Treatment Modalities LC Flashcards
drugs that deplete or inhibit proliferation of MDSCs
Liposomal clodronate
Gemcitabine
5-FU
Sunitinib
Docetaxel
Cox 2 inhibitor (SC58236)
KIT-specific Ab
25-Hydroxyvitamin D
CXCR2 antagonist (S-265610)
CXCR4 antagonist (AMD3100)
PROK2-specific Ab
drugs that promote maturation of MDSCs
Zoledronate
ATRA
Docetaxel
Sunitinib
Decitabine
Activated NKT cells
VSSP vaccine
drugs that inhibit recruitment of MDSCs
cFMS kinase inhibitor (GW2580)
NSAIDs
drugs that block interaction of MDSCs
Anti-CD40 Ab
Anti-PD-1/PD-L1 Ab
drugs that block function of MDSCs
Nitroaspirin
Arginase 1 inhibitor (NOHA)
Triterpenoid
Sildenafil
drugs that cause pulmonary fibrosis
Tanovea, bleomycin, gemcitabine, EGFR-directed therapies, MTOR inhibitors, immune checkpoint inhibitors, methotrexate
indications for bone marrow transplant
Hematopoietic Disorders:
Acute leukemias (e.g., acute lymphoblastic leukemia, acute myeloid leukemia) with a high risk of relapse or refractory disease.
Aplastic anemia, where the bone marrow fails to produce adequate blood cells.
Immune-mediated disorders affecting bone marrow function.
lymphoma
risks of bone marrow transplant
Graft-versus-Host Disease (GVHD): A major risk of BMT, where donor immune cells attack the recipient’s tissues, leading to severe inflammation and organ damage.
Infection: Immunosuppression post-transplantation increases the risk of infections, including bacterial, fungal, and viral infections.
Graft Failure: The transplanted bone marrow may fail to engraft and produce sufficient blood cells.
Toxicity: Conditioning regimens and immunosuppressive drugs used in BMT can cause systemic toxicity, including gastrointestinal, hepatic, and renal toxicity.
Secondary Malignancies: Long-term immunosuppression increases the risk of secondary malignancies, including lymphoma and other cancers.
graft vs host disease
allogeneic stem cell transplantation - ~33% of patients in one paper 3/9 dogs
Donor T cells present in the graft recognize alloantigens (foreign antigens) on recipient tissues, such as major histocompatibility complex (MHC) molecules. leads to the activation and expansion of donor T cells.
Activated donor T cells differentiate into effector T cells, including CD4+ T helper cells and CD8+ cytotoxic T cells.
Activated T cells secrete pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and interferon-gamma (IFN-γ).
These cytokines contribute to tissue inflammation, damage, and recruitment of additional immune cells.
Effector T cells attack and damage recipient tissues, primarily the skin, gastrointestinal tract, and liver.
Skin manifestations include erythematous rash, blistering, and desquamation.
Gastrointestinal manifestations include diarrhea, abdominal pain, and mucosal damage.
Liver involvement can lead to hepatomegaly, jaundice, and hepatic dysfunction.
graft vs host disease acute vs chronic
Acute GVHD typically occurs within the first 100 days after transplantation and is characterized by a rapid onset of symptoms.
Chronic GVHD develops later, usually after day 100 post-transplant, and can persist for months to years. It often resembles autoimmune disorders and can affect multiple organs.
Direct Cytotoxicity: Effector T cells directly attack and kill recipient cells through cytotoxic mechanisms, including perforin and granzyme-mediated apoptosis.
Indirect Pathways: Effector T cells activate macrophages and other immune cells, leading to tissue inflammation and damage.
Antibody-Mediated Damage: B cells activated by donor T cells produce antibodies against recipient tissues, contributing to tissue damage.
prevention and treatment of graft vs host disease
Prevention and Treatment:
GVHD prophylaxis strategies aim to suppress donor T cell activation and function while preserving graft-versus-tumor effects.
Treatment options for established GVHD include immunosuppressive drugs such as cyclophosphamide, corticosteroids, calcineurin inhibitors (e.g., cyclosporine, tacrolimus), and anti-T cell antibodies (e.g., anti-thymocyte globulin).
Severe cases of GVHD may require additional therapies, such as extracorporeal photopheresis or mesenchymal stem cell therapy, to modulate immune responses and reduce tissue damage.
limitations of BMT
Donor Availability: Finding an appropriate donor (allogeneic) or preparing the recipient as its own donor (autologous) can be challenging.
Cost: BMT is an expensive procedure, including pre-transplant workup, conditioning regimens, transplantation, post-transplant care, and potential complications.
Specialized Facilities: BMT requires access to specialized facilities and expertise, including hematologists/oncologists, aphoesis, and specialized laboratories.
Intrinsic Limitations: Some conditions may not be suitable for BMT due to poor prognosis or lack of response to prior chemo treatment
Success Rates of BMT
Success rates for allogeneic BMT in dogs ~89%
Reported success rates for autologous BMT in dogs with lymphoma range from 33 - 40%
allogeneic bmt can cure ~50% more dogs than those treated with autologous
Survival Time: Dogs that successfully undergo BMT may achieve long-term remission or cure, with survival times ranging from months to several years.
Quality of Life: Dogs that undergo successful BMT can regain a good quality of life, with resolution of clinical signs associated with the underlying disease.
Complications: Even in successful cases, dogs may experience complications such as GVHD, infections, and long-term organ toxicities.
aphoresis
Blood Collection: Apheresis begins by drawing blood
Separation Process: The collected blood is then processed through a machine called an apheresis machine. This machine separates the blood into its individual components, such as red blood cells, white blood cells, platelets, and plasma.
Targeted Component Removal: Depending on the purpose of the procedure, specific components of the blood may be removed, such as:
White Blood Cells: Used for patients with certain immune disorders or to reduce the risk of organ rejection in transplant recipients.
Return of Remaining Blood: After the targeted component is removed, the remaining blood components are returned to the body
Filgrastim (G-CSF)
Granulocyte colony-stimulating factor (G-CSF) is used to stimulate the production of neutrophils and accelerate bone marrow recovery after transplantation.
Neupogen
human may not work in dogs
Anti-Thymocyte Globulin (ATG):
ATG is a polyclonal antibody preparation derived from animals (e.g., horse or rabbit) that targets and depletes T cells. It is used as part of the conditioning regimen before BMT to reduce the risk of GVHD
how does Cyclophosphamide work as an immunosuppressant in BMT
inhibiting the function of T and B lymphocytes. only cyclophosphamide and methotrexate can induce apoptosis of alloantigen-activated human T cells. Another unique cyclophosphamide mode of action is upregulation of CD95 expression, which leads to activation-induced apoptosis within 6 days, further preventing T-cell activation
By suppressing the immune system, cyclophosphamide helps prevent rejection of the transplanted bone marrow and reduces the risk of graft-versus-host disease (GVHD).
used to eliminate any remaining cancer cells in the bone marrow and peripheral blood and prevent gvhd.
is often used in combination with other chemotherapy drugs or radiation therapy to maximize its effectiveness in conditioning the recipient
cyclophosphamide dose for BMT
Cyclophosphamide is often administered at high doses, typically ranging from 200 to 400 mg/m^2.
The dose may be given as a single dose or divided into multiple doses over several days.
Some protocols may use higher doses of up to 600 mg/m^2, particularly in aggressive lymphoma protocols.
radiation for BMT
Fractionated total body irradiation involves dividing the total dose into multiple smaller fractions delivered over several days.
Single dose total body irradiation delivers the entire radiation dose in one session.
Typical doses for single dose TBI in dogs range from 8 to 12 Gray (Gy).
Mushroom-Derived Products evidence
Certain mushroom-derived products, such as polysaccharopeptide (PSP) from Coriolus versicolor ( turkey tail) and lentinan from Shiitake mushrooms, have been studied for their potential anticancer properties in both humans and animals.
Sulforaphanes use
Evidence: Sulforaphanes are bioactive compounds found in cruciferous vegetables like broccoli and cauliflower, known for their antioxidant and anti-inflammatory properties.
Effectiveness: Limited studies have investigated the use of sulforaphanes in dogs and cats with cancer. Some research suggests potential anticancer effects by modulating signaling pathways involved in tumor growth and progression.
Yunnan Baiyao:
Evidence: Yunnan Baiyao is a traditional Chinese herbal medicine used for its hemostatic and anti-inflammatory properties.
Hepatoprotectants:
Hepatoprotectants, such as S-adenosylmethionine (SAMe) and milk thistle (silymarin), are commonly used to support liver function in dogs and cats with cancer, especially those undergoing chemotherapy.
Herbal Supplements:
Evidence: Various herbal supplements, such as astragalus, turmeric, and green tea extract, have been studied for their potential anticancer effects in animals.
Effectiveness: While some preclinical studies suggest possible benefits, clinical evidence in dogs and cats with cancer is limited and often inconclusive.
sulforaphane modulating several signaling pathways involved in tumor growth and progression
Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Pathway:
activate the Nrf2 pathway, regulates the expression of antioxidant and detoxification enzymes.
Activation of Nrf2 leads to increased expression of glutathione S-transferases (GSTs) and NAD(P)H:quinone oxidoreductase 1 (NQO1).
Glutathione helps neutralize reactive oxygen species (ROS) and free radicals, which can damage DNA and promote cancer development.
Anti-Inflammatory Pathways:
inhibiting the production of pro-inflammatory cytokines and enzymes, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS).
reducing chronic inflammation, suppress tumor-promoting processes and inhibit tumor growth
Apoptosis (Programmed Cell Death) Pathway:
upregulate pro-apoptotic proteins Bax and Bak while downregulating anti-apoptotic proteins Bcl-2. activate caspases,
modulate cell cycle progression by arresting cancer cells at different checkpoints, such as the G1/S and G2/M transitions.
Epigenetic Regulation:
inhibit DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), leading to changes in gene expression patterns that may favor tumor suppression.
Angiogenesis Inhibition:
downregulate angiogenic factors like vascular endothelial growth factor (VEGF)
literature evidence of sulforaphane
Clinical Trials:
Study 1: A clinical trial investigated the effects of sulforaphane-rich broccoli sprout extract (BSE) in dogs with lymphoma.
- no clinical response and no adverse events
- affected proteome -14 proteins were significantly downregulated, and 10 proteins were significantly upregulated. Proteins and gene sets impacted by SFN were commonly involved in immunity, response to oxidative stress, gene transcription, apoptosis, protein transport, maturation and ubiquitination.
In Vitro Studies:
Study 1: effects of sulforaphane on canine osteosarcoma cells.
SFN could not induce cell death at potentially physiological concentrations (<50 μM), but significantly diminished cell invasion and downregulation of focal adhesion kinase (FAK) signaling. Modest cell cycle changes were observed in each cell line
Cruciferous Vegetables and Bladder Cancer
Epidemiologic evidence suggests that diets rich in cruciferous vegetables, particularly broccoli, are associated with lower bladder cancer risk
In vitro studies have shown inhibition of bladder cancer cell lines, cell cycle arrest, and induction of apoptosis
research shows dogs can absorb sulforaphane and it has activity
Evaluation of the anti-tumour activity of Coriolus versicolor polysaccharopeptide (I’m-Yunity) alone or in combination with doxorubicin for canine splenic hemangiosarcoma
Dogs treated with PSP alone, female dogs, decreased HCT at diagnosis, and stage III disease associated with poor outcome
Addition of PSP to dox post splenectomy did not improve survival
This study shows the PSP alone does not improve survival compared to splenectomy alone
Single agent polysaccharopeptide effect on metastases and survival in naturally occurring hemangiosarcoma
double-blind randomized multidose pilot study, high-dose PSP significantly delayed the progression of metastases and afforded the longest survival times reported in canine hemangiosarcoma
2012 - before the paper showing it had no effect
Median time to development or progression of abdominal metastases was significantly delayed in dogs receiving 100 mg/kg/d I’m-Yunity (112 days ) compared with dogs receiving 25 mg/kg/d (30 days), but was not significantly different than in dogs receiving 50 mg/kg/d
maitake (Grifola frondosa) mushroom extract in 15 dogs with intermediate-grade and high-grade lymphoma
extract was well-tolerated and induced no negative effects, no decrease greater than 50% (objective response) in lymph node size occurred in 13 of 15 dogs
protective effects of a combination of S-adenosylmethionine (SAMe) and silybin for lomustine (CCNU)-induced hepatotoxicity
More dogs receiving CCNU alone had an increase in ALT compared with dogs receiving CCNU with Denamarin (84% vs 68%)
using 2 canine B-cell lymphoid cell lines evaluated genistein (4,5,7-trihydroxyisoflavone), a readily available isoflavone found in soy-based products, and genistein-combined polysaccharide (GCP)
genistein and GCP led to cell death via apoptosis, and the treated cells exhibited increased Bax:Bcl-2 ratios.
GCP was also found to inhibit cell proliferation, increase apoptosis, and induce G2/M arrest in 3 human and 4 canine lymphoid cell lines.
in vivo, dose-escalating pharmacokinetic study determined that therapeutic serum levels of genistein were not reached with oral dosing of GCP in normal dogs
study in canine osteosarcoma D-17 cells, treatment with α-mangostin, a xanthone derived from the mangosteen fruit (Garcinia mangostana),
nuclear condensation and fragmentation, typical of apoptosis
Other reported antitumor effects are in human breast and prostate cancer and leukemia
calcitriol and chemotherapy
Calcitriol induces G1/G0 cell-cycle arrest and apoptosis, while down-regulating Bcl-2, decreasing epidermal growth factor, and inhibiting tumor invasion through decreased metalloproteinase (MMP)-2 and metalloproteinase-9 activity.
Calcitriol was synergistic with cisplatin using in vitro canine tumor cells and a phase I clinical study
synergistic, antiproliferative in vitro activity when used with other chemotherapeutics, including CCNU, vinblastine, imatininib, or toceranib
Calcitriol inhibited canine transitional cell carcinoma cells via G0/G1 cell-cycle arrest
Retinoids
A 42%-58% response rate (33% CR) to isotretinoin treatment has been seen in dogs with cutaneous lymphoma, and positive results have been seen with in vitro canine mast cells and osteosarcoma cell lines
25% of dogs experiencing adverse effects that resolve quickly or do not affect quality of life.
selenium supplementation
anticarcinogenic effect by reducing the naturally occurring genotoxic stress within the aging prostate.
In a translational RCCT using 49 intact male elderly beagles, the extent of DNA damage in prostate cells and in peripheral blood lymphocytes was lower among the selenium-supplemented dogs.
recommended to be discontinued during RT since rt works by oxidation
nasal malignant carcinomas were given dietary menhaden oil (DHA and EPA) or soybean oil (control) before radiation therapy (RT)
dogs fed menhaden oil had significantly higher plasma concentrations of DHA (increased by 500%) and EPA (200%), lower tissue inflammatory eicosanoids, and decreased resting energy expenditure (by 20%) compared with controls. Increased plasma DHA was significantly associated (P<.05) with decreased plasma lactic acid and MMPs. This study suggests EPA and DHA may reduce some detrimental inflammatory eicosanoids and metabolic consequences of RT
drug-herb interactions with chemo
likely occur due to altered expression of the functional CYP450 isoenzymes that metabolize chemotherapeutic drugs
Hypericum perforatum, more commonly known as St. John’s Wort (SJW), which interferes with both CYP450 isoenzymes and P-gp - vincristine, vinblastine, and EGFR-TK inhibitors
in Vitro effects of Yunnan Baiyao on canine hemangiosarcoma cell lines after treatment with increasing concentrations of Yunnan Baiyao
herbal supplement did cause dose and time dependent hemangiosarcoma cell death through initiation of caspase-mediated apoptosis
The effect of Yunnan Baiyao on platelet activation, buccal mucosal bleeding time, prothrombin time, activated partial thromboplastin time, and thromboelastography in healthy dogs
no induction of hypercoagulability.
Use of Yunnan Baiyao and epsilon aminocaproic acid in dogs with right atrial masses and pericardial effusion
no side effects attributed to the use of Yunnan Baiyao. The study did not show a significant improvement in survival time from the study dogs compared to the control dogs.
Incompletely excised STS grade II owner cannot afford def RT
– recurrence < 34%, tx with metronomic chemotherapy, hypofract RT
metronomic chemotherapy mechanism
therapeutic target : slowly proliferating tumor endothelium
mechanisms
- inhibition of tumor angiogenesis: possibly though thrombosponin-1 inhibiting vegf and blocking circulating endothelial cells
- activation of anti-tumor immunity: decreases in the number and function of Treg (inhibiting their blocking of NK cell and inhibiting secretion of TGFb/IL10) , dendritic cell activation, and stimulation of tumor-specific cytotoxic T cells
- induction of tumor dormancy AND inhibition of cancer stem cells;
may be able to target CSCs and dormant tumor cells because of the tendency of both cell populations to reside in close proximity to tumor vasculature
function in acidic and hypoxic environments
low doses of paclitaxel to mice with metastatic lung tumors
decrease in Treg number and function without interfering with tumor-specific cytotoxic T cell function
The majority of human studies have paired a conventional chemotherapy drug with a noncytotoxic drug that also targets angiogenesis such as
COX inhibitors, tetracyclines, and thalidomide or those with more direct effects such as bevacizumab
metronomic chemo what pre treatment biomarker (protein) was important
pilot study of MC and celecoxib therapy in 15 dogs with various cancers found low baseline plasma VEGF was predictive of response
side effects of bevacizumab
hypertension, edema, hemorrhage, thromboembolism, proteinuria, intestinal perfo- ration, and impaired wound healing
side effects for TOC
hypertension, protein- uria, dose-dependent gastrointestinal upset, bleeding, myelosup- pression, azotemia, anemia, lethargy, lameness, or disruption of the hypothalamic–pituitary–thyroid axis
metronomic cytoxan causes sterile hemorrhagic cystitis T/F
true
incidence of SHC may be more frequent in metronomic protocols. Recent reports document that cystitis may occur in up to 34% of cases, and SHC risk increases with longer treatment duration
myelopthesis
Combination of Metronomic Chemotherapy
with Other Treatment Modalities
MTD DOX with concurrent metronomic CYC 15 mg/m2 was found to be well tolerated in a recent phase I study - DOX was associated with nonselective depletion of circulating lymphocytes such that any potential benefits of Treg depletion by low- dose CYC would have been lost
pRT plus daily oral piroxicam and thalidomide plus every other day oral CYC significantly longer OST compared with dogs treated with pRT alone (757 vs 286 days, respectively)
RT has been combined with metronomic dosing of lomustine in the treatment of dogs with OSA - no diff in ost
splenic hsa and metronomic chemo
- alternating cytox and etoposide daily with piroxicam let to similar efficacy to dox
- cytox alone vs dox also similar but both were better than splenectomy alone- doxo 4.5 mths, mc ctx 2 mths, splenectomy 1.5 mths. doxo group had higher toxicity.
- splenectomy and six doses of DOX, daily or every other day CYC plus an NSAID had no effect on PFS or OST
administration of lomustine at a daily oral dose of 2.84 mg/m2
high incidence of adverse events occurred and led to the discontinuation of the therapy in nearly 30%
13 dogs with gastrointestinal toxicosis, 4 dogs with thrombocytopenia, 3 dogs with increased alanine transaminase, 1 dog with neutropenia, and 1 dog with progressive azotemia
SE of bisphosphonates
renal tubular damage - azotemia
hypocalcemia
osteonecrosis of the jaw
1 report of allergic rxn
What impact do bisphosphantes have on OSA?
Palliative for pain 28% responded >4months, RT+dox+pam-bloodwork better but owner did not notice;
Another RT+chemo+pam-the RT+pam group did the worst 69days
Aminobisphosphonates bind strongly to hydroxyapatite at which site?
R1 (R2 determines amino-BP (ex. ZOL) vs. nonamino-BP (ex. clodronate))
MOA of zoledronate
binds to HAP via R1. uptake into the osteoclast Synthetic analogs of inorganic pyrophosphate inhibits farnesyl pyrophosphate synthaze preventing conversion of geranyl pp to farnesyl pp
- Induction of osteoclast apoptosis net attenuation of pathologic bone resorption
- Interfere with post translational prenylation of small GTP-binding proteins including Ras, Rho and Rac
Inhibit bone resorption without inhibiting bone mineralization
What effect does ZOL have on expression of chemokine receptors in OSA?
reduced CXCR4 expression by 40% within primary tumor.
cxcr4 is a transmembrane g protein coupled chemokine receptor involved in metastasis and growth
Evaluation of Zoledronate as Treatment for Hypercalcemia
worked
reports prev. Unreported allergic reaction in one dog. Otherwise well tolerated.
Dexrazoxane MOA
Chelation of iron-free radicals, resulting in reduced oxidative damage
also poss dec in ROS
Increased cardiotox secondary to dox function of what?
peak drug level ( within first 30- min) and total cumulative dose
dosing 20 - 30 mg/m2 decreases cardiotox
96 hour infusion is less cardiotox
use of vitamin b6
one study showed protective against Chemotherapy-induced neuropathy - may work against taxane or vinca neuro toxicity
B6 intake from food is also associated with reduced risk of death from stroke, heart disease, and heart failure. B6 may reduce high blood pressure in animals
Pyridoxal phosphate (PLP) is the major coenzyme form, the most abundant in animal tissue, and the cofactor for over 100 enzymes used in amino acid metabolism, including aminotransferases, decarboxylases, racemases, and dehydrases
excess-pyridoxine diet actively influenced cell-mediated immunity via enhanced IFN-γ production and Th1-polarizatio
vit b6 pyridoxine and cisplatin
potentiates intracellular effects intracellularly in vitro
What is the mechanism of action of MESNA (hydrolysis/conjugation in which areas)?
MESNA conjugates with acrolein in the urinary tract in the bladder to render it inactive. - cant work for cisplatin bc it only activates in bladder
Mesna dimerizes to an inactive metabolite in blood so it does not affect the cytotoxicity of cyclophosphamide or ifosfamide
Why are carboplatin and gemcitabine synergistic/what results when given together?
gemcitabine causes decreased NER DNA repair in s phase by inhiting dna polymerase - which is how carboplatin adducts are repaired (induces cell cycle arrest and apoptosis)
Elspar deactivates which chemotherapy?
Methotrexate (can also “rescue” from methotrexate toxicity)
o L-asparaginase depletes the asparagine reserve, and Elspar blocks conversion of MTX to polyglutamates as well as progression into S phase by depletion of asparagine so inhibits MTX action; upreg of MDR
How is MESNA metabolized?
Autooxidation → reduction (by GSHR) → conjugation with acrolein and other urotoxic metabolites in bladder
denamarin + ccnu
dec liver enzyme elevation
84% va 68%
Tavocept
is a water‐soluble disulfide form of mesna
converted to mesna in the kidneys, which then locally inactivates the toxic platinum species - use as protectant form cisplatin
Tavocept decreased the required diuresis time with cisplatin from > 6 hours to 90 minutes, while also decreasing occurrence of azotemia
but may have reduced efficacy of platinum- dogs had worse rr than historic controls
Amifostine
used to protect kidneys from cisplatin
sulfur compound that has the potential to limit severe mucositis caused by RT
reduces neutropenia from cytox
amifostine is not commonly used clinically for a variety of reasons. Clinically, it is difficult to administer, with hypotension being a major side effect.
vinc / lspar together
dose dependent neutropenia
reduce vinc dose
myelosuppressive effects can be additive,
Doxorubicin + Cyclophosphamide
combination has shown synergistic effects, leading to enhanced tumor cell kill, particularly in lymphomas and sarcomas.
Doxorubicin + Cisplatin:
combining them can increase the risk of cardiotoxicity, as both drugs have cardiotoxic effects
RARE
lspar and ccnu
When used together, L-asparaginase and CCNU have shown synergistic effects against lymphoma cells, leading to enhanced tumor cell kill and improved treatment outcomes.
inc rr fro ~50% ccnu alone to 77-87%
what is worse intermittent high dose exposure or chronic low levels of exposure to chemo as the provider
chronic low levels of cytotoxic chemotherapy exposure actually may have increased risk, because cytotoxic effects are less likely to occur with similar mutagenic effects
risks of chemo exposure to people
could harm a fetus, inc risk for other cancers
Human healthcare workers (eg, pharmacy employees, nurses) handling chemotherapeutics have been found to have variably increased chromosomal aberrations compared to the general population, as well as urinary excretion of these drugs or their metabolites, which could lead to similar reproductive complications found in cancer patients treated with cytotoxic drugs
incremental increased risk of infertility and early pregnancy loss with occupational exposure to chemotherapeutics
increased risk was found for the development of multiple myeloma (6 cases out of 12 000), and a decreased risk for lung cancer
things that reduce the risk of chemo exposure
closed-system transfer devices (CSTD)
biologic safety cabinets (BSCs)
personal protective equipment (PPE)
markedly decreases,but does not always eliminate, evidence of drug contamination
PPE recomendations
Chemotherapy-rated (ASTM International [American SocietyTesting Materials]) double-gloving
Long-sleeved coated impermeable gown with back closure
Shoe coverings
Shoe & hair coverings to maintain sterility (if needed)
Eye shield/Face shield if potential for splashing/aerosolization
Respirator (fitted)
closed-system transfer devices (CSTD)
during compounding and administration and methods of preventing aerosol formation and spread of contamination
mechanically prevents the escape of a drug or vapor out of the system into the environment. decrease the risk of needle accidents during administration
adaptor for the drug vial, a piece that attaches to a luerlock syringe (needleless system), and adaptors to allow connection of the needleless syringe to the fluid lines
FDA approved systems:
Chemoclave/Chemolock
Equashield
Onguard
PhaSeal
drawing up chemo
negative-pressure room preferred
compounding aseptic containment isolator - vertical laminar flow, which carries contaminated air away from the operator (horizontal flow only protects the drug and not the worker);
- High-efficiency particulate arrestance filter; 100% ventilation to the outside; and, a continuouslyrunning fan
risk of aerosolization is highest when
during transfer of the drug from the vial to syringe and from the syringe into a fluid line
preparation of chemo
Orders and prescriptions should be independently calculated and verified by at least 2 separate individuals, but ideally including the prescribing clinician, a second person trained in handling
Full PPE should be worn during preparation. A plastic-backed absorbent pad should be placed under the preparation site, and should be replaced at least once daily, or anytime a spill occurs or the pad is contaminated
operations should be done at least 3 inches above the work surface. Fluid bags should be spiked and tubing should be primed with a compatible fluid before adding chemo.
Outer gloves should be removed before final preparation andsurface decontamination. The outside of the container should be wiped with gauze moistened with a deactivating substance before removal
work surface area in the BSC should be decontami-nated and disinfected. A fresh pair of outer gloves should be donned before removing the product
inal product shouldbe clearly labeled as cytotoxic and sealed in a plastic bag that allowsvisualization of the product, then placed into the transport bag orplastic box
Most commonly used cleaning agents for chemo spills
detergent and hypochlorite solution
use of alcohol for primary disinfection will not deactivate chemo and may result in spread of contamination
dont spray chemo directly
disposed of in chemotherapy waste containers
chemo metabolites exerted by the patient
found in urine, feces, saliva, vomitus, and sebum
found in the urine for days to weeks after administration, although concentrations are markedly decreased within 3 days
oral drug excretion for 5–7 days post-administration in the feces
handle excreta from patients that have received injectable chemotherapy as contaminated for a minimum of 48–72 hours post-administration, and as long as 7 days after PO chemotherapy
patient should be allowed to urinate and defecate outside in a separate, designated, sunny low-traffic area - ultraviolet light is believed to inactivate many drugs
what to do if exposed to excreta from a chemo patient
If inadvertent direct contact with chemo or contaminated urine or feces of a patient occurs, the skin should be rinsed with water and washed using dishwashing detergent for a minimum of 5 minutes
recommendation when giving chemo at home
Chemotherapy-rated gloves should be dispensed with any HD for use by the client when giving medications, and hands should be washed after each administration
pet’s medications should not be stored with medications for humans, near food, or where accessible by children
Animals receiving chemotherapy should remain in a controlledenvironment and not be allowed to urinate or defecate in communityareas, areas where children may be exposed, or areas that cannot beeasily cleaned for at least 48 hours after drug administration. Ideally alow-traffic, sunlit area would be preferred for elimination. If excreta arefound in the house, the area should be cleaned, and hands should bewashed afterwards
Cat litter boxes should be cleaned daily and litter should be double-bagged and discarded with household trash.
Any soft items (eg, bedding, towels, toys) should be washed twice, separately from other laundry, after exposure, and ideally bleached
Extracellular vesicular microRNAs as potential biomarker for early detection of doxorubicin-induced cardiotoxicity
Associated cardiac troponin with extracellular vesicle associated microRNAs
Downregulation of miR-502 was detected before significant changes in cTnI concentrations or echocardiographic parameters
VEGF concentrations in the cerebrospinal fluid of dogs with neoplastic or inflammatory central nervous system disorders
Vegf present in 77.8% of neoplastic samples
Vegf present in 92% of inflammatory samples
Only in 20% of normal samples
Targeted sequencing of candidate gene regions for myelofibrosis in dogs
Somatic variants might initiate or perpetuate myelofibrosis in dogs.
findings suggest the occurrence of clonal hematopoiesis in dogs, with increasing incidence with age, as observed in humans
In humans, most primary myelofibrosis cases develop secondary to driver mutations in JAK2, CALR, or MPL.
CDC6: A novel canine tumour biomarker detected in circulating extracellular vesicles
VCO 2021
CDC6 extracellular vesicle may be a non invasive biomarker to diagnose canine tumors in serum
Various tumor types included (epithelial, neuroendocrine, round cell, melanoma, sarcoma)
Extracellular cyclic adenosine monophosphate-dependent protein kinase A auto antibody and C-reactive protein as serum biomarkers for diagnosis of cancer in dogs
There was a significant positive correlation between the neoplastic index, which was developed using ECPKA-Ab and CRP levels, and the presence of cancer in dogs
ECPKA-Ab is a potential serum biomarker for a broad spectrum of cancers.
Combined measurement of CRP and ECPKA-Ab levels in serum improves the sensitivity and accuracy of a diagnosis of cancer in dogs
MOA of electrochemotherapy?
electrical pulses lead to Increased membrane permeability allows drug to access cytosol → cell death and activation of APCs
repair pathways
tumor evasion
