Medical Archive

I. Cells and tissues

1. Effects of radiation on normal tissue

• cell killing (most)
• radiation-induced inflammatory cytokines: N/V, fatigue, Acute edema, Somnolence

2. Radioresponsiveness of a tissue

1. inherent sensitivity of cells
2. kinetics of the tissue
3. the way cells are organized in that tissue

3. Radioresponse of tissues

: functioning differentiated cells < dividing cells

II. Early and late effects

	Early effect	Late effect
α/ß ratio	About 10 Gy	About 2 Gy
Fx		More sensetive
Tissue	Rapidly proliferating	Slowly proliferating
	Skin, GI epithelium, hematopoietic	Lung, kidney, heart, liver, CNS
Cause	Death of large amount cells	Vascular damage loss of parenchymal cells
Onset	Days~ weeks	Months ~ years
Repair	Rapidly, maybe completely	Never completely reversible

* Consequential late effect: late effect consequent to a persistent severe early effect

ex) fibrosis, necrosis of skin consequent to desquamation and acute ulceration

III. Functional subunits (FSUs) in normal tissue

1. Structurally defined FSUs

• kidney, liver, lung, exocrine organs
• small self-contained entity independent of its neighbors
• tissue survival depends on the No & radiosensitivity of clonogenic cells within FSU

2. Structurally undefined FSUs

• skin, mucosa, spinal cord
• clonogenic cells can migrate – repopulation of a depleted FSU

3. Tissue rescue unit

 : minimum number of FSUs required to maintain tissue fuction

IV. The volume effect in radiotherapy : tissue architecture

1. Tolerance dose

: dose that produces an acceptable probability of treatment complication

2. Spatial arrangement of the FSUs in the tissue

1. serial organization
2. the integrity of each FSUs is critical to organ function (ex. spinal cord)
3. binary response with a threshold dose
4. volume effect

• parallel organization
• ex) kidney, lung: radiosensitive but small volumes can be treat to higher dose -> d/t functional reserve capacity
• graded response with a threshold volume

V. Radiation pathology of tissues

1. Casarett’s classification of tissue radiosensitivity

 : based on histologic observation of early cell death

 2. Michalowski’s H- and F-type populations

1. H-type population (hierarchical): hematopoietic BM, intestinal epi, epidermis
   1. stem cells: crypt cells in the intestinal mucosa
   1. functional cells: circulatory granulocyte, cells that make up the villi of the intestinal mucosa
   1. mature partially differentiated cells: erythroblast and granullblasts
2. F-type population (flexible): liver, thyroid, dermis

: rarely divide under normal conditions but can be triggered to divide by damage

no compartment, no strict hierarchy

* Many tissues are a hybrid of H-type and F-type

VI. Growth factors

• RT -> interleukin-1, linterleukin-6 ↑
• interleukin-1: radioprotectant of hematopoietic cells by increasing shoulder and D0
• Basic fibroblast growth factor: ↑ endothelial growth , ↓ apoptosis

-> protects microvascular damage (branching midsize capillary > nonbranching capillary)

• platelet-derived growth factor ß: ↑ vascular damage
• TGF-ß (transforming growth factor)
  • : strong inflammatory response (ex. Pneumonitis)
  •  ↑ connective tissue growth, ↓ epithelial cell growth à fibrosis, vascular damage
  •  ↓ interleukin-1, TNF (tumor necrosis factor): ↑ hematopoietic tissue damage
•  TNF
  • : cytotoxic agent
  •  ↑ proliferation of fibroblast, inflammatory cell, and endothelial cell
  •  protect hematopoietic cells, sensitizes tumor cells to radiation
  •  serum consentration: correlate with severity of pneumonitis, hepatic dysfunction, renal insufficiency, and demyelination

VII. Specific tissues and organs (Table 20.2)

Skin

1. Epidermis: Early radiation reactions

It takes about 14 days from the time a newly formed cell from basal layer to the time it is desquamated from the surface

2. Dermis: Late radiation reactions

1~3mm thick
Vasculature of the dermis plays a major role in the radiation response

Few hours after doses greater than 5Gyà erythema

Orthovoltage -> Full dose is deposited in the superficial layer -> Erythema develops in the 2^nd to 3^rd week, followed bydry or moist desquamation

Megavoltage -> Dmax occurs at deep layer -> 60Gy or more are tolerate

Hematopoietic system

• 60% in the pelvis and vertebrae
• TBI
  • 0.3 Gy leads to a reduction in the number of lymphocytes
  • General pattern of the blood counts after amodest dose of radiation (fig. 20.4): LGPR
• Partial body radiation
  • Compensatory hyperplasia attempts to maintain the total production of blood elements at long bones, spleen, liver
  • Doses greater than about 30Gy may cause permanent aplasia
• Chemotherapy agents
  • The marrow of patients irradiated to a large volume is always more sensitive to cytotoxic drugs because a greater proportion of stem cells are dividing actively

Lymphoid tissue and the immune system

• Lymphocytes are very radiosensitive, because of apoptosis. B cell more sensitive than T cell
• Total body dose 3.5~4 Gy inhibits the immune response

Digestive tract

Oral mucosa

• 1^st week: asymptomatic focal hyperemia and edema
• 2^nd week: increasing pain and loss of desire to eat, early desquamative mucositis occurs.
• 3^rd week: mucositis and swelling with depletion of gland secreation. Diffulty in swalling
• 4^th week: progression of signs
• 5^th week maximum radiation damage apparent.
  • In 2 to 4 weeks complete resolution
  • Xerostomia. TD5/5 32Gy, TD50/5 46Gy

Esophagus

• 10 to 12 days after therapy, substernal burning with pain and swalling
• Late effects are related to the muscle layer

Stomach

• Delayed gastric emptying and epithelial denudement: early radiation effectPeptic ulcer: more than 40Gy

Small and large intestines

• Acute mucositis: interruption of treatment for a few days alleviates the symptom
• Late effect: fibrosis and ischemia
• Tolerance dose for small intestine 50 Gy, rectal tolerance 70Gy

Lungs

The most sensitive of late-responding organ

• Acute pneumonitis at 2 to 6 month
• Fibrosis: several months to year
• Difficulties in respiratory function: volume irradiated, dose, fraction size
  • a/b: 3Gy (particulary sensitive to fractionation)
  • Most sensitive to late response

Kidneys

• Radiosensitive late-responding organ
• 30Gy/15fx -> Nephropathy with arterial HTN, anemia
• Increasing treatment time does not allow higher doses to be tolerated
  • FSUs are arranged in parallel, with each containing only about 1,000 stem cells

Liver

• Fatal hepatitis may result from only 35 Gy if the whole organ is irradiated
• Parenchyma: parallel, Hilum: serial

Bladder epithelium

• low cell renewal rate / lifespan of superficial cell: several months
• frequency increases in parallel with bladder damage and loss of surface cells
• Late effect: fibrosis, reduction in bladder capacity

Central and peripheral nervous systems

Brain

• Cells
  • neurons: nonproliferating end cells in adults
  • glial cells: slow turnover, small stem-cell compartment (1%)
  • vascular endothelial cells: slow turnover, rapid proliferation after injury
• < 6mo: transient demyelination (somnolence syndrome), leukoencephalopathy
• Radiation necrosis: 6mo ~ 2 to 3 years

Spinal Cord

• Lhermitte’s sign: demyelating injury, months~a year, reversible, 35 Gy
• Late damage: demyelination and necrosis of white matter (6-18 mo), Vasculopathy (1-4 years)
• TD5/5 50 Gy(10cm), 55 Gy(5cm)  TD50/5 70 Gy
• Serially arranged FSU -> the probability of a myelopathy depends critically on the length irradiated for very small lengths, but once the length of the field exceeds a few centimeters, the treatment volume has little effect
• Neurotoxic chemotherapy agents: methotrexate, cis-platinum, vinblastine, AraC
• Animal data: about 2years, most of the damage repaired.

Peripheral nerves:

more radioresistant (few quantitative data),TD5/5 60 Gy (2 Gy/fx)

Genital

Testis

• germinal cells: radiosensitive, stem cell~ spermatozoa 74days
  • 0.1 Gy: temporary reduction in the number of spermatozoa
  • 0.15 Gy: temporary sterility
  • 2 Gy: azoospermia for years
  • 6-8 Gy (2 Gy/fx): permanent azoospermia
• Leydig cells: secrete testosterone, radioresistant

Ovaries

radiosensitive, D0 0.12 Gy, immediate sterilization, menopause

Female genitalia

1. vulva: tolerance dose 50-70Gy
2. vagina
   • acute: erythema, moist desquamation, mucositis -> 3~6months
   • Gross abnormalities: pale color, thin atrophic mucosa, inflammation, necrosis
   • Tolerance dose: 90 Gy (~ulceration), 100Gy (~fistula)
   • Uterus
     • ICR: Cx, uterus dose 200Gyà atrophy of the endometrial gland and stroma

Blood vessels and the vascular system

• denudation of surface of vessels à thromboses, capillary necrosis
• loss of muscular fibers à replaced by collagen fibers: blood flow ↓
• capillary 40 Gy, artery 50 ~ 70Gy, vein most resistant

Heart

1. intermediate tolerance, a/b ratio = 1Gy
   • Acute pericarditis: m/c, > 1yr, transient pericarditis~cardiac constriction
     • 20Gy (>50% volume)
     • fractionated 45-50Gyà 11% incidence
2. Cardiomyopathy: dense and diffuse fibrosis, many years
   • In some Hodgkin disease (30Gy to most of the heart)
   • Adriamycin (doxorubicin): ↑ severity of radiation-induced complication

Bone and cartilage

1. Children: growing cartilage
   • 10Gy can slow growth
   • 20Gy: deficit in growth is irreversible
   • damage ↑: higher dose, younger age (esp. <2 years)
2. Adult
   • Osteonecrosis: lower maxilla, large volume – TD5/5 50~60 Gy, TD50/5 70Gy
   • Fracture of humeral and femoral head – TD5/5 52 Gy, TD50/5 65 Gy

VIII. QUANTEC, LENT and SOMA

1. QUANTEC (2010): QUantitative Analysis of Normal Tissue Effects in the Clinic

• guideline on dose-response relationships in normal tissues

2) LENT, SOMA

• EORTC, RTOG (1992) – LENT conference: SOMA classification for late toxicity
• LENT: Late Effects of Normal Tissue
• SOMA: Subjective, Objective, Management criteria with Analytic laboratory and imaging procedures

QUANTEC (Table 20.3), SOMA (Table 20.4-20.6)

IX. Application of stem cells to regenerate radiation sensitive organs –salivary gland regeneration

Salivary gland: radiosensitive organs – apoptotic cell death

Autologus stem cell transfer

1. Mouse model 
   invitro culture of salivary stem cell -> reinjected after irradiation
   à repopulate the salivary gland and increased the salivary production
2. Limitation
   • in vitro culture: needs at least for several months, spontaneous differentiation must be prevented
   • radiation induced fibrosis