25 Onco Flashcards
general concept of how normal cells become tumor cells
transformation through genetic alterations1. activation of tumor promoting factors–oncogenes2. loss of tumor inhibitory effects–loss of tumor suppressor gene fxinitiation, promotion and progression
most familiar tumor suppressor gene
p53guardian of the genomecrucial to normal cell cycle regulation and entry into apoptosiscancer cells find a way to mutate this gene (mammary tumors, lymphoma, OSA)
genotypic changes that result in phenotypic characteristics of tumor cells
- self sufficiency in growth signals2. insensitivity to antigrowth signals3. tissue invasiveness/metastatic potential4. limitless replicative potential5. sustained angiogenesis6. evasion of apoptosis
recent advances in veterinary oncology
- PCR assay to detect ckit mutations (found in mast cell tumors)2. Metronomic therapies to prevent tumor angiogenesis and minimize toxicity3. tyrosine kinase inhibitors, toceranib (palladia) or mastinib (kinavet)
cell biology: cell cycle and division
DIVISION OF SOMATIC CELLS1. interphase: doubling of genetic material occurs—G1, S, G2 phases2. mitosis: division of genetic materials into 2 daughter cells
What phases make up interphase during the cell cycle
INTERPHASE–G1: growth factors signal cell division, restriction point–S: synthesis/doubling of new DNA occurs–G2: growth
regulation of the entry and progression of the cell cycle occurs through what
cyclin dependent kinases (important growth signals in the progression of both normal and neoplastic cells)
define initiation, promotion, progression as it is applied to cancer formation
- initiation–IRREVERSIBLE; heritable mutation 2. promotion–must come after initiator; a second mutation that promotes the growth advantage of a mutated cell over surrounding cells3. progression–invasion into surrounding tissues, establishing a new blood supply and potential for metastatic disease
T/Finitiation of cells is an irreversible process and all cells will go on to develop clinical neoplasia
FALSEinitiation is irreversibleBUT not all initiated cells will develop into clinically detectable neoplasia (needs a promoting agent)
T/F Golden retrievers have a heritable risk for lymph proliferative disease
TRUEsome good data supports
True genetic heritability has been established in what breeds with what tumors?
Scottish Deerhounds—OSAGSD–renal cystadenocarcinoma and nodular dermatofibrosis (autosomal dominant)
well established neoplasia and biological viral link in veterinary medicine
–retroviral FeLV and lymphoproliferative dz–feline retroviral sarcoma virus and FSA (co-infection with FeLV required)–papilloma virus–papillomas and SCC
well established neoplasia and biological parasite link in vet med
–spirocerca lupi (esophageal parasite) and esophageal sarcomas in dogs
how is transmissible veneral tumor transmitted
contagious veneral tumorDIRECT cell contact (tumor cell itself is the causative agent of disease)
types of physical carcinogenesis
–Asbestos–canine mesothelioma–Aluminum based adjuvant in vaccines–injection site sarcomas (cats)–trauma–ocular sarcoma–microchip implantation–FSA–metallurgy (slocum TPLO plates)–canine OSA
UV light carcinogenesis
UV B light 290-320 nm wavelengthdamage to basal cells of skin via dimerization of the pyrimidine bases (T, C) of DNASCC white catscutaneous hemangiomas in whippetsmay also suppress cutaneous T cell mediated immunity
mechanisms in which a protooncogene (normal gene) becomes and oncogene
- retroviral mediated2. translocation mutation3. amplification4. proviral insertiononcogenes become dominant form and drive formation of cancer thru cell signaling, differentiation, ECM production, and control of apoptosis
key transcription proteins made in response to oncogene translation
- growth factors2. growth factor receptors3. cytoplasmic kinases/Ras4. transcription factors* 5. anti-apoptotic proteins** difficult targets for drug therapy given sub cellular location
Ckit and mast cell tumors
ckit receptor = tyrosine kinase receptor made my tumor cells; binding with ligand leads to cell proliferationimportant for tyrosine kinase inhibitors (palladia–toceranib) for treatment of high stage or grade III MCT)
met and OSA
met = hepatocyte growth factor receptorplays a role in malignant nature of canine OSA
mutations in which oncogene family are the most common found in human and canine neoplasia
Ras oncogenes–> lead to the production of membrane bound proteins with key roles in relaying signals from cell surface/growth receptors to their down stream targets
enzymes responsible for intracellular signaling for oncogenes
cytoplasmic kinasesusually work by phosphorylating various proteins and signaling for transcription factors
most notable oncogene for production of anti-apoptotic proteins
Bcl-2overexpressed in tumors leading to continual growth and proliferation
difference btwn oncogenes and tumor suppressive genes
Oncogenes–DOMINANT, gain of function mutationtumor suppressive genes–recessive/loss of function mutations, BOTH alleles must be damaged (loss of heterozygosity)
Knudson’s two hit hypothesis
first mutation in tumor suppressor gene occurs in germline (heritable)second mutation in tumor suppressor gene occurs later on
two types of tumor suppressor genes
- gate keeper: function to inhibit growth while promoting cell death (p53 gene aka guardian of the genome)2. caretakers: ensure that SNA repair occurs while maintaining genomic stability
Vet sx 2008 Kirpenstein et al p53 gene and canine OSA survival times
dogs WITH p53 mutations had survival time 81 daysdogs WITHOUT p53 mutations had survival time 256 daysmutations in p53 seem to be a negative prognostic factor
in veterinary medicine, best examples of tumors resulting from an orderly progression (normal, dysplasia, cancer)
SCCTCCmay start normal–>dysplastic–>carcinoma in situ–> cancerous, local–> disseminated
characteristics of dysplasia
anisocytosisanisokaryosismitotic figureschromatin changes
define carcinoma in situ
dysplastic or now transformed cells exhibit a greater number of criteria of malignancy and occupy the entire thickness of the epithelium but have NOT invaded the basement membrane(once past basement membrane–> invasive)
T/Ftelomerase expression has been shown in 92-95% of canine maligancies
TRUEboth human and canine neoplastic tissues have been shown to exhibit HIGH levels of telomerase activity
which cells/tissues do NOT express telomerase activity
stem cellslens tissuemale germ line cellsactivated lymphocytessomatic tissues
T/Flack of apoptosis is a hallmark of carcinogenesis
TRUEapoptosis is an ACTIVE processnecrosis is a PASSIVE process
morphologic changes associated with apoptosis
- membrane blebbing2. contraction of cytoplasm3. nuclear condensation(different from necrotic cells—cell swelling, rupture of cell membranes)
what does entry into apoptosis depend on
balance btwn1. proapoptotic genes (p53), caspases2. antiapoptosis genes (Bcl-2)
3 major routes for metastasis to occur
- hematogenous2. lymphatic3. direct seedinginvolves detachment, migration thru tissue, intravasation, survival in vasculature, attachment to endothelial cell, extravasation, prolix/angiogenesis in new site
difference btwn carcinomas, round cells and sarcomas in terms of routes that they metastasize
carcinomas–lymphaticsround cell tumors (LSA)–lymphaticssarcomas–hematogenous
crucial factor for metastasis to occur as tumor cells leave primary bed and travel through tissue
MMP matrix metalloproteinases
what is anoikis
apoptotic signal that occurs when a group of cells lose contact with each other and surrounding matrix
Angiogenesis necessary for cancer cells to survive in a new environment depends on what
progressive hypoxia (HIF-1a)tumor cells need to be within 100-200 microns of a capillary bed (for growth and waste removal)
nuclear scintigraphy in detection of canine OSA and mets
radio labeled technetium 99m hydromethylene diphosphate7.8% w appendicular OSA had a second lesion (therefore may not be good candidates for amputation)
examples for how scintigraphy may be a useful staging procedure in animals with neoplastic disease
- canine OSA2. thyroid neoplasia (ectopic or metastatic thyroid tissue)3. GFR rates prior to nephrectomy4. pancreatic neoplasia (primary or met tissue identification)
pros of CT over MRI
- better bone quality2. faster3. less effected by respiratory motion4. can plan for radiation tx5. CT guided biopsies possible6. can have metal in CT but artifacts will be presentBUT have less contrast resolution and require iodinated contrast and ionizing radiation
what is a PET scan
positron emission tomography (PET)provide in vivo information of biochemical and physiologic processes such as glucose metabolismutilizes radiopharmaceutical FDG (f-fluorodeoxyglucose)which is transported and trapped in tumor cells bc it is NOT utilized in glycolytic pathwaymay be combined with CT
size of metastatic lesions detected on plain radiographs vs CT
6 mm on radiographs1 mm on CTJAVMA Paoloni et al 2006
staging imaging of choice for canine MCT
pulmonary mets are rareabdominal US with FNA liver/spleen are recommended to evaluate for systemic mastocytosis
TNM world health organization tumor staging
T characteristics of primary tumorN regional LN involvementM evidence of mets
Prognostic importance of canine splenic HSAlocalized vs ruptured vs metastatic
localized stage Iruptured stage 2disseminated stage 3better px with stage 1
name a cardiotoxic chemo and a nephrotoxic chemo
use in caution with onco patients with comorbiditiesdoxorubicin cardiotoxiccisplatin nephrotoxic
tumor pain can arise from what….
mechanical or chemical stimulation of nociceptors by the tumoror result of therapeutic or diagnostic procedures
list aggressiveness of surgical resection options
- intralesional (debulking)2. marginal3. wide4. radical**considered curative to remove both macro and microscopic disease
margin definition for most solid tumors using wide surgical resection
1 cm lateral for benign tumors, carcinomas, gd I MCT2 cm lateral for gr 2 MCT3 cm lateral for most ST sarcomas5 cm lateral for injection site sarcomasone fascial plane deep for mosttwo fascial planes deep for injection site sarcomas
T/Fconnective tissues (fascia, cartilage, bone) are resistant to neoplastic invasion
TRUEconnective tissues (fascia, cartilage, bone) are resistant to neoplastic invasion and provide a natural tissue barrier
definition of marginal surgical excision
peripheral to pseudocapsule (likely still within the reactive zone which may contain satellite tumor cells in malignant tumors)successful for benign neoplasiascan be planned (after knowing incisional bx results) or unplanned (considered excisional bx)
T/Fmarginal resection + radiation tx has similar survival rates compared to definitive surgical resection alone of ST sarcomas
TRUEbenefit of planned marginal excision if owner willing to follow up with radiation therapy
four techniques used to manage unplanned marginal resections
- no treatment (maybe an option for low grade)2. staging resection (< 10mm margins to determine if cancer is still there)3. wide resection 4. combination therapy (radiation, chemo)
T/Fdespite incomplete margins on histopath, 78% of ST sarcomas had no evidence of residual tumor following a staging resection
TRUEmay not require additional treatment
T/Flymph node size is a good predictor of metastasis
FALSELN size is NOT a good predictor of mets2003 study with 100 dogs with oral melanoma40% normal LN palpation had mets49% of abN LNpalpation did NOT have metsrecommend biopsy or cytology
sentinel LN definition
local LN that may serve as a filter/barrier for disseminating tumor cels. likely to drain there prior to dissemination ID: lymphoscintigraphy, peritumoral injection blue dye, intraop cytology, histopathology
Halstead vs Cady Fisher theory for sentinel LN
Halstead: LN are effect barrier; don’t remove it unless it is known to contain tumor cellsCady Fisher: ineffective barrier but may be a biological indicator therefore remove them for staging purposes but removal may not necessarily affect survival; may decr tumor burden though
T/Fyou should close a wound made from tumor removal with use of axial pattern or transpositional flap at the same time as the original surgery
FALSEneed to wait until his to margins are confirmed clean or dirty39% of dogs in which an axial pattern gap was used to reconstruct a defect from tumor excision was considered dirty based on histopathology
most useful reconstructive techniques
- axial pattern flap2. local pedicle flap3. tension relieving patterns4. mesh graft
excisable margins for intestinal tumors
4-8 cm
excisable margins for bone
1-3 cm
Fulcher et al JAVMA 2006how many MCT were considered complete margins for tumors < 3.1 cm
grade 1 and 2= 2 cm lateral, 1 fascial plane deep91% were considered clean complete excision
Based on feline injection site sarcoma….what % of clean tissue was seen at 1, 2, 3 cm away from the palpable mass
1 cm away from mass 13% clean2 cm away from mass 32% clean3 cm away from mass 94% cleansingle plane deep 94% clean
types of IHC stains for carcinoma vs sarcoma
carcinoma cytokeratinsarcoma, melanoma vimentinboth are cytoplasmic proteins
types of IHC for T cell vs B cell lymphoma
T cell lymphoma CD3B cell lymphoma CD79a
types of IHC for gastrointestinal stromal tumors and MCT
CD117 (KIT)
greatest proportion of tissue shrinkage in a study of healthy dogs
greatest proportion shrinkage occurred immediately upon resection
T/FTissue shrinkage is less if muscle is included in specimen
true
healthy dog skin tissue shrinkage
decr length and width by 32%incr thickness by 75.8%
T/FPositive microscopic margins (residual cancer cells in a wound) following soft tissue sarcoma excision are associated with a 10.5 times increased risk of local recurrence compared with a cleanly excised tumor.
True Kuntz et al 1997
incompletely vs completely excised grade 2 MCT and rate local recurrence
complete excision grade 2 MCT– recurrence rate 11%butincomplete excision grade 2 MCT–recurrence rate only 18% to 35% proliferation marker Ki-67 may be prognostic for local recurrence
recurrence rate after primary REexcision of an incompletely excised ST sarcoma
incomplete resection studied 41 dogs undergone aggressive scar revisionLocal tumor recurrence 15% median time to recurrence of 142 days
recurrence rate on distal extremity for LOW grade sarcomas following intentional marginal excision Stefanello et al Vet Surgery 2008
11%
how does surgical removal of tumor help adjuvant therapies
- removes tumor burden2. IDs tumor margins3. rids drug/chemical/radiation resistant cells4. decreases circulating immune complexes5. decreases circulation tumor associated immunosuppressants
goals of neoadjuvant (preop) therapy
- reduce tumor size2. decrease risk of satellite cells and in transit mets3. eliminate microscopic tumor from extension into normal marginsall of which may help decr surgical “dose” required to achieve resection
why is radiation therapy a more effective method of neoadjuvant therapy
because preoperatively the blood supply to the tumor is unimpaired tumor cells are better oxygenated and more radiosensitive
disadvantages of neoadjuvant radiation therapy
deleterious effects on regional vasculaturehigher rates of delayed wound healing and other wound complications
post operative adjuvant radiation therapy in dogs with ST sarcomas
much more effective against microscopic disease 1-year disease-free control rates >95% for residual microscopic disease and only 50% for dogs with macroscopic tumor burden.Adjuvant radiation therapy can still increase the risk of wound complications, especially if started before 7 days postoperatively.
advantages and disadvantages of post op adjuvant radiation therapy
advantages1. no delay in surgery2. good evidence that it rids 95% of microscopic disease in ST sarcomas3. fewer local wound complicationsDisadvantages1. larger radiation field to encompass surgical site2. hypoxia in cells from an altered environment post op may make cells more radioresistant
how does chemotherapy work
kills rapidly dividing cells (non selectively)–GI epith, hair, bone marrow1. cell cycle specific (in S of Mitosis)2. non cell cycle specificusually start 10-14 days post op
types of cell cycle specific chemotherapeutics
specifically kill cells in M and S phases1. vinca alkaloids2. nucleoside analogues,
types of NON cell cycle specific chemotherapeutics
- alkylating agents2. anthracyclines3. platinum drugs
T/FNo difference in median survival in dogs receiving chemotherapy for OSA 2 days post limb amputation vs 10 days post limb amputation
TRUE
define metronomic drug therapy
frequent (even daily) administration of chemotherapeutics at doses significantly below the maximum tolerated dose with no prolonged drug free intervalsaim is control or minimize angiogenesis and invasion (NOT cytotoxicity)
examples of metronomic therapy
CyclophosphamideNSAID for COX inhibitionDoxycycline for MMP inhibition
types of alkylating agents
insert bulky alkyl groups into DNA/RNA NON cell cycle specific1. cyclophosphamide (ex. C in CHOP–lymphoma and metronomic tx)2. lomustine ( can be used to tx lymphoma or MCT)
what drugs causes sterile hemorrhagic cystitis 10%
cyclophosphamidean alkylating non cell cycle specific chemo agentdue to renal metabolism and exertion of ACROLEINconcurrent treatment with furosemide may decrease occurrence
types of vinca alkyloids
microtubule inhibitors that affect the spindle apparatus during mitosisCELL CYCLE SPECIFIC (M)1. vincristine (O-in CHOP for lymphoma)2. vinblastine (tx MCT)3. vinorelbine (primary pulmonary tumors)side effects: phlebitis; paralytic ileus (vincristine)
MOA doxorubicin
Anthracyclin–noncell cycle specific chemo agentinhibits topoisomerase activity, damage DNA with iron free radicals, and causes DNA intercalationside effects: cardiomyopathy with cumulative doses (180-204 mg/m2, vesicant with extravasation, renal insufficiency (cats), myelosuppression, GI toxicity
platinum chemotherapeutic agents
carboplatin most commoncovalently bind to DNA preventing replication/protein synthesisNON cell cycle specificused to tx OSAcisplatin led to fatal pulmonary edema in cats and is not used much
Bisphosphonates
palliative option for osteolytic diseasesinhibits osteoclastic activity to decrease bone resorption and have improved bone mineralizationpamidronate
T/FClinical trials of maropitant and highly emetogenic cisplatin, ashowed 95% of dogs receiving prophylactic maropitant did not vomit. In contrast, 95% of dogs receiving placebo vomited after cisplatin chemotherapy
trueother antiemetics include: odansetron, dolasetron, metoclopramide
bone marrow nadir for most chemotherapeutics
7 day BM nadir (EXCEPTION carboplatin 10–14 day nadir)always check CBC before chemoadministrationdelay chemo 5-7 days if PMN < 1500 or platelets < 50,000may need to consider reducing chemo dose by 20%
most accessible immunotherapy in veterinary medicine
melanoma vaccine DNA vaccine against human tyrosinase
what is the most common acquired mechanism of resistance for canine chemotherapeutics
mutations in MDR-1 genenormally keeps xenobiotic substances OUT; located in blood brain barrier, proximal renal tubule and intestinal epith cells.when mutated, drugs accumulate and increase toxicities are seencollies, shelties, Australian cattle dogs
innate resistance most often occurs with what types of chemotherapies
cell cycle specific drugsbc not all cells are in the same phase and resistant tumor cells have a selective advantage may also occur due to improper dosing and limited access in areas (ie. CNS)
