Transcript 328040_1_En_10_MOESM2_ESMx

Contents:
 Introduction
 Hepatocellular Carcinoma Ablation
 Ductal Breast Carcinoma Ablation
 Ribosomal Ablation
 Conclusions
Introduction
• Soft-tissue laser surgery is now common practice; many specific
laser treatments and procedures have been developed.
• The use of laser scalpels in surgery has shown a reduced risk of
infection as well as improved patient recovery time.
• This has been attributed to the laser’s ability to seal small blood
vessels and nerve endings at the cutting site, thus reducing pain and
blood loss.
• LASIK surgery utilizes excimer lasers to vaporize small layers of
corneal stroma and thus reshape the lens of the eye.
• Many applications have been found for laser resurfacing, from the
treatment of sun damage and stretch marks to the removal of scars
and tattoos.
• Lasers used for soft-tissue medical applications are chosen mainly
for the strong absorption of their radiation by water, the primary
constituent of soft-tissues.
Introduction (continued)
• In this section, we perform time-dependent simulations of soft-tissue
laser ablation to determine the potential for cancer treatments via
organelle specific ablation.
• Simulating both single- and multipulse modes of heating, we
calculate the time-temperature profiles for a variety of cancerous and
healthy cell organelles.
• Each form of cancer is in its own way distinct, so having a common
treatment for all forms of cancer requires methods that also harm
healthy cells, such as radiation or chemotherapy.
• Biologically speaking, cancer is a result of abnormal cells in the
body that rapidly and uncontrollably replicate.
• Normally cells undergo several checkpoints before division, as
discussed earlier; these checkpoints are used to determine whether or
not the cell should replicate its DNA and divide, and whether it
should undergo apoptosis due to faulty DNA.
Introduction (continued)
• By utilizing the physical changes experienced by the organelles of
abnormal cells, we can determine how laser irradiation would affect
the cancerous cells in comparison to healthy cells.
• The critical temperature for organelle ablation is 425 K, as that
results in protein denaturing and alters membrane permeability.
• Thus, the thermal ablation of the soft tissues is defined here as
irreversible changes in the biological medium due to the protein
denaturation at the critical temperature, which causes cell death.
• Our procedure consists of two primary steps: (1) determining the
absorption characteristics of the organelle and (2) numerically
solving the heat transfer equation to determine the temperature of
the organelle over time.
• For our analysis, we look at several specific cases from which we
extrapolate the result to other forms of cancer.
Hepatocellular Carcinoma Ablation
• Hepatocellular carcinoma (HCC) is a cancer located in
the liver that is normally a secondary effect of hepatitis or
cirrhosis.
• It is historically difficult to treat due to the late recognition
of tumors as well as difficulty removing the entire tumor
upon discovery. HCC is not effectively treated by either
chemotherapy or radiation therapy, and stands to be an
area where a new cancer treatment would be invaluable.
• Using the experimental data, we determine the effective
radius of the mitochondria and nucleus for HCC, which
is the term we use in our calculations for absorption
efficiency and then solving the one-temperature model.
Hepatocellular Carcinoma Ablation
(continued)
• The results of the calculations for
the absorption efficiency of
normal and cancerous cell
organelles are presented in the
figure for each of the three levels
of differentiation for both the
mitochondria and nuclei.
• Using these values and organelle
specific data, we then calculate
time-temperature profiles for
both normal and cancerous cell
organelles at the different
differentiation levels.
Hepatocellular Carcinoma Ablation
(continued)
• Looking at the single-pulse
mode of heating, the healthy
nuclei are heated to the highest
temperature of all the organelles.
• As the cell passes from well- to
poorly-differentiated,
the
maximum nucleus temperature
decreases.
•
Alternatively, the healthy mitochondria reaches a maximum
temperature slightly below the well-differentiated and
moderately-differentiated cell mitochondria, while the poorlydifferentiated cell mitochondria reach the highest
mitochondrial temperature.
Hepatocellular Carcinoma Ablation
(continued)
• This result indicates that trying
to
target
hepatocellular
carcinoma cells with singlepulse laser irradiation may not
be an effective treatment due to
the probable damage of healthy
cell nuclei.
•
In the multipulse mode of heating, the mitochondria reach a
higher temperature than the nuclei as a result of the different
densities used for the nuclei and the mitochondria; these
densities are used in the OTM and affect the heating and
cooling kinetics of the organelles.
Ductal Breast Carcinoma Ablation
• Ductal breast carcinoma is a prevalent form of breast cancer
that has the therapeutic advantage of being near the surface,
allowing it to be surgically removed or treated with radiation
therapy.
• To test the results of nuclear heating in hepatocellular
carcinoma against another form of cancer, we are using data
acquired from the experimental work on the morphometric
analysis of benign, in situ and invasive ductal breast
carcinoma.
• In situ ductal breast carcinoma has a high prevalence of
becoming invasive, so early treatment via laser irradiation
would allow safe prohibitive therapy that could decrease
cancer incidence rates for those that are diagnosed early with
in situ ductal carcinoma.
Ductal Breast Carcinoma Ablation
(continued)
• The figure shows time-temperature
profiles for multipulse ablation of
the varying cell nuclei of ductal
breast carcinoma.
• Once again, the calculations show
progressively higher temperatures
as the
tumor becomes more
benign.
•
•
This is due to the increased size of the nucleus that follows from
cancer development.
The larger the organelle, the larger the absorption efficiency; the
increase in absorption efficiency is not enough to offset the increase
in size.
Ribosomal Ablation
• Ribosomes are key contributors to healthy cells, along
with cells that have become cancerous.
• As shown earlier, the ribosomes in cancer cells have
much greater scattering efficiency than normal cells in
the spectral range 200-500 nm, meaning that they might
be useful organelles for cancer detection.
• Strong absorption of light for cancerous ribosomes is
observed in the wavelength range 600-1000 nm, which
will be optimal for ablation of cancer.
• Since the optical properties are considerably different
between normal and cancer cells, the use of ribosomes
holds much potential to facilitate diagnosis and therapy of
cancer.
Ribosomal Ablation (continued)
• The figure demonstrates a timetemperature profiles for heating
ribosomes of various small
sizes.
• For the single-pulse mode of
heating, the moderately large
ribosome (D = 2.9 nm) is
heated for most of all the
organelles.
• Alternatively, in the multipulse
mode of heating, the largest
ribosome (D = 4.6 nm) exhibits
the highest level of heating.
Ribosomal Ablation (continued)
• This change shows a similar
dynamic between size (absorption
efficiency)
and
maximum
temperature.
• These results indicate that with a
given increase in organelle size, the
single- or multipulse mode of
heating could be effective at killing
the organelles.
• In the case of the nucleus, at a
certain increase in size (after
progression of cancer reaches a
certain point), it may be possible to
use single-pulse laser irradiation
as a method of killing cancerous
cell nuclei.
Conclusions
• Due to biological variability, the availability of organelle
characteristics are minimal, even for specific cases.
• While it is hard to be concrete, several generalities can be
made when considering tumor cells versus healthy cells:
 A cancerous nucleus increases in size, and the cell
has an increased nucleus-to-cytoplasm ratio.
 Mitochondrial activity fluctuates while mitochondrial
cristae decrease, and the total number of mitochondria
decreases.
• Using an average value for organelles in healthy and
cancerous forms, we can determine the relative singleand multipulse heating characteristics that produce
thermal ablation in individual cases.
Conclusions (continued)
• For example, due to the heating and cooling kinetics of
mitochondria, we find that for both single-pulse and
multipulse modes of heating, tumor mitochondria will reach
a higher maximum temperature than healthy mitochondria.
• A comparative analysis of mitochondrial and nuclear ablation
shows that all types of mitochondria will heat to a
temperature well above the nucleus.
• The differences in cancer organelle morphology could all
result from the numerous stages, grades and origins of
cancer.
• Investigations into cancer organelle morphology would need
to be done under specific conditions, with the intent and
purpose to provide more data for thermal ablation
calculations.