CABCO Flashcards
1
Q
Are alterations in cell cycle regulation that increase cell proliferation sufficient for carcinogenesis and tumorigenesis?
A
No, other mutations are needed for premalignant cells to acquire traits and behaviors that lead to invasiveness and metastasis
2
Q
What are the two most desirable therapeutic outcomes when treating cancerous cells?
A
Apoptosis or permanent cell cycle arrest
3
Q
It takes how many hours for most human cells to complete the cell cycle?
A
24 hours
4
Q
What is the shortest phase in the cell cycle? The longest?
A
Shortest: mitosis (~1 hour)
Longest: S phase (1/3 to 2/3 cell cycle)
5
Q
What is the difference between an inactive CDK and an active CDK?
A
Inactive has no cyclin + a T-loop blocking the active site containing ATP
Active has cyclin bound + phosphorylated T-loop does not block the active site
6
Q
In what phase of the cell cycle are CDKs not active?
A
G0
7
Q
What cyclin-CDK complexes are present in mid G1?
A
Cyclin D-Cdk 4
Cyclin D-Cdk 6
8
Q
What cyclin-CDK complexes are present in late G1?
A
Cyclin E-Cdk 2
9
Q
What cyclin-CDK complexes are present in S phase?
A
Cyclin A-Cdk 2
10
Q
What cyclin-CDK complexes are present in M phase/mitosis?
A
Cyclin A-Cdk 1
Cyclin B-Cdk 1
11
Q
What kinase phosphorylates mitotic CDK-cyclin complexes with an inhibitory phosphate?
A
Wee1
12
Q
What kinase phosphorylates mitotic CDK-cyclin complexes with an activating phosphate?
A
CDK Activating Kinase (CAK)
13
Q
What phosphatase removes inhibitory phosphate from the mitotic CDK-cyclin complex?
A
Cdc25
14
Q
What does an activated mitotic CDK-cyclin complex phosphorylate?
A
Histones, mitotic spindle proteins, lamins
15
Q
What causes degradation of mitotic cyclins and cohesion proteins holding metaphase chromosomes together?
A
Anaphase Promotion Complex (APC)
16
Q
What transcription factor does Rb protein regulate?
A
E2F
17
Q
What checkpoint is Rb present in?
A
G1/S phase
18
Q
Describe Rb/E2F interaction
A
Active Rb is bound to E2F, inactivating it
An active G1-Cdk can phosphorylate Rb, inactivating it and releasing E2F. E2F is now free to increase S-phase gene transcription and produce the needed Cyclins (A and E) at this stage
19
Q
What is the function of the Cip/Kip family of proteins? Name them.
A
Bind and inactivate dimeric complexes of cyclin D-Cdk4/6, cyclin A-Cdk2 or Cyclin E-Cdk2
p21, p27, and p 57
20
Q
What is the function of the INK4 family? Name them.
A
Bind and inactivate Cdk4 and Cdk6 kinases
p15, p16, p18, and p19
21
Q
What two CDK inhibitors regulate the G1/S transition?
A
p16 and p27
22
Q
Ras increases the transcription of what proto-oncogene?
A
Myc
23
Q
What does Myc increase the expression of?
A
Entry into S phase via increased Cyclin D, decreased p27, and increased E2F synthesis & activity
24
Q
What does p53 do (in general terms)?
A
Arrest the cell cycle and cause apoptosis
25
Where are most oncogenic point mutations in p53?
The DNA binding domain
26
Is p53 active when phosphorylated or dephosphorylated?
Phosphorylated
Inhibits Mdm2 from binding and tagging p53 for degradation
27
What does it mean to describe p53 mutations as "dominant negative"?
The mutant allele overrides the normal allele
p53 is normally a tetramer and it cannot bind to DNA properly if half of the tetramer is damaged/unable to bind
28
How does p53 activate the intrinsic pathway of apoptosis?
Via BCL2 family of proteins & cytochrome C release from the mitochondria
29
What types of cells do tumors contain?
Cancerous AND normal cells (they need the nutrients that normal cells provide)
30
What type of cancer cell is relatively rare and has a high replicative potential that can effectively "seed" new tumors?
Cancer stem cell
31
How many viruses are associated with human cancers?
7
32
What percentage of human cancers are due to viruses?
20%
33
What is the most common STD in the US?
HPV
34
How many HPV strains are classified as high-risk?
12
35
What are the two HPV strains that cause the majority of cervical cancers?
HPV16 and HPV18
36
What type of tissues does HPV normally infect?
Skin or mucosa (genital tract, oral, nasal)
37
What two low-risk strains of HPV cause 90% of all genital warts
HPV6 and HPV11
38
How many genes does a papilloma virus typically have?
8-10
39
What does HPV transmission require?
A microabrasion
40
What does HPV's E7 protein do?
Activates cell cycle progression by binding to Rb
Rb is normally bound to E2F to inhibit cell-cycle progression. E7 binds Rb very tightly, allowing uncontrolled actions of E2F
41
What does HPV's E6 protein do?
E6 blocks apoptosis by inducing p53 degradation
E6 complexes with cellular E6AP and this complex can bind to p53 and cause its degradation in the proteosome
42
The combination of HPV's E6 and E7 proteins are oncogenic because...?
Their actions result in uncontrolled proliferation AND loss of the ability of the cell to kill itself
43
Do most people with HPV get cancer?
No, most people clear the virus over time. A small percentage get cancer.
44
What is the key step in the transition from benign cervical lesion to invasive cervical cancer?
Circular HPV DNA becomes linear and inserts into the host's genome
45
What protein is lost in the transition from circular HPV DNA to linear? This protein normally keeps E6 and E7 in check
E2
46
What are koilocytes?
Cells in the cervical epithelium full of 1000s of HPV viruses
47
How do you treat persistent HPV infections not associated with abnormal cell changes?
You don't
48
What are the three FDA-approved HPV vaccines?
Ceravix, Gardasil, Gardasil 9
49
What cells of the epithelium does HPV first infect?
Basal cells
50
What component of the HPV capsid do most of the vaccines target?
L1 protein
51
What enzyme has increased activity in Chronic Lymphocytic Leukemia?
Bruton's tyrosine kinase
52
Can capacitated patients refuse life-sustaining treatment?
Yes
53
Can patients use advanced directives to refuse life sustaining treatment when they become incapacitated?
Yes
54
What is the ethical and legal difference between withholding and withdrawal of life sustaining treatment?
There isn't one
55
When are advanced directives legally enforceable?
When a patient loses decisional capacity
56
Can ordinary power of attorney be used for decision-making for incapacitated patients?
No, only a durable power of attorney continues through incapacity
57
Define neoplasia
general process of new growth
58
Define neoplasm
A new growth
59
Define cancer
general term for all malignant tumors
60
Are tumor and malignancy synonymous?
No
Tumor = neoplasm
61
Name of benign and malignant tumors affecting squamous epithelium?
Benign: squamous papilloma
Malignant: squamous cell carcinoma
62
Name of benign and malignant tumors affecting glandular epithelium
Benign: adenoma
Malignant: adenocarcinoma
63
Name of benign and malignant tumors affecting surface epithelium?
Benign: papilloma
Malignant: papillary carcinoma
64
Name of benign and malignant tumors affecting smooth muscle
Benign: leiomyoma
Malignant: leiomyosarcoma
65
Name of benign and malignant tumors affecting striated muscle?
Benign: Rhabdomyoma
Malignant: Rhabdomyosarcoma
66
Name of benign and malignant tumors affecting blood vessels?
Benign: Hemangioma
Malignant: Angiosarcoma
67
Name of benign and malignant tumors affecting fat?
Benign: Lipoma
Malignant: Liposarcoma
68
Name of benign and malignant tumors affecting cartilage?
Benign: chondroma
Malignant: chondrosarcoma
69
Name of benign and malignant tumors affecting bone?
Benign: osteoma
Malignant: osteosarcome
70
Name of benign and malignant tumors affecting fibroblasts?
Benign: fibroma
Malignant: fibrosarcoma
71
Name of benign and malignant tumors affecting melanocytes?
Benign: nevus
Malignant: malignant melanoma
72
Name of benign and malignant tumors affecting totipotent germ cells?
Benign: mature teratoma
Malignant: immature teratoma (teratocarcinoma)
73
Name of benign and malignant tumors affecting lymph nodes/bone marrow?
Benign: low grade lymphoma
Malignant: high grade lymphoma
74
Six steps in the invasion-metastasis cascade?
1. Local invasion
2. Intravasation into blood/lymphatic vessels
3. Transit in vessel
4. Arrest/extravasation into distant tissue
5. Micrometastasis formation (small nodules)
6. Colonization
75
What is the first transformation cancer cells must make in order to complete metastasis?
Epithelial to mesenchymal transition
76
Is metastasis an efficient or inefficient process?
Very inefficient
Less than 0.01% of cancer cells in circulation develop into metastases
77
Define hypertrophy
Increase in tissue mass without cellular proliferation (aka increase in cell size)
78
Define hyperplasia
Increase in tissue mass due to an increase in cell number
79
Define metaplasia
A reversible change in which a differentiated cell type is replaced by another cell type. Most common in mucosal/epithelial surfaces
Usually happens in response to a stimulus
Becomes a problem when stimulus/irritant continues and produces genetic changes leading to autologous growth and cancer
80
What are four types of non-neoplastic growth & differentiation?
1. Reparative proliferation (granulation tissue)
2. Hypertrophy
3. Hyperplasia
4. Metaplasia
81
Characteristics of benign neoplasms?
Autonomous growth that is slow and progressive
Growth by expansion NOT invasion
Encapsulation/clear demarcation from normal tissue
Cells with high degree of differentiation/preserved architecture
82
Define ectopic
Normal tissue in abnormal location
83
Define hamartoma
normal tissue components in an abnormal/disorganized configuration ("at home")
84
Define choristomas/heterotopia
Normal tissue but in the wrong place
Ex: normal pancreatic tissue ectopically present in the wall of the stomach
85
Define polyp
Grossly visible growth projecting from a surface, often a mucosal surface
General term. Can be hyperplastic (non-neoplastic), benign, or malignant
86
Define hyperplastic polyp
Most common type of colonic polyp; lacks malignant potential . Has "saw-tooth"/serrated/tufted appearance
In many organs/locations
87
Is benign neoplastic growth reversible?
"the process is not generally considerable reversible"
88
What does "oma" mean?
Tumor (no distinction between benign or malignant though!)
89
What is Von Hippel-Lindau Syndrome?
Autosomal dominant genetic condition characterized by visceral cysts, benign masses, and the potential for malignant transformation in multiple organ systems
90
Clinical features of Von Hippel-Lindau Syndrome?
Eye tumor, brain tumor, kidney tumor, adrenal gland tumor, pancreatic tumor, Cafe Au Lait spots, CVS (strokes and heart attacks)
91
Most common type of disease-causing mutation?
Single point mutation
92
Three ways proto-oncogenes are converted into oncogenes?
1. Point mutation
2. Gene amplification
3. Chromosomal rearrangement
93
What does Ras bind in its active state? Does this induce or inhibit cell growth?
GTP
Induces cell growth
94
What oncogene in responsible for Neuroblastoma? What is its mechanism from proto-oncogene to oncogene?
N-myc
Amplification
95
How do Burkitt lymphoma tumor cells appear on H&E?
Round, homogenous, and display a high mitotic rate
96
Chromosomal translocation responsible for Burkitt lymphoma?
8 and 14 (14q has new IgH-myc gene)
Places the myc gene adjacent to IgH enhancer/promoter
97
Chromosomal translocation responsible for Chronic Myelogenous leukemia (CML)?
9 and 22 (9q has new Bcr-Abl gene)
Bcr-Abl is a constitutively active tyrosine kinase that leads to cell growth
98
What drug inhibits Bcr-Abl function?
Imatinib (Gleevec)
Binds into the ATP site of Bcr-Abl and inhibits tyrosine kinase functionality
Gleevec is a synthetic ATP mimic
99
Effect of mutations on tumor suppressor genes?
Inactivation
100
Effect of mutations on oncogenes?
Activation
101
First tumor suppressor gene identified?
Rb
13q
102
Main job of Rb?
"Molecular policeman" of the cell cycle: serves as a guard at the G1/S transition
103
What is the most commonly mutated gene in human cancer?
p53
104
95% of p53 mutations are found where?
point mutations in the DNA-binding domain
105
The cancer cell phenotype is (dominant or recessive) to the normal cell phenotype?
Recessive
| per cell fusion experiment
106
Are viral oncogenes derived from viral or host genomes?
Host
107
Define log cell kill
A given dose kills a fixed percentage of cells
Note: established in vitro, not in vivo
108
Define dose dependent
Different depending on whether or not the agent is cell cycle specific
109
The growth fraction of tumor cells depends on what?
The size of the tumor
As tumor size increases, growth fraction decreases
110
When is chemotherapy most effective?
When cell turnover is highest
111
When is cell turnover highest?
When tumor volume is below the level of detection (10^9 tumor cells)
112
Log cell kill effect depends on the tumor ______ at diagnosis
volume
113
What results in the best chance of cure?
Dose intensity - the concept that the highest dose at the most frequent intervals will result in the best chance of cure
114
If a tumor has a stable growth fraction, a given dose of drug will kill what?
A fixed percentage of tumor cells regardless of the tumor mass
** he stressed this in class **
115
Define palliative chemotherapy
Chemotherapy given to patients with metastatic/incurable cancer with the intent of prolonging life or alleviating symptoms
116
Define curative chemotherapy
Chemotherapy, almost always combination of drugs, given with the intent of inducing remission and curing the patient
Used with testicular cancer, lymphomas, leukemia, and a few solid tumors
117
Define adjuvant chemotherapy
Chemotherapy given after a local procedure (surgery or radiotherapy) with the intent of eradicating microscopic metastases
Commonly used in breast cancer, colon cancer, and selected other tumors
*** Patients generally do not have clinically detectable metastases
118
Define neoadjuvant chemotherapy
Chemotherapy given when a tumor is large/unresectable with the intent of making it more amenable to local therapy and at the same time treating the subclinical metastatic diseases
119
What is the order of gene mutations seen in colon cancer progression?
1. APC/B-catenin
2. K-RAS
3. p53
120
Two categories of molecular changes seen in colon cancer development?
1. Genomic changes/genetic (chromosomal instability or microsatellite instability)
2. DNA methylation/epigenetic
121
In which part of the colon are hyperplastic polyps most common?
Left colon
| Result from decreased cell turnover; no malignant potential
122
What are three types of adneomas/neoplastic polyps found in the colon?
1. Tubular adneoma
2. Villous adneoma
3. Sessile serrated adenoma
123
Define tubular adenoma
small, pedunculated, "tubular glands," and often have a stalk
Nucleus appears elongated
124
Define villous adenoma
larger, long, slender villi
Has a wide base and grows as a sessile ("attached along the base of lesion") rather than as a pedunculated lesion with a long stalk
125
Define sessile serrated adenoma
Similar to hyperplastic polyps but crypt dilation and budding into the lamina propria (wider base)
126
In which portion of the colon are sessile serrated adneomas most commonly found?
Right colon
127
What precedes the development of macroscopic polyp (adenoma)?
An aberrant crypt focus (ACF)
128
What are the precursor lesions in Familial Adenomatous Polyposis (FAP)?
aberrant crypt foci (ACF)
129
Outside of the colon, where do lesions typically present in those with FAP?
Retinal lesions, gastric & duodenal polyps, desmoid tumors
130
What is Gardner syndrome?
FAP, osteomas, skin cysts
131
What is Turcot syndrome?
FAP, brain tumors
132
What germline mutation is present in people with FAP?
APC gene
** know this!!!
133
What does APC regulate?
B-catenin
When Wnt signaling is present, APC is constantly degraded and B-catenin signaling is always "on"
This leads to constitutive proliferation
134
What precursor lesions are present in patients with Lynch Syndrome (HNPCC)?
Tubular adenomas (but smaller and flatter)
135
Median age of CRC diagnosis in HNPCC? FAP?
HNPCC: 60
FAP: 35-40
136
Where is CRC most commonly present in those with Lynch Syndrome?
right colon
137
People with Lynch Syndrome are at a higher risk for what other cancers?
Endometrial, small bowel, ovarian, gastric and ureteral
138
What is the distinctive histology present in Lynch Syndrome?
Mucinous and "medullary/solid" differentiation
139
Germline mutations in Lynch Syndrome?
hMLH1, hMSH2, hPMS1, hPMS2, hMSH6
140
What gene is methylated/silenced in SSA adenomas?
MLH1
141
Which side of the colon has more goblet cells?
Left side
142
Which side of the colon has more Paneth cells?
Right side
143
Most common neoplastic polyp?
Tubular adenoma
144
Favorite places for colon cancer metastasis?
Lymph nodes, liver, lungs, and bones
145
What cancer(s) are associated with Epstein-Barr virus?
Nasopharyngeal carcinoma
Burkitt lymphoma
146
What cancer(s) are associated with human herpes virus type 8 (HHV8)?
Kaposi sarcoma
147
What cancer(s) are associated with Human T-cell leukemia/lymphoma virus (HTLV-1)?
T-cell leukemia/lymphoma
148
What cancer(s) are associated with Human T-cell leukemia/lymphoma virus (HTLV-2)?
Hairy cell leukemia (very weak association)
149
What cancer(s) are associated with HPV 16 & 18?
Cervical, head & neck cancers
150
What cancer(s) are associated with Hepatitis B & C?
Hepatocellular carcinoma
151
What are examples of AIDS-defining cancers?
Kaposi sarcoma, non-hodgkin lymphoma, invasive cervical cancer
152
What are examples of cancers that can develop in persons with HIV infection while they are being treated with HAART?
Hepatocellular carcinoma, anal cancer, hodgkin lymphoma
| Note: NON-hodgkin lymphoma is an AIDS-defining cancer. Don't let Winter trick you!!!
153
What is Post-transplant lymphoproliferative disorder (PTLD)?
A neoplasm that can develop after organ transplantation due to immunosuppression (linked to EBV B-cell infection)
154
List the three tumor markers Winter gave in his presentation
M-spike, PSA, CEA
155
What type of lymphocyte do we need for tumor resistance?
T cells
156
What is "cancer immunoediting"?
Cancer cells that escape immune system recognition are able to survive and proliferate
"selective outgrowth of antigen-negative variants"
157
What are three ways tumors escape immune recognition?
"Greased pig phenomenon"
1. Loss of MHC 1 due to TAP or proteasome mutation
2. Loss of adhesion molecule expression
3. Lack of B7 expression (no co-stimulus -> leads to T Cell anergy
158
How do tumor cells prevent killing by NK cells?
They express other MHC 1 molecules that prevent this
| just missing the MHC 1 class that T cells interact with
159
What two cytokines do tumors secrete that suppresses the immune system?
1. TGF-beta
2. IDO enzyme
Both of these suppress CD4 and CD8 cells
160
What does TGF-beta activate?
Tregs (CD4+, CD25+, FoxP3+)
161
What do Tregs secrete?
TGF-beta, IL-10 (also suppresses immune response!), and IDO
162
How can a tumor cell induce apoptosis in a CD8 T cell?
Tumor Fas-ligand binds to CD8 Fas and causes apoptosis of CD8 cell
163
What two tissues lack lymphatics?
Brain and gonads
164
How do tumor cells mask themselves?
With connective tissue and glycocalyx molecules
165
What does Anti-CD22-pseudomonas toxin do?
It is a toxin-labeled antibody that binds to CD22 on tumor cells. The tumor cell internalizes the receptor-Ab conjugate and dies
Causes remission in 2/3 of hairy cell leukemia patients
166
How can antibodies be used to attack tumor cells?
Monoclonal antibodies that make it easier for NK cells to find the tumor cells
Toxin, radiation or drug-labeled antibodies
167
Does immunizing cancer patients with tumor proteins mixed with bacterial adjuvants work?
Nope, largely ineffective
168
What are Immune Stimulatory Complexes (ISCOMs)?
lipid micelles containing tumor antigen
APCs take up these ISCOMs and present the antigens to CD8 t cells. Now they're activated and looking for tumor cells
169
What are Lymphokine-activated killers (LAKs)?
mononuclear cells are isolated from peripheral blood and given IL-2 (T cell growth factor!). Enhanced CD8 t cells & NK cells are infused back into the patient
170
What are Tumor-Infiltrating lymphocytes (TILs)?
Lymphocytes and NK cells are isolated from a tumor and given IL-2 (T cell growth factor!). Enhanced CD8 t cells & NK cells are infused back into the patient
171
What is KRAS?
Proto-oncogene GTPase
Oncogenic form is stuck in the "on" position with GTP
172
What are "CAR-T cells"?
Chimeric antigen receptor modified T cells
A patient's t cells are modified to include a receptor that targets tumor cell antigen
Structure is a single chain fragment that is mostly variable region
173
What kind of malignancies have CAR-T cells been effective in treating?
Hematologic
174
How can CAR-T cells be made effective against solid tumors?
Diapedesis into the solid tumor needs to be increased
This can be done by re-engineering CD6 (5HS) to increase transit into the tumor
175
What are immune checkpoint inhibitors?
Normally, T-cell signaling can lead to down-regulation of T-cell actions; this can be via CTLA4-B7 or PD1-PDL1 interactions
Monoclonal antibodies, aka checkpoint inhibitors, can be developed that bind to PDL1, PD1, and CTLA4 and stop this down regulation
176
What immunologic toxicities are caused by anti-PD1/anti-PDL1 monoclonal antibodies?
Immune-related adverse reactions (irARs) like pneumonitis, diarrhea/colitis, vitiligo, T1DM, thyroid changes, etc
177
What does CD47 do?
It's a protein present on tumor cells that binds to SIPalpha on macrophages and says "don't eat me!"
An anti-CD47 monoclonal antibody can bind to CD47 and increase macrophage phagocytosis
178
What type of biopsy just gives cells?
Fine needle
179
What type of biopsy gives architecture and allows more tests to be performed?
Core needle biopsy
180
What type of biopsy is the gold standard for initially assessing image detectable lesions in the breast?
Core needle
181
What percentage of biopsies should require open surgical biopsy?
5-10%
182
What is en bloc resection?
Removing the cancer with a rim of normal tissue
Well-established benefit in clinical trials for most cancers
183
What is the "gold standard" trial for breast cancer surgery? What did it show?
NSABP B-06
Mastectomy = lumpectomy + radiation
Lumpectomy with radiation is better than without
184
In which types of cancer surgeries is laparoscopic technique not an accepted surgical treatment?
Ovarian, adrenal, thyroid, uterine
OAT U
185
Screening is best understood as _______ _______?
Therapeutic intervention
186
Possible good outcomes of screening?
Decreased morbidity and mortality
187
Possible bad outcomes of screening?
Side effects, labeling with a diagnosis, false positives & negatives, over-diagnosis
188
Sources of bias in screening?
Selection bias, lead-time bias, and length-time bias
189
What is "up staging"?
Introduction of a new staging modality such as CT, PET, or surgical staging that gives one more accurate staging
190
What is the Will Rogers effect?
New staging makes it look like the survival is better for each stage but really patients have just migrated from one stage to another
All stages of the disease look better, but the overall population has the same survival
191
What is the number needed to screen?
The number of individuals you would need to screen to achieve one additional desirable outcome
1/Absolute risk reduction
**he said this was an exam question!!!**
192
How do you calculate absolute risk reduction?
Control Event Risk - Experimental Event Risk = ARR
193
What is fallacy of division?
What is true for the group is true for each individual
194
What is fallacy of composition?
What is true for an individual is also true of the group
195
Majority of cancer survivors are over what age?
65
196
What percentage of children with cancer will be cured?
80%
197
What are late effects of cancer treatment?
Complications that occur or persist more than 5 years from the end of therapy
They are unrecognized toxicities that are absent or subclinical at the end of therapy but manifest later
Ex: growth & development abnormalities, infertility, psychosocial effects, problems with vital organ function, etc
198
What are long-term effects of cancer treatment?
Side effects or complications of treatment that begin during treatment and continue beyond the end of treatment
ex: lymphedema, malabsorption, loss of voice
199
Which cancer treatment method has systemic effects?
Chemotherapy
200
What are the culprits of cardiac toxicity following cancer treatment?
Radiation
Anthracycline-type chemotherapy (Doxorubicin)
Tyrosine kinase inhibitors (Pazopanib, Sunitinib, Nilotinib)
Monoclonal antibodies (Trastuzumab, Bevacizumab)
201
How long after anthracycline-therapy is cardiac risk elevated?
5 years
202
The risk of second cancer is highest for who?
Those diagnosed at a younger age
| because their bodies are growing/DNA is active when initial treatment is occurring
203
When is the risk for a second cancer highest?
Within first 5 years after initial cancer but risk persists beyond 10 years from diagnosis
204
What can be viewed as a cell cycle disease?
Cancer
205
What three phases/blocks of treatment are used to treat childhood leukemia?
Induction, consolidation, maintenance
206
What were the downsides of craniospinal radiation used in the 1970s to treat leukemia?
Myelosuppression, growth issues, altered intellectual and psychomotor function, endocrine abnormalities
207
What treatment combination was found to be equivalent to brain radiation?
Intensive systemic chemotherapy and intrathecal therapy combined
(intrathecal therapy was less effective than radiation when less intensive chemo was used)
208
What is the Goldie Coldman hypothesis?
Intensive cytoreduction leads to fewer surviving tumor cells to undergo mutation & lead to resistance
"If mutations are chance events during cell division, having more cells around increases the risk of mutation leading to resistance."
209
Combination of what three induction phase drugs brought remission rates to greater than 95%?
Vincristine + steroid + asparaginase
| Note: anthracycline could be added to further improve remission rates but its highly toxic
210
What is the criteria for standard risk pediatric leukemia patients? High risk?
Standard: between 1 and 10 years old; WBC less than 50,000/mL
High: Over 10 and WBC greater than 50,000/mL
211
How many leukemia cells are left after induction phase treatment? Why?
~ 10 billion
They persist due to resistance, sanctuary sites, quiescent state (were not dividing when chemo was given)
212
What are two improvements of post-induction therapy?
1. Intensifying therapy of slow responders (if minimal residual disease is left then increase therapy)
2. Identifying low/high risk subgroups through cytogenetics (i.e. Philadelphia chromosome, MLL rearrangements, hypoploidy, etc)
213
What is the Norton Simon hypothesis?
Cells remaining post-induction are relatively/absolutely resistant; late/delayed intensification (new agents) may be beneficial here
He gave the example of a second round of induction and consolidation treatments (dexamethasone + anthracycline (low risk) or doxorubicin (high-risk)
214
Has the introduction of new chemotherapy agents played a large or small role in pediatric leukemia outcome improvements?
Small role
Major improvements came via clinical trials assessing traditional drugs
215
Disease-free survival rate for Ph+ Acute Lymphoblastic Leukemia with chemotherapy alone and with BMT from sibling?
Chemo: 20%
BMT from sibling: 60%
216
What gene is expressed in Ph-like acute lymphoblastic leukemia?
R8
| Note: their outcomes are inferior to those who are actually Ph+
217
What is the single best criterion of malignancy?
Metastasis
218
What is the most common benign neoplasm of the female breast?
Fibroadenoma
219
What is the most common benign tumor of the salivary glands?
Pleomorphic adenoma
220
What features reflect a lack of cell differentiation/become more prominent in malignant tumors?
1. Variation in cell size (pleomorphism)
2. Increased nuclear size (higher N:C ratio)
3. Increased DNA content & irregular nuclear borders
4. Large nucleoli
5. Increased mitoses
6. Abnormal mitoses
221
In what type of cancer do we see Reed-Sternberg cells ("owl eyes") on H&E?
Hodgkin Lymphoma
222
In what type of tumor do we see multipolar mitotic figures?
Wilms tumor
223
In what type of cancer will we see keratin?
Squamous cell carcinoma
224
If a cancer cell is TTF+ and CK7+, what type of cancer is it?
Adenocarcinoma
225
If a cancer cell is p63+, what type of cell is it?
Squamous cell carcinoma
226
What two organs are most commonly involved with metastatic cancer?
Lungs and liver
227
What property (or finding) gives a tumor the potential opportunity for metastasis?
Invasion through the basement membrane (gaining access to blood vessels or lymphatics)
228
What is the most common general type of human cancer?
Carcinoma
229
What are the two main types of carcinoma?
Squamous cell carcinoma and adenocarcinoma
230
How common are sarcomas?
Less than 1% of all human malignant tumors
231
When are tumor cells most chemo-sensitive?
When they are small and have a high growth fraction
232
What is growth fraction?
The fraction of tumor cells that are actively dividing
233
What does the Norton-Simon hypothesis predict?
Greater log-kill in smaller tumors due to rapid growth and supports chemotherapy in the postoperative setting
234
Five forms of cancer immunotherapy?
1. Bone marrow transplant
2. Monoclonal antibodies
3. Cancer vaccines
4. Checkpoint inhibitors
5. CAR T cells
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What is a dendritic cell vaccine?
Its used to enhance a patient's T cell immunity
Dendritic cells are pulsed with tumor antigens and then injected into the patient. DCs present tumor antigen to the patient's T cells and then tumor-specific T-cells are activated
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Most common malignancy in children?
B-cell acute lymphoblastic leukemia (ALL)
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What are three targets of targeted therapy?
1. Oncogenic signaling pathways (EGF, MAP kinase, BCR-ABL)
2. Angiogenesis (VEGF)
3. Apoptotic machinery (HDAC, proteasome inhibitors)
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What is a basket trial for precision medicine?
Genomic aberrations are recurrent across multiple organ sites & the presence of a specific mutation may be more predicative of drug response
aka people with similar mutations, not necessarily in the same organ, are enrolled to see if a treatment approved in another disease will work for their disease or a rare one
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What is an umbrella trial?
Evaluates many treatments (aka many "treatment arms") within the same cancer type
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What is a super-umbrella trial?
Captures umbrella trial AND basket trial under on super umbrella. Lots of arms that people go be assigned
Downside is that patients could be eligible for multiple arms or that the trial may require a large number of drugs and biomarkers
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What are SERMS? Example of one?
Selective Estrogen Receptor Modulators
Ex: Tamoxifen
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What is the cause of non-small cell lung cancer?
EGFR is aberrantly activated (oncogene)
Activation due to overexpression of receptor or mutations that cause constitutive activation of receptor tyrosine kinase activity
"oncogene addiction"
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What receptor is overexpressed in 25-30% of patients with metastatic breast cancer?
HER-2/neu (human epidermal growth factor receptor 2)
244
95% of Chronic Myelogenous Leukemia (CML) are associated with what?
The Philadelphia chromosome t(9;22)
Joins BCR locus on chromosome 22 with the ABL locus on chromosome 9 to make the mutant tyrosine kinase BCR-ABL
245
What type of mutation is found in 60% of melanomas?
BRAF mutations
BRAF is a component of the MAP kinase pathway that transmit growth-stimulatory signals from the cell surface to the nucleus
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90% of BRAF mutations affect a single amino acid residue. What is it?
V600E
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What is the equation for how x-rays interact with matter?
High energy x-ray + water ----> H20^+ + e^-
H20^+ quickly decays into H+ and OH* (free radical)
Free radical causes DNA damage
DNA damage leads to cell death
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When do we see the biologic effects of DNA damage after radiation?
Days to weeks after the lethal event
Most cells do not show evidence of radiation damage until they attempt to divide
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DNA damage can be lethal and ______?
Sublethal
Sublethal damage can be repaired
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Do cancer cells take longer or shorter to repair than normal cells?
Longer
Fractionating radiation dosage takes advantage of this! The same small dose is applied over multiple exposures so less damage is caused to normal cells & they can repair themselves
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What are the two different types of radiation used?
1. Teletherapy (external beam RT) - photon therapy/x-rays, most common
2. Bracytherapy (internal RT) - radiation implants, ingested radioactive pills, intravascular radiation injections
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What is 3D conformal RT?
3D conformal radiation therapy is a cancer treatment that shapes the radiation beams to match the shape of the tumor
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What is intensity modulated radiotherapy (IMRT)?
Divided into various beamlets; varying intensities allow you to conform to the shape and carve out things you don't want to hit like the spinal cord
254
What is Stereotactic Body Radiation (SBRT) or Stereotactic Ablative Radiotherapy (SABR)?
Administration of very high doses of radiation, using several beams of various intensities aimed at different angles to precisely target the tumor
SBRT is typically used to treat small, well-defined tumors
255
What are the goals of CT simulation?
Immobilization and reproducibility
256
In which age group is cancer the #1 cause of death?
45-64
257
Are most cancer cytotoxic agents specific or nonspecific?
Nonspecific
258
Hereditary cancer gene in Familial Melanoma?
p16INK
259
Hereditary cancer gene in Li Fraumeni Syndrome?
p53
260
Hereditary cancer gene in Familial Gastric Cancer?
CDH1
261
The occurrence of translocations as a sole karyotypic event in carcinomas are common/uncommon?
Uncommon
Generally associated with loss of heterozygosity, specific gene mutations, or aberrant patterns of expression
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Tumors of ______ origin are often associated with translocations thought to be causally related to the development of the neoplasia
mesodermal
263
What was the first therapeutic target?
Estrogen
264
What type of non-small cell lung cancer has the worst survival: squamous or adenocarcinoma?
Squamous
Most of the research and treatment effort has been focused on adenocarcinoma
