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Guidelines for Cancer and Radiation Biology

These guidelines are meant to indicate the topics of which residents should have knowledge. They are not intended to indicate the depth of knowledge or the order in which they are taught.

I. Interaction of Radiation with Biological Systems (++)
    Definition of ionizing radiation
Types of ionizing and non-ionizing radiation 
Definition of LET and quality of ionizing radiation
Generation of free radicals
Direct and indirect action of ionizing radiation
II. Molecular Mechanisms of DNA Damage (+)
    Assays for DNA damage
      neutral and alkaline elution, pulsed field electrophoresis, comet, plasmid-based assay
    Types of DNA lesions and numbers per cell/Gy
Multiply damaged sites
Single lethal hits and accumulated damage (inter- and intra-track)
Role of oxygen in the generation of damage
Role of LET and radiation quality
III. Molecular Mechanisms of DNA Repair (+++)
    Different types of DNA repair mechanisms
Mechanisms involved in repair of base damage and DNA single strand breaks 
Mechanisms involved in repair of double strand breaks
      Homologous recombination 
Non-homologous end joining
IV. Chromosome and Chromatid Damage (++)
    Assays
      Conventional smears, banding, comparative genomic hybridization (CGH) and FISH
    Dose response relationships
Use of peripheral blood lymphocytes in in vivo dosimetry
Stable and unstable chromatid and chromosome aberrations
Human genetic diseases that affect DNA repair, fragility, and radiosensitivity
V. Mechanisms of Cell Death (+++)
    Apoptotic death
      Developmental and stress induced
Morphological and biochemical features of apoptosis
Molecular pathways leading to apoptosis
Radiation-induced apoptosis in normal tissues and tumors
    Necrotic death
      Morphological, pathological, and biochemical features of necrosis
    Mitotic death following irradiation
      Types of mitotic death - mitotic catastrophe vs. apoptosis
Cell division post-radiation and time to clonogenic cell death
    Radiation-induced senescence
VI. Cell and Tissue Survival Assays (+)
    In vitro clonogenic assays
      Calculation of plating efficiency and surviving fraction
    In vivo clonogenic assays
      Bone marrow stem cell assays, jejunal crypt stem cell assay, skin clones, kidney tubules
    Functional endpoints
VII. Models of Cell Survival (+++)
    Random nature of cell killing and Poisson statistics
Doses for inactivation of viruses, bacteria, and eukaryotic cells after irradiation 
Single hit, multi-target models of cell survival
Two component models
Linear quadratic model
Calculations of cell survival with dose
Effects of dose, dose rate, cell type
VIII. Modifiers of Cell Survival: Linear Energy Transfer (+)
    Definition of RBE
RBE as a function of LET
Effect of LET on cell survival
Endpoint dependence of RBE
Effects of dose, dose rate, cell type
IX. Modifiers of Cell Survival: Oxygen Effect (++)
    Definition of OER
Effect of dose, dose rate, cell type
OER as a function of LET
Impact of O2 concentration
Time scale of oxygen effect
Mechanisms of oxygen effect
X. Modifiers of Cell Survival: Repair (++)
    Sub-lethal damage repair
Potentially lethal damage repair
Half-time of repair
Effects of dose, dose rate, and cell type
Effect of dose fractionation
Effect of LET
Effects of oxygen/hypoxia
XI. Solid Tumor Assay Systems (+)
    50 limiting dilution assay
Tumor regrowth assay
TCD50 tumor control assay
Lung colony assay
In vitro/in vivo assay
Monolayers vs. 3-D spheroid cultures
XII. Tumor Microenvironment (+++)
    Tumor vasculature
Angiogenesis
Hypoxia in tumors
      Measurement of hypoxia
Transient and chronic hypoxia
    Reoxygenation following irradiation
Relevance of hypoxia in radiation therapy
Hypoxia as a factor in tumor progression
Hypoxia-induced signal transduction
Cellular composition of tumors
XIII. Cell and Tissue Kinetics (+++)
    Cell cycle
      Measurement of cell cycle parameters by 3H-thymidine 
Measurement by flow cytometry, DNA staining and BrdU
    Cell cycle synchronization techniques and uses
Effect of cell cycle phase on radiosensitivity
Cell cycle arrest and redistribution following irradiation
Cell cycle checkpoints, cyclins, cyclin dependent kinase inhibitors
Tissue kinetics
      Stem, progenitor, differentiated cells 
Growth fraction
Cell loss factor
Volume doubling times
Tpot
    Growth kinetics of clinical and experimental tumors
XIV. Molecular Signaling (++)
    Receptor/ligand interactions
Phosphorylation/dephosphorylation reactions
Transcriptional activation
Radiation-induced gene expression
      Gene expression profiling
Proteomics
    Radiation-induced signals
      DNA damage response
Non-DNA damage responses
    Cell survival and death pathways
XV. Cancer (+++)
    Cancer as a Genetic Disease
Oncogenes
Tumor suppressor genes
Telomeric changes in cancer
Epigenetic changes in cancer
      e.g hypermethylation
    Multi-step nature of carcinogenesis
Repair genes in carcinogenesis
The metastatic process
Molecular profiling and staging of cancer
      Gene expression profiling
Proteomics
    Signaling abnormalities in cancer
Effects of signaling abnormalities on radiation responses
Prognostic significance of tumor characteristics
Therapeutic targets and strategies for intervention
      Monoclonals, small molecule inhibitors, gene therapy
XVI. Total Body Irradiation (++)
    Prodromal radiation syndrome
Cerebrovascular syndrome
Gastrointestinal syndrome
Hematopoietic syndrome
Mean lethal dose and dose/time responses
Immunological effects
Assessment and treatment of radiation accidents or terrorism
Bone marrow transplantation
XVII. Clinically Relevant Normal Tissue Responses to Radiation (+++)
    Responses in skin, oral mucosa, oropharyngeal and esophageal mucous membranes, salivary glands, bone marrow, lymphoid tissues, bone and cartilage, lung, kidney, testis, ovary, eye, central and peripheral nervous tissues
Scoring systems for tissue injury
      LENT and SOMA
XVIII. Mechanisms of Normal Tissue Radiation Responses (+++)
    Differences between slowly and rapidly proliferating tissues
Molecular and cellular responses in slowly and rapidly proliferating tissues
      Cytokines and growth factors
Regeneration
Remembered dose
Functional subunits
    Mechanisms underlying clinical symptoms
      Latency 
Inflammatory changes
Cell killing
Radiation fibrosis
Vascular damage
Volume effects
    Pharmacological modification of normal tissue responses
XIX. Therapeutic Ratio (+++)
    Tumor control probability (TCP) curves
      Calculation of TCP
Factors affecting shape and slope of TCP curves
Influence of tumor repopulation/regeneration on TCP
    Normal tissue complication probability (NTCP) curves
      Influence of normal tissue regeneration on responses
    Response of subclinical disease
Causes of treatment failure
Factors determining tissue tolerance
      Normal tissue volume effects
Dose-volume histogram analysis
    Effect of adjuvant or combined treatments on therapeutic ratio
XX. Time, Dose, Fractionation (+++)
    The 4 R's of fractionation
The radiobiological rationale behind dose fractionation
The effect of tissue type on the response to dose fractionation
Effect of tissue/tumor types on a/b ratios
Quantitation of multifraction survival curves
BED and isoeffect dose calculations
XXI. Brachytherapy (+)
    Dose rate effects (HDR and LDR)
Choice of isotopes
Interstitial and intracavitary use
Radiolabeled antibodies
BED and Isoeffective dose calculations
XXII. Radiobiological aspects of alternative dose delivery systems (+)
    Protons, high LET sources, BNCT
Stereotactic radiosurgery/radiotherapy, IMRT, IORtd class="spacing"ose distributions and dose heterogeneity
XXIII. Chemotherapeutic agents and radiation therapy (+++)
    Classes of agents
Mechanisms of action
The oxygen effect in chemotherapy
Multiple drug resistance
Interactions of chemotherapeutic agents with radiation therapy (chemoradiation therapy)
  Photodynamic therapy
XXIV. Radiosensitizers, Bioreductive drugs, Radioprotectors (++)
    Tumor radiosensensitization
      Halogenated pyrimidines, nitroimidazoles
    Hypoxic cell cytotoxins
      tirapazamine
    Normal tissue radioprotection
      Mechanisms of action, sulfhydryl compounds, WR series, dose reduction factor (DRF)
    Biological response modifiers
XXV. Hyperthermia (+)
    Delivery modalities
Cellular response to heat
Heat shock proteins
Thermotolerance
Response of tumors and normal tissues to heat
Combination with radiation therapy
XXVI. Radiation Carcinogenesis (++)
    Initiation, promotion, progression
Dose response for radiation-induced cancers
Importance of age at exposure and time since exposure
Malignancies in prenatally exposed children
Second tumors in radiation therapy patients
Effects of chemotherapy on incidence
Risk estimates in humans
Calculations based on risk estimates
XXVII. Heritable Effects of Radiation (+)
    Single gene mutation
Chromosome aberrations
Relative vs. absolute mutation risk
Doubling dose
Heritable effects in humans
Risk estimates for hereditable effects
XXVIII. Radiation Effects in the Developing Embryo (+)
    Intrauterine death
Congenital abnormalities and neonatal death
Microcephaly, mental retardation
Growth retardation
Dose, dose rate, and stage in gestation
Human experience of pregnant women exposed to therapeutic dose
XXIX. Radiation Protection (++)
    General philosophy
Stochastic and deterministic effects
Effective dose - relative weighting factors
Equivalent dose - tissue weighting factor
Committed dose 
Collective exposure dose
Dose limits for occupational and public exposure
ICRP and NCRP

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