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
Finotello et al. A retropsective analysis of chemotherapy switch suggests improved outcome in surgically removed, biologically aggressive canine HSA
Metronomic chemotherapy (MC) preceded by adjuvant DOX-bases MTDC was compared with MTDC
12 dogs received MTDC and 10 received MC after
Median TTM and ST
Significantly longer for dogs receiving MTDC-MC (not reached vs. 150 days and not reached vs. 168 days)
Cleveland et al. 2016. Incidence of malignant and outcomes for dogs undergoing splectomy for incidentally detected nonruptured splenic nodules or masses: 105 cases (2009-2013)
How many had benign vs. malignant lesions? Most common?
Hazard of death decreased as?
What was associated with increased hazard of death?
Median life expectancy of dogs with benign and malignant lesions?
Median life expectancy of dogs with HSA?
70.5% benign and 29.5% malignant lesions, most commonly HSA (58%)
Preoperative PCV increased
Histopathological diganosis of malignant neoplasia
436 (14.5 mo) and 110 days (4 mo)
132 days (4 mo)
Sherwood et al. 2016. Occurrence and clinicopathologic features of splenic neoplasia based on body weight: 325 dogs (2003-2013)
Cutoff of 27.8kg anhd had two groups in study
Malignancy diagnosed in how many? difference between small and large?
How many of splenic masses were HSA?
Was the diagnosis of HSA, non-HSA mlaignancy, or benign splenic disease different between the groups?
HSA comprised what %
Dogs with HSA were likely to have?
58%, no difference between small (55%) and large (61%)
32% - 25 and 39% of all masses in small and large dogs
Yes
46 and 65% of small and large dogs
preoperative anemia, hemoabdomen, thrombocytopenia, and blood trasnfusion compared to dogs with non-HSA malignancy or benign lesions
Dogs had similar odds of having malignant lesions regardless of weight, but dogs <27.8kg were less likely to be diagnosed with HSA
Anwar et al. Overexpression of peroxiredoxin 6 protects neoplastic cells against apoptosis in canine HSA
PRDX family of peroxidases, comprises 6 members in mammals (PRDX 1-6) might contribute to cancer cell survival in the face of oxidative stress as these proteins are frequently upregulated in cancer cells
Expression levels of PRDX 6 in canine HSA by IHC
What was the expression of PRDX6 mRNA and protein?
What did small interfering RNA-induced downregulation of PRDX6 do?
Both increased in HSA cell lines compared to normal canine endothelial cells with variations among the cell lines
Apoptosis in HSA cell lines
PRDX6 might play a cytoprotective role
Adachi et al. 2016. Effects of inhibitors of vascular endothelial growth factor receptor 2 and downstream of receptor tyrosine kinases involving PI3K/Akt/mammalian target of rapamycin or mitogen-activated protein kinase in canine HSA cell lines
What effect did the inhitors of MAPK have?
What reduced cell viability?
Reduce proliferation by inducing?
No affect on canine HSA cell viability
Inhibitors of VEGFR2 and PI3k/Akt/m-TOR pathway - induced apoptosis
These inhibitors reduce the proliferation of canine HSA cells by inducing apoptosis
Chen et al. Identification of the two KIT isoforms and their expression status in canine HSA
IHC staining confirmed KIT expression in what % of HSA? HA?
Sequencing of c-kit gene revealed?
94.4% (34/36) and 0% HA (0/16)
GNSK deletion in exon 9
GNSK-deletion c-kit accounted for 48.6% colonies amplified from 12 KIT-positive HSA, a significantly higher frequency than 14.1% of colonies amplified from 6 normal canine cerebellums
Patten et al. 2016. Outcome and prognostic factors for dogs with histological diagnosis of splenic hematoma following splenectomy: 35 cases
Overall MST
List the 3 statistically significant variable?
What % had metastasis?
647 days (1.8 yr)
Palpable abdominal mass, subclinical coagulopathy, and metastasis
4 cases (11%)
Prognosis is excellent but small cases may have an undiagnoses malignant component
Chan et al. Primary nodal HSA in four dogs
All dogs had surgery followed by adjuvant chemotherapy - 2 got curative intent chemo, 1 metronomic with CTX, and 1 metronomic with chlorambucil
Survival time?
259 days in 1 dog, 3 were alive at 615, 399, and 365
Regan et al. Role of monocyte recruitement in HSA metastasis in dogs
IHC used to quantify CD18+ monocytes compared with metastases from other tumor types
HSA produced what?
HSA cells were the highest producers of monocyte chemokine CCL2 and stimulated canine monocyte migration in a CCL2 dependent manner
Grimes et al. 2016. A comparison of microRNA expressio profiles from splenic HSA, splenic nodular hyperplasia, and normal spleen of dogs
How many miRNAS were found?
22 differentially expressed in HSA samples (4 between HSA and both nodular hyperplasia and normal spleen and 18 between HSA and normal spleen only).
miR-26a, miR-126, miR-139, miR-140, miR-150, miR-203, miR-424, miR-505, miR-30e, miR-33b, mir-365, mir-758, mir-22, mir-452 are of interest in pathogenesis of HSA
Witter et al. 2017. Evaluation of procoagulant tissue factor expression in canine HSA cell lines
What was the expression of TF in 4 canine HSA cell lines?
A greater percentage of ___ cells expressed TF antigen
All cell lines generated signifcantly more ____ than did CnAoEC
Thrombin generaion by SB-HSA was unaffected by addition of corn trypsin inhibitor
All expressed mRNA and antigen, signifcantly greater expression of both in SB-HSA and Emma cells than in CnAoEC
SB-HSA
Thrombin
Thrombin generation induced byu SB-HSA cells was signifcantly lower in factor-VII deficient plasma than in factor-replete plasam and was abolished in fac tor-X deficent plasma
Borgatti et al. 2017. Safe and effective sarcoma therapy through bispecific targeting of EGFR and uPAR
eBAT improved 6 month survival from <40% in a comparison population to approximately 70% in dogs treated at biologically active dose (50ug/kg)
6 dogs were long term survivros >450 days
Borgatti et al. 2017. Evaluation of FDG positron emission tomography/computed tomography as staging and monitoring tool for dogs with stage 2 splenic HSA - A pilot study
9 dogs underwent 18FDG-PET-CT following splenectomy and prior to starting chemo
Pet-CT was repeated in 3 dogs at Day 21 and noted?
Right atrial mass and hepatic nodule which were larger and had higher metabolic activity on second scan
Corbin et al. 2017. Splenomegaly in small breed dogs: 45 cases (2005-2011)
21 dogs had malignant neoplasia and 24 had benign splenic disease
What was the most common malignancy? Most common benign disease?
Breed most likely to have malignant splenic disease than other breeds? Association with hemoperitoneum?
What 2 factors had negative association with survival time?
What was not associated with presence of hemorpitoneum?
HSA (67% 14/21). Lymphoid hyperplasia, hematoma, or EMH (71%)
Wheaton terriers. Was not associated with hemoperitonerum
Malignant splenic disease and hemoperitoneum
Malignant disease
Moore et al. 2017. Evaluation of clinical and histologic factors associayed with survival time in dogs with stage II splenic HSA treated by splenectomy and adjuvant chemotherapy: 30 cases (2011-2014)
30 dogs with stage II HSA
MST for dogs? 1 year survival rate?
On multivariable analysis what was associated with survival time?
MST with mitotic score of 0 (<11 mitoses/10 hpf)? 1 year survival rate?
158 days (5.3 mo), 16%
Mitotic score
292 days (~10 mo) and 1 year survival rate of 42%
Matsuyama et al. 2017. Adjuvant doxorubicin with or without metronomic cyclophosphamide for canine splenic HSA
33 dogs with splenic HSA tx with surgery followed by adjuvant DOX with or without low-dose metronomic cyclophosphamide maintenance therapy
Median PFS and OS?
What 2 factors were prognostic for PFS?
Difference in PFS or OS with addition of metronomic?
125 days and 133 days
Clinical stage and tumor burden
None
Addition of metronomic chemo is not recommended
Wang et al. 2017. Actionable mutations in canine HSA
Sequence analysis of 20 samples identified mutation in?
PIK3CA, PTEN, TP53, PLCG1 - all drivers in human cancers
Bray et al. 2017. Does thalidomide prolong survival in dogs with splenic HSA?
15 dogs received thalidomide until death (following splenectomy)
MST for dogs receiving thalidomide?
Difference in stage of disease?
How did dogs die?
172 days, 5 dogs (33%) survived more than a year after surgery
Dogs with stage 2 survived longer than dogs with stage 3 (303 vs 40 days)
13 (87%) died of metastatic HSA
Carlson et al. 2017. Anticancer effects of resveratrol in canine HSA cell lines
Resveratrol has strong anti-proliferative and proapoptotic properties in human cancer cell lines
Results in canine HSA cell lines?
Activated what?
Inhibited growth and induced apoptosis in Frog and DD-1 cell lines
p38 MAPK but did not affect the AMPK or ERK1/2 pathways
Ciepluch et al. 2017. Removal of HSA cells from canine blood with a cell salvage system and leukocyte reduction filter
Whole blood from 3 healthy dogs combined with cultured HSA cells
Intraoperative cell salvage system (IOCS) combined with leukocyte reduction filter results?
Able to remove HSA cells from canine blood
Alternatiove to allogeneic blood transfusion in dogs with hemoabdomen
Roof-Wages et al. Histology and clinical outcome of benign and malignant vascular lesions primary to feline cervical lymph nodes
16 cases of feline lymphadenopathy attributed to abnormal vascular proliferation were identified and evaluated.
Lesions diagnosed as?
Mean age of cats? Breeds?
Survival time?
HSA
11 years. DSH and DMH
<1 month to > 30 months
Differential for cervial lymphadenopathy in cats not widely recognized
Sloan et al. 2018. In vitro effects of doxorubicin and tetrathiomolybdate on canine HSA cells
Exposure of cells to TM and DOX resulted in?
Treatment increased what?
Ascorbic acid did what?
Greater decrease in proliferation and clonogenic survival rates than exposure to each drug alone
ROS formation and apoptosis than with each drug alone
Inhibited both TM-iunduced ROS formation and apoptosis
Alexander et al. 2018. The addition of metronomic chemotherapy does not improve outcome for splenic HSA
Group 1 - dogs underwent splenectomy followed by adjuvant MTD anthracycline, cytoxan, or both
Group 2 - dogs underwent splenectomy followed by adjuvant MTD anthracycline, cytoxan, or both, plus metronomic chemotherapy
Median PFS and Median OS for group 1?
Median PFS and Median OS for group 2?
Overall survival in dogs that received MTD cyclophosphamide?
165 days (5.5 mo) and 180 days (6 mo)
185 days (6 mo) and 212 days (7 mo)
Both groups was shorter
Aoshima et al. 2018. Notch2 signal is required for the maintenance of canine HSA cancer stem cell-like cells
Notch2 signal was upregulated in CSC-like cells and Notch signal inhibition by a g-secretase inhibitor signifcantly represses their growth
Notch2 was highly expresses in CSC-like cells
Notch2 is important in maintaining HSA CSC-like cells
Histopathologic characteristics of biopsies from dogs undergoing splenectomy with concurrent gross splenic and hepatic masses: 125 cases (2012-2016)
What percent had malignancy in liver or spleen?
What % had malignancy in spleena and liver? How may had the same malignany in both?
What % of dogs with concurrent gross splenic and liver masses discovered intraoperatively had benign lesions in both locations
27%
48%, 93.3%
27%
Fleming et al. Anatomic site and etiology of hemorrhage in small versus larger dogs with spontaneous hemoperitoneum
Splenic hemorrhage in small and large dogs?
Prevelance of hemorrhage from spleen and liver in small dogs?
Hemangiosarcoma was associated with ___ and occured more frequently in ___?
43.2% and 61.3%
Lower prevalence from spleen and higher prevalence from liver
splenic hemorrhage, large vs. small dogs
Ciepluch et al. 2018. Long-term postoperative effects of administration of allogeneic blood products in 104 dogs with HSA
Median DFI in dogs that received blood trasnfusion than in dogs that did not?
In the multivariable Cox regression model, what shortened DFI? what prolonged DFI?
76 days versus 120 days
Administration of blood products and presence of gross metastatic disease. Administration of yunnan baiyao
Mayhew et al. 2018. Complications and short term outcomes assocaited with single-port laproscopic splenectomy in dogs
22 dogs
Median maximal diameter of the largest splenic mass?
Conversion occured in how many cases?
Reasons for conversion?
What was associated with conversion? What factors were not?
2.0 cm
6/22 (27%)
large splenic dimensions (3), adhesion formation (1), poor visualization from intrabdominal fat (1), or hemorrhage (1)
Heavier body weight. BCS, having splenic mass, splenic mass size, and surgical time
Regan et al. 2017. Role of monocyte recruitement in HSA metastasis in dogs
HSA cells were the highest producers of monocyte chemokine CCL2 and stimulated monocyte migration in a CCL2 dependent manner
May expain aggressive nature of canine HSA
Therapies to block monocyte recruitement may be an effective treatment strategy for suppressing HSA metastasis
Reckelhoff et al. 2018. In vitro effects of the chemotherapy agent water soluble micellar paclitaxel on canine HSA cell line
Paccal Vet caused what in HSA cell lines?
What is the IC50?
Cell cycle analysis through flow cytometry showed?
Annexin V and caspace 3/7 assays showed?
Cell death in dose and time dependent manner
7-610 ng/ml
arrest in G2/M phase
increase in apoptosis in correlation with IC50
Tanaka et al. 2019. Contrast enhanced CT findings of canine primary renal tumors inclusing renal cell carcinoma, lymphoma, and HSA
15 dogs met criteria - 9 RCC, 4 LSA, 2 HSA
RCC?
Renal LSA?
Renal HSA?
Showed heterogeneous enhancement and unilateral renal involvement and vessel enhancement was noted in corticomedullary phase in dog
Homogenoeus enhancement, bilateral renal involvement, and multiple masses - no vessel enhancement was noted in corticomedullary phase, incidence of lymphadenopathy was low
Heterogeneous enhancement with non-enhanced area and unilateral renal involvement - vessel enhancement was detected in the nephrogenic phase with enhancement expanding around the vessel
No significant difference
Dongaonkar et al. 2019. Partial splenectomy for incidentally detected non-ruptured splenic lesions in dogs: 18 cases (2004-2018)
Incidence of splenic malignancy?
Median diameter of splenic nodules?
Splenic HSA in 1 dog and 17 had benign lesions
Overall MST after surgery?
MST in dogs with malignant disease and nonmalignant disease?
Partial splenectomy appropriate for?
5.6%
2 cm
300 days
67 days and 727 days
small, incidental non-ruptured splenic lesions in dogs
Treggiari et al. 2019. Retrospective comparison of first-line adjuvant anthracycline vs. metronomic based chemotherapy protocols in the treatment of stage I and stage II canine splenic HSA
93 dogs in study: 50 in AC group (anthracycline), 23 in AMC (treated with MC following AC), and 20 MC group
Overall MST? Overall TTP?
Median TTP of stage I dogs compated to stage II?
MST for AC, AMC, and MC group?
200 days (6.7 mo), 185 days (6.0 mo)
Significantly longer 338 (11 mo) vs. 151 days (5 mo)
154 days, 338 days, 225 days
Difference was not statistically significant between groups
Study suggest adjuvant MC may result in similar outcome when compared to other treatment protocols
Morita et al. 2019. High drug efflux pump capacity and low DNA damage response induce doxorubicin resistance in canine HSA cell lines
Cell lines exposed to DOX at gradually increasing doses. When cells grow in 16x higher conc. designated DR-HSA cell lines.
Characterization of DR-HSA cell lines revealed?
Higher drug efflux pump capacity compared to parenteral cell lines
Did not show activation of DNA damage response, apoptosis was not induced
Megguier et al. 2019. Comparative genomics reveal shared mutational landscape in canine HSA and human angiosarcoma
47 golden retreiver HSA and RNA sequencing (74 HSA from multiple breeds)
Somatic coding mutation frquently occured in?
Predominant mutational signature?
Tumor suppressor TP53 (60%) and PI3K pathway: the ocogen PIK3CA (30%) and PIK3R1 (8.5%)
Age associated deamination of cytosine to thymine
AS reported in humans, CDKN2A/B was recurrently deleted and VEGFA, KDR, and KIT recurrently gained
Herman et al. 2019. Understanding the efficiency of splenic HSA diagnosis using monte carlo simulations
Simulations suggest?
Recommendations?
examination of 5 sections from spleen with HSA yields 95% chance of diagnosing HSA while examination of 10 sections yields 99% chance of diagnosis
Submit entire spleen and examine 5 sections by a trained individul are likely sufficient for diagnosis
Marconato et al. Adjuvant anthracycline based vs. metronomic chemotherapy to no medical treatment for dogs with metastatic splenic HSA
103 dogs: 23 adjuvant MTD, 38 MC, and 42 were not treated (Stage III disease)
Overall TTP and ST?
Which dogs had significantly longer TTP and ST?
Dogs treated with splenectomy alone TTP and ST?
Treatment related AEs?
50 and 55 days
Adjuvant MTD compared with dogs treated with MC (134 vs 52 days)
28 days and 40 days
Highest in MTD group
O’Byrne et al. 2019. Splenic mass diagnosis in dogs undergoing splenectomy according to breed size
54 small, 139 medium, 41 large breed dogs
% with malignant and benign disease
Prevalence of malignant vs. benign disease for the different size breeds?
Small breeds were likely to?
Small breed dogs with malignant disease were ___ more likely than ___ breeds to have HSA
55% and 45%
Not statistically different
2.3x more likely to have benign disease than larger breed dogs
1/3rd, larger
Carloni et al. 2019. Prevalence, distribution, and clinical characteristics of HSA-associated skeletal muscle metastases in 61 dogs: A whole body CT study
61 dogs
Skeletal metastasis detected in how many? Sites?
Skleteal metastsis was higher in? Not related to?
How many showed lameness or reluctance to move
15 (25%), >1 sites
Males but not significantly releated to age, neuter status, breed, localization, and dimensions of primary tumor
9/15 (60%)
Goto et a. 2019. Tumor necrosis factor-related apoptosis inducing ligand induces apoptosis in canine HSA cells in vtiro
Evaluated the proapoptotic effect of TRAIL in 9 HSA cell lines cultered with 3 different TRAILs
TRAIL-TEC
TRAIL-TIL and izTRAIL? Which one was more effective?
Did not decrease cell viability in any cell lines
Decreased viability of all cell lines. izTRAIL more effective at inducing apoptosis
izTRAIL increased activation of caspace-3 and caspace-8 and caused poly(ADP-ribose) polymerase degradation
TRAIL could be an effective therapeutic target, but the MOR needs to be determined
Nobrega et al. 2019. Canine cutaneous HSA: Biomarkers and Survival
60 samples were evaluated for expression of FVIII, COX-2, VEGF, PCNA, Casp-3 by IHC
Markers that had weak to moderate staining pattern?
Strong staining pattern?
Median OS?
Variable related to survival?
Females or Males had lower OS?
Labeling indices related to survival? Labeling intesity?
FVIII, COX-2, VEGF
PCNA, Casp-3
12 months
None, dog age, tumor invasiveness, histological differentiating scoring, mitotic rate, tumor size were not related to survival
Females
Labeling indices FVIII, COX-2, VEGF, PCNA, Casp-3 had no relationship to OS. Neither did labeling intensity of FVIII, COX-2, VEGF
Konduri et al. 2019. Dendritic cell vaccination plus low-dose DOX for the treatment of spontaneous canine HSA
Patients got low-dose DOX plus alpha IFN and an autologous dendritic cell therapy reported to enhance durable CD8+ memory
Median OS?
109 days and 1 of 5 animals died cancer free at 16 months
Dowling et al. 2019. Overexpression of prostate specific membrane antigen by canine HSA cells provides opputunity for the molecular detection of disease burdens within hemorrhagic body cavities
Batschinski et al. 2018. Canine visceral HSA treated with surgery alone or surgery and doxorubicin: 37 cases (2005-2014)
Most common primary orgen affected?
Affect of primary tumor location and prognosis?
23 dogs tx with surgery alone and 14 tx with surgery and DOX
Difference in survival between 2 groups?
Dogs with stage I tumor MST? Stage II? Stage III?
Overall MST and 1-year survival rate
Spleen
None
66 days (2.2 mo) vs. 274 days (9 mo)
196 days (6.5 mo), 117 days (4 mo), 23 days (1 mo)
179 days (6 mo) and 29.2%
Pyuen et al. 2018. In vitro effects of PI3k/mTOR inhibition in canine HSA
In vitro effects of PI3k/mTOR inhibitor, VDC-597, in 3 canine HSA cell lines (DEN-, CIN, SB-HSA)
Results?
Combined with DOX?
VDC-597 dose-dependently reduced prolideration, migration, VEGF production in HSA cells while promoting apoptosis
Additive antiproliferative effects when combined with DOX
Maharani et al. 2018. Cellular atypia is negatively correlated with immunohistochemical reactivity of CD31 and vWF expression levels in canine HSA
How was cellular atypia correlated?
Negatively correlated with CD31 and vWF expression levels but no significant correlation was found between growth patterns and cellular atypia or CD31 or vWF expression levels
Cellular atypia is useful for identifying differentation levels in HSA cases
