Canine Multicentric Lymphoma Flashcards
Burton et al. Evaluation of a 15-week CHOP protocol for the treatment of canine multicentric LSA
31 client owned dogs
Overall response rate?
Median PFI?
Dogs with treatment delays had?
Did dose intensity correlate with patient outcome?
100%
140 days (~ 5 months)
Longer PFI and overall survival in multivariable analysis
No
Dogs with delays may receive MTD while dogs with no AE may be underdosed
Martini et al. Peripheral blood abnormalities and bone marrow infiltration in canine large B-cell LSA: is there a link?
Determine if blood abnormalities can predict BM involvement assessed by flow cytometry (BM involvement)
Difference between no hematological abnormalities and atleast 1?
Degree of infiltration was correlated with? Negatively correlated with? Positively correlated with?
None
Higher in dogs with thrombocytopenia, leukocytosis, or lymphocytosis and was negatively correlated to platelet count and positively to blood infiltration
Blood abnormalities do not always predict marrow involvement - do a BM!
Lucas et al. Pilot clinical study of carmustine associated with a lipid nanoemulsion in combination with vincristine and prednisone for the treatment of canine LSA
Safety of LDE as carmustine carrier (50 mg m(-2) , intravenous) combined with vincristine and prednisone for the treatment of dogs with lymphoma was tested and compared with commercial carmustine with vincristine and prednisone.
CR in how many dogs?
PR in how many dogs?
Median PFI?
OS?
5 dogs with LDE-carmustine and 6 with commercial carmustine
2 from each group
119 ( 4 months) and 199 days (6.6 months)
207 (7 mons) and 247 days (8 mons)
No difference between treatments
Regan et al. Diagnostic evaluation and treatment recommendations for dogs with substage a-a high grade multicentric LSA: results of a survery of veterinarians
Survey veterinarians about initial diagnostic and treatment recommendations
Most commonly recommended staging diagnostics?
Most common treatment recommendation?
___% of responsed treated B and T cell differently
Protocol lenghts?
CBC (100%), chemistry (100%), UA (85%), LN cytology (88%), CXR (84%), immunophenotyping (76%) and AUS (75%)
L-CHOP (51%), CHOP (30%) other CHOP based protocol (12%)
31%
<16 weeks to > 2 years
Elliot et al. Epirubicin as part of a multi-agent chemotherapy protocol for canine LSA
Report outcome in 97 dogs with LSA tx multiagent chemo protocol containing epirubicin
75 dogs received 25-week protocol and non maintenance and 22 got maintenance phase
CR rate?
Time to first relapse (TTR) and OS?
Who had poorer TTR and OS?
96%
216 (7.2 months) and 342 days (11.4 months)
Dogs with T-LSA and substage b
Higginbotham et al. 2013. Intermittent Single-Agent Doxorubicin for the Treatment of Canine B cell LSA
Overall CR rate?
Median total doxorubicin remission time
Median OS?
Median # of doxorubicin treatment?
First remission times affected by?
78%
80.5 days
170 days
4.5
Clinical stage and substage of disease
Valli et al. Canine LSAs: Association of classification type, disease stage, tumor subtype, mitotic rate, and treatment with survival
Mitotic rates with indolent or low grade vs. high grade?
Most cases were?
Higher mortality rates? Lower motality rates?
MST for low grade T-cell (T-zone) lymphoma? High grade T cell LSA?
MST for centroblastic large B cell LSA?
low vs. high mitotic rate
Centroblastic large B-cell LSA
High grade LSA, low grade T-cell LSA
622 days (1.7 years). 162 days (5.4 months)
127 days with low stage and 221 days with intermediate and 215 with advanced stage
A histological diagnosis with immunophenotyping is a minimal requirement for diagnosis of specific subtype
Back et al. Mechlormethamine, vincristine, melphalan, and prednisone (MOPP) for the treatment of relapsed LSA in dogs
MOPP on 28 day tx cycle to 88 dogs with relapsed LSA
ORR for median of?
How many experienced CR for median of how many days?
How many experienced PR for median of how many days?
ORR with T-LSA?
ORR with B-LSA?
OSS?
Toxicity?
51% for a median of 56 days (~2 months)
12% for median of 81 days
38.6% for median of 50 days
55% for median of 60 days
57% for median of 81 days
183 days (~6 months)
54% with majority classified as grade I
Kol et al. Serial hemostatic monitoring of dogs with multicentric LSA
Characterize hemostatus of dogs with LSA - 27 dogs
How many had altered hemostatic status consistent with hypercoagulability?
Laboratory evidence of hypercoagulability did not resolve for up to ___ following atainment of clincial remission
What was associated with decreased survival time?
81% (22/27)
1 month
Accelerated rate of clot formation at the time of chemotherapeutic completions
Dogs with multicentric LSA were frequently hypercoagulable though 4 weeks after completion of chemotherapy
Arico et el. The role of vascular endothelial growth factor and matric metalloproteinases in canine LSA: in vivo and in vitro study
MTI-MMP, TIMP-1 and RECK mRNA levels were higher in T or B-cell LSA?
Higher mRNA and protein expression of MMP-9 and VEGF-A were observed in?
Positive correlation noted between?
MMP-9, MTI-MMP, VEGF-A were expressed at highest level?
T cell LSA than B cell LSA
T-cell LSA
MMP-9 and VEGF-A in T cell LSA
High-grade T cell LSA
Warry et al. 2014. Autologous Peripheral Blood Hematopoeitic Cell Transplantation in Dogs with T-cell LSA
Examine apharesis and PBHCT outcomes in dogs with TCL - 15 dogs
How many died?
Other complication?
Median DFI and overall survival of the 13 dogs transplanted?
Stage and substage effect on OS?
How many were alive long term?
13% died in hospital
1 dog developed B-cell LSA 120 days post-PBHCT
184 days (6 months) and 240 days (8 months)
None
2/13 (15%) - 741 (2 years) and 772 days (2.1 years)
Barber et al. Criteria for designation of clinical substage in canine LSA: a survery of veterinary oncologists
What were the most commonly indentified clincial factors?
How may considered metabolic, neurologic, and nutritional parametes?
What was the severity of clincial signs to designate substage B?
GI, constitutional, and respiratory signs - 90% indicating inappetance, vomiting, diarrhea, changes in attitude, weakness, dyspnea were integral in assigning clincial stage
3/4
Mild to moderate
Aubry et al. Evaluation of bone marrow aspirates from multiple sites for staging of canine LSA and MCTs
40 dogs enrolled (24 LSA and 16 MCT) but onlt 33 (82.5%) had BM from 2 sites
How many with LSA had BM involvement?
Were neoplastic cells present in both BM sites?
How many with MCT had BM involvement?
Were neoplastic cells present in both BM sites?
31.6%
Yes in all dogs
20%
Yes in 2 dogs and 1 site in 3rd
Multiple sites not needed for LSA but studies needed for MCT
Fine et al. 2014. Hemodynamic and Biochemical alterations in dogs with LSA after induction of chemotherapy
Baseline echocardiogram showed significantly ____ chamber dimensions in dogs with LSA compared to control
These changes were reversed by?
Systolic BP and urine Na concentration?
Bromide dilution space, PCV, USG, urine K concentrations?
Smaller - volume depletion due to systemic hypertension and subsequent pressure natriuresis
Fluid administration
Increased
Decreased
Canine LSA as a comparative model for human NHL: a recent progress and applications
Hwang et al. The effects of oncolytic reovirus in canine LSA cells lines
Treated 10 cell lines with reovirus
Reovirus caused what in cell lines?
The level of Ras activation
Injection of intratumoral reovirus injection?
Cell death, virus replication and infectivity were confirmed in 4 cell lines
Varied among the cell lines
Suppressed growth of LSA SQ tumor
Nerschbach et al. Splenic and hepatic US and cytology in canine LSA: effects of findings on stage migration and assessment of prognosis
Stage migration occurs using more sensitive diagnostic methods
186 with LSA and conventional staging with US and cytology of liver and spleen
Addition of cytology lead to?
Findings of hepatic and splenic US and cytology exerted what effect on CR and survival durations?
Shift from Stage IV to Stage III
None
Alexandrakis et al. Ultility of a multiple serum biomarker test to monitor remission status and relapse in dogs with LSA undergoing treatment with chemotherapy
Compare clinicians assessement using palpation and cytology to biochemical tests for haptoglobin (hapt) and CRP - termed canine LSA blood test (cLBT)
cLBT of remission and recurrence with clinicians assessment?
cLBT demonstrated prognostic potential based on ___ values on dogs with __ survival times and those achieving lower cLBT score showed ___ survival times
Comparble
pre-treatment, shorter, longer
Potential to assist in monitoring treatment of canine LSA
Jankowska et al. The animal dependent risk factors in canine T-cell LSA
Characterize animal-dependent risk factors in canine TCL in Poland
Dogs predisposed to TCL?
Dogs predisposed to BCL?
Age for dogs with low-grade LSA and high-grade LSA?
Boxer and dog de Bordeaux
None
older and younger
Gillem et al. Efficacy and toxicity of carboplatin and cytarabine chemotherapy for dogs with relapsed or refractory LSA (2000-2013)
22 dogs tx carboplatin and 14 tx both
Clinical response rate?
Median time to progression?
Median overall survival time?
Thrombocytopenia and neutropenia occurence?
Grade IV thrombocytopenia and neutropenia?
Response rate for the combination?
18%
18 days
28 days
84% and 52.6%
56% and 60%
28.6%
High toxicity and no durable response
Fogle et al. CD45+ and CD45- lymphocyte populations identified by flow cytometry from dogs with LSA exhibit similar morphology and the same clonal (B cell or T cell) lineage
What was the similarity between CD45+ and CD45- samples?
PARR was done on both population, indicating ___ were of same lineage, B cell or T Celll (__%)?
CD45-population identified in dogs with LSA represents a phenotypic variant of CD45+ population
95%
100% 95%
Ema et al. Investigation of the cytotoxic effect of flavopiridol in canine LSA cell lines
flavopiridol - CDK inhibitor
Effect on 10 cell lines? Due to?
Mechanims of apoptosis showed?
Cell death in 8/10, apoptosis
Rb phosphorylation was inhibited, possibly due to CDK4 or CDK6 inhibition
Decreased expression of pRb protein and anti-apoptotic proteins, Mcl-1 and XIAP - possibly through transcriptional regulation of CDK7 and CDK9 activation
Aresu et al. Canine indolent and aggressive LSA: clinical spectrum with histologic correlation
DLBCL vs. peripheral TCL vs. indolent LSA prevalence?
Stage of disease for dogs with DLBCL?
Dogs with indolent LSA and TCL had what stage?
Liver and BM involvement?
Clinical stage was related to?
Median survival for aggressive and indolent TCL
Median survival for indolent and aggressive BCL
44%, 20% and 30%
Stage IV
Stage V and symptomatic
BCL and TCL
Substage, sex, LDH levels
55 days
200 and 256 days
Prognosis of advanced indolent LSA does not appear to be different from that of aggressive disease
Wang et al. Chemotherapy induced neutropenia is associated with prolonged remission duration and survival time in canine LSA
50 dogs with multicentric LSA received CHOP
How many dogs had neutropenia?
What was a negative prognostic factor?
Median first remission duration in the neutropenia and no neutropenia groups?
13 dogs had neutropenia, and 37 had no neutropenia
Bodyweight
812 and 219 days
Induce neutropenia to achive longer remission and survival times!!! HAHAHAHA
Munasinghe et al. Evaluation of LN aspirates at diagnosis and relapse in dogs with high-grade multicentric LSA and comparison with survival times
Compare cytologic features of LN aspirates at diagnosis and at relapse
What was higher at relapse?
Nuclear morphology?
Presence of ___ at diagnosis was associated with shorter remission and decreased total survival?
Increased ___ at relapse was associated with longer remission and total survival?
Increased minimum ___ and ___ at diagnosis was associated with decreased time from relapse to death
Mitoses and total cytologic score
No difference
Binucleated or multinucleated cells
mean nucleoli
Nuclear radius and diameter
Chikazawa et al. Hyperferritinemia is associated with short survvial time in dogs with multicentric LSA
MST for dogs with high ferritin (>3000 ng/ml, n=7)?
MST for dogs with low ferritin (<3000 ng/ml, n=7)?
40 days
360 days
Childress et al. Inter- and intra-rater reliability of calliper based LN measurements in dogs with peripheral nodal LSA
3 rates measured LNs from 20 dogs twice prior to and once after chemo
ICC for inter-rater and sumTV and sum LD prior to chemotherapy were 0.86 and 0.80
ICC for inter-rater and sumTV and sum LD after chemotherapy were 0.96 and 0.94
Tierny et al. Phase I clinical pharmacology study of F14512, a new polyamine vectorized anticancer drug, in naturally ocurring canine LSA
New topoisomerase type II inhibitor
23 dogs with stage III-IV LSA - 5 dose levels were evaluated
Toxicity?
Response rate?
Well tolertaed except for dose-dependent hematologic toxicity
91%
Mutz et al. Prognostic value of baseline absolute lymphocyte concentration and neutrophil/lymphocyte ratio in dogs with newly diagnosed multi-centric lymphoma
Lymphopenia at diagnosis and N:L ratio>3.5 are negative prognostic factors for survival
77 dogs
What was significant for PFS?
Immunophenotype only
Curran et al. 2016. Retropsective analysis for treatment of naiive canine multicentric LSA with 15 week maintenance-free CHOP protocol
134 dogs treated with 15-week CHOP protocol
Overall RR?
Median PFS
Median OS
Prognostic factors significant for PFS?
98%
176 days (6 months)
311 days (10 months)
Substage, immunophenotype, hospitalization for AEs, need for dose reduction, presence of neutrophilia at diagnosis, anemia and experiencing CR as best response to therapy
Comazzi et al. CLL transformation into high grade LSA: a secriptions of Richters symdome in 8 dogs
RS - Development of aggressive LSA in patients with CLL
8 dogs with CLL progressed to RS
Percent of RS?
When RS occured ____ were decreased compared to CLL
5 dogs had anemia and 2 thrombocytopenia
Clincical signs - LN swelling, coughing, vomiting, neurological signs, weight loss
Survival?
5.2% - with T-cell (2.2%) and 6 with B cell (10.9%)
Lymphocytes
41 days
Tsuji et al. Anti-tumor effects of perphenazine on canine LSA
Wang et al. Assessement of temporal association of relapse of canine multicentric LSA with components of the CHOP protocol: Is cyclophosphamide the weakest link?
When did relapse occur more frequently?
Administration of cyclophosphamide compared with vincristine or doxorubicin
Relapse cyclophosphamide with other cytotoxic drugs!!!
Romano et al. 2016. Association between BCS and cancer prognosis in dogs with LSA and OSA
In humans, obesity promotes some cancers
270 with LSA and 54 with OSA
Which dogs with LSA had shorter survival?
OSA?
Underweight dogs than ideal or overweight dogs
No asociation
Obesity is not associated with worse outcome but being underweight for LSA is bad
Wang et al. Comparison of efficacy and toxicity of doxorubicin and mitoxantrone in combination chemotherapy for canine LSA
Treated with either CHOP or CMOP
Median PFI for CHOP and CMOP?
MST for CHOP and CMOP?
Anorexia and diarrhea?
222 days (7.4 months) and 162 days (5.4 months)
318d (10 mo) and 242 d (8 months)
Higher in CHOP than CMOP
CMOP causes fewer side effects - another tx choice for LSA
Ruple et al. Differences in the geographic distribution of LSA subtypes in Golden retrievers in the USA
What regions were more likely to be diagnosed with TZL?
Northeast and East north central compared to Mountain regions (B-cell?)
Blake et al. Hypersentivity reactions associated with L-asparaginase administration in 142 dogs and 68 cats with lymphoid malignancies: 2007-2012
Hypersentivity were documented in how many dogs? Associated with __% of L-aspraginase doses admnitered?
Hypersentivity were documented in how many cats?
5%, 1.6%
None
HSR are uncommon among dogs and cats even with repeated dosings
Zamani-Ahmadmahmudi et al. Prognostic efficacy of the human B-cell LSA prognostic genes in predicting DFS in canine counterpart
CCND1 as an important gene that can be used as a potential predictor
Thiman et al. Prospective evaluation of the safety of compounded bulk material L-asparaginase in dogs with LSA
Manufacturing of ELSPAR was discontinued in 2012 - Evaluate safety of compounded ELSPAR
Dogs tx with 10,000 IU/m2 CLASP or Elspar SQ and steroids administered concurrently
AE to CLASP?
AE to Elspar?
Response rate to CLASP and steroids?
None
grade I and II AE
80%
Childress et al. A randomized controlled trial of the effect of prednisone omission from a multidrug chemotherapy protocol on treatment outcome in dogs with peripheral nodal LSAs
Tx was L-CHOP (18) or L-CHO (22)
Median PFS?
142.5 days (4.75 months) for L-CHO and 292 days (9.7 months) for L-CHOP
Goodman et al. Treatment of canine non-indolent T cell using VELCAP-TSC protocol: A retrospective evaluation of 70 dogs (2003-2013)
Evaluate prognostic factors in 70 dogs with T cell LSA
Overall remission
Dogs that were ____ were more likely to achieve CR?
Median PFS? 1-, 2-, 3 year survival
Median OST was significantly longer for dogs that ____, and shorter for ___ and ___
More than 30% of dogs survived >1 years
73%
Neutropenic
175 days. 26.8%, 15%, 12.6%
achieved CR, Boxers, substage b disease
Lautscham et al. Comparison of a CHOP-LAsp-based protocol with and without maintenance for canine multicentric LSA
Lenz et al. Vinblastine as a second rescue for the treatment of canine multicentric LSA in 39 cases (2005-2014)
39 dogs - Median starting dose was 2.6 mg/m2 administered weekly until disease progression
CR? PR? SD? PD?
Most common toxicity?
Median PFS?
MST?
Duration of first remission was identified as positive predictor of outcome
7.7%, 18%, 46%, 28%
Grade 3 or 4 neutropenia (25%), grade 2 or 4 thrombocytopenia (10%)
1 month
45 days
Thamm et al. 2017. Alternating Rabacfosadine/Doxorubicin: Efficacy and tolerability in Naiive Canine Multicentric LSA
54 dogs with untreated LSA - alternating RAB (1.0 mg/kg 0, 6, 12) and DOX (30mg/m2 3, 9, 15)
Overall RR?
Median PFI?
AEs?
84%
194 days (6.5 months)
Mild and self limiting: GI and hematological most common
Jones et al. CT findings in 12 cases of canine multicentric LSA with splenic and hepatic involvement
Splenic nodule appearance? After contrast?
Hepatic nodules? After contrast?
Hypoattenuating in 4/5 dogs and isoattenuating in 1. 3/5 appreaed hypoattenuating and 2/5 isoattenuating
Normal liver in 10 dogs and nodules in 2 dogs. All nodules isoattenuating. Hypoattenuating after contrast.
FNA recommended when using CT to stage dogs with multicentric LSA
Boye et al. Dose escalation study to evaluate safety, tolerability and efficacy of IV etoposide phosphate administration in 27 dogs with multicentric LSA
Topoisomerase inhibitor, water soluble prodrug
MTD?
Overall RR at MTD dose?
Toxicity?
300 mg/m2
83.3%
Moderate reversible GI toxicity
Yamazaki et al. Effects of toceranib phosphate monotherapy on multidrug resistant lymphoma in dogs
PDGFRa expression in T cell LSA?
c-KIT expression?
Response to TOC in 5 dogs?
Higher with MDR TCL than those with untreated TCL
higher in TCL than in BCL
PR in 2/5 (40%)
Fontaine et al. Evaluation of the modified Glasgow Prognostic Score to predict outcome in dogs with newly diagnosed lymphoma
mGPS assigns score of 0-2 from pretreatment CRP and albumin to predict patient outcome
mGPS distribution was associated with?
On univariate analysis, mGOS was significantly associated with?
What reduced OS and PFS?
What was significant on univariate and mulivariate analysis?
Clincial stage, substage b, weight loss, GI disturbances, and lethargy at presentation
OS and PFS with shorter times for 2 vs. 0 and 1
Hypoalbuminemia but increased CRP had no effect
Clinical stage
Wilson-Robles et al. Geographical differences in survival of dogs with NHL treated with CHOP based chemotherapy protocol.
Geographic difference in PFS exists
Significant differences in sex, weight, stage, immunophenotype and # of doxorubicin doseas were seen between regions
On univariate analysis, PFS differed by regions, stage, substage, and immunophenotype
Multivariable model showed dogs in wetern regions had significantly shorter PFS when compared to south or east
Riondoto et al. Identification of peripheral blood involvement in dogs with large B cell LSA: Comparison of different methods
Assessed the aggrement among FC, blood smear evaluation, and ADVIA (LUC and BASO) to quanity PB infiltrastion in 100 dogs with LBCL
Significant errors were noted on all methods compared to FC
Moderate aggremment between FC and blood smear evaluation, LUC and BASO had excellent specificity but unsatisfactory sensitivity
Brown et al. LOPP as first-line treatment for dogs with T-cell LSA
LOPP -lomustine, vincristine, procarbazine, prednisolone for treatment of naive T-cell LSA
31 dogs
Overall RR?
Median DFI
MST
97%
176 days (~6 months)
323 days (10.8 mo)
Boss et al. Potential for a novel manganese porphyrin compound as adjuvant canine LSA therapy
Redox active drugs and superoxidise dismutase mimics that chemosensitize LSA
Peak plasma concentrastion occured 30 mins post-injection
Toxicity?
MTD was 0.25 mg/kg - given 3x/week for 2-3 weeks
Highest drug level?
Anaphylactic reaction and tachycardia
LNs then kidney and liver
Treggiari et al. Temozolomide alone or in combination with doxorubicin as a rescue agent in 37 cases of canine multicentric LSA
26 patients in TMZ group and 11 in TMZ/DOX group
Overall MST for both groups?
TMZ group TTP? MST?
ORR for TMZ group? Toxicity?
TMZ/DOX group - TTP, MST - ORR and toxicity?
40 days
15 days and 40 days
32% and 46%
19 days and 24 days, 60% and 63%
Harrington et al. Preclinical evaluation of the novel BTK inhibitor Acalabrutinib in Canine Modeuls of B cell NHL
Seoncd generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased targert selectivity and potency compared to ibrutinib
Acalabrutinib inhibited BTK activity and downstream effectors in CLBL1 (BCL cell line)
20 dogs treated at 2.5 to 20 mg/kg 12 or 24 hours
Well tolerated
ORR? Median PFS
Clinical Benefit?
25% 22.5 days
30%
Safe and effective in canine BCL and supports use of canine LSA as relevant model for human NHL
Deravi et al. 2017. Specific immunotypes of canine T cell LSA are associated with different outcomes
Saba et al. Rabacfosadine for relapsed canine BCL: Efficacy and adverse event profiles of 2 different doses
Novel prodrug of the acyclic nucleotide phosphate PMEG, preferentially targets neoplastic lymphocytes with reduced off target toxicity
Two doses - 0.82 mg/kg or 1 mg/kg as 30 min infusion every 3 weeks for 5 treatments
Overall RR and CR?
Median PFI for all dogs? all responders? all CR?
Response rate and PFI for the 2 groups?
Toxicity?
74% with 45% achieveing CR
108 days (3.6 mo), 172 days (6 mo), and 203 days (6.7 mo)
Similar
Hematologic, GI, dermatologic, and pulmonary
Craft et al. Characterization of a low expression haplotype in canine glutathione S-transferase (GSTT1) and its prevalence in golden retrievers
Muir et al. Prevalence of FoxP3+ cells does not correlate with Ki67 expression in canine DLBCL
FoxP3 cells in DLBCL LNs compared to reactive LNs?
Relationship between the number on intratumoral Foxp3 and neoplastic transformation?
Foxp3 cells are reduced in LNs effaced by DLBCL and is unrelated to Ki67 expression
Fewer in nodes effaced by DLBCL than in reactive LNs
None
Kumar et al. PDLI is expressed in canine B cell lyphoma and downregulated by MEK inhibitors
PDL1 expression in canine B cell LSA?
PDL1 and singal transducer and activator transcription 1 mRNA was reduced in the presence of MEK1/2 inhibitors
PDL1 is expressed in BCL and inhibition by MEK1/2 inhibitors suggest a possible treatment strategy
Observed
Smith et al. Clinical response and AE profile of Bleomycin chemotherapy for canine multicentric LSA
Response noted?
Toxicity limited to grade 1 GI and grade 1 constitutional toxicity
1PR/10 dogs that died 24 days later
Schopper et al. Melting curve analysis in canine LSA by calculating maximum flourescence decrease
MCA is used in humans instead of PARR
27/34 cases showed monocloncal rearragement (specificity 93%).
Detection limits was 25% for B-cell LSA and 100% of T cell LSA, suggesting PCR consition could still be optimized
Poggi et al. Prognostic significance of Ki67 evaluated by flow cytometry in dogs with high grade B cell LSA
Assessed prognostic significance of Ki67% evalujated by FC in 40 dogs
By multivariate analysis what were prognostic for LSS?
Dogs with ___ Ki67% presented longer LSS and RFI?
Ki67% and achivement of CR
Intermediate (median 866 and 428 days) low (median 42 days), high (173 days)
Sato et al. 2012. Evaluation of the prognostic significance of BCL6 expression in canine high-grade B cell lymphoma
44 dogs with centroblastic or B-cell immunoblastic type LSA
PFS and OS between high BCL6 and low BCL6 group?
Correlation between BCL6 and prognosis?
BCL6 not detected in 11 dogs by IHC
Most canine high grade B cell LSA correspond to human DLBCL with no IHC expression of BCL6
No difference
None observed
Woldesberger et al. Angiogenic markers in canine LSA tissues do not predict survival times in chemotherapy treated dogs
VEGF, VEGFR1, VEGFR-2 and MVD (used to evalute angiogensis) evaluated by IHC in 34 dogs
VEGF?
VEGFR1, VEGFR-2?
MST?
Relationsthip between markers and OS?
71% positive
62% and negative
266 days (8.9 mo)
No relationship found between OS and expression of VEGF, VEGFR1, VEGFR-2 and MVD
Escobar et al. 2012. Hematologic changes after total body radiation and autologius transplantation of hematopoeitic peripheral blood progenitor cells in dogs with LSA
Hematologic toxicities of TBR in 10 dogs and subsequent recovery of affected cell lines
Toxicity?
All peripheral blood cell lines, except RBC, experienced grade 4 toxicities
All dogs had >500 neutrophils by day 12, thrombocytopenia persisted for weeks
All dogs clinically normal at discharge
Palus et al. 2012. MRI features of CNS lymphoma in dogs and cats
8 dogs and 4 cats
Intracranial lesions affected rostrotentorial structures in 6 dogs and caudotentorial in 2 cats. Lesions in SC in 2 dogs and 2 cats
Hyperintesene in T2-weighted when compared to white matter, most were hypointense in T1-weighted (7/12), hyperintense in fluid-attenutating recovery (FLAIR) 5/9
When compared to gray matter, lesions appear isointense (5/12) or hyperintense (7/12)
Lesion margins indistinct on T2 (10/12) and has perilesional hyperintesity in FLAIR (7/9)
Majority of lesions (10/12) had abnormal meninges and half (6/12) had generalized contrast enhancement
Mass effect evident on all lesions
Affinity of the alpha4-beta1 integrin-targeting peptide LLP2A to canine LSA
Berlato et al. 2012. RT in the management of localized mucocutaneous oral LSA in dogs: 14 cases
Surgery and chemotherapy do not provide effective long term control
Mean survival
Median survival
Overall RR to RT?
1129 days
770 days (2.1 years)
67%
Survival advantage seen in dogs with no evidence of LN metastasis
Effective treatment for localized oral LSA
Sharif et al. 2012. A sensitive and kinetically defined radiochemical assay for canine and human TK1 to monitor canine malignant LSA
Marker of cell proliferation, an optimised 3H-thymidine phosphorylation assay is described
Mean S-TK1 activity in healthy dogs? Healthy humans?
S-TK1 activity in dogs with hematological malignancy?
Sensitivity and specificity?
TK1 during chemotherapy?
Relapse?
- 11, 1.15
- 2
- 94 and 0.88
Reduced
Increased prior to relapse
TK1 did not differ in dogs with solid tumors compared to healthy controls
Joetzke et al. Flow cytometric evaluation of peripheral blood and bone marrow and fine needle aspirate samples from multiple sites in dogs with multicentric lymphoma
Extent of disease can be determined by flow cytometry and to evaluate the suitability of FNA from the liver and spleen of dogs. Logarithmic transformed T-cell-to-B-cell percentage ratio were calculated
Log (T:B) values in dogs with BCL
Of the samples analyzed how may tested positive via FC? Aggreement with cytology?
Lower than with TCL or control dogs
In dogs with TCL, log (T:B) of LN, BM, and spleen samples was significantly higher than in control dogs
70%, 83%
FC may aid in detection of extranodal LSA in dogs
Wilcox et al. 2012. Autologous peipheral blood hematopoeitic cell transplatation in dogs with B cell LSA
Peripheral blood CD34+ PBHCT is used to treat human patients - to determine the safety and feasibility to treat canine B-cell LSA
How many were engrafted appropriately? Died?
Delayed engraftment?
Median DFI and OS
Relapse?
87.5 (21/24), 2 died (8.3%)
1 dog (5%) and died 45 days after PBHCT
1 dog developed TBI-induced pulmonary fibrosis 8 months after
271 days (9 months) and 463 days (15 months)
33% at median OS 524 days (17 months)
Frantz et al. 2013. Molecular profiling reveals prognostically significant subtypes of canine LSA
What were the 3 groups identified based on gene expression profiles?
Low grade T cell LSA - T zone LSA
High grade T cell LSA - lymphoblastic and peripheral T cell LSA not otherwise specified
B cell LSA - marginal BCL, DLBCL, Burkitt’s LSA
Di Bella et al. 2013. Proteinuria in canine patients with LSA
Results?
Canine patients with LSA more likely to be proteinuric compared with healthy dogs
Not linked with stage or substage of LSA
Atherton et al. 2013. Changes in serum proteome of canine LSA identified by electrophoresis and mass spectrometry
21 dogs with LSA had elevated levels of?
Further separation was performed using PAGE
a2 globulins
36 proteins were identified - haptoglobin was identified in 3 dogs which could account for a2 globulins
a2 Macroglobulin, a-antichymotrypsin, and inter-a-trypsin were noted in dogs with LSA
Kininogen was present in 3 dogs, present in healthy dogs
Canine LSA has an inflammatory component
Dettwiler et al. 2013. Immunohistochemical expression study of proapoptotic BH3-only protein bad in canine nonneoplastic tissues and canine lymphomas
Bad is proapoptotic Bcl-2 family members - contributes to tumorigenesis
Expression in nonneoplastic tissues?
Of 81 LSA, expression?
Expressed in cytoplasm of nonneoplastic tissues especially epithelial cells
35.8% had moderate to strong Bad labeling, strong increase in B cell LSA compared to nonneoplastic LNs
Dhaliwal et al. 2013. Clinicopathological significance of histologic grade, pgp, and p53 expression in canine LSA
How may were positive for pgp and p53?
OS and remission duration?
What was correlated with survival?
80% and 22%
246 days and 137 days
Histologic grade was not associated with either survival or duration of first remission
Expression of p53 was correlated with survival
Mooney et al. 2013. Comparative RNA-Seq and microarray analysis of gene expression changes in BCL of Canis familiaris
Gentilini et al. 2013. Retrospective monitoring of minimal residual disease using hairpin shaped clone specific primers in BCL
Using hairpin-shaped primers to quantify MRD (minimal residual disease - cause of relapse) - 8 dogs that underwent chemotherapy
Median DFI and MST
At admission, except 1 had circulating neoplastic cells
Persistence of MRD despit CT indicated?
What is anticipated with reappearance of MRD?
254.5 days, 313.5 days
Worse prognosis and short duration of CR
Relapse anticipated with reappearance of MRD in peripheral blood
Marconato et al. 2013. Assessment of bone marrow infiltration diagnosed by flow cytometry in canine large B cell LSA: prognostic significance and proposal of a cut-off values
Degree of BM infiltrasion by large CD21 cells with LBCL was assessed using FC and related to TTP and LSS
BM infiltration was correlated with?
In univariate analysis, association between?
Multivariate analysis?
Cut-off associated with prognostic value?
Peripheral blood infiltration, high LDH, and substage b disease
BM infiltration diagnosed by FC and TTP and LSS
Substage associated with TTP and substage and anemia associated with LSS
3% - discriminated dogs with poorer prognosis (TTP 69 days and LSS 155 days) and better prognosis 9TTP 149 days and LSS 322 days)
Presence of BM infiltration by FC at diagnosis is a negative prognostic indicator in canine LBCL
Suran et al. 2014. Imaging findings in 14 domestic ferrets with lymphoma
Most common malignant neoplasia in domestic ferrets
14 ferrets - radiographs (12), US (14), CT (1), MRI (1)
Median age at diagnosis?
Clinical signs?
Imaging lesions detected in?
Appearance of lesions on US?
Most common thoracic abnormality?
5.2 years
Nonspecific
abdomen, intraabdominal lymphadenopathy (12/14), splenomegaly (8/14), peritoneal effusion (11/14)
Hypoechoic
Pleural effusion (3/12)
Imaging characteristics in ferrets are similar to dogs, cats, humans
Zandvliet et al. 2013. Prednisolone inclusion in a first-line multidrug cytostatic protocol for the treatment of canine LSA does not affect therapy results
Treated with L-CHOP (prednisolone) and 1/2 dogs receiving prednisolone
Initial treatment?
Rescue treatment?
Overall survival and AEs?
CR 75%, disease free period 176 days (6 mo)
CR 45% and disease free period 133 days (4.4 mo)
Similar in both groups - 283 days (9.4 months)
Prednisolone as part of chemo protocol has no additional effect on treatment results and can be omitted from first line protocols
Mudaliar et al. 2013. Comparative gene expression profiling identifies common molecular signatures of NF-kB activation in canine and human DLBCL
Activation of the NF-KB/p65 canonical pathway in human and canine DLBCL - can be used as models to study therapeutic targets for human LSA
Fujiwara et al. 2014. Prognostic significance of the expression levels of the p16, p15, and p14 genes in dogs with high-grade LSA
Evaluate the relationship between inactivation of p16, p15, and p14 genes and prognosis in canine LSA
Of 62 dogs examined, p16, p15, and p14 mRNA levels?
CpG methylation of p16 gene?
What correlated with OS?
p16 mRNA?
p15 and p14 mRNA?
Undectable in 21, 18, and 10 dogs
20/68 were methylated
p16 expression status and anatomic form/immunopehnotype were found to correlated with OS
p16 mRNA over its cutoff correlated with poor prognosis
p15 and p14 mRNA and methylation status did not influence prognosis
Expression levels of p15 and p14 mRNA and p16 methylation did not influence prognosis in dogs
Childress et al. 2014. Assessment of folate receptor expression and folate uptake in multicentric LSA in dogs
FR detection by IHC in LN samples an archival specimens?
Nuclear scintigraphy?
Results of treatment?
Strong evidence for folate uptake in substantial protion of multicentric LSA dogs
None detected
uptake of radioactive tracer in 6/10 dogs - 5 treated with FR-targeted chemotherapeutic agent
CR in 1 dog, SD 2 dogs, PD in 2 dogs
Ferraresso et al. 2014. Epigenetic silencing of TFPI-2 in canine DLBCL
Tissue factor pathway inhibitor-2 is a tumor suppressor involved in invasiveness inhibition
Hypermethylation of the TFPI-2 was found in __% of DLBCL and _ normal LN
Gene expression revealed ___ of TFPI-2 in DLBCL compared with normal LNs?
77%, 1
Downregulationn- hypermethylation negatively regulates its transcription
A significant positive correlation was found between TFPI-2 methylation and age - age-associated epigenetic modification in canine DLBCL
Aresu et al. 2014. Minimal residual disease decetion by FC and PARR in LN, peripheral blood and bone marrow, following treatment of dogs with DLBCL
The concordance rate between FC and PARR for LN, PB, BM?
At the end of treatment the corcordance rate?
Which test was more sensitive in predicting TTR?
Which test was more sensitive in predicting LSS?
100%, 78.6%. and 64.3 for LN, PB, BM
35.7%, 50%, 57% LN, PB. BM
PARR
PARR and FC combination
Immunological and molecular techniques should be used in combination when monitoring MRD in canine DLBCL
Mochizuki et al. 2014. Demonstration of the cell clonality in canine hematopoeitic tumors by X-chromosome inactivation pattern analysis
XCIP has been used in human neoplasms to assess clonality
PCR reaction canine XCIP of the androgen receptors was applied in assessement of cell clonality
Examined polymorphisms of 2 CAG tandem repeats in aht AT in 25 males and 159 females
Of the 150 females, ___ were heterozygous for the first and second polymorphic CAG tandem repeats - indicating utility in these dogs
Of the 10 LSA samples, __ showed skewed XCIPs whereas nonneoplastic LN showed balanced XCIP
Bone marrow specimen from dog with AML and peripheral leukocyte specimen from CML showed skewed XCIP
49.3%
90% (9)
XCIP was successfully employed
Ndikuyeze et al. 2014. A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like DLBCL
Selective IKK inhibitor, NBD peptide blocls constitutive activity and induces apoptosis in ABC-DLBCL cell in vitro
Determine safety and efficacy of NBD peptide in dogs
LN biopsies were taken before and 24 hr after peptide administration
IV administration of <2mg/kg NBD peptide was safe and inhibited NF-KB activity in 6/10 dogs
Reductions in mitotic index and cyclin D occured in subset of dogs 24 hours post in 3 dogs marked
PK suggested rapid uptake of peptide into tissue
NBD peptide is safe and blocks NF-KB signaling and reduced malignant B cell proliferation
Graff et al. Hematologic findings of predictive bone marrow disease in dogs with multicentric large B cell LSA
What were the variable for predicting bone marrow involvement?
When considered independently, either positive blood smear or thrombocytopenia had sensitivy and specificty?
How did sensitivity increase?
Thrombocytopenia and presence of >10% neoplastic lymphocytes on blood smears
low sensitivity 60% and moderate specificity 89% and 87%
When evaluated together - 80%
Tomiyasu et al. 2014. Evaluation of DNA methylation profiles of the CpG island of the ABCB1 gene in dogs with LSA
19 chemotherapy sensitive dogs and 8 chemotherapy resistant dogs
The CpG island of the ABCB1 gene was ___ in dogs with chemotherapy sensitive and resisatnt groups?
Hypomethylated in dogs with chemotherapy sensitive and resistant groups
No significant difference was dected in the methylation rate between the 2 groups, and no correlation between methylation rate and mRNA expression levels
Expression of ABCB1 gene was not suppresses by hypermethylation of its CpG island in most dogs with LSA
Arico et al. 2014. PDGF and receptors in Canine LSA
Use of PDGFR antagonits in therapy for aggressive TCL but not in DLBCL
Arico et al. 2014. Array based comparative genomic hybridization analysis revealed chromosomal copy number aberrations associated with clinical outcome in canine DLBCL
Identify copy number aberration (CNAs) by genomic hybridization in 12 dogs with DLBCL
90 different genomic imbalances were counted, 46 gains and 44 losses
Two gains in Chr13 were correlated with clinical stage
Losses of IGK, IGL, IGH were always found, and gains along chr13 and chr31 were observed (>41%) - MYC, LDHB, HSF1, KIT, PDGFRa are annotated
Zandvliet et al. 2015. A longitudinal study of ABC transporter expression in canine multicentric LSA
ABC transporter mRNA expression was assessed in 63 dogs treated with doxorubicin-based protocol
ABC transporter expression was independent of sex, weight, age, stage, substage
What were associated with increased ABCB5 expression and decreased ABCC1 mRNA?
Drug resistance ocurred how often?
What effect did glucocorticoids have?
Hypercalcemia and TCL
55.6% and was associated with increased ABCB1 mRNA expression in dogs with BCL and decreased ABCB8, abCC1, and ABCC3 mRNA expression in T cell LSA
No effect on ABC transporter mRNA expression
Drug resistance is due to upregulation of ABCB1 and ABCG2 mRNA
Zamani et al. 2015. Reconstruction of canine DLBCL gene resulatory network: detection of functional modules and hub genes
The PI3K, p53 signaling pathway Rac CycD pathway, G1/S checkpoint, chemokine signaling pathway and telomere maintenance were main pathways protein products of hub gene are invovled.
Larsdotter et al. 2015. Serum TK1 activity in clinically healthy and diseased horses: a potential marker for LSA
TK1 activity in horses with LSA?
Non-hematopoeitic neoplasia?
Inflammatory disease?
- 3
- 3
- 5
Potentially useful maker for LSA
Rue et al. 2015. Identification of a candidate therapeutic antibody for treatment of canine BCL
Generation and characterization of rituximab like CD20 Ab
1E4 binds to approximately the same location in the EC domain of CD20 as rituximab
1E4-clgGB and 1E4-clgGC significantly deplete B cell levels in healthy dogs
Half life was 14 days
Marconato et al. 2015. Peipheral blood lymphocyte/monocyte ratio as a useful prognostic factor in dogs with DLBCL receiving chemotherapy
Dogs with LMR of ___ were found to have significantly shorter TTP and LSS
<1.2 (30% of cases)
Koshino et al. 2016. Mutation of p53 gene and its correlation with clincial outcome in dogs with LSA
7 dogs (16%) had p53 mutation and 36 dogs (84%) had no mutation
Overall RR was ___ in dogs with LSA having p53 mutation than those without
Overall survival was ___ in dogs with p53 mutation
lower - 33% versus 88%
lower - 67 days vs. 267 days
Meichner et al. 2016. Ezpression of Apoptosis regulating Bcl-2 and Bax in LN aspirates from dogs with LSA
55 dogs with LSA and 5 healthy dogs
Bcl2/Bax ratio was higher in dogs with ___ compared to ____
Dogs with Bcl2/Bax ratios higher than the median of the group experienced a median PFS of ___ and dogs with ratio equal and lower than the median had PFS ___
TCL, BCL
101 days, 130 days
Mani et al. 2017. Non-immunosuppressive FTY720 derivative OSU-2S mediates reactive oxygen species mediated cytotoxicity in canine BCL
OSU-2S is a FTY720 derivative that lacks immunosuppressive properties and exhibits strong anti-tumor activity
OSU-2S mediated apoptosis in canine B cell lines and primary BCL cells obstained from LSA bearing dogs
Induced ROS in canine LSA cells and inhibition of ROS rescued from cell death
Thomas et al. 2017. Integrated immunohistochemical and DNA copy number profiling analysis privides insighe into the molecular pathogenesis of canine follicular LSA
FLs have chromosome translocation that induces constitutive activation of anti-apoptotic bcl2 protein
10 dogs with FL, they exhibit ___ in frequency and intensity of bcl2 protein expression
Genomic copy number abberations were ____
None of the canine FL exhibited rearragement consistent with the hallmark translocation of human FL
Marked heterogeneity
Infrequent
Siso et al. Canine nervous system lymphoma subtypes display characteristics neuroanatomical patterns
Lymphoma infiltration within which areas were characteristics of DLBCL?
Frequent feature with PTCL?
Cell counts ___ correlated best with meningeal and periventricular LSA?
Meningeal, perivascular, periventricular
Peripheral nerve involvement
>64 cells/uL
Curran et al. 2017. Bcl2 and Myc are expressed at high levels in canine DLBCL
Canine DLBCL patients with high IHC expression of MYC and BCL2 were ___ with clincial outcome
Not associated
Calvalido et al. 2016. Comparison of serum cytokine levels between dogs with multicentric LSA and healthy dogs
Multiple cytokines have been linked in development of LSA in people
BCL (20) TCL (10)
Which cytokines were higher in LSA than healthy dogs?
Which were higher in BCL than healthy dogs?
Which were higher in TCL than healthy dogs?
Which was higher in TCL than BCL?
MCP-1, IL6, IL-10
MCP-1 and IL-10
MCP-1 and IL-6
IL-6
Davis et al. 2017. Validation of a Multiplexed gene signature assay for diagnosis of canine cancers from FFPE tissues
Significant differenced were found between BCl2, E2F TF1, MDM2, COX-2, MET protooncogene receptor kinase and other biologically relevant gene expression tumor types.
Yamazaki et al. 2017. Hypoxia activated prodrug TH-302 decreased survival rate of canine LSA cells under hypoxic conditions
Hypoxic stimulation enhances growth potentials of canine LSA cellls by activating HIF-1a and hypoxia actviated prodrug (TH-302) inhibits growth potential
Hypoxic cell culture upregulated?
HIF-1a, ABCB1, ATP binding cassette G2 (ABCG2), PDGFF, VEGF, and survivin - an enhanced growth rate, DOX resistance, invasiveness of cells
TH-302 decreased survival rate of cells under hyposix condition
Hypoxic stimulation may contribute to development of TH-302 based hypoxia targeting therapies for canine LSA
Savag et al 2018. Prognostic significance of morphocytes in canine lymphomas: A systematic review of literature
Mastromauro et al. 2018. Oral melphalan for the treatment of relapsed canine lymphoma
19 cases of relapsed LSA - 16 high dose protocol and 15 dogs got steroids
Clinical benefit?
Time to progression for responders and those with SD?
Toxicity?
31.6%
14, 24, and 34 days for responders and 20, 28, 103 days for SD
Hematological toxicity common (11/17 or 65%) and GI rare (1/17 or 6%)
Lu et al. 2017 JAK1/2 Inhibitors AZD1480 and CYT387 Inhibit canine BCL growth by increasind apoptosis and disrupting cell proliferation
JAK/STAT pathway play a role in hematologic malignancies in humans
What was observed after AZD1480 and CYT387 treatments?
Significant decrease in viable canine LSA cells. Decreased prolifration and induced apoptosis.
Pawlak et al. 2017. Methotrexate induces high level of apoptosis in canine LSA/leukemia cells lines
Evaluate methotrexate concentration-dependent cytotoxicity and capability of inducing apoptoaia in 3 cell lines
Concentration-dependent inhibitory effect on proliferation of all cell lines with different degree of apoptosis.
Most sensitive cell line was CL-1 - derived from TCL
Lane et al. 2017. Low grade GI LSA in 20 dogs: 20 cases (2010-2016)
Common clinical signs?
Immunophenotype?
Required for definitive diagnosis?
Most commonly used drugs?
ORR? MST?
Weight loss, vomiting, diarrhea
T-cell (95%) and epitheliotrophism commonly described (60%)
IHC, or PARR, or both were required for definitive diagnosis
CHB and pred
70% and 424 days (14 months)
Assumocao et al. 2018. STAT3 expression and activity are upregulated in DLBCL of Dogs
43 dogs diagnosed with DLBCL
The % of STAT3 and pSTAT3 immunolabeled cells in DLBCL compared to normal canine LN?
In STAT3 immunolabeled cells, STAT3 had ___ in LSA sampled than in normal or reactive LN
Mitogen activaed ERK1/2 activation?
Higher percentage
Higher nuclear expression
Upregulated in DLBCL dogs
Childress et al. 2018. Retrospective analysis of factors affecting clinical outcome following CHOP-based chemotherapy in dogs with primary nodal DLBCL
Factors associated with achieving partial remission included?
Factors associated with PFS in lowest quartile (<93 days) included?
Thrombocytopenia, baseline globulin concentrations, and greater age
Thrombocytopenia, greater age, baseline neutrophil counts
Gavazza et al. 2018. Fecal microbiota in dogs with multicentric lymphoma
Determine differences in fecal microbiotia between healthy and dogs with multicentric LSA
Lower abundance of what organisms in LSA than healthy dogs?
What was higher in dogs with LSA?
Dysbiosis index?
Faecalibacterium spp., Fusobacterium spp. Turicibacteria spp.
Streptococcus spp.
Higher in dogs with LSA
Significant differences in microbial communities of dogs with LSA compared with healthy dogs
Suenaga et al. 2017. Comprehensive analysis of gene expression profiles reveals novel candidates of chemotherapy resistant factors in canine LSA
10 dogs with LSA at chemotherapy sensitive and chemotherapy resistant phases
During chemotherapy resistance which genes were decreased compared to chemetherapy sensitive phase?
Immune response and inflammatory reaction
McQuown et al. 2017. Preliminary investigation of blood concentrations of insulin-like growth factors, insulin, lactate, and B-hydroxybutyrate in dogs with LSA as compared to matched controls
IGF-1, insulin, glucose, and insulin:glucose rate between the 2 groups?
What was higher in dogs with LSA compared to control dogs?
Not different
Lactate and B-hydroxybutyrate
Cozzi et al. 2017. Canine nodal maginal zone LSA: Descriptive insight into the biological behaivour
nMZL is an indolent LSA. Describe the clinical features.
35 cases
All dogs showed ___ ?
How may were systemically unwell?
Stage of disease?
LN population was composed of?
Histology showed?
Median TTP and LSS?
Generalized lymphadenopathy
1/3
Stage V, 1/3 had extranodal involvement
CD21+ cells
diffuse LN involvement - “late-stage” MZL
149 days (5 months) and 259 days (8.6 months)
Oucome is poor despite the indolent designation.
Davis et al. 2017. A retrospective review of acute myeloid leukemia in 35 dogs diagnosed by combination of morphologic findings, flow cytometric immunophenotypinc and cytochemical staining results (2007-2015)
Presenting clinical signs?
Common hematological findings?
Overall median survival from diagnosis?
Hematological response to various chemotherapies documented in 3 dogs with associated survival?
Dogs treated with prednisone or combination of chemo and prednisone had?
Inappetance (66%), lethargy (57%), peripheral lymphadenopathy (74%), and tachypnea (64%)
Circulating blasts (85%), anemia (median hematocrit 24%), theombocytopenia (median 57k)
19 days
62, 103, 121 days
Improved survival
Matsumoto et al. 2018. IgA antibodies against Gliadin and Tissue Transglutaminase in dogs with chronic enteritis and intestinal TCL
Dog with intestinal LSA were likely to have?
High levels of serum IgA against gliadin and tTG and serum IgG Ab against tTG
Association between inflammatory stimulation by gliadin peptides and subsequent intestinal LSA in dogs
Davies et al. 2017. Prognostic significance of clinical presentation, induction and rescue treatment in 42 cases of canine centroblastic DLBCL in UK
DLBCL treated with either COP-type(35%) or CHOP-type (64%) induction chemotherapy
Objective RR to induction therapy?
Median PFS
What factors were independently predictive of longer PFS?
Median OS? 1- and 2- year survival rate?
What factors were independently predictive of longer OS?
94% - greater CR vs. PR
182 days (6 months)
Absence of anemia at diagnosis and pretreatment neutrophil:lymphocye ratio (NLR) below 9.44
322 days (10.7 mo) - 38% and 9%
L:M ratio above 1.43, NLR below 11.44, combination of induction and rescue therapy, and total number of doxorubicin disease
Comazzi et al. 2018. Effects of preanalytical variables on flow cytometric diagnosis of canine LSA: A retrospective study (2009-2015)
Assess preanalytical variables that might influence LN and FNA specimens from dogs with lymphoproliferative disease
What affected having a diagnostic sample?
What increased the odds of obtaining a diagnostic sample?
Major artifacts affeting the diagnostic utility?
Submitting veterinarian, sample material, sample cellularity and artifacts
Specimens from different sites and cytological smears
Poor cellularity and presence of dead cells
Bennett et al. 2018. Demographic risk factors for LSA in Australian dogs: 6201 cases
30 breeds at increased risk for LSA - 15 not previously reported and 26 breeds at decreased risk and 18 not previously reported
Which sex was overepresented?
Neuter status?
Males over females with OR 1.1
Neutered animals were at higher risk with OR 3.2 in both males and females
Fournier at al. 2018. Impact of pretreatment neutrophil count on chemotherapy administration and toxicity in dogs with LSA treated with CHOP chemotherapy
All dogs with ANC ___ recovered without medical treatment?
The number of dose delays are minimized with a prechemotherapy ANC cutoff?
Prechemotherapy ANC class not associated with increased toxicity?
Further investigation of an ANC cutoff near .75 x 103/uL in which to prescribed antibiotics is indicated
.75 x 103/uL
- 5 x 103/uL
- 5-1.99 x 103/uL
Moore et al. 2018. Usefulness of chemotherapy for the treatment of very elderly dogs with multicentric LSA
Duration of remission and survival time in dogs >14 years of age with stage 2 to 5 multicentric LSA
22 received chemotherapy and 7 got prednisolone alone
MST for dogs receiving prednisolone?
CR achived in how may dogs? PR?
Median duration of remission?
Which dogs had briefer remission?
MST? 1- and 2-year survival?
AEs grade 3 or worse?
Chemotherapy should not be withheld, dose adjusted because of age.
27 days
95% and 5%
181 days
Anemic dogs (110 days) than nonanemic (228 days)
202 days, 31% and 5%
27%
Moetgi et al. 2018. Prognostic value of CD44 variant isoform expression in dogs with multicentric high grade BCL
45 dogs with multicentric BCL and 10 healthy dogs
CD44 variants of exons 3, 6, 7 and CD44 whole isoform
For all isoforms evaluated mRNA expression in dogs with BCL was ___ that control dogs
Dogs with BCL had ___ CD44, ___ ORR, median PFS, and median OST?
Lower
High, lower
High expression of 3, 6, 7 was associated with poor prognosis in dogs with BCL
Ambrosius et al. 2018. Quantification and prognostic value of programmed cell death ligand-1 expression in dogs with DLBCL
How many dogs with DLBCL had PD-L1 fold change >1?
Median PFST?
Was PFST associated with PD-L1 expression?
50%
249 days (8.3 months)
NO, but was assosciated with thrombocytopenia
PD-L1 overexpressed in half the study population - anti-PDL1 therapies may be beneficial in some dogs
Miniscalco et al. 2018. Flow cytometric characterization of S-phase fraction and ploidy in LN aspirate
Describe DNA content analysis uaing LN aspirated from 112 dogs with LSA
S-phase fraction accurately descriminated between low- and high-grade LSA with ___ being the best cutoff value
No significant results was obstained with regards to survival and SPF
3.15%
Hartlet et al. 2018. Cancer stem cell population in LSA in dogs and impact of cytotoxic chemotherapy
Quantitated CSC in dogs with BCL and TCL uring tumor aspirates and FC with a panel of CSC markers
The percentage of tumor cells expressing CSC marekrs were ___ in dogs with BCL, compared with B cells from normal LNs? TCL?
In vitro studies revealed that LSA cells selected for resistance to CHOP had significantly ___ expression of CSC markers, and expressed greater ___, compared to chemotherapy sensitive cells
Significantly increased, similar in TCL
Significantly greater, aldehyde dehydorgenase activity
Similar results in relapsed BCL
Cytotoxic chemotherapy can lead to enrichment of CSC properties and may be associated with relapse
Morgan et al. 2018. Canine TCL treated with lomustine, vincristine, procarbazine and prednisolone chemotherapy in 35 dogs
Used a modified protocol
Median PFS?
6-month, 1-year, 2-year, and 3-year PFS?
MST?
How many dogs had AEs?
431 days (14.4 mo)
69%, 54%, 29%, 12%
507 days (17 mo)
30 dogs (85%) with 73% being grase 1 or 2
Assumpcao et al. 2018. Targeting NEDD8-activating enzyme is a new approach to treat canine DLBCL
Harding et al. 2018. Response rate to a single dose of vinblastine administered to dogs with treatment-naive multicentric LSA
22 dogs
How many of the 14 dogs receiving vinblastine at 2 mg/m2 had response?
How many of the 5 dogs receiving vinblastine at 2.5 mg/m2 had response?
GI toxicity?
How many dogs developed neutropenia at 2.5 mg/m2?
1/14 PR
3/5 PR
Low in both groups
80% at 1 week post-administration
Treatment at 2.0 mg/m2 is not recommended. Higher does may have improved efficacy
Sato et al. 2018. Prognostic significance of hypermethylation of death-associated protein kinase (DAPK) gene CpG island with high-grade BCL
DAPK is a serine/threonine tumor suppressor genes
47 dogs
Hypermethylation of DAPK was detected in how many dogs?
PFS and OS with hypermethylation?
In the multivariable analysis, what was prognostic factor indicating shorter PFS?
20/47 (42.5%)
220 and 266 days and shorter than without hypermethylation (301 vs. 412)
Hypermethylation of DAPK
Tanis et al. 2018. Evaluation of a multiagent chemotherapy protocol combining lomustine, procarbazine and prednisolone (LPP) for treatment of relapsed canine non-Hodgkin high-grade LSA
41 dogs
How may dogs responded?
What was the time from initiation to discontinuation (TTD) in responders?
How common was neutropenia?
How many had elevated ALT?
Treatment discontinued in how may?
61% - 12 CR and 13 PR
84 days for CR and 58 days for PR
57% - 12 grade I to II, 8 grade III to IV
59% - 9 grade I to II, 10 grade III to IV
19% 8 dogs
Hartley et al. 2018. Checkpoint molecule expression by B and T cell LSA in dogs
FC used to analyze expression of PD-1 and PD-L1 from 34 BCL, 6 TCL, 11 relapsed
Expression of PD-L1 B cells?
Expression of PD-L1 and PD-1 T cells?
Expression on tumor infiltrating lymphocytes?
In-vitro chemotherapy resistant BCL and TCL had ___ PD1 and PD-L1?
Increased expression by malignant B cells compared to normal B cells
Low to normal expression on tumor cells and normal T cells
Increased expression of PD-L1 and PD-1 on TCL and BCL
Increased expression
Canine LSA upregulate checkpount molecule expression
Ku et al. 2017. Cytologic-histologic concordance in the diagnosis of neoplasia in canine and feline LNs: a retropsective study of 367 cases
Determine the accuracy of cytologic diagnosis in LNs using histology as gold standard
Cytology sensitivity? specificity? Accuracy?
Likelihood of malignancy with positive cytologic diagnosis of neoplasia?
High proportions of false negative found in?
Factors contributing to discrepancy?
66.6%, 91.5%, 77%
93%
mesenteric TCL (63%, mainly cats), metastatic sarcoma (57%), metastatic MCT (31%, mainly dogs)
well differentiated lymphocyte morphology, focal distribution of metastases and poorly defined criteria for metastatic MCT
Pawlak etl al. 2017. A novel B-cell leukemia cell lines. Establishment
Noland et al. 2018. Subcutaneous Panniculitis-Like TCL in dogs: Morphologic and Immunohistochemical Classification
Canine nonepitheliotropic cutaneous T-cell lymphoma (NECTCL) are poorly characterized.
5 dogs with Subcutaneous Panniculitis-Like TCL (SPTCL)
Median age
Breed and sex predilection?
Location?
Treatment with CCNU?
Histologically?
Cloncal TCR rearrgement in 5 cases
8.5 years
None
Shoulder, neck, ventral abdomen
7 months post-diagnosis
Proliferation of small to intermediate or large sized, CD3+ T cells infiltrated the subcutis in a lace like pattern and frequently rimmed adipocyts - No epitheliotropism was observed
Noted in 4/5 cases
Chimura et al. 2013. Transcription profile of chemokine receptors, cytokines and cytotoxic markers in peripheral blood of dogs with epitheliotropic cutaneous LSA
10 dogs with MF and 10 healthy dogs
What was the expression of CCR4, epitheliotropism (CXCR3), LN homing (CCR7), and type-1 cytokine (LT-a) and cytotoxic markers (perforin and granzyme) in circulation?
Lower in dogs with MF compared to healthy dogs
Peripheral cytotoxic T cells with skin-homing phenotype could be decreased in peripheral blood because of sequestration in lesional skin
Holtermann et al. 2016. Masitinib monotherapy in canine epitheliotropic lymphoma
CR occured in how many of the 10 dogs? Median?
PR? Median?
IHC available in 8 dogs - KIT expression?
2/10, 85 days
5, 60.5 days
KIT-, 6/8 positive for SCF, PDGF-AA weakly positive in 2, PDGF-BB negative 4, weakly positive 1, strong positive 3.
Strongly positive for PDGFR-B in 1, 7 negative
Strongly positive for PDGFR-a in 5, 2 weak, 1 negative
Effects of masitinib are not through KIT.
Morges et al. 2014. Phase II evaluation of VDC-1101 in canine cutaneous TCL
12 dogs received drug as 30min IV infusion every 21 days, prednisone 1 mg/kg q48 given concurrently
Responses?
ORR? BRR?
Median PFS?
How may dogs developed dematopathy?
1CR, 4PR, 2SD, 4PD
45% and 64%
37.5 days
3 and 1 of these was removed from the study
van Stee et al. 2015. Outcome and prognostic factors for canine splenic LSA treated by splenectomy (1195-2011)
28 dogs
1 year survival rate?
Which immunphenotype had better prognosis?
Most common subtypes of BCL?
What were 4 poor prognostic indicators?
Positive prognostic indicator?
Adjuvant chemotherapy?
58.8%
BCL than other variants of splenic LSA
Marginal zone LSA and mantle cell LSA
Hemoabdomen, abdominal distension, lethargy, anorexia
Disease confined to the spleen
No survival benefit
O’Brien et al. 2013. Clinical characteristics and outcome in dogs with splenic marginal zone LSA
34 dogs, 29 splenectomy and 5 necropsy
Immunophenotype?
How may had cloncal rearragemnet of Ig gene of 33 dogs?
MST for 29 dogs that underwent splenectomy?
MST for 14 dogs that were asymptomatic?
All BCL
24, 3 pseudocloncal, and 6 polyclonal
383 days
1153 days (3 years) compated to 309 with CS
Albonico et al. 2013. The expression ratio of miR-15-5p and miR-155 correlates with grading in canine splenic LSA
The molar ratio between miR-15-5p and miR-155 correlated with?
WHO grading
New molecular tool for grading canine splenic LSA
Wiggans et al. 2014. Presumed solitary intraocular or conjunctival LSA in dogs and cats: 9 cases
Animals with introcular LSA represented ___% of patients with ___
Animals with conjunctival LSA represented ___% of patients with ___
Tumors included B-cell (2 IO and 1 conj), non-B cell, non Tcell (1 IO), and T cell (3 conj)
Treatments?
All dogs with IO developed?
LN mets?
Median PFS and OST for PSOL
Median PFS and OST conj LSA
- 19, uveitis
- 16, conjunctivits
enucleation (4 IO) and chemotherapy (3 IO and 2 conj)
Neurologic signs
2 patients with conjunctival LSA
178 days for IO
221 and 549 days
Prongnosis better for conjunctival LSA than IO LSA
George et al. 2016. Outcome of dogs with intranasal LSA treated with various radiation and chemotherapy protocol: 24 cases
18 cases were intermediate to high grade and 6 were low-grade
Overall MST for high-grade?
Cases treated with RT +/- chemo?
Chemotherapy alone?
MST for low grade group?
375 days (1 year)
455 days (15 months)
157 days (5 months)
823 days (2.25 years)
Support the use of RT for intranasal LSA. Role of chemo requires further investigation
Nemec et al. 2012. Erythema multiformer and epitheliotropic TCL in the oral cavity of dogs: 1989-2009
14 dogs with erythema multiforme or epitheliotropic TCL
What was common?
Histologic features diagnostic in how many cases?
IHC?
What was also used to determine clonality?
Ulcerative stomatitis
7 cases (50%)
3 cases (21%)
PARR - 1 case
Histologic features are not always diagnostic. IHC and clonality testing may assist between the two disease
Hiyoshi et al. 2015. Association between lymphocyte antigen receptor gene rearrangement and histopathological canine chronic enteropathy
Investigate the relationship between PARR and histopath diagnosis
Endoscopic biopsies form 96 dogs with chronic enteritis and 21 GI LSA
Clonality observed in how many chronic enteritis? mild enteritis?
Dogs with marked enteritis, rate of PARR was ___ than those with lymphocyte epitheliotropism than without epitheliotropism
Sensitivity of PARR with GI LSA?
Who had shorter survival?
51%, 29% of those with mild enteritis
Higher
76%
Dogs with marked enteritis those with mild or moderate enteritis
Ohmura et al. 2017. Detecttion of monoclonality in intestinal LSA with PCR for antigen receptor gene rearrangement analysis to differentiate from enteritis in dogs
Assessed clonality of 29 canine intestinal LSA, 14 enteritis, and 15 healthy controls
Detect monoclonal rearragements in how many of intestinal LSA?
Polycloncal rearragements?
Immunophenotype?
76% (22/29)
100% enteritis and healthy controls
T cell was 85% vs. B cell
Desmas et al. 2017. Clinical presentation, treatment and outcome in 31 dogs with presumed primary colorectal LSA (2001-2013)
What were the predominant features?
Substage?
1 dog had surgery and 30 received chemotherapy (13 had surgery or RT)
PFS and MST?
Which dogs had longer survival?
Presence of hematochezia corresponded with?
Addition of local treatment to chemotherapy did not significantly improve the outcome
high grade (18) and B cell immunophenotype (24)
b (25) with hematochezia (20)
1318 days (3.6 y) and 1845 days (5 years)
Younger dogs
Longer PFS
Flood-Knapik et al. 2013. Clinical, histopathological and immunohistochemical characterization of canine indolent LSA
Indolent LSA comprise 29% of all canine LSA
What was the most common histopathological subtype?
The addition of IHC resulted in?
Did the use of systemic chemotherapy influence survival?
Dogs treated with CHB and pred MST?
Dogs treated with CHOP?
T-zone (61.7% (MST 33.5 months), then marginal zone 25% (MST 21.2 months)
Revised diagnosis 20%
No
Not reached
21.6 months
Seelig et al. 2014. Canine T-zone LSA: unique immunophenotypic features, outcome, and population characteristics
Hypothesis - Loss of expression of CD45 is specific feature for TZL
All 20 CD45- cases were classified as?
The 15 CD45+ were classified as?
MST of TZL?
Immunophenotyping demonstarted most cases are in what breed and median age? Presented with what 2 signs?
TZL
Aggressive TZL
637 days (1.7 years)
Golden retrivers and 10 years and have lymphadenopathy and lymphocytosis
Harris et al. 2017. Clinicopathologic features of lingual canine T-zone LSA
12 dogs with tongue masses were diagnosed with lingual TZL
11 dogs had?
3 cases were initially diagnosed as?
How many achieved clinical remission
lymphocytosis and/or LN enlargement
Plasma cell tumors
7 dogs (58%) and 4 achieved SD
1 case had PD and failed to respond to treatment - had histologic features of high grade neoplasm
Martini et al. 2016. Canine small clear cell/T-zone LSA: clinical presentation and outcome in a retrospective case series
Most dogs had what stage of disease?
Was blood or BM more infiltrated?
Prognosis?
Stage V
Blood
Favourable in most cases but few dogs died in a short time
Martini et al. 2015. Flow-cytometric detection of phenotypic abberancies in canine small clear cell LSA
All cases showed antigen abberancies and neoplasia was always confirmed
Combined use of cytology and FC allows solving the differential diagnosis between small clear cell LSA and non-neoplastic reactive conditions
Bromberek et al. 2016. Breed distribution and clinical characteristics of B cell chronic lymphocytic leukemia in dogs
Median age of dogs?
Clinical signs?
What breeds had increased risk?
What single breed had increased risk and possible unique features?
11 years
50% peripheral lymphadenopathy or splenomegaly, 26% anemia
Small breeds
English Bulldogs - median age 6 years and lower MHC II and CD25
Giantin et al. 2013. Evaluation of tyrosine-kinase receptos c-KIT mutation, mRNA, and protein expression in canine leukemias: might c-KIT represent a therapeutic target?
11 ALL and AUL and 12 CLL
Higher c-KIT mRNA was found in?
ALL/AUL (acute undifferentiated leukemia) compared to CLL
Might represent rationale for using TKIs
Stokol et al. 2015. Alkaline phosphatase is a useful cytochemical marker for the diagnosis of acute myelomonocytic and monocytic leukemia in the dog
ALP is expressed in immature canine monocytes - possible marker for AML
ALP activity in LSA and CLL?
ALP activity in ALL?
ALP activity in AML?
How many of the AML were CD34+? MHCII-
None
31% had weak ALP activity
100%
80% and 100% MHCII-
ALP activity may useful to confirm AML if neoplastic cells only express CD34+ on immunophenotyping
Moore et al. 2017. Patient characteristice, prognostic factors and outcome of dogs with high-grade mediastinal LSA
Common clinical signs?
2 other common findings?
Phenotype?
Overall PFS and OS?
Treatment with CHOP improved PFS in comparison to other medical therapies? OS?
Absence of pleural effusion was associated with?
Lethargy, anorexia, PU/PD
Hypercalcemia and pleural effusion
T-cell
133 days (4.4 mo) and 183 days (6 months)
144 days (5 months) and 194 days (6.5 months)
Increased OS but not PFS
Hughes et al. 2017. Increased frequency of CD45 negative T cells (T zone cells) in older Golden Retrievers
TZL is characterized by T cells lacking expression pan-leukocyte antigen CD45 (TZ)
Gene expression analysis on confirmed TZL showed what compared to normal dogs?
Peripheral blood from senior dogs, 242 GRs and 42 non-GR were assessed for TZ cells by FC
What % of GR had TZ cells?
How many of these had clonal rearragement?
How may GR without TZ cells had clonal rearragement?
Decrease in CD45 expression compared
31% vs. 14% non-GR
34% for TCR
20%
GR have increased risk due to increased frequency of TZ cells
Thamm et al. 2013. DNA repair deficiency as a susceptibility marker for spontaneous LSA in goldn retriever dogs: a case-control study
Evaluate DNA repair capability after exposure to ionizing radiation or bleomycin
GR with LSA demonstrated elevated sensitivity to induction of chromosome damage compared to healthy GR or mixed breed dogs (MBD)
Findigns suggest individual (rather than breed) susceptibility and suggest deficiencies in heirtable factors related to DNA repair capabilites may be invovled in development of LSA
Patterson et al. 2014. Sonographic characteristics of thymoma compared with mediatinal LSA
Appearance of thymomas sonographically compared to LSA?
Lymphomatous LNs were more like to be?
Cystic (57%) and heterogeneous (94%) in echogenicity
Solid (80%) and divided between hypoechoic (47%) and heterogeneous (53%)
Taylor et al. 2014. Ultrasonographic characteristics of canine renal lymphnoma
All dogs with renal LSA had what feature?
Other US findings?
Bilateral lesions seen in?
FNA performed in 9 dgos and yielded a diagnosis in 7 dogs on first attempt (78%)
Pyelectasia
Loss of corticomedllary distinction (9/10), renomegaly (8/10), renal deformity (6/10), hypoehoic lesion (6/10), hyperechoic lesions (2/10)
90%
Linta et al. 2017. The feasibility of contrast enhanced ultrasonography in the diagnosis of non-cardiac thoracic disorders of dogs and cats
Majority of neoplastic lesions showed?
Inflammatory lesions showed?
Mediastinal malignant lesions showed?
Lung and mediastinal abscesses?
Inhomogenoeus distribution of contrast medium
Homogenoeus distribution
Inhomogeneous distribution pattern
Peripheral enhancement of the wall with an avascular center
Watton et al. 2017. Can malignant and inflammatory pleural effusion in dogs be distinguished using CT?
20 dogs with malignant pleural effusion (13 mesothelioma, 6 carcinoma, 1 LSA) and 32 pleuritis (18 pyothorax and 14 chylothorax)
Age of dogs with malignant pleural effusion?
CT findings with malignant pleural effusion?
Signs of thoracic wall invasion were seen in?
Older (median 8.5 years vs. 4.9 years)
Pleural thickening (65% vs. 34%), tended to have thickening of the parietal pleural only (45% vs. 3%) and more marked pleural thickening (3mm vs. 0 mm)
Only with malignant pleural effusion
No difference in pleural fluid volume, attenuation, contrast enhancement, amount of pannus, prevalence of mediastinal adenopathy
Marked thickening of the parietal pleural and signs of thoracic wasll invasion support malignant neplasia
Allett et al. 2016. MRI findings in the spine of 6 dogs diagnosed with LSA
Common findings included multifocal disease (4/6), vertebral invovlement (5/6), spinal cord compression (4/6), involvement of more than one spinal compartment (medullary cavity, vertebral canal, paraspinal soft tissues) (6/6)
All spinal and paraspinal lesions identified were T2-W isointense to hyperintense, STIR hyperintense, T1-W hypointense to isointense, showed variable moderate to strong enhancement
The STIR and T1-W postcontrast sequences were subjectively most useful to identify spinal and paraspinal lesions.
Feeney et al. 2013. Applicability of 3T body MRI in assessemnof nonfocal BM invovlement of hematopoeitic neoplasia in dogs
Out-of-phase MR pulse sequence was useful in distinguising diffuse bone marrow infiltrate from minimally or unaffected marrow using skeletal muscle for signal intensity comparison on whole body MRI
Tater et al. 2017. Assessment of cardiac troponin I and tissue velocity imaging in 14 dogs with malignant lymphooma undergoing chemotherapy treatment with doxorubicin.
Did the standard echocardiographic parametgers, tissue doppler indices or cTnI concentrations differ at any time point in 12-week cycle?
No
Use of doxorubicin at standard doses for LSA may not be associated with significant myocardial damage.
Mizutani et al. 2016 Evaluation of CD25 positive cells in relation to the subtypes and pronoses in various lymphoid tumors in dogs
IHC of DLBCL, TZL, follicular lymphoma
CD25 positive cells for consistently detected in?
CD-25 positivity in LN was higher in?
PFS with relation to CD25-high and CD25-low group?
TZL and FL, variable in DLBCL
High grade BCL or TZL than healthy dogs
Shorter in CD25-high group than CD25-low group
Fujiwara et al. 2015. Expression profile of corculating serum micRNA in dogs with LSA
The expression levels of 4 miRNA were reduced in LSA group- let-7b, miR-223, miR-25, miT-92a
miR-423a was significantly increased to the controls
Johnston et al. 2014. The immunosignature of canine LSA: characterization and diagnostic application
An individual immunosignature and a generalized immunosignature was observed.
General LSA immunosignature was able to predict disease status in independent set of dogs (97% accuracy)
A seperate immunosignature was eblt to distinguish LSA based on immunophenotype (88% accuracy)
Individual immunosignature was capable of confimring remission 3 months following diagnosis.
Was able to predict which dogs with BCL would relapse in <120 days (accuracy 97%)
Rutgen et al. 2015. Composition of lymphocyte subpopulation in normal canine LNs
CD11a(+) 92.2 ± 12.3%, CD3(+) 55.0 ± 14.1%, CD3-12(+) 57.3 ± 14%, CD5(+) 52.3 ± 12.7%, CD21(+) 33.9 ± 11.8%, CD79αcγ(+) 46.9 ± 14.8%, CD56(+) 4.9 ± 5.9%, and CD14(+) 5.5 ± 6.8%. There were 58.7 ± 9% CD4(+) and 21.3 ± 7.8% CD8(+) cells inside the gate of CD3(+) cells. Cytology revealed a mixed population of mostly lymphoid cells in all samples. The absence of a monoclonal or oligoclonal neoplastic population was confirmed by PARR.
Deravi et al. 2017. Specific immunotypes of canine T cell lymphoma are associated with different outcomes
Compared to multicentric T cell lymphoma, gastrointestinal lymphoma had shorter survival and progression free interval, and hepatosplenic lymphoma had shorter survival.
Among dogs with multicentric T cell lymphoma, immunotypes of CD4+/CD8-/MHCII+, CD4-/CD8+/MHCII+ and CD4-/CD8+/MHCII- were associated with longer survival times than the immunotype of CD4+/CD8-/MHCII-, and immunotypes of CD4+/CD8-/MHCII+, CD4-/CD8+/MHCII-, and CD4-/CD8-/MHCII+ were associated with longer progression free intervals.
Dogs with multicentric T cell lymphoma and concurrent leukemia had shorter survival but similar progression free interval compared to those without leukemia. Body weight, sex, hypercalcemia, cell size, expression of CD3 and use of combination or single agent chemotherapy did not significantly affect outcome of multicentric TCL.
Flesner et al. 2014. 6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells
6-TG is epigenetically active as a demethylating agent casuing downregulation of DNA methyltransferase 1(DNMT1) through ubiquiting targeted degradation
Zebularine a cytidine analog also has demethylating activity as oral bioavilability
Cell line were treated with each agent, DNMT1 protein and global DNA methylatinn was significantly __?
Decreased
Dose-dependednt decrease in cel survival with apoptosis being the main cause of death
de Mello Souza et al. 2014. Detection of retinoid receptors in non-neoplastic canine lymph nodes and in lymphoma
Non-neoplastic lymphocytes were ___ for all retinoid receptors?
Retinoic acid receptor-g was detected in __ BCL and __ TCL
Retinoid X receptor-g was positive in __?
Negative
100%, 78%
78% of TCL
Fujiwara et al. 2014. Inhibition of p16 tumor suppressor gene expression via promoter hypermethylation in canine lymphoid tumor cells
Methylation status was examined in 4 cell lines
In 3 cell lines with low level p16 mRNA expression, ___ CpG sites in promoter region wee methylated but not in 1 cell line
Expression of p16 mRNA was restroed after cultivation with methylation inhibitor, 5-Aza-2’deoxycytidine
Inactivation of p16 gene by hypermethylation of its CpG island in a fraction of canine lymphoid tumor cells
20
Asproni et al. 2014. Immunohistochemical expression of COX-2 in normal, hyperplastic, and neoplastic lymphoid tissues
24 hyperplastic samples and 44 lymphoma samples (22 BCL and 22 TCL)
How many were positive in hyperplastic LN?
How many LSAs were positive?
Few macrophages were COX-2 positive
Six of 44 LSA (13.6% - 3B and 3 T) overexpressed COX-2
Axiak-Bechtel et al. 2014. Chemotherapy and remission status do not alter pre-existing innate immune dysfunction in dogs with LSA
Dogs had ___ production following LPS stimuation and ___ following peptidoglycan stimuation - did this imrpove following remission of LSA?
Dogs had ___ E.coli induced respiratory burst function after chemotherapy induced complete or partial remission
decreased TNF, increased IL-10, did not improve
Reduced
Poggi et al. 2015. Flow cytometric evaluation of Ki67 for the determination of malignancy grade in canine lymphoma
High grade showed compared to low grade LSA?
Was there a difference between B and T immunophenotype?
higher ki67 compared to low grade LSA
Significant difference was detected
Cut-off value of 12.2% with sensitivity 96.3% and specificity 100%
Tomiyasu et al. 2014. The regulation of the expression of ABCG2 gene through mitogen-activated protein kinase pathways in canine lymphoid cell lines
Tomiyasu et al. 2014. Epigenetic regulation of the ABCB1 gene in drug-sensitiveand drug-resiatnt lymphoid tumor cell lines obtained from canine patients
In 2 drug sensitive cell lines, GL-1 and CLBL-1, ABCB1 mRNA was lower than drug resistant cell line, UL-1, Ema
CpG island present in the upstream regions of exon 2 was hypermethylated in GL-1 and CLBL-1, but hypomethylated in UL-1 and Ema
Histone H3 was increased in UL-1 and Ema compared to GL-1 and CLBL-1
Treatment with inbhitor increased ABCB1 mRNA expression in GL-1 and CLBL-1
Thalheim et al. 2013. Lymphoma immunophenotype of dogs determined by IHC, FC, and PCR for antigen receptor rearragements
Sensitivity of FC vs. PARR for B cell
Sensitivity of FC vs. PARR for T cell
Percent agreement between FC and IHC?
Between PARR and IHC?
FC and PARR?
Among all 3
91% vs. 67%
100% vs. 75%
94%
69%
63%
63%
FC is superior to PARR for immunophenotyong
Avery et al. 2014. Flow cytometric characterization and clincial outcome of CD4+ TCL: 67 cases
The majority of CD4+ TCL were? Median survival?
Histologically classified as either?
What had an effect on PFI and survival?
Which had a more indolent course?
CD45+, low MHCII and aggressive clinical course, 159 days
lymphoblastic or peripheral T cell
Size of the neoplastic lymphocytes
CD45- and MHCII high
Woldemeskel et al. 2014. Tumor microvessel density-associated mast cells in canine nodal LSA
Mast cells are associated with angiogenesis
What was the mast cell count in LSA compared to control?
Was mast cell count correlated with tumor microvessel density?
Was there a difference in mast cell count and tumor microvessel density among different grade of LSA?
Higher
Yes
No
Giantin et al. 2013. Evaluation of tyrosine-kinase receptor c-kit mutations, mRNA, and protein expression in canine LSA: might c-KIT represent a therapeutic target?
25 BCL and 21 TCL
KIT mRNA was amplifiable but low limit in?
Which showed higher expression of KIT?
Gain of function mutations?
76% BCL and 33% TCL
High grade TCL - higher mRNA observed
None
Potential use in HG TCL
Gramer et al. 2015. Determination of MDR1 gene expression for prediction of chemotherapy tolerance and treatment outcome in dogs with LSA
MDR1 expression analyzed in 27 dogs with malignant LSA receiving chemotherapy
Dog developing severe AEs under treatment had?
In longitudinal MDR1 expression analysis, 4 dogs showed greater than 2-fold MDR1 upregulation - all 4 of these had disease progression but none of the other dogs
Signifcantly lower basal levels compared to those who tolerated the drugs well
Ginn et al. 2014. Positive association between a glutathione-S-transferase polymorphism and LSA in dogs
Plays a role in detoxification of carcinogens
Low activity of GSTT1 are risk factors for NHL in people
93 LSA and 86 age-matched controls
Of the 27 canine GSTT1 variants the 12+28 G?A was assocaited with LSA with the AA genotype found in 18.3% but only 3.5% controls
Elliot et al. 2013. Thymidne kinase assay in canine LSA
TK correlated with duration of first remission or survival in dogs with LSA
How may had TK above the reference interval at initial?
Difference between BCL and TCL?
TK and higher stage of disease?
TK activity prior to treatment and DFR and survival?
TK at remission?
47%
BCL had higher than TCL
Not higher
No association
Fell into normal range at remission if elevated
Seiser et al. 2013. Reading between the lines: molecular characterization of 5 widely used canine LSA tumor cell lines
Aberrant gains of what genes were noted?
Deletions of what genes?
MYC, KIT, FLT3
PTEN and CDKN2
Aresu et al. 2014. VEGF and MMP-9: biomarkers for canine LSA
TGF-B stimulates VEGF and MMP production (useful biomarkes in human LSA)
Expression of MMP-9 and VEGF and TGF in dogs with LSA?
Act-MMP9 and VEGF were higher in?
VEGF in high grade vs. low grade TCL
During chemotherapy, what happend to MMP-9 and VEGF?
MMP9 and VEGF were higher and TGF-B was lower than control dogs
TCL, stage V compared to stage III-IV regardless of immunophenotype
Higher in HG TCL
No correlation between cytokines and outcome
Decreased in BCL
Kiser et al. 2017. Lymphoma classification in goats
Age and breed?
Sexes?
How many had TCL? BCL?
Which distribution was common?
TCL invovlved?
TCL were further classified as?
BCL were classified as?
You (median 3 years) and dwarf breeds (pygmy)
Similar
73% amd 27%
Multicentric
Thoracic cavity and neck - thymic origin
lymphoblastic (27%), LGL (9%), diffuse small lymphocytic LSA (27%), pripheral/mature TCL not otherwise specified (36%)
DLBCL (50%), B-cell lymphocytic lymphoma intermediate type (50%)
Goats get TCL!!!
Sogame et al. 2018 Intestinal lymphoma in dogs: 84 cases
Overall MST
Factors associated with shorter survival times?
Most common changes noted in intestinal tract?
Protocols used?
MST with treatments used?
62 days
Anorexia, septic peritonitis and tumor location (intestinal tract only, intestinal tract and abdominal LN, or intestinal tract and extraintestinal organs)
Altered wall thickening with loss of layering (41) and presence of >1 discrete mass (24)
L-CHOP or CHOP (48) and CCNU (14)
60 days vs. 144 days - but did not differ significantly
Anorexia and septic peritonitis are associated with poor prognosis
Sadowski et al. 2018. Phase II study of the oral selective inhibitor of nuclear export (SINE) KPT-335 (verdinexor) in dogs with LSA
Verdinexor is a orally bioavailable selective inhibitor of SINE
58 dogs with naive or progressive B or TCL - 1.5 mg/kg 3x/weekly
Treatment with single agent resulted in ORR of? TCL had ORR?
Toxicity?
37%, 71%
Well tolerated with grade 1 or 2 anorexia
Comazzi et al. 2018. Breed-associated risks for developing canine LSA differ among countried: an European canine LSA network study
Which breeds had significant predisposition to LSA?
Which breed developed TCL?
Which breed developed BCL?
Were labradors predisposed to LSA?
How about Golden Retriever?
Boxers, Rottie, Doberman, and Bernese mountain dog
Boxers
Rottie
Nope b ut developed high grade TCL
No predisposition to LSA to TZL
Yamazaki et al. 2018. Dynamic changes in DNA methylation patterns in canine LSA cell lines demonstrated nu genome-wide quantitatice DNA methylation analysis
Bonemblante et al. 2018. Cytomorphological description and intraobserver agreement in whole slide imaging for canine LSA
The overall intra-observer agreement for cytomorphological features was fair to moderate (κ=0.34-0.52) for the three observers and moderate (κ=0.44-0.53) for the evaluation of grade of malignancy.
The diagnostic agreement between FC and digital slides was slight (κ=0.16) for the inexperienced observer, fair (κ=0.32) for the mildly experienced observer and moderate (κ=0.50) for the very experienced observer.
The diagnostic agreement between FC and glass slides was fair (κ=0.37) for the inexperienced observer, substantial (κ=0.63) for the mildly experienced observer and moderate (κ=0.50) for the very experienced observer.
These findings underline the importance of observer experience in determining the grade of malignancy, especially if digital slides are used. The study also identifies some technical limitations of the WSI scanner used in this study, mainly linked to image quality, which might affect the morphological evaluation of neoplastic cells.
Couto et al. 2018. Clinical characteristics and outcome on dogs with small cell T-cell intestinal LSA
Most common clinical sign?
US abnormalities were present in?
14 dogs received the same tx
MST for all dogs? for those that got tx?
Which dogs had short survival?
Diarrhea (13)
8/13 dogs (61%) - abnormal wall layering (7), hyperechoic mucosal strictions (7) representing the most common findings
279 days (9.3 months) and 628 days (1.7 years)
Anemia and weight loss
Dog that received alkylating agent and steroids had long survival time
Tomiyasu et al. 2018. Clinical and clinicopathological characteristics of acute lymphoblastic leukemia in cats
Clinical signs?
Lymphoblasts orignated from what?
5/6 cats were treated with chemotherapy, MST?
lethargy and anorexia common and anemia and thrombocytopenia
B-cell lineage in 4 cats and T-cell lineage in 1, and 1 was positive for both B-cell markers (CD21) and T cell marker (CD8)
55 days
LaRue et al. 2018. CNS lymphoma in 18 dogs (2001-2015)
15/18 received treatment other than prednisone
3 dogs chemo + RT after surgical decompression
5 dogs chemo
2 dogs RT after surgical decompression
2 dog RT and chemo
Overall MST?
171 days
Dogs receiving any tx lived longer than cases in historical reports
Noland et al. 2018. Coexpression of CD3 and CD20 in Canine enteropathy-associated TCL
Increasing evidence some canine and human TCL express the B cell marker CD20
Describe 3 cases of CD3+, CD20+ Pax5-, EATL type 1 in dogs
3 cases had clonal rearrgament?
Inital CS?
Mean age?
Survival?
TCR gene
Weight loss, inappetance, diarrhea, and/or vomiting
9 years
variable - 20 days to 1.6 years
Prognostic significance of T cells expressing CD20 is unclear
Matsumoto et al. 2018. Immunohistochemical profiling of canine intestinal TCL
Degl’Innocenti et al. 2018. Canine cerebral intravscular LSA: neuropahtological and immunohistochemical findgins
IVL is a rare angiotropic larger-cell LSA where neoplastic cells proliferate in the lumina of the small blood vessels in the absence of mass or leukemia
10 cases of IVL
Average age?
CS?
Phenotype?
Marked expression of? CD29?
8 years
Depression, seizres, ambulatory deficits
3 Tcell, 3 B-cell, 4 non-T non-B
Marked expression of CD44, CD29 positive cells seen in 4 IVL
CD44 expression is as seen in humans but CD29 was variable confirming partial pathogenic mechanism
CD44 and CD29 are needed for intravascular aggregation of neoplastic lymphocytes
Coy et al. 2017. PD-1 expression by canine T cells and functional effects of PD-1 blockade
What % of CD4 T cells and CD8 T cells expressed PD-1 in healthy dogs?
Expression in dogs with cancer?
Levels of IFN-g?
5-10% and 20-25%
Upregulated
PD-1 enhanced T cell activation as assessed by proliferation and IFN-g production
PD-1 Abs also reversed T cell suppression
Kumar et al. 2017. Programmed death ligand 1 is expressed in canine B cell LSA and downregulated by MEK inhibitors
PD-L1 is expressed in canine B cell LSA
Gareasu et al. 2018. In vitro efficacy of a first-generation valosin-containing protein inhibitor (CB-5083) against canine LSA
Plays a role in protein homeostatis. Exerts cytotoxicity through induction of irreversible proteotoxic stress
CD-508 treatment resulted in preferential cytotoxicity in canine LSA cell lines
Disrupted the ubiquitin-dependent protein degradation system, by inducing ER stress as indicated by increase in DDIT3
Activation of the unfolded protein response occured through the increase eIF2a phosphorylation and increased transciption of ATF4
Cells underwent apoptosis through caspase cascade
Matsumoto et al. 2018. Pathological features of intestinal TCL in Shiba dogs in Japan
7 breeds had increased risk of developing intestinal TCL?
Phenotye?
CD20 expression?
Age?
Survival difference between Shiba and Miniature Daschund?
Shiba dogs, GSD, Cairn terriers, Boston terriers, Papillions, Pugs, Maltese
IHC revealed ubiquitous cyctotoxic immunophenotype
CD20 co-expression noted in 11%
Shiba were younger than Miniature Daschund
None
