Radiation Biology Board Review for Radiation Oncology | Timoteo Almeida, MD, PhD

Formula Dashboard

Survival and Hits

SF = e^-X

One average lethal hit per cell gives 37% survival. That is the meaning of D0 in an exponential survival curve.

Linear-Quadratic Survival

SF = e^-(αD + βD^2)

α is single-hit / non-repairable; β is interaction / repairable damage and depends more on fraction size and dose rate.

Alpha/Beta

αD = βD^2 -> D = α/β

The α/β ratio is a dose, not a survival fraction. It is where linear and quadratic killing are equal.

BED and EQD2

BED = nd[1 + d/(α/β)]

EQD2 = BED / [1 + 2/(α/β)]

Low α/β tissues are punished by large dose per fraction.

OER

OER = dose hypoxic / dose oxygenated

For low-LET photons, typical OER is about 2.5-3. For high LET, OER approaches 1.

RBE

RBE = dose reference / dose test

RBE depends on endpoint, LET, dose per fraction, cell type, and oxygenation. It is not the same thing as radiation weighting factor.

TCP by Poisson

TCP = e^-N

N is average surviving clonogens. For 90% TCP, aim for N = 0.1; for 99% TCP, N = 0.01.

Cell Kinetics

Tpot = TC / GF

Tvol = Tpot / (1 - CLF)

Diameter doubling takes about 3 volume doublings.

Thermal Dose

CEM 43 C T90

Above 43 C, each 1 C increase roughly halves the time for the same thermal effect. Below 43 C, the time penalty is larger.

Question Decoder: The Fast Move

If the question mentions...	Think first	Likely answer direction
One lethal hit per cell	Poisson survival	SF = e^-1 = 0.37
α/β	Dose where αD equals βD^2	Late tissue low; early tissue and most tumors high
Late effects	Low α/β, fraction-size sensitive	Overall time matters less than dose/fraction
Early effects / mucosa	High α/β, repopulation	Overall time and dose/week matter
High LET	Clustered direct damage	Less shoulder, less repair, less oxygen effect, higher RBE until overkill
Hypoxia	Oxygen fixation missing	Radioresistant for photons; less relevant for high LET
NHEJ vs HR	Template availability	NHEJ in G0/G1, error-prone; HR in late S/G2, accurate
XP / CS / TTD	NER problem	UV sensitivity; XP cancer risk; not classic X-ray radiosensitivity
ATM / NBS / Ligase IV	DSB response/repair	Marked X-ray radiosensitivity
Bystander vs abscopal	Distance scale	Bystander nearby unirradiated cells; abscopal distant tumor/site

1. Radiation Interactions and Initial Biology

Direct vs Indirect Action

Action	What happens	Where boards go
Direct action	Radiation deposits energy directly in DNA or critical biomolecule	More important for high LET; less oxygen-dependent
Indirect action	Radiation ionizes water, generating free radicals that damage DNA	Dominant for low LET photons; oxygen and sulfhydryl scavengers matter
Critical distance	Free radicals must be generated very close to DNA, roughly a few nanometers	Indirect action is local even though it is chemically mediated

Memory: low LET damage is mostly indirect; high LET damage is more direct and clustered. That one sentence explains most OER, RBE, repair, and dose-rate questions.

Free Radical Timeline

Physical stage: energy deposition and ionization occur almost instantly.
Chemical stage: radicals form within nanoseconds to microseconds; oxygen can fix radical damage into more permanent peroxides.
Biologic stage: DNA damage response, repair, checkpoint arrest, death, senescence, mutation, inflammation, and tissue response unfold over minutes to years.

Water Radiolysis Products

Species / concept	Board meaning
Hydroxyl radical	Highly reactive, major mediator of indirect DNA damage
Hydrogen peroxide	Yield rises with LET in the range where radical clustering becomes important
Glutathione and sulfhydryls	Free radical scavengers; radioprotective for low LET, much less useful for high LET
Spurs and blobs	Low LET creates sparse spurs; high LET creates dense blobs with clustered damage

2. DNA Damage and Repair

Damage Types

Lesion	Cause / meaning	Repair / board point
Base damage	Oxidation or chemical modification of a base	BER; common and usually repairable
Base mismatch	Replication error	MMR; Lynch/MSI when defective
Pyrimidine dimer	UV-induced bulky lesion	NER; XP is UV-sensitive and cancer-prone
Single-strand break	One DNA backbone broken	Often repaired rapidly; dangerous when clustered or converted to DSB
Double-strand break	Both strands broken	Main lethal lesion for ionizing radiation
Crosslink	DNA strands or DNA-protein links held together	Fanconi/HR pathways; platinum-like biology

Numerical anchor: per Gy, cells get thousands of base lesions, about a thousand SSBs, and a few dozen DSBs. DSBs are far fewer but correlate best with cell killing.

Repair Pathways

Pathway	Repairs	Key proteins / genes	Exam trap
BER	Small base lesions and many SSB intermediates	Glycosylases, APE, XRCC1, PARP, Pol beta, ligase	Human BER defects are often embryonic lethal, so named clinical syndromes are less classic
NER	Bulky lesions, UV dimers, platinum-type lesions	XPA-XPG, ERCC1, CSA/CSB	XP is UV/cancer sensitivity, not classic therapeutic X-ray hypersensitivity
MMR	Replication mismatches and microsatellite errors	MSH2, MSH6, MLH1, PMS2	Defect causes MSI/Lynch; think immunotherapy relevance too
NHEJ	DSBs without template	Ku70/80, DNA-PKcs, Artemis, XRCC4, ligase IV	Predominant in G0/G1; fast and error-prone
HR	DSBs and crosslinks with homologous template	RAD51, BRCA1/2, MRN, BLM/WRN	Predominant late S/G2; relatively error-free
Alt-EJ / Pol theta	Microhomology-mediated end joining	POLQ	Error-prone backup pathway; can support HR-deficient cells

DNA Damage Signaling

ATM: central DSB response kinase, especially for ionizing radiation; activates checkpoint and repair signaling.
ATR: replication stress / single-stranded DNA response, often linked to stalled forks.
MRN complex: MRE11-RAD50-NBS1 senses DSBs and helps recruit/activate ATM.
gamma-H2AX: phosphorylated H2AX at DSB sites; sensitive foci assay for DSB response.
p53: damage-responsive tumor suppressor; induces p21, arrest, repair, senescence, or apoptosis depending on context.

Radiosensitivity Syndromes

Syndrome	Gene / pathway	Rad bio takeaway
Ataxia telangiectasia	ATM	Extreme X-ray radiosensitivity, neuro/immunologic features, cancer predisposition
Nijmegen breakage syndrome	NBS1 / MRN	DSB signaling defect, radiosensitivity
Ligase IV syndrome	NHEJ	DSB rejoining defect, radiosensitivity
Fanconi anemia	Interstrand crosslink repair	Chromosomal instability, marrow failure, cancer risk, treatment sensitivity
Bloom / Werner	RecQ helicases	Genomic instability and cancer predisposition
Li-Fraumeni	TP53	Multiple early cancers; high concern for radiation-induced malignancy
Xeroderma pigmentosum	NER	UV sensitivity and skin cancer; not the classic X-ray radiosensitivity answer

3. Chromosomes, Cell Cycle, and Cell Death

Chromosome vs Chromatid Aberrations

Aberration type	When irradiation occurred	What you see	Board use
Chromosome aberration	Before DNA replication, typically G0/G1	Both sister chromatids carry the same abnormality	Dicentrics and rings are unstable and useful for biodosimetry
Chromatid aberration	After DNA replication, S/G2	Only one chromatid or both chromatids affected depending on lesion	Anaphase bridges are lethal/unstable
Stable aberration	Misrepair compatible with mitosis	Balanced translocation, deletion	Can persist for years; FISH detects stable translocations
Unstable aberration	Misrepair that disrupts segregation	Dicentric, ring, anaphase bridge	Declines with time because cells die

Cell Cycle Sensitivity

Phase	Radiosensitivity	Why
M / G2	Most sensitive	Little time for repair before mitosis; mitotic catastrophe
G1	Intermediate to sensitive	Checkpoint quality matters; p53 can arrest cells
Early S	Intermediate	Some repair and replication stress effects
Late S	Most resistant	HR is active; more repair capacity

Trap: lymphocytes are highly radiosensitive even though they are mostly non-dividing. They die by apoptosis and are the classic exception to Bergonie and Tribondeau.

Cell Death Modes

Mode	Signature	Board point
Mitotic catastrophe	Cell enters mitosis with unrepaired damage	Dominant practical endpoint for many solid tumor cells after RT
Apoptosis	Programmed, energy-dependent, membrane blebbing, DNA fragmentation, no inflammation	Lymphocytes, thymocytes, spermatogonia, some tumors; TUNEL detects DNA ends
Necrosis	Cell swelling, membrane rupture, inflammation	Often high-dose or severe injury context
Senescence	Permanent growth arrest without immediate death	Can contribute to tumor control and late tissue phenotype
Autophagy	Lysosomal recycling response	Can be protective or lethal depending on context

4. Cell Survival Assays and Models

Clonogenic Survival Assay

The clonogenic assay measures reproductive death: can a single treated cell retain the ability to form a colony, usually about 50 cells? It is not a short-term apoptosis assay.

Plating efficiency: colonies formed / cells plated in untreated control.
Surviving fraction: colonies after treatment / (cells plated x plating efficiency).
Feeder layer: irradiated non-dividing cells can provide growth factors without forming colonies.
Plot: survival on log scale, dose on linear x-axis.

Survival Curve Models

Model	Core idea	High-yield use
Single-hit single-target	One lethal hit kills cell; exponential curve	High LET, M phase, repair-deficient cells; D0 gives 37% survival
Multi-target	Multiple targets must be inactivated	Produces shoulder; Dq reflects repair/shoulder width
Two-component	Mix of sensitive and resistant populations	Explains biphasic curves
Linear-quadratic	Cell kill = αD + βD^2	Clinical fractionation, BED/EQD2, α/β

D0, D10, Dq, n

Parameter	Meaning	Board shortcut
D0	Dose that reduces survival to 37% on exponential portion	Measure on final straight slope, not necessarily at first 37% point if curve has shoulder
D10	Dose that reduces survival by one log	D10 = 2.3 x D0
Dq	Quasi-threshold dose; shoulder width	More repair means larger Dq
n	Extrapolation number	Dq = D0 ln n
SF2	Surviving fraction after 2 Gy	Common clinical radiosensitivity shorthand

Dose-Rate Effects

Lowering dose rate allows sublethal damage repair during exposure, especially for low LET radiation.
At very low dose rates, repopulation can outpace killing in fast-growing tissues.
High LET radiation has less dose-rate sparing because repairable shoulder is small.
Classic low-dose-rate biology is most relevant for brachytherapy and prolonged exposures.

5. LET, RBE, and Oxygen

LET and Track Structure

Radiation	Approximate LET / category	Board meaning
Co-60 gamma rays	Low LET, about 0.2 keV/µm	Reference-like low LET
150 MeV protons	Low LET, about 0.5 keV/µm in entrance region	Clinical RBE usually 1.1, but LET/RBE rises near distal edge
250 kV X-rays	Low-intermediate, about 2 keV/µm	Classic RBE reference in many definitions
Alpha particles	High LET, roughly 100-200 keV/µm	Dense damage, short range, high RBE until overkill
Carbon ions	High LET with Bragg peak	Physical range plus biologic advantage
Neutrons	Indirect high LET via recoil protons	Low OER and high late toxicity; radiation weighting high

RBE Patterns

RBE rises as LET increases because damage becomes denser, more clustered, and less repairable.
RBE peaks near 100 keV/µm, roughly one ionization spacing over the DNA diameter.
Above that, RBE falls because of overkill: energy is wasted in cells already killed.
RBE is higher at small fraction size because low-LET reference radiation shows more repair sparing.
RBE can be greater in hypoxic cells because low-LET reference radiation is weakened by hypoxia while high LET is less affected.

Oxygen Effect

Oxygen fixation: oxygen must be present during or within microseconds after irradiation. Oxygen seconds before or after does not rescue the effect if the radical chemistry has already resolved.

Oxygen level / concept	High-yield value	Meaning
Fully anoxic	Near 0 oxygen	No oxygen effect
Half-maximal sensitization	About 3-4 mmHg	Small oxygen changes at low pO2 matter a lot
Full sensitization	About 20-40 mmHg	Venous blood range; more oxygen adds little
Photon OER	2.5-3	Hypoxic cells need about 3x dose for same kill
High LET OER	Approaches 1	Oxygen is much less important

Trap: RBE and OER move in opposite directions as LET rises. RBE rises then falls after overkill; OER falls toward 1.

6. Fractionation and the 4 Rs

The 4 Rs Plus Radiosensitivity

R	Time scale	Helps	Board translation
Repair	Hours	Normal tissue and tumor	Sublethal damage repair; drives fractionation sparing
Reassortment / redistribution	Hours	Can help tumor kill	Cells move from resistant S phase into sensitive G2/M
Repopulation	Weeks	Normal acute tissue; hurts tumor control	Accelerated repopulation after kickoff time
Reoxygenation	Hours to days	Tumor kill	Hypoxic cells become better oxygenated between fractions
Radiosensitivity	Intrinsic	Depends	Cell type, genetics, repair capacity, microenvironment

Early vs Late Effects

Feature	Early-responding tissue	Late-responding tissue
Typical α/β	High, about 10 Gy	Low, about 1-3 Gy
Dominant determinant	Overall time, dose/week, total dose	Dose per fraction and total dose
Repopulation during RT	Important	Usually minimal during a standard course
Curve shape	More linear at clinical dose range	More curved; greater fraction-size sensitivity
Examples	Mucosa, skin epidermis, marrow	Spinal cord, kidney, lung fibrosis, heart, CNS

Altered Fractionation

Strategy	Biologic intent	Classic issue
Hyperfractionation	Smaller fractions spare late tissue, allowing higher total dose	More acute toxicity; logistics
Acceleration	Shortens overall time to beat tumor repopulation	More acute toxicity unless dose adjusted
Hypofractionation	Larger fractions exploit convenience or low tumor α/β	Late effects increase if OARs not protected
Split-course	Allows acute recovery	Can allow tumor repopulation; usually biologically unattractive for cure

7. Tumor Microenvironment

Hypoxia Types

Type	Mechanism	Clinical consequence
Chronic diffusion-limited hypoxia	Cells too far from capillary	Often adjacent to necrosis; improves slowly if at all
Acute perfusion-limited hypoxia	Transient vessel opening/closing or flow changes	Can change between fractions; important for reoxygenation
Anemic hypoxia	Low oxygen-carrying capacity	Transfusion logic historically explored, mixed clinical value

Oxygen Diffusion and Necrosis

Oxygen diffusion in tumor tissue is roughly on the order of 100-150 µm.
Small tumor spheroids below roughly 160 µm radius usually avoid necrotic centers.
Larger tumor regions develop hypoxia, low pH, low glucose, low nutrients, and necrosis.

HIF-1 Logic

Oxygen state	HIF-1 alpha behavior	Downstream meaning
Normoxia	Hydroxylated by oxygen-dependent prolyl hydroxylases, recognized by VHL, degraded	HIF pathway off
Hypoxia	Not hydroxylated, stabilizes, dimerizes with HIF-1 beta	Angiogenesis, glycolysis, invasion, survival signaling
VHL loss	HIF not degraded even if oxygen present	Pseudohypoxia; classic in RCC biology

Hypoxia Detection and Modification

Approach	Examples	Board point
Direct measurement	Oxygen probe	Invasive historical gold standard
Chemical markers	Pimonidazole, nitroimidazole binding	Hypoxic cells retain marker
PET hypoxia imaging	FMISO, Cu-ATSM, oxygen tracers	Noninvasive, but practical limitations
Modification	Carbogen, nicotinamide, hyperbaric oxygen, transfusion	Biologically sound; clinical use selective
Hypoxic sensitizers	Nitroimidazoles, nimorazole	Mimic oxygen; limited by toxicity and reoxygenation
Hypoxic cytotoxins	Mitomycin C, tirapazamine-type concept	Preferential activity in hypoxic cells

8. Cell and Tumor Kinetics

Cell Cycle Control

Checkpoint / phase	Core regulators	Board point
G1/S	Cyclin D-CDK4/6, cyclin E-CDK2, Rb/E2F, p16, p21	Frequently defective in cancer; p53 induces p21 after DNA damage
S	Cyclin A-CDK2	DNA synthesis; BrdU or tritiated thymidine labels S phase
G2/M	Cyclin B-CDK1	Often preserved even when G1/S is defective
Damage checkpoint	ATM/ATR -> CHK1/CHK2 -> p53/p21	Arrest allows repair or triggers death/senescence

Kinetic Terms

Term	Meaning	Typical board use
Mitotic index	Fraction of cells in mitosis	Light microscopy can identify M phase
Labeling index	Fraction in S phase	Thymidine/BrdU labeling
Growth fraction	Fraction of cells actively cycling	High in lymphoma, lower in many adenocarcinomas
Cell loss factor	Fraction of produced cells lost	Explains slow growth despite fast cell cycling
Tpot	Potential doubling time without cell loss	Tpot = TC / GF
Tvol	Observed volume doubling time	Tvol = Tpot / (1 - CLF)

Accelerated Repopulation

For squamous cancers, accelerated repopulation often begins after about 3-4 weeks. After that kickoff, a treatment break can cost roughly 0.4-0.8 Gy/day depending on model and disease context.

9. Cancer Biology and Solid Tumor Assays

Oncogenes vs Tumor Suppressors

Class	Biologic idea	Board examples	Trap
Oncogene	Gain-of-function growth/survival signal	RAS, MYC, EGFR/ERBB family, HER2, RET, BCR-ABL	One activated allele can be enough
Tumor suppressor	Loss-of-function in brake/checkpoint/repair pathway	TP53, RB1, APC/FAP, WT1, NF1, DCC, PTEN	Often needs both alleles hit, but haploinsufficiency/context can complicate
Caretaker gene	Maintains genome integrity	BRCA1/2, MMR genes, ATM	Mutation increases mutation rate rather than directly pushing proliferation
Driver mutation	Confers growth advantage	Targetable oncogene, tumor suppressor loss	Selected during tumor evolution
Passenger mutation	Carried along without clear advantage	Background mutational burden	May still be useful as neoantigen or lineage marker

p53, Rb, and INK4A/ARF

Node	What it does	High-yield details
p53	Damage-responsive tumor suppressor	Induces p21, G1 arrest, repair, apoptosis, senescence; targets include MDM2, GADD45, BAX, PUMA, NOXA
MDM2	Negative regulator of p53	Targets p53 for degradation; ARF inhibits MDM2
Viral p53 inhibition	Viral oncogenesis mechanism	HPV E6, adenovirus E1B, and SV40 T antigen can impair p53 pathways
Rb	Controls E2F and G1/S transition	Hypophosphorylated Rb restrains E2F; cyclin-CDK phosphorylation releases E2F
p16 / INK4A	CDK4/6 inhibitor	Keeps Rb active; loss promotes G1/S progression
ARF	p53-supporting tumor suppressor	Inhibits MDM2, stabilizing p53

Signaling and Tumor Evolution

NF-kB: inflammatory and survival signaling. TNF, IL-1, and TLR pathways converge on IKK, degrade I-kappaB, and allow p50/p65 nuclear transcription.
TGF-beta: context-dependent tumor suppressor early, but pro-fibrotic, pro-invasive, and immunosuppressive in many established tumors and normal tissue injury states.
Telomerase: supports replicative immortality by maintaining telomeres; most somatic cells have limited replicative potential.
Chromothripsis: catastrophic clustered chromosomal rearrangement in one event; a single genomic crisis can reshape cancer evolution.
Cancer stem cell model: a minor clonogenic subpopulation may drive regrowth after apparent complete response.

Solid Tumor Assay Systems

Assay	Endpoint	What boards test
Tumor growth delay	Time for treated tumor to reach preset size compared with control	Good for relative response; not direct cure endpoint
TCD50	Dose controlling 50% of tumors	True tumor cure endpoint; requires long follow-up and many animals
TD50	Number of viable tumor cells needed to produce tumors in 50% of hosts	Measures clonogenic tumor-initiating capacity
In vivo-in vitro assay	Irradiate tumor in animal, then plate cells for clonogenic survival	Connects microenvironmental exposure to clonogenic endpoint
Spheroids	3D growth with gradients	Can model hypoxia/nutrient gradients and necrotic core better than monolayer
Xenograft / syngeneic model	Tumor response in host	Immune competence matters: syngeneic models preserve immune interactions

Memory: clonogenic assay asks whether a cell can make a colony. TCD50 asks whether a tumor-bearing host is cured. Growth delay asks how long the mass takes to regrow. Do not treat those as interchangeable endpoints.

10. Normal Tissue Radiation Biology

Early, Late, and Consequential Late

Effect	Timing	Mechanism	Examples
Early	During RT to about 60 days	Stem/progenitor depletion in rapidly renewing tissues	Mucositis, dermatitis, marrow suppression
Late	Months to years	Vascular injury, fibrosis, parenchymal loss, chronic inflammation	Myelopathy, fibrosis, nephropathy, cardiotoxicity
Consequential late	Late sequela of severe acute injury	Acute injury fails to heal and becomes permanent	Ulcer, stricture, necrosis after severe mucositis/dermatitis

Functional Subunits and Volume Effect

Organ type	Model	Dose-volume implication	Examples
Serial	One damaged segment can break the chain	Max dose dominates	Spinal cord, optic nerve, bowel segment
Parallel	Organ function persists if enough subunits remain	Mean dose / volume dominates	Lung, liver, kidney, parotid
Mixed / surface	Local injury tolerable if limited	Area/volume matters clinically	Skin, mucosa

Normal Tissue Pearls by Organ

Tissue	Board biology	Useful anchor
Skin	Epidermis acute, dermis late; desquamation delayed by epithelial turnover	Epilation delayed weeks; late telangiectasia/fibrosis vascular-stromal
Marrow	Stem cells sensitive; mature RBCs resistant; lymphocytes rapidly apoptose	WBC/platelet nadir weeks; lymphocytes fall early
Mucosa	Early proliferative tissue	Overall treatment time matters
Salivary glands	Early xerostomia with limited recovery; parallel-like dose response	Mean parotid dose matters
Lung	Subacute pneumonitis then late fibrosis; parallel organ	Mean lung dose and V20 style constraints reflect volume effect
Kidney	Late parallel organ; comorbid injury important	Whole kidney tolerance low relative to many organs
Liver	Parallel organ with regenerative capacity	Cirrhosis lowers tolerance
Heart	Late vascular, pericardial, myocardial, coronary effects	Decades-long latency possible
CNS	Low α/β, serial, fraction-size sensitive	Myelopathy/necrosis are late; Lhermitte/somnolence can be transient
Gonads	Germ cells very sensitive; hormones require higher dose	Spermatogenesis more sensitive than testosterone production

Casarett and Michalowski

Casarett

Radiosensitivity generally increases with mitotic rate and future divisions, and decreases with differentiation. Lymphocytes are the favorite exception.

H-Type vs F-Type

Hierarchical tissues have predictable turnover latency after stem-cell loss. Flexible tissues may show delayed injury when normally quiescent cells are forced to divide.

11. Therapeutic Ratio, TCP, and NTCP

Therapeutic Window

The therapeutic ratio is not just "more tumor dose." It is tumor control relative to normal tissue complication, and it depends on endpoint definitions, target coverage, tumor heterogeneity, OAR geometry, systemic therapy, and time.

Concept	Meaning	Board point
TCP curve	Sigmoid dose-response for tumor control	Steepest in middle; shallow at low and high extremes
NTCP curve	Sigmoid dose-response for complication	Often steeper than tumor; volume dependence differs by organ
Gamma	Slope of dose-response	Absolute response change per relative dose change
Geographic miss	Clonogens outside field	Dose escalation cannot rescue a miss
Heterogeneity	Mixture of resistant and sensitive tumors	Population curve looks less steep than homogeneous tumor curve

12. Systemic Agents, Protectors, Sensitizers, and Heat

Combined Modality Logic

Class	Examples	Rad bio pattern
Platinums	Cisplatin, carboplatin, oxaliplatin	DNA crosslinking; strong radiosensitizers, not cell-cycle specific
Antimetabolites	5-FU, capecitabine, gemcitabine, methotrexate, hydroxyurea	S-phase related; many are strong radiosensitizers
Taxanes	Paclitaxel, docetaxel	M-phase/spindle effects; radiosensitizing
Topoisomerase poisons	Etoposide, irinotecan, topotecan	Create strand breaks; partially S-phase related
PARP inhibitors	Olaparib-type concept	Synthetic lethality in HR-deficient cells; can radiosensitize by impairing SSB repair
EGFR/HER2/VEGF pathway drugs	Targeted agents	Signaling, repair, proliferation, vascular effects; toxicity context matters

Radioprotectors and Sensitizers

Agent / concept	Mechanism	Board takeaway
Amifostine	Prodrug converted to active thiol WR-1065 by alkaline phosphatase; free radical scavenger	Give shortly before RT; normal tissue selectivity; hypotension/nausea; poor CNS penetration
Nitroimidazoles	Hypoxic cell sensitizers that mimic oxygen chemistry	Limited by cumulative neurotoxicity; nimorazole is the classic clinical example
Mitomycin C	Hypoxic cytotoxic and crosslinking activity	Used clinically as chemotherapy/radiosensitizer in selected sites
DRF	Dose with protector / dose without protector for same effect	Protector metric
ER	Dose without sensitizer / dose with sensitizer for same effect	Sensitizer metric

Hyperthermia

Hyperthermia means non-ablative heating, usually 39-47 C.
Heat kills by protein denaturation/aggregation and inhibits repair of radiation-induced DNA damage.
Heat preferentially affects hypoxic, acidic, poorly vascularized tumor regions and S-phase cells.
Best radiosensitization occurs when heat is simultaneous with or very close to RT.
Thermotolerance is mediated by heat shock proteins and can last days to 1-2 weeks, so heat is usually not delivered daily.

13. Brachytherapy, Particles, TBI, and Alternative Delivery

Brachytherapy Biology

Feature	Biology	Board point
LDR	Continuous low dose rate allows intrafraction repair	Normal tissue sparing if dose rate not too high
HDR	High dose per fraction, no meaningful intrafraction repair	Fraction size matters; use BED/EQD2 logic
PDR	HDR pulses designed to mimic LDR average dose rate	Biologic compromise between HDR logistics and LDR repair
Inverse dose-rate effect	Some cycling cells progress into sensitive phases at intermediate low dose rates	Cell-cycle effect, not simple repair sparing
Permanent seeds	Very low and declining dose rate	Best for slowly proliferating tumors

Particles and RBE

Modality	Biology	Clinical guardrail
Protons	Mostly physical advantage; clinical RBE often 1.1	RBE/LET may rise at distal edge; avoid stopping in serial OARs
Neutrons	High LET via recoil protons, low OER	Can control resistant tumors but late toxicity is limiting
Carbon ions	Bragg peak plus high LET, higher RBE, low OER	Powerful but RBE modeling and late toxicity uncertainty matter
BNCT	Boron captures slow neutron, emits alpha particles locally	Requires tumor-selective boron delivery; limited penetration for slow neutrons
FLASH	Ultra-high dose rate may spare normal tissue in some models	Mechanism and clinical role still developing; do not assume tumor sparing

Total Body Irradiation and Acute Radiation Syndromes

Syndrome	Dose scale	Timing / cause
Hematopoietic	Begins around a few Gy	Death over weeks from infection/bleeding; LD50/60 roughly 3-4 Gy without care, higher with care
GI	Higher, around 8-10+ Gy	Crypt stem cell loss, sepsis, electrolyte loss; transplant cannot rescue GI mucosa
CNS / cardiovascular	Very high, tens of Gy	Hours to days; vascular collapse/neurologic injury
Biodosimetry	About 0.25 Gy and above	Dicentrics/rings in lymphocytes estimate whole-body exposure; translocations persist longer

14. Carcinogenesis, Heritable Risk, and Fetal Effects

Stochastic vs Deterministic

Effect	Threshold?	Severity with dose?	Examples
Stochastic	No assumed threshold	Probability rises; severity not dose-dependent	Cancer, heritable mutation
Deterministic / tissue reaction	Yes	Severity rises above threshold	Cataract, skin injury, sterility, normal tissue necrosis

Radiation-Induced Cancer

Radiation-induced mutations are often large deletions, translocations, chromosomal aberrations, or aneuploidy rather than unique point mutations.
Leukemia has shorter latency: begins around 2 years, peaks around 7-12 years, and declines by about 20 years.
Thyroid cancer latency is several years, often peaking around a decade.
Most solid tumors have long latency, often decades.
Children and younger patients have higher lifetime attributable risk; women have higher modeled risk largely because of breast cancer.

Human Exposure Patterns to Remember

Exposure group	Associated cancers / lesson
Atomic bomb survivors	Core long-term human risk dataset; leukemia and solid tumors
Ankylosing spondylitis RT	Leukemia and other second cancer risk after therapeutic spine irradiation
Tinea capitis scalp RT	Thyroid, brain tumors, skin, salivary tumors
TB fluoroscopy	Breast cancer risk
Radium dial painters	Bone tumors from internally deposited alpha emitter
Uranium/radon exposure	Lung cancer from alpha exposure
Thorotrast	Liver tumors from radioactive thorium contrast

Heritable Effects

Heritable radiation effects are clear in animal models but have not been convincingly demonstrated as a statistically significant human signal. Risk estimates are extrapolated and depend on gonad dose, not whole-body effective dose.

Embryo and Fetus

Stage	Timing	Dominant effect
Preimplantation	0-2 weeks	All-or-none: embryonic death or no malformation
Organogenesis	2-6 weeks	Malformations and pregnancy loss at sufficiently high dose
Early fetal CNS	8-15 weeks especially high risk	Severe intellectual disability risk, microcephaly, growth effects
Later fetal period	16-25 weeks lower but present; after 26 weeks lower still	Less severe neurodevelopmental risk; carcinogenesis remains stochastic
Childhood cancer	Any fetal exposure	Small absolute risk; low-dose obstetric exposure data drive concern

15. Molecular Techniques and Molecular Imaging

Technique Decoder

Technique	Detects	Board shortcut
Western blot	Protein	"Western = protein"
Northern blot	RNA	Gene expression at RNA level
Southern blot	DNA	Rearrangements/amplifications
PCR / RT-PCR	DNA amplification / RNA expression after reverse transcription	Amplifies specific sequences
FISH	Chromosomal location, translocations, copy number	Stable aberration detection
Comet assay	DNA fragmentation in single cells	Alkaline for SSBs and alkali-labile sites; neutral for DSBs
gamma-H2AX foci	DSB response foci	Very sensitive DSB assay
TUNEL	DNA ends in apoptosis	Labels fragmented DNA, not clonogenic survival
Flow cytometry	Cell cycle, markers, apoptosis, immune phenotypes	Propidium iodide for DNA content; BrdU for S phase
EMSA	DNA-protein binding	Electrophoretic mobility shift
ChIP	Protein binding at genomic loci	Chromatin immunoprecipitation
siRNA / miRNA	Gene silencing	Short RNAs inhibit translation or promote mRNA degradation
NGS	Massively parallel sequencing	Short reads, adaptor/matrix-based, many simultaneous reads

Molecular Imaging

Imaging concept	What it means	Trap
FDG PET	Glucose analog; Warburg/glycolysis signal	Inflammation can be FDG-avid too
FLT PET	Thymidine analog, DNA synthesis/proliferation	Not the same as FDG metabolism
PET detection	Detects two 511 keV annihilation photons	Scanner does not directly image positrons
SUV	Activity concentration normalized by injected dose and body size	Timing, body weight, glucose, inflammation affect interpretation
CT HU	Attenuation relative to water	Water = 0 HU; air about -1000 HU
PSMA PET	Prostate-specific membrane antigen targeting	Physiologic uptake in salivary/lacrimal glands, kidneys, bowel; small lesions can be missed

16. Cancer Immunology and Radiation

Immune System Basics

Concept	Meaning	Board point
Innate immunity	Pattern recognition, fast nonspecific response	TLRs and other PRRs detect PAMPs/DAMPs
Adaptive immunity	Antigen-specific T and B cell response	T cells recognize peptide in MHC cleft via TCR
MHC I	Endogenous antigen presentation	To CD8 cytotoxic T cells; requires beta-2 microglobulin
MHC II	Exogenous antigen presentation by APCs	To CD4 helper T cells
Cross-presentation	Exogenous antigen presented on MHC I	Dendritic-cell bridge to CD8 priming

Radiation and Antitumor Immunity

Radiation can release tumor antigens and DAMPs, increase MHC I expression, activate dendritic cells, and promote epitope spreading.
Radiation can also recruit suppressive myeloid cells, Tregs, TGF-beta signaling, lymphodepletion, and vascular injury depending on dose/fractionation and field.
The abscopal effect is regression of disease outside the irradiated field, usually discussed in an immune-mediated context.
The bystander effect is a biologic effect in nearby unirradiated cells after neighboring cells were irradiated.

Checkpoint Decoder

Target	Where it acts	Examples / key point
CTLA-4	Early T-cell priming, competes with CD28 for CD80/CD86	Ipilimumab; generally more immune toxicity than PD-1 axis blockade
PD-1	Peripheral tissue effector response/exhaustion	Pembrolizumab, nivolumab
PD-L1	Ligand on tumor/immune cells; induced by IFN-gamma	Atezolizumab, durvalumab, avelumab
LAG3 / TIM3	Inhibitory receptors	Checkpoint family members
OX40 / 4-1BB / CD40	Costimulatory	Not inhibitory checkpoint receptors

Trap: immune-related adverse events can affect almost any organ system. Skin, gut, endocrine, lung, and musculoskeletal toxicities are common; cardiac, renal, neurologic, hematologic, and ophthalmic events are less common but important.

Cram Tables

High-Yield Numbers

Number	Meaning
1 Gy	Thousands of base lesions, about 1000 SSBs, and a few dozen DSBs per cell
37%	Survival after one average lethal hit; e^-1
D10 = 2.3 x D0	One-log kill relationship for exponential survival
OER 2.5-3	Typical low-LET photon oxygen enhancement
3-4 mmHg	Approximate half-maximal oxygen radiosensitization
20-40 mmHg	Near-full oxygen radiosensitization
100 keV/µm	LET near maximal RBE before overkill
6 hours	Common minimum interfraction interval for BID RT to allow repair
21-28 days	Common kickoff window for accelerated repopulation in squamous tumors
3 volume doublings	Approximately one diameter doubling
8-15 weeks gestation	Highest fetal neurodevelopmental sensitivity window

Repair Disease One-Liners

Disease	Pathway	Do not miss
XP	NER	UV sensitivity and skin cancer, not classic X-ray hypersensitivity
AT	ATM / DSB response	Extreme radiosensitivity
Nijmegen	NBS1 / MRN	DSB response, radiosensitivity
Lynch	MMR	MSI, colorectal/endometrial spectrum
BRCA1/2	HR	HR deficiency, PARP vulnerability; not automatically extreme RT sensitivity
Li-Fraumeni	TP53	Second malignancy concern
Fanconi	Crosslink repair	Radial chromosomes, marrow failure, cancer risk

Final Board Pearls

DSBs kill; misrepaired DSBs mutate. Most other lesions matter because they become DSBs or mutations if unrepaired.
Low LET has a shoulder. High LET removes the shoulder, repair sparing, dose-rate sparing, oxygen dependence, and sulfhydryl protection.
Oxygen is a chemical timing problem. It fixes radicals within microseconds; oxygenation seconds later is too late for that event.
Late toxicity hates big fractions. Low α/β plus serial anatomy is the classic danger combination.
Fractionation is a compromise. It helps normal tissue repair and tumor reoxygenation, but gives tumor repopulation time.
TCP is unforgiving. If a billion clonogens start and you need 90% control, you need about 10 logs of kill.
Technique questions ask what molecule is measured. Western protein, Northern RNA, Southern DNA, FISH chromosome, gamma-H2AX DSB foci.
Radiation protection uses Sv; radiotherapy effect uses Gy/BED/RBE. Do not mix protection weighting factors with tumor RBE.