driven cancer therapy issues.

scholarly journals Hypoplastic Myelodysplastic Syndromes: Just an Overlap Syndrome?

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 132
Author(s):  
Bruno Fattizzo ◽  
Fabio Serpenti ◽  
Wilma Barcellini ◽  
Chiara Caprioli
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Clonal Selection ◽  
Cytotoxic T Cells ◽  
Immunosuppressive Treatment ◽  
Young Patients ◽  
Suppressor Cells ◽  
Molecular Alterations ◽  
Molecular Features ◽  
Increased Risk

Myelodysplasias with hypocellular bone marrow (hMDS) represent about 10–15% of MDS and are defined by reduced bone marrow cellularity (i.e., <25% or an inappropriately reduced cellularity for their age in young patients). Their diagnosis is still an object of debate and has not been clearly established in the recent WHO classification. Clinical and morphological overlaps with both normo/hypercellular MDS and aplastic anemia include cytopenias, the presence of marrow hypocellularity and dysplasia, and cytogenetic and molecular alterations. Activation of the immune system against the hematopoietic precursors, typical of aplastic anemia, is reckoned even in hMDS and may account for the response to immunosuppressive treatment. Finally, the hMDS outcome seems more favorable than that of normo/hypercellular MDS patients. In this review, we analyze the available literature on hMDS, focusing on clinical, immunological, and molecular features. We show that hMDS pathogenesis and clinical presentation are peculiar, albeit in-between aplastic anemia (AA) and normo/hypercellular MDS. Two different hMDS phenotypes may be encountered: one featured by inflammation and immune activation, with increased cytotoxic T cells, increased T and B regulatory cells, and better response to immunosuppression; and the other, resembling MDS, where T and B regulatory/suppressor cells prevail, leading to genetic clonal selection and an increased risk of leukemic evolution. The identification of the prevailing hMDS phenotype might assist treatment choice, inform prognosis, and suggest personalized monitoring.

scholarly journals NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1561
Author(s):  
Haitang Yang ◽  
Sean R. R. Hall ◽  
Beibei Sun ◽  
Liang Zhao ◽  
Yanyun Gao ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Checkpoint Inhibitors ◽  
Cancer Cell Line ◽  
Cell Mediated Immunity ◽  
Pleural Mesothelioma ◽  
Precision Oncology ◽  
Hippo Signaling ◽  
Loss Of Function ◽  
Cell Viability Assay ◽  
Molecular Features

(1) Inactivation of the tumor suppressor NF2 is believed to play a major role in the pathogenesis of malignant pleural mesothelioma (MPM) by deregulating the Hippo-YAP signaling pathway. However, NF2 has functions beyond regulation of the Hippo pathway, raising the possibility that NF2 contributes to MPM via Hippo-independent mechanisms. (2) We performed weighted gene co-expression analysis (WGCNA) in transcriptomic and proteomic datasets obtained from The Cancer Gene Atlas (TCGA) MPM cohort to identify clusters of co-expressed genes highly correlated with NF2 and phospho (p)-YAP protein, surrogate markers of active Hippo signaling and YAP inactivation. The potential targets are experimentally validated using a cell viability assay. (3) MPM tumors with NF2 loss-of-function are not associated with changes in p-YAP level nor YAP/TAZ activity score, but are characterized by a deficient B-cell receptor (BCR) signaling pathway. Conversely, MPM tumors with YAP activation display exhausted CD8 T-cell-mediated immunity together with significantly upregulated PD-L1, which is validated in an independent MPM cohort, suggesting a potential benefit of immune-checkpoint inhibitors (ICI) in this patient subset. In support of this, mutations in core Hippo signaling components including LATS2, but not NF2, are independently associated with better overall survival in response to ICI in patients. Additionally, based on cancer cell line models, we show that MPM cells with a high Hippo-YAP activity are particularly sensitive to inhibitors of BCR-ABL/SRC, stratifying a unique MPM patient subset that may benefit from BCR-ABL/SRC therapies. Furthermore, we observe that NF2 physically interacts with a considerable number of proteins that are not involved in the canonical Hippo-YAP pathway, providing a possible explanation for its Hippo-independent role in MPM. Finally, survival analyses show that YAP/TAZ scores together with p-YAP protein level, but not NF2, predict the prognosis of MPM patients. (4) NF2 loss-of-function and dysregulated Hippo-YAP pathway define distinct MPM subsets that differ in their molecular features and prognosis, which has important clinical implications for precision oncology in MPM patients.

scholarly journals Immunological Backbone of Uveal Melanoma: Is There a Rationale for Immunotherapy?

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1055 ◽  
Author(s):  
Ernesto Rossi ◽  
Giovanni Schinzari ◽  
Ilaria Grazia Zizzari ◽  
Brigida Anna Maiorano ◽  
Monica Maria Pagliara ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Uveal Melanoma ◽  
Clinical Benefit ◽  
Standard Treatment ◽  
Checkpoint Inhibitors ◽  
Phase Iii ◽  
Phase Iii Clinical Trials

No standard treatment has been established for metastatic uveal melanoma (mUM). Immunotherapy is commonly used for this disease even though UM has not been included in phase III clinical trials with checkpoint inhibitors. Unfortunately, only a minority of patients obtain a clinical benefit with immunotherapy. The immunological features of mUM were reviewed in order to understand if immunotherapy could still play a role for this disease.

scholarly journals Molecular Determinants of Soft Tissue Sarcoma Immunity: Targets for Immune Intervention

2021 ◽  
Vol 22 (14) ◽  
pp. 7518
Author(s):  
Marcella Tazzari ◽  
Laura Bergamaschi ◽  
Alessandro De Vita ◽  
Paola Collini ◽  
Marta Barisella ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Malignant Tumors ◽  
Soft Tissue Sarcomas ◽  
Point Of View ◽  
Molecular Features ◽  
Molecular Determinants ◽  
Genetic Landscape ◽  
Current Therapies ◽  
Cumulative Evidence

Soft tissue sarcomas (STSs) are a family of rare malignant tumors encompassing more than 80 histologies. Current therapies for metastatic STS, a condition that affects roughly half of patients, have limited efficacy, making innovative therapeutic strategies urgently needed. From a molecular point of view, STSs can be classified as translocation-related and those with a heavily rearranged genotype. Although only the latter display an increased mutational burden, molecular profiles suggestive of an “immune hot” tumor microenvironment are observed across STS histologies, and response to immunotherapy has been reported in both translocation-related and genetic complex STSs. These data reinforce the notion that immunity in STSs is multifaceted and influenced by both genetic and epigenetic determinants. Cumulative evidence indicates that a fine characterization of STSs at different levels is required to identify biomarkers predictive of immunotherapy response and to discover targetable pathways to switch on the immune sensitivity of “immune cold” tumors. In this review, we will summarize recent findings on the interplay between genetic landscape, molecular profiling and immunity in STSs. Immunological and molecular features will be discussed for their prognostic value in selected STS histologies. Finally, the local and systemic immunomodulatory effects of the targeted drugs imatinib and sunitinib will be discussed.

Molecular determinants of therapy response of venetoclax-based combinations in acute myeloid leukemia

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Philipp Makowka ◽  
Verena Stolp ◽  
Karoline Stoschek ◽  
Hubert Serve
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Therapy Response ◽  
Secondary Resistance ◽  
Molecular Alterations ◽  
Molecular Features ◽  
Slow Progress ◽  
Molecular Aberrations ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous, highly malignant disease of the bone marrow. After decades of slow progress, recent years saw a surge of novel agents for its treatment. The most recent advancement is the registration of the Bcl-2 inhibitor ventoclax in combination with a hypomethylating agent (HMA) in the US and Europe for AML patients not eligible for intensive chemotherapy. Treatment of newly diagnosed AML patients with this combination results in remission rates that so far could only be achieved with intensive treatment. However, not all AML patients respond equally well, and some patients relapse early, while other patients experience longer periods of complete remission. A hallmark of AML is its remarkable genetic, molecular and clinical heterogeneity. Here, we review the current knowledge about molecular features of AML that help estimate the probability of response to venetoclax-containing therapies. In contrast to other newly developed AML therapies that target specific recurrent molecular alterations, it seems so far that responses are not specific for a certain subgroup. One exception is spliceosome mutations, where good response has been observed in clinical trials with venetoclax/azacitidine. These mutations are rather associated with a more unfavorable outcome with chemotherapy. In summary, venetoclax in combination with hypomethylating agents represents a significant novel option for AML patients with various molecular aberrations. Mechanisms of primary and secondary resistance seem to overlap with those towards chemotherapy.

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