Hemangiosarcoma Flashcards
Burton et al. Clinical outcome in 20 cases of lingual HSA in dogs: 1996-2011
Retrospective study of 20 dogs
What was median PFS and MST?
Grade of tumors and location?
2 prognostic factors associated with increased survival?
524 days (1.4 yr) and 533 days (1.5 yr)
Low to intermediate grade, ventral surface of tongue
Small tumor size and absence of clinical signs at time of diagnosis
Goritz et al. Canine splenic HSA: Influence of metastases, chemotherapy, and growth pattern on post-splenectomy survival and expression of angiogenic factors
Splenic HSA from 122 dogs
Most common growth pattern?
Survival time post-splenectomy was influenced by what factors?
IHC marker expression?
Cavernous, capillary, and solid tumor tissue
Chemotherapy and metastases but not growth pattern
Variable expression of angiogenic factors angiogenic factors (fetal liver kinase-1, angiopoetin 1, angiopoetin-2, and VEGFA) and endotherlial markers (factor VIII-related antigen, CD31) in undifferentiated tumors
Schappa et al. 2013. HSA and its cancer stem cell subpopulation are effectively killed by a toxin targeted through epidermal growth factor and urokinase receptors
EGFuPA-toxin, bispecific ligand-targeted toxin (BLT) consisteing of Pseudomanas exotoxin (PE) conjugated to EGF and urokinase, would kills cells derived from canine HSA
Results in HSA cell line? Concentration?
Showed cytotoxicity in 4 HSA cell lines (Emma, Frog, DD-1, and SB), <100nM and cytotoxicity was dependent on ligand receptor interactions
IC50 of CSCs (cancer stem cells) was higher by 2 orders as compared to non-CSC
Abou Asa et al. Analysis of genomic mutation and IHC of platelet derived growth factor receptors in canine vascular tumors
Examined whether mutation of PDFGR-A and PDGFR-B contribute to their overexpression in canine vascular tumors
Genomic sequences analyzed by IHC and PCR in 27 HSA and 20 HA (hemangiomas)
How many were positive by IHC in HA?
IHC staining in HSA?
Mutation in HA?
Mutation in HSA?
75% of HA were positive for PDGFR-A and all were negative for PDGFR-B
55.6% were negative PDGFR-A and 63% were positive for PDGFR-B
1 missense mutation PDGFR-A exon 18 and 1 in PDGFR-B exon 17
2 cases had missense mutation in exon 14 and 1 in exon 17 of PDGFR-B
genomic mutation of trans- or juxtamembrane regions of PDGFRs was not the main mechanism driving the activation of receptors in HA and HSA
Chikazawa et al 2013. Hyperferritinemia in dogs with splenic HSA
Measured serum ferritin using a sandwich ELISA assasy in 11 dogs with HSA, 6 hematomas, and 1 hemangioma, 3 LSA
Results in HSA?
Results in other cases?
Is it a sensitive test or specific test?
All dogs with HSA had serum ferritin concentration above normal limit (1357, 2x SD of normal)
Increased ferritin was noted in few cases of hematoma, hemangioma, and LSA
Not specific for splenic HSA but may be a sensitive test for the disease
Andersen et al. 2013. Pharmacologic inhibition of MEK signaling prevents growth of canine HSA
Primary cells isolated from HSA showed constitutive extracellular signal-regulated kinase (ERK) activation
MEK inhibitor Cl-1040 when used in vitro?
Sorafenib (inhibitor of B-raf and other multireceptor tyrosine kinase) activity on HSA-derived primary cells?
In vivo activity on cutaneous cell derived xenografts and cardiac derived tumorgrafts, Cl-40 ? Sorafenib?
In human angiosarcoma how many stained positive for phosphorylated ERK1/2 and expression of MEK-responsive TFs?
Reduced ERK activation and viability of primary cells derived from visceral, cutaneous, and cardiac HSA in vitro
Also sensitive to HSA-derived primary cells
Decreased the growth of cutaneous cell derived xenografts and cardiac derived tumorgrafts. Sorafenib also decreased both but more sensitive to cardiac tumorfradts
50% ans several were upregulated
Yamamoto et al. 2013. Epidemiological, clinical, and pathological features of primary cardiac HSA in dogs: a review of 51 cases
Tumors occured in what 3 dog breeds?
Location? Size of mass?
Echocardiographic detection rate? Cause
Survival time?
Most frequently golden retrievers, then Maltese and miniature daschunds
right auricle (25/51) and right atrium (21/51). Larger RA masses than right auricle masses.
RAu group (60%) lower than RA group (95%) - related to tumor size and/or location
Longer in dogs that got chemo after tumor resection
Motegi et al. 2013. Evaluation of anticancer effects and enhanced doxorubicin cytotoxicity of xanthine derivatives using canine HSA cell lines
Xanthine derivatives with or without DOX were administered to cells
What do methyxantines do?
What effect did caffeine and theophylline have? Expression of annexin V and caspase 3/7
What did they do with DOX? Hypoxanthine?
Increase cAMP and have diuretic, cardiac, and CNS stimulatory effects. Caffine inhibits tumor development.
Induced apoptosis, treated cells expressed annexin V and caspase 3/7
Both drugs enhanced DOX-induced cytotoxicity by inhibiting ATM/ATR kinases. Hypoxanthine showed no effect
Caffeine and theophylline have anti-cancer effects
Kahn et al. Doxorubicin and deraxocib adjuvant therapy for canine splenic HSA: a pilot study
21 dogs received adjuvant therapy following splenectomy
Overall MST?
Survival based on stage of disease?
150 days
No significant difference but dogs with stage II had MST 149 days, longer than previously reported
Alvarez et al. 2013. VAC protocol for treatment of dogs with Stage III HSA
67 dogs with HSA in different anatomic locations. VAC protocol as adjuvant to surgery (50), neoadjuvant (3) or as sole treatment (14)
Difference in MST for dogs with stage III and stage I/II?
For dogs presenting with splenic HSA alone, Difference in MST for dogs with stage III and stage I/II?
Overall response rate?
Toxicities?
No significant difference
No significant difference
86% (CR and PR)
None
Cagle et al. 2014. Diagnostic yield of cytologic analysis of pericardial effusion in Dogs
259 dogs with cytologic analysis of pericardial effusion performed
What % were diagnostic and non-diagnostic?
What % were hemorrhagic, neoplastic, infectious, other?
Overall cytologic analysis diagnostic utility? What caused this to increase?
Did echocardiographic evidence of mass increase diagnostic utility?
92.3% and 7.7%
hemorrhagic (90%), neoplastic (4.6%), infectious (3.1%), other (2.3%)
7.7% and increased to 20.3% if effusion Hct <10%
It did not
Fukuda et al. 2014. CT features of canine nonparenchymal HSA
Describe pre- and postcontrast CT characteristics in 17 dogs. 2 observers.
What were the CT features?
What was an unexpected finding in this study?
Similar to other STS with most tumors being heterogeneous in precontrast images, invasive into adjacent tissues and heterogenously contrast enhancing
13/17 (76%) had intense foci of contrast enhancement which is not consistent with STS - consistent with contrast medium residing in vascular channels
Gorden et al. 2014. Identification of the three molecular and functional subtypes in canine hemangiosarcoma through gene expression profiling and progenitor cell characterization
What were the 3 distinct tumor subtypes?
Cultured HSA cell under normal and sphere-forming culture conditions to enrich tumor cell progenitors
Cells from sphere-forming cultures exhibited what characteristics?
Angiogenesis (group 1), inflammation (2), and adipogenesis (3)
Self-renewal capacity and exhibited genotypic, phenotypic, and functional properties consistent with each of the 3 molecular subtypes seen in primary tumor inclusing expression of endothelial progenitor cell (CD133 and CD34) and endothelial cell (CD105, CD146, and avB3 integrin) markers, expression of early hematopoeitic (CD133, CD117, and CD34) and myeloid (CD115 and CD14) differentiation markers in paralele with increased phagocytic capacity, and acquisition of adipogenic potential
Results suggest canine HSA arise from multipotent progenitors that differentiate into distinct subtypes
Kim et al. 2014. Interleukin 8 promotes canine HSA growth by regulating the tumor microenvironment
What was the constitutive expression of IL-8 mRNA, protein, and receptor?
What happened after the addition of IL-8?
Did the addition of exogenous IL-8 or IL-8 Ab affect proliferation?
What were the IL-8 high cells enriched for?
Effects of IL-8 are direct or indirect?
Variable amoung different tumor samples and cell lines but showed steady state in each cell line
Transient intracellulat calcium influx, suggesting IL-8 receptors are functional and IL-8 binding activates signaling pathways
It did not
Genes associated with “reactive microenvironment” including activation of coagulation, inflammation, and fibrosis networks
Indirect, regulating interactions with microenvironment
IL-8 contributes to establishing a permissive microenvironment during the early stages of tumorigenesis in HSA
Halsey et al. The use of novel lymphatic endothelial cell-specific IHC markers to differentiate cutaneous angiosarcomas in dogs
Lymphangiosarcomas are uncommon vascular neoplasm that arise from?
F8RA and CD31 fail to differentiate between lymphangiosarcoma and HSA
What 2 markers can differentiate between the two?
lymphatic endothelial cells
Lymphatic vessel endothelial receptor-1 (LYVE-1) and prospero-related hemobox gene-1 (PROX-1)
Thomas et al. 2014. Genomic profiling reveals extensive heterogeneity in somatic DNA copy number aberrations of canine HSA.
Genome-wide microarray based somatic DNA copy number profiling of 75 primary intra-abdominal HSAs from 5 popular dog breeds
Exhibited ____ genomic instability compared to other canine sarcomas and DNA copy number were _____
What were the copy number aberrations?
CNAs involving what oncogenes?
What was different about Golden Retrievers?
limited, low amplitude
Copy number gains of dog chromosome 13, 24, and 31 and loss of chromosome 16
CDKN2A, VEGFA, SKI oncogene as potential driver aberrations
Twofold lower incidence of VEGFA gain versus other breeds (22 versus 40%)
Wirth et al. In vitro effects of Yunnan Baiyao on canine HSA cell lines
Evaluated in vitro effects of Yuanna Baiyao in 3 HSA cell lines with increasing concentrations at 24, 48, 72 hr
Results?
Yuannan Baiyao causes dose and time dependent HSA cell death through caspase-mediated apoptosis (caspase3/7 activity increased)
Clendaniel et el. 2014. Association between macroscopic appearance of liver lesions and liver histology in dogs with splenic HSA: 79 cases
79 dogs with splenic HSA
How many dogs with abnormal liver had HSA metastasis?
Dogs with grossly normal livers?
What gross lesions were associated with malignancy?
Performing biopsy in grossly normal liver was high or low yield?
50%
None
Multiple nodules, dark-colored nodules, and active bleeding nodules
Low-yield
Khammanivong et al. Identification of drug-resistant subpopulations in canine hemangiosarcoma?
Sphere cell populations contain distinct subpopulations of drug-resistant cells that utilize multiple mechanisms to evade cytotoxic drugs
Frenz et al. 2014. Serum vascular endothelial growth factor in dogs with HSA and hematomas
Investigate serum VEGF concentrations between dogs with splenic HSA and those with non-malignant splenic lesions and healthy subjects using canine ELISA
Results?
Utility?
Serum VEGF was significantly higher in dogs with splenic masses with healthy dogs but did not differ in dogs with HSA or hematomas
Utility as diagnostic marker for dogs with splenic lesions but does not differentiate among the
Finotello et al. Comparison of doxorubicin-cyclophosphamide with doxorubicin-dacarbazine for the adjuvant treatment of canine HSA
27 dogs and 18 were treated with AC and 9 with ADTIC
Median time to metastasis (DTTM) in ADTIC compared to AC?
Median survival time?
>550 days versus 112 days
>550 versus 142 days
Fukumoto et al. 2015. Big endothelin-1 as a tumor marker for canine hemangiosarcoma
Using serum big endothelin-1 as tumor markers for canine HSA. Measured in dogs with spleninc HSA (14), splenic malignant tumors (10), bening spleninc lesions (11), and normal healthy dogs (17)
Serum big ET-1 levels?
Sensitivity and specificity?
Utility?
Higher in dogs with HSA than in other dogs.
100% and 95% for HSA using a cutoff of 17 pg/ml
Could be used as a diagnostic marker
Gardner et al. Maintenance therapy with toceranib following doxorubicin-based chemotherapy for canine splenic hemangiosarcoma
43 dogs with stage I and II splenic HSA were given 5 cycles of DOX every 2 weeks within 14 days after splenectomy. Restaged 2 weeks later and started toceranib at 3.25 mg/kg EOD (31 dogs without mets).
Median DFI for all dogs (n=43)? MST?
Median DFI for dogs thay received toceranib (n=31)? MST?
138 days or 4.6 mo/169 days or 5.6 mo
161 days or 5.3 mo/172 days or 5.7 mo
Rodriguez et al. 2015. Association of Sphingosine-1-phosphate/SIP Receptor-1 pathway with cell proliferation and survival in canine HSA
SIP regulated cell growth and survival . 13 HSA tissues, 9 cell lines, 8 nonmalignant tissues, including 6 splenic hematomas and 2 livers with vacuolar degeneration and 1 endothelial cell line derived from dog with splenic HSA
mRNA expression?
Protein?
Exogenous SIP effect?
Treated with inhibitor of SIP1 (FTY720)?
Canine HSA cells expressed higher levels of mRNA than nonmalignant endothelial cells
SIP1 protein was present in HSA tissues and cell lines
Induced increase in intracellular Ca and increased proliferation and viability of HSA cells
Decreased SIP1 protein expression and induced apoptosis in HSA cells
Wong et al. 2015. Erythrocyte and Biochemical Abnormalities as Diagnostic Markers in Dogs with HSA Related Hemoabdomen
40 dogs with non-traumatic hemoabdomen
Erythocyte morphology in abdominal effusion or peripheral blood between dogs with HSA or non-HSA related hemoabdomen?
Platelet concentration and peripheral blood PCV?
No significant difference
Signiifcantly lower in HSA group
Wendelburg et al. 2015. Survival time of dogs with splenic HSA treated by splenectomy with or without adjuvant chemotherapy: 208 cases (2001-2012)
154 dogs treated with surgery alone and 54 treated with surgery and chemo. 28 received conventional chemo, 13 cyclophosphamide-based metronomic chemo, 13 got both conventional and metronomic.
MST of dogs treated with surgery alone?
Prognostic factor associated with survival time?
When the entire follow up period was considered was there a difference in survival?
During the first 4 months of follow-up was there a significant difference?
1.6 months
Clinical stage
No significant difference in survival between dogs treated with surgery alone and dogs treated with surgery and chemotherapy.
Survival time was prolonged for dogs receiving any type of chemotherapy (HR 0.6) and among dogs receiving both chemos (HR 0.4)
Anwar et al. Immunohistochemical detection of urokinase plasminogen activator and urokinase plasminogen activator receptor in canine vascular endothelial tumors
57 primary HSA and 26 cutaneous HAs
uPA expression in HSA and HA?
uPAR expression in HSA?
Expression of both molecules in HSA and cutanoeus HA?
Ki67 labeling index?
73.2% splenic HSA and 75% non-splenic HSAs
100%
Higher in HSAs than in cutaneous HAs (3.8% uPA and 30.7% for uPAR)
uPA+/uPAR+ was significantly higher than that of uPA-/uPAR+ HSA s and HA tissues
uPA and uPAR play significant role in malignant proliferation of canine HSA
Heishima et al. 2015. MicroRNA-214 promotes apoptosis in canine HSA by targeting the COP1-p53 Axis
miR-214 expression in cell lines and samples of canine HSA?
Restoration of miR-214 resulted in?
What was the target of miR-214?
miR-214 functions as?
What contributes to tumorigenesis of HSA?
Significantly downregulated
Apopotosis thorugh transcriptional activation of p53-regulated genes and slight inhibition in normal endothelial cells
COP1 - critical negative regulator of p53
Tumor suppressor gene by inducing apoptosis
miR-214 downregulation and COP1 overexpression
Im et al. Interactions between CXCR4 and CXCL12 promote cell migration and invasion of canine HSA
CXCR4/CXCL12 plays a role in locomotion and metastasis in many cancers
Transcriptome analysis of 12 HSA cell lines and 58 HSA tumor tissues - what was the expression of CXCR4 and CXCL12?
In vitro, CXCL12 causes?
Response to CXCR4 antagonist?
Heterogenous expression
calcium immobilazation, cell migration and invasion that were proportional to surface expression of CXCR4
Responses were decreased - CXCL12 causes migration and invasion of HSA
CXCR4/CXCL12 axis contributes to HSA progression
Adachi et al. 2016. Immunohistochemical detection of a potential molecular therapeutic target for canine HSA
Investigate the overexpression of PI3K/Akt/m-TOR proteins by IHC. 10 splenic HSA and 2 normal splenic samples
Expression of RTKs, c-kit, VEGFR-2, PDGFR-2 and PI3K/Akt/m-TOR and MEK?
Higher in canine splenic HSA compared to normal spleens
Jones et al. 2016. Association between dual-phase computed tomography features and histopathologic diagnoses in 52 dogs with hepatic or splenic masses
Pre- and postcontrast CT features
Hepatic masses?
Splenic HSA and nodular hyperplastic lesions? Splenic hematomas?
Substantial overlap of malignant and nonmalignant hepatic and splenic masses
Marked, generalized enhancement in early phase images that persisted in delayed phase
Marked generalized enhancement in early phase images that perisisted in delayed. Slight enhaceemnt in early phase
All splenic hematomas and 77% of HSA had contrast accumulation compatible with active hemorrhage
