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Clinical Ophthalmic
Oncology

Basic Principles
Arun D. Singh
Bertil E. Damato
Editors
Third Edition

123
Clinical Ophthalmic Oncology
Arun D. Singh • Bertil E. Damato
Editors

Clinical Ophthalmic
Oncology
Basic Principles

Third Edition
Editors
Arun D. Singh Bertil E. Damato
Department of Ophthalmic Oncology Nuffield Department of Clinical
Cole Eye Institute, Cleveland Clinic Neurosciences, University of Oxford
Cleveland, OH John Radcliffe Hospital
USA Oxford, UK

ISBN 978-3-030-04488-6    ISBN 978-3-030-04489-3 (eBook)

https://doi.org/10.1007/978-3-030-04489-3

Library of Congress Control Number: 2019932849

© Springer Nature Switzerland AG 2019

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or
part of the material is concerned, specifically the rights of translation, reprinting, reuse of
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Preface

Ophthalmic tumors are rare and diverse so that their diagnosis can be quite
complex. Treatment usually requires special expertise and equipment and in
many instances is controversial. The field is advancing rapidly, because of
accelerating progress in tumor biology, pharmacology, and instrumentation.
Increasingly, the care of patients with an ocular or adnexal tumor is provided
by a multidisciplinary team, consisting of ocular oncologists, general oncolo-
gists, radiotherapists, pathologists, psychologists, and other specialists.
For all these reasons, we felt that there was a need for the new edition of
the textbook providing a balanced view of current clinical practice. Although
each section of Clinical Ophthalmic Oncology, 3rd Edition, now represents a
stand-alone volume, each chapter has a similar layout with boxes that high-
light the key features, tables that provide comparison, and flow diagrams that
outline therapeutic approaches.
The enormous task of editing a multiauthor, multivolume textbook could
not have been possible without the support and guidance by the staff at
Springer: Caitlin Prim, Melanie Zerah, ArulRonika Pathinathan, and Karthik
Rajasekar. Michael D. Sova kept the pressure on to meet the production
deadlines.
It is our sincere hope that our efforts will meet high expectation of the
readers.

Cleveland, OH, USA Arun D. Singh, MD

Oxford, UK Bertil E. Damato, MD, PhD, FRCOphth

v
Acknowledgments

To my parents who educated me beyond their means, my wife Annapurna,

and my children, Nakul and Rahul, who make all my efforts worthwhile.
(ADS)
To my family, Frankanne, Erika, Stephen, and Anna. (BED)

 Arun D Singh
 Bertil E Damato

vii
Contents

1 Principles of Cancer Epidemiology������������������������������������������������   1

Annette C. Moll, Michiel Robert de Boer, Lex M. Bouter, and
Nakul Singh
2 Etiology of Cancer���������������������������������������������������������������������������� 11
Brian T. Hill
3 Cancer Pathology ���������������������������������������������������������������������������� 19
Gustav Stålhammar, Katarina Bartuma, Charlotta All-Eriksson,
and Stefan Seregard
4 Pathology Specimen: Handling Techniques���������������������������������� 33
Hardeep Singh Mudhar
5 Cancer Angiogenesis������������������������������������������������������������������������ 49
Werner Wackernagel, Lisa Tarmann, Martin Weger,
and Arun D. Singh
6 Immunology of Ocular Tumors������������������������������������������������������ 71
Martine J. Jager and Inge H. G. Bronkhorst
7 Cancer Genetics ������������������������������������������������������������������������������ 79
Elaine M. Binkley and Luke A. Wiley
8 Cancer Staging �������������������������������������������������������������������������������� 87
Claudine Bellerive and Arun D. Singh
9 Principles of Cryotherapy �������������������������������������������������������������� 93
Dan S. Gombos and Kayla Walter
10 Principles of Laser Therapy������������������������������������������������������������ 99
Hatem Krema
11 Principles of Radiation Therapy���������������������������������������������������� 107
Abigail L. Stockham, Allan Wilkinson, and Arun D. Singh
12 Ocular Complications of Radiotherapy ���������������������������������������� 117
Mitchell Kamrava, James Lamb, Vidal Soberón, and
Tara A. McCannel
13 Principles and Complications of Chemotherapy�������������������������� 129
Stacey Zahler, Nicola G. Ghazi, and Arun D. Singh

ix
x Contents

14 Ocular Complications of Targeted Therapy���������������������������������� 143

Ashley Neiweem, Denis Jusufbegovic, and Arun D. Singh
15 Counseling Patients with Cancer���������������������������������������������������� 161
Bertil E. Damato
16 Tumor-Associated Cataract������������������������������������������������������������ 173
Carlos A. Medina Mendez, Mary E. Aronow,
Guillermo Amescua, and Arun D. Singh
17 Tumor-Associated Glaucoma���������������������������������������������������������� 185
Reena Garg, Annapurna Singh, and Arun D. Singh
18 Graft-Versus-Host Disease�������������������������������������������������������������� 195
Edgar M. Espana, Lauren Jeang, and Arun D. Singh
19 Diagnostic Techniques: Angiography �������������������������������������������� 209
Kaan Gündüz and Yağmur Seda Yeşiltaş
20 Diagnostic Techniques: OCT���������������������������������������������������������� 235
Rubens Belfort and Arun D. Singh
21 Diagnostic Techniques: Autofluorescence�������������������������������������� 257
Edoardo Midena, Luisa Frizziero, Elisabetta Pilotto, and
Raffaele Parrozzani
22 Diagnostic Techniques: Ultrasonography�������������������������������������� 271
Brandy H. Lorek, Mary E. Aronow, and Arun D. Singh
23 Diagnostic Techniques: FNAB�������������������������������������������������������� 295
Hassan A. Aziz, David Pelayes, Charles V. Biscotti, and
Arun D. Singh
24 Diagnostic Techniques: Other Biopsy Techniques������������������������ 309
Bertil E. Damato, Armin Afshar, Sarah E. Coupland,
Heinrich Heimann, and Carl Groenewald

Index���������������������������������������������������������������������������������������������������������� 317
Contributors

Armin Afshar, MD, MBA Ocular Oncology Service, Department of

Ophthalmology, University of California San Francisco, San Francisco, CA,
USA
Charlotta All-Eriksson, MD, PhD Department of Ophthalmic Pathology
and Oncology Service and Department of Clinical Neuroscience, St. Erik Eye
Hospital and Karolinska Institutet, Stockholm, Sweden
Guillermo Amescua, MD Department of Cornea and External Diseases,
Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA
Mary E. Aronow, MD Department of Retina Service and Ocular Oncology,
Massachusetts Eye and Ear and Harvard Medical School, Boston, MA, USA
Hassan A. Aziz, MD Clemenceau Medical Center, Beirut, Lebanon
Katarina Bartuma, MD, PhD Department of Ophthalmic Pathology and
Oncology Service and Department of Clinical Neuroscience, St. Erik Eye
Hospital and Karolinska Institutet, Stockholm, Sweden
Rubens Belfort, MD, PhD Department of Ophthalmology and Visual
Sciences, Escola Paulista de Medicina – Federal University of São Paulo, São
Paulo, Brazil
Claudine Bellerive, MD, MSc Centre universitaire d’ophtalmologie,
Hôpital Saint-Sacrement, Centre hospitalier universitaire de Québec, Québec,
QC, Canada
Elaine M. Binkley, MD Department of Ophthalmology & Visual Sciences,
University of Iowa Hospitals and Clinics, Iowa City, IA, USA
Charles V. Biscotti, MD Department of Anatomic Pathology and Cole Eye
Institute, Cleveland Clinic, Cleveland, OH, USA
Lex M. Bouter, PhD Department of Epidemiology and Biostatistics, VU
University Medical Centre, Amsterdam, The Netherlands
Inge H. G. Bronkhorst, MD Department of Ophthalmology, Jeroen Bosch
Hospital, ‘s-Hertogenbosch, The Netherlands
Sarah E. Coupland, MBBS, PhD Department of Molecular and Clinical
Cancer Medicine, Institute of Translational Medicine, University of Liverpool,
Liverpool, UK

xi
xii Contributors

Bertil E. Damato, MD, PhD, FRCOphth Nuffield Department of Clinical

Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3
9DU, UK
Michiel Robert de Boer, PhD Department of Health Sciences, VU
Amsterdam, Amsterdam, The Netherlands
Edgar M. Espana, MD Department of Ophthalmology, University of South
Florida, Tampa, USA
Luisa Frizziero, MD IRCCS – Fondazione Bietti, Rome, Italy
Reena Garg, MD Department of Ophthalmology, Emory University
Hospital, Atlanta, GA, USA
Nicola G. Ghazi, MD Division of Ophthalmology and Vitreoretinal Service,
King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
Department of Ophthalmology, The University of Virginia, Charlottesville,
VA, USA
Dan S. Gombos, MD, FACS Section of Ophthalmology-Department of
Head and Neck Surgery, MD Anderson Cancer Center, The Retinoblastoma
Center of Houston (MD Anderson/Texas Children’s/Baylor/Methodist
Hospital), Houston, TX, USA
Carl Groenewald, MD Liverpool Ocular Oncology Centre, St Paul’s Eye
Unit, Royal Liverpool University Hospital, Liverpool, UK
Kaan Gündüz, MD Department of Ophthalmology, Ankara University
Faculty of Medicine, Ankara, Turkey
Heinrich Heimann, MD Liverpool Ocular Oncology Centre, St Paul’s Eye
Unit, Royal Liverpool University Hospital, Liverpool, UK
Brian T. Hill, MD, PhD Department of Taussig Cancer Institute, Cleveland
Clinic, Cleveland, OH, USA
Martine J. Jager, MD, PhD Department of Ophthalmology, LUMC,
Leiden, The Netherlands
Lauren Jeang, MD Department of Ophthalmology, New England Eye
Center/Tufts Medical Center, Boston, MA, USA
Denis Jusufbegovic, MD Department of Ophthalmology, Indiana University
School of Medicine/Glick Eye Institute, Indianapolis, IN, USA
Mitchell Kamrava, MD Department of Radiation Oncology, University of
California, Los Angeles, CA, USA
Hatem Krema, MD, MSc, FRCS Ocular Oncology Service, Princess
Margaret Cancer Center/ University Health Network, Toronto, ON, Canada
James Lamb, PhD Department of Radiation Oncology, University of
California, Los Angeles, CA, USA
Brandy H. Lorek, BS Cole Eye Institute, Cleveland Clinic, Cleveland, OH,
USA
Contributors xiii

Tara A. McCannel, MD, PhD Ophthalmic Oncology Center, Jules Stein

Eye Institute, Department of Ophthalmology, University of California, Los
Angeles, CA, USA
Carlos A. Medina Mendez, MD Retinal Consultants, Sacramento, CA,
USA
Edoardo Midena, MD, PhD Department of Ophthalmology, University of
Padova, Padova, Italy
IRCCS – Fondazione Bietti, Rome, Italy
Annette C. Moll, MD, PhD Department of Ophthalmology, VU University
Medical Center, Amsterdam, The Netherlands
Hardeep Singh Mudhar, BSc, PhD, MBBChir, FRCPath National
Specialist Ophthalmic Pathology Service (NSOPS), Department of
Histopathology, E-Floor, Sheffield Teaching Hospitals NHS Foundation
Trust, Royal Hallamshire Hospital, Sheffield, UK
Ashley Neiweem, MD Department of Ophthalmology, Indiana University
School of Medicine/Glick Eye Institute, Indianapolis, IN, USA
Raffaele Parrozzani, MD, PhD Department of Ophthalmology, University
of Padova, Padova, Italy
David Pelayes, MD Department of Ophthalmology, Buenos Aires University
and Maimonides University, Buenos Aires, Argentina
Elisabetta Pilotto, MD Department of Ophthalmology, University of
Padova, Padova, Italy
Stefan Seregard, MD PhD Department of Ophthalmic Pathology and
Oncology Service and Department of Clinical Neuroscience, St. Erik Eye
Hospital and Karolinska Institutet, Stockholm, Sweden
Annapurna Singh, MD Department of Ophthalmic Oncology, Cole Eye
Institute, Cleveland Clinic, Cleveland, OH, USA
Arun D. Singh, MD Department of Ophthalmic Oncology, Cole Eye
Institute, Cleveland Clinic, Cleveland, OH, USA
Nakul Singh, MS School of Medicine, Case Western University, Cleveland,
OH, USA
Vidal Soberón, MD Department of Retina/Oncology, Jules Stein Eye
Institute, Los Angeles, CA, USA
Gustav Stålhammar, MD, PhD Department of Ophthalmic Pathology and
Oncology Service and Department of Clinical Neuroscience, St. Erik Eye
Hospital and Karolinska Institutet, Stockholm, Sweden
Abigail L. Stockham, MD Department of Radiation Oncology, Mayo
Clinic, Rochester, MN, USA
Lisa Tarmann, MD, PhD Department of Ophthalmology, Medical
University Graz, Graz, Styria, Austria
xiv Contributors

Werner Wackernagel, MD Department of Ophthalmology, Medical

University Graz, Graz, Styria, Austria
Kayla Walter UT McGovern School of Medicine, Houston, TX, USA
Martin Weger, MD Department of Ophthalmology, Medical University
Graz, Graz, Styria, Austria
Luke A. Wiley, PhD Department of Ophthalmology & Visual Sciences,
Institute for Vision Research, University of Iowa, Iowa City, IA, USA
Allan Wilkinson, PhD Department of Radiation Oncology, Cole Eye
Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
Yağmur Seda Yeşiltaş, MD Department of Ophthalmology, Ankara
University Faculty of Medicine, Ankara, Turkey
Stacey Zahler, DO, MS Department of Pediatric Hematology, Oncology
and Blood & Marrow Transplantation, Cleveland Clinic Children’s Hospital,
Cleveland, OH, USA
 Principles of Cancer Epidemiology
Annette C. Moll, Michiel Robert de Boer,
Lex M. Bouter, and Nakul Singh
Introduction
During the last decade, evidence-based medicine
(EBM) has become a dominant approach in many
medical fields, including ophthalmology [1, 2].
Clinical epidemiological studies provide evidence
that can aid decision-making processes. An over-
whelming amount of clinical epidemiological
papers are being published every year, and critical
appraisal of the findings can be challenging, espe-
cially for the busy clinician who is not formally
trained in the field of clinical epidemiology.
Therefore, the available evidence is increasingly
bundled in clinical guidelines. The aim of this
chapter is to provide readers with some basic
knowledge to allow them to judge the value of
clinical epidemiological papers and thus of the pil-
lars of evidence-based clinical guidelines.
A. C. Moll (*)
Department of Ophthalmology, VU University
Medical Center, Amsterdam, The Netherlands
e-mail: a.moll@vumc.nl
M. R. de Boer
Department of Health Sciences, VU Amsterdam,
Amsterdam, The Netherlands
L. M. Bouter
Department of Epidemiology and Biostatistics,
VU University Medical Centre,
Amsterdam, The Netherlands
N. Singh
School of Medicine, Case Western University,
Cleveland, OH, USA
© Springer Nature Switzerland AG 2019
A. D. Singh, B. E. Damato (eds.), Clinical Ophthalmic Oncology,
https://doi.org/10.1007/978-3-030-04489-3_1
1
Examples from ocular oncology will be used to
illustrate the methodological principles.
Research Question
A clinical epidemiological study should always
start with a well-defined research question.
Similarly, when reading a paper, one should
always first identify the question(s) the authors
wish to address (Fig. 1.1). Research questions
can be aimed at explanation or description.
Explanatory research examines causal relation-
ships, while descriptive research is merely
descriptive. In addition, research questions are
also often being categorized as etiological, diag-
nostic, or prognostic (Table 1.1). For example, an
explanatory research question related to etiology
in the field of ocular oncology is as follows: are
children born after in vitro fertilization at higher
risk of developing retinoblastoma as compared to
children born after natural conception? [3] A cor-
rect explanatory research question should contain
information on the patients, interventions, con-
trast, and outcomes (PICO) at issue.
Outcome Measures
Traditionally, prevalence, incidence, and mortality
(survival) have been the outcome measures in clin-
ical cancer epidemiology studies. More recently,
1
2 A. C. Moll et al.

Research question(s)

• Identify patients, interventions

(exposures), controls and outcome
(PICO)
• Descriptive or explanatory purpose
• Focus on aetiology (including
prevention), diagnosis or prognosis
(including therapy)

Design Sample Measurements

Case series Source population Outcome

Cross sectional Target population Potential confounders
Cohort study Control population Validity, reproducibility and
RCT Sampling strategy responsiveness
Case control Inclusion/Exclusion criteria Time to follow-up

Other considerations

• Ethical aspects
• Practical limitations
• Budget constraints

Fig. 1.1 Steps in designing a clinical epidemiological research

Table 1.1 Types of epidemiological research

Type of research Purpose
Etiology (including prevention) To examine possible
etiological factors for the
occurrence of a disease
Diagnosis To examine the usefulness of
diagnostic tests for the
disease
Prognosis (including To examine possible
interventions) prognostic factors for the
disease
Example
Association between ultraviolet radiation and
uveal melanoma
Accuracy of magnetic resonance imaging in
determining choroidal invasion of
retinoblastoma
Association between external beam therapy for
retinoblastoma and the incidence of second
malignant neoplasms
1 Principles of Cancer Epidemiology
quality of life measures have become increasingly
popular. In ophthalmic oncology, visual acuity is
also an important outcome measure.
Prevalence
Prevalence refers to the proportion of the study
population with the condition of interest. Usually
prevalence is given for a specific moment in time
(point prevalence), but sometimes it is estimated
for a period of time (e.g., 1 year or lifetime preva-
lences). For example, the lifetime prevalence of
uveal melanoma in a Caucasian population with
oculo(dermal) melanocytosis is estimated to be
0.26% [4].
Incidence
Whereas prevalence relates to existing cases,
incidence relates to the proportion of new cases
in the study population. It is important that the
population under investigation is at risk of devel-
oping the condition. For example, persons with
bilateral enucleation are no longer at risk of
developing uveal melanoma. There are two dif-
ferent measures of incidence: cumulative inci-
dence (CI) and incidence density (ID). CI is the
proportion of new cases in a population at risk
over a specified period of time. For example, the
CI of second malignant neoplasms in hereditary
retinoblastoma patients is 17% at the age of
35 years [5]. ID refers to the rate of developing
the condition during follow-up, usually expressed
as a proportion per person-year at risk.
Mortality
Cancer is among the leading causes of mortality.
In order to understand the processes that either
hasten or delay this outcome, it is necessary to rig-
orously define the burden of disease. Clinical epi-
demiologists have created several concepts of
mortality, all with their own definition, interpreta-
tion, and uses. Unfortunately, many of these con-
cepts use similar nomenclature, so it is important
to always clarify the definition of mortality at
3
hand. Broadly speaking, mortality rate refers to the
incidence of death, and survival rate is its comple-
ment, i.e., survival rate = 100 – mortality rate.
Population mortality is the chance that a per-
son in the general population will die from a spe-
cific disease over a specified time frame. It is a
useful concept for measuring the burden of dis-
ease in a population. For example, the population
mortality for heart disease was 197.2 per 100,000
population per year in 2015. Therefore, it is a
measure more important for public health policy-
makers as opposed to clinicians. This measure is
calculated from death certificates, where cause of
death is known [6].
Overall mortality is the chance that a person
with a disease will die within a time period after
diagnosis. It is important to specify a time period
for the mortality statistics – in the long run, mor-
tality is 100% for any condition. Of note, this
definition is indifferent to cause of death. Overall
mortality is the most common measure of mortal-
ity in the literature and is often used to guide
prognosis. This measure is helpful in identifying
risk factors for poor prognosis, as well as measur-
ing disparities between populations. The inter-
pretation of this measure is complicated by
biases, including lead time, length, and overdiag-
nosis biases.
Cause-specific mortality is the chance that a
person with a disease will die within a time
period after diagnosis due to the disease. This is
in contrast to overall survival, which does not dis-
tinguish between causes of death. Cause-specific
mortality most closely measures the “deadliness”
of a disease, but similar to overall mortality, it
can be affected by lead time, length, and overdi-
agnosis bias.
Relative mortality is a proportion that com-
pares the overall mortality of people with a dis-
ease to that of an unaffected, but otherwise
identical population. Relative mortality measures
the excess mortality associated with a diagnosis
compared to the general population. It is a conve-
nient measure to calculate because it does not
require cause of death to be recorded. It is also a
helpful measure for understanding the deadliness
of a disease that affects the elderly, where patients
are at risk from dying from other causes. To cal-
culate relative survival, overall survival of a
4 A. C. Moll et al.

cohort of patients is compared to life tables of the endpoints argue that they are preferable for rea-
general population, matched by age, sex, race, sons of feasibility, cost, and length of study, with
and other important demographic features. possible expediency of the drug approval pro-
Conditional mortality is another clinically cess. Critics of surrogate endpoints point out that
informative measure of mortality, which mea- the evidence base for surrogate endpoints corre-
sures the chance that a person with a disease will lating closely with clinical outcomes is often
die within a specified time period after having tenuous.
already lived with the disease for a certain amount
of time. It is a helpful measure to assess how
prognosis changes over time. Conditional sur- Quality of Life
vival requires a cohort of patients where long-­
term follow-up is close to complete. With increasing survival rates and with severe
side effects of some treatment modalities, quality
of life measures have become increasingly
Time to Event important in ophthalmic oncology. These mea-
sures encompass symptoms and physical, social,
Another class of outcomes that is of interest to and psychological functioning from a patient’s
clinical epidemiologists is time to event. Time to perspective. Usually, quality of life is assessed
event measures the length of time that elapses with a structured questionnaire, and scores are
from some start point to a defined endpoint, the summarized assuming an interval scale. Several
most common time-to-event measure being sur- questionnaires have recently been developed for
vival, which is defined as time from diagnosis to patients with ocular diseases, such as the measure
death (not to be confused with survival rate). of outcome in ocular disease [MOOD]) [9].
Other events can be used as the endpoint, such as
relapse or radiographic progression. Time-to-­
event data is typically graphically presented with M  easures of Association
a Kaplan-Meier plot, which displays a nonpara-
metric estimation of the rate of survival in a pop- In epidemiological research, we are usually inter-
ulation as a function of time [7]. ested in how certain interventions or exposures
are associated with outcomes; for example, is
there an association between paternal age and
Surrogate Endpoints retinoblastoma in the offspring? [10]. There are
several statistical approaches that can be used to
While overall mortality and cause-specific mor- quantify associations, either as a ratio or as a dif-
tality are the two gold standard measures of mor- ference, depending upon the study design and
tality when evaluating the efficacy of statistical method used (Table 1.2).
interventions, other measures of efficacy are
being proposed, such as surrogate endpoints,
which are biomarkers that are intended to substi- Relative Risk
tute for a clinical endpoint. Of note, these are not
clinical quantities of interest but are correlated The ratio of cumulative incidences of exposed
with them. Examples of surrogate endpoints and unexposed individuals (or between treated
include evidence of radiographic progression, and untreated patients) is the relative risk (RR).
biochemical markers, and physical signs [8]. For example, in the Netherlands, the RR of reti-
These are controversial measures and are not uni- noblastoma in children conceived by in vitro fer-
formly accepted within the scientific and regula- tilization is between 4.9 and 7.2. This implies that
tory community. Proponents of surrogate the risk of getting retinoblastoma is between 4.9
1 Principles of Cancer Epidemiology 5

Table 1.2 The relation between outcome, measures of association, study designs, and statistical methods
Measure of
Outcome association Computation Study designs Statistical methods
Prevalence Prevalence rate P1/P2 Cross-sectional Chi-square test
Logistic regression
analysis
Prevalence P1 − P2 Cross-sectional Chi-square test
difference
Odds of exposure Odds ratio Odds of exposure group 1/ Case-control study Chi-square test
odds of exposure group 2 (cohort study, RCT) Logistic regression
Cumulative Relative risk CI1/CI2 Cohort study/RCT Chi-square test
incidence (CI) Risk difference CI1 − CI2 RCT
Incidence density Hazard ratio ID1/ID2 Cohort study/RCT Kaplan-Meier
(ID) Cox regression
Risk difference ID1 − ID2 RCT Kaplan-Meier
O/E ratio Observed ID/expected ID in Cohort study/registry
general population study
Quality of life Difference in X1 − X2 Cohort study/RCT Independent t-test
mean score Linear regression
analyses
P1 prevalence group 1, P2 prevalence group 2, CI cumulative incidence, CI1 CI group 1, CI2 CI group 2, ID incidence
density, ID1 ID group 1, ID2 ID group 2, O/E ratio observed to expected ratio, RCT randomized controlled trial,
X1 = mean score group 1; X2 = mean score group 2

and 7.2 times higher for children conceived after expected. This data can be expressed as stan-
IVF than naturally conceived children. dardized mortality ratio of 5.41 [11].

Hazard Ratio Odds Ratio

The ratio of incidence densities of unexposed
and exposed patients (or between treated and
untreated patients) is the hazard ratio (HR),
which has a similar interpretation as the RR. This
measure is often used in relation to mortality,
because we are generally interested not only in
the proportion of patients that die but also in the
time from baseline (diagnosis or start of treat-
ment) until death. A special application of the
HR is the ratio of the observed to the expected
number of cases (O/E ratio). In this case the
observed incidence density is calculated for the
study population, and this is compared to the
expected incidence density derived from a popu-
lation registry (e.g., cancer registration). For
example, in a study of lifetime risks of common
cancers among 144 hereditary retinoblastoma
survivors, 41 cancer deaths were observed,
whereas only 7.58 deaths due to cancer were
The odds ratio (OR) is the most commonly
reported measure of association in the literature,
due to the fact that this is the statistic that can be
derived from the popular logistic regression anal-
ysis. The OR is the ratio of the odds of outcome
of interest between the exposed and the
­unexposed. Generally speaking, the OR is a good
approximation of the RR or HR.
Differences in Risk
Differences in risks (RD) are preferably reported as
outcome in randomized controlled trials. The RD is
easy to interpret and can be used to calculate the
number of patients needed to treat (NNT) to pre-
vent one extra event (e.g., death) compared to the
standard treatment or placebo. The NNT can be
calculated as inverse of RD (1/RD). A related
6 A. C. Moll et al.
c­oncept is that of the number needed to screen
(NNS). This refers to the number of patients needed
to screen to prevent one extra event compared to
the situation without a screening program. The
NNS thus depends on the predictive probability of
the screening test as well as on the efficacy of treat-
ment for people that are diagnosed with that screen-
ing test. The value of routine neuroimaging
screening of pineoblastoma in retinoblastoma
patients is uncertain and a point of discussion [12].
Differences in Mean Score
For scores on interval scales, such as quality of
life, differences in mean score between exposed
and unexposed participants are the most impor-
tant measure of interest. These can be derived
from independent samples t-test of general linear
models (e.g., linear regression analysis).
Precision of the Estimate
When interpreting an outcome, we do not only
want to know the numerical value of the point
estimate but also the precision with which it has
been assessed. In other words, can we be confi-
dent that the outcome is not just a chance find-
ing? The usual standard for accepting an outcome
as being beyond chance is p (probability) <0.05.
A more informative description is provided by
the 95% confidence interval (CI). The rough
interpretation of the 95% CI is that there is a 95%
probability that the real value lies within the con-
fidence interval.
Statistical significance and the width of confi-
dence intervals are strongly dependent on the
sample size of a study. This means that in very
large samples, weak (and potentially unimport-
ant) associations can be statistically significant.
In contrast, in small samples, strong (and poten-
tially important) associations are sometimes not
statistically significant. Such findings should of
course not be dismissed as being irrelevant.
Instead they should be replicated in larger study
populations. Associations, although statistically
significant, need not be clinically important.
Therefore, interpretation of findings should never
solely rely on statistical significance.
Bias
An estimate can be very precise but nevertheless
inaccurate, because of bias. Three main sources
of bias exist: confounding, selection, and infor-
mation bias.
Confounding
Confounding occurs when the association
between exposure and outcome is influenced by a
third variable that is related both to the exposure
and the outcome (Fig. 1.2). A recent study found
an association between cooking (as occupation)
and the incidence of ocular melanoma [13]. It
could be argued that as many cooks work at night,
it is possible that they could have relatively high
exposures to sunlight due to daytime leisure
activities compared to people working during the
daytime. It is implied that the association between
cooking and ocular melanoma could potentially
(in part) be explained by a higher exposure to
sunlight by cooks.
Selection Bias
Selection bias may occur when the chance of
being included in the study population is not ran-
dom for all members of the source population. For
example, patients with advanced tumor stage are
more likely to be referred to a special cancer cen-
Exposure
Disease
(intervention)
r≠0
r≠0
Confounder
r = correlation
Fig. 1.2 Schematic representation of confounding
1 Principles of Cancer Epidemiology 7

Table 1.3 Advantages and disadvantages of different study designs

Considerations Type of study
Methodological Cross-sectional Cohort RCT Case-control
Confounding − − + −
Selection bias − ± ± −
Information bias ± ± ± −
Prior exposure − + + −
Incident cases − + + +
Practical Length of study + − ± +
Organization + ± − ±
Expenses + − − +
RCT randomized controlled trial
Negative score (−) indicates disadvantage compared to other study designs
Positive score (+) indicates advantage compared to other study designs
Equivocal score (±) indicates neither advantage nor disadvantage as compared to other study designs

ter than patients with a less advanced tumor stage.
This form of selection bias is called referral bias.
Selection bias could also be introduced in a study
by choosing the wrong control group, especially
if controls are selected from hospital patients.
adopted in order to address a research question.
Each of the study designs has its advantages and
disadvantages (Table 1.3).
Case Series

Information Bias In case series, the authors present the clinical

Information bias occurs when outcome or expo-
sure variables are not accurately assessed. This is
especially problematic when this occurs differ-
ently for exposed versus nonexposed cases or for
cases versus controls. A well-known type of
information bias is recall bias. This refers to the
phenomenon that patients tend to remember
more details about exposures that are possibly
related to their disease than controls. For exam-
ple, the patients with uveal melanoma are proba-
bly more aware of the fact that their disease could
be related to sunlight exposure. In turn, they
reflect upon their own past exposure to sunlight
in much more detail than healthy controls. This
can lead to a relative underestimation of exposure
in controls and hence an overestimation of the
association with sunlight exposure.
Study Designs
There are several research designs, such as case
series, cross-sectional, cohort, randomized con-
trol trial, and case-control study, which can be
data regarding a group of patients (e.g., tumor
response to chemotherapy combined with diode
laser in retinoblastoma patients). The major dis-
advantage is that this kind of study does not have
a comparative design and does not permit an
answer to a question such as “there is a good
response, but compared to what, as there is no
control group?” [13].
Cross-Sectional Study
In a cross-sectional study, the outcome (and
exposure) is assessed at one point in time. In
prevalence studies, only the outcome is measured
(e.g., prevalence of retinoblastoma in Denmark).
In addition, the outcome between exposed and
unexposed study participants can be compared in
order to explore etiological questions. In a cross-­
sectional study on the association between iris
color and posterior uveal melanoma, melanoma
patients (N = 65) with light iris color were sig-
nificantly more likely to have darker choroidal
pigmentation than controls (N = 218) (p = 0.005).
In addition, darker choroidal pigmentation was
8 A. C. Moll et al.
associated histologically with increased density
of choroidal melanocytes (p = 0.005). The authors
concluded that increased choroidal pigmentation,
as a result of an increase in the density of pig-
mented choroidal melanocytes, is not protective
but may actually be a risk factor for the develop-
ment of posterior uveal melanoma in white
patients [14].
The cross-sectional study design has the
advantage that it is relatively easy to plan, that
only one measurement is needed, and that it is
inexpensive and quick to perform. From a meth-
odological point of view, however, the design has
some disadvantages. As both exposure and out-
come are measured at the same time, we cannot
be sure that the exposure preceded the outcome
(the most important criterion for causality).
Moreover, the outcome is always measured in
terms of prevalent cases, and prevalent cases may
have a relatively better prognosis (they are still
alive) than the incident cases. Therefore, the
associations found in a cross-sectional study can
only rarely be interpreted as being causal.
Cohort Study
Some of the problems listed above can be over-
come by conducting a (prospective) cohort study.
At baseline, one starts with a cohort of people
free from the outcome of interest. During or at
the end of follow-up, incident cases in both the
unexposed and the exposed groups are identified,
and RRs or HRs can be calculated. Despite theo-
retical advantages of a cohort design, there are
some practical disadvantages. The cohort studies
often need large sample sizes and/or long follow-
up to accumulate enough incident cases for
­ case-control studies is not to assess the exposure
meaningful analyses. These studies are often
expensive. From a methodological point of view,
the potential bias of (residual) confounding can
never be totally excluded.
Randomized Controlled Trial
Randomized controlled trials are a specific type
of cohort study. At the start of the study, partici-
pants are randomly assigned to the intervention
group (treatment under investigation) or a control
group (no treatment, placebo, or standard treat-
ment). After the start of a treatment, patients
often get better. This may be due to the treatment
or to other circumstances such as spontaneous
resolution, effective co-interventions, and pla-
cebo effects. Only a sufficiently large random-
ized, blinded trial is useful to estimate the efficacy
of drugs and other treatments. The best compari-
son is often between the new treatment and the
best available one, not the sham treatment [15].
The randomization, if successful, ensures that
confounding factors are evenly distributed
between the intervention and control groups. As
with the cohort studies, incident cases in both
groups are determined during or at the end of
follow-up, allowing for the risk estimates to be
calculated.
For clinicians interested in evidence pertain-
ing most directly to a particular class of patients,
subgroup analyses can be very informative. The
strength of evidence for subgroup effects depends
on the question whether hypotheses have been
defined prior to analysis, whether potential prob-
lems regarding multiple comparisons have been
considered, and whether there is biological plau-
sibility of the effects found. Using these guide-
lines, the reader of a trial report should be able to
decide if presented subgroup effects are of clini-
cal importance or if the overall result is a better
estimate of treatment effect [16].
Case-Control Study
In contrast to cohort studies, the starting point in
status, but the disease status. People with the dis-
ease of interest are selected, and a control group
of people without the disease is subsequently
recruited. The control group should include peo-
ple from the same source population as the cases,
implying that if any of the controls had developed
the disease, they would have been eligible for
inclusion in the study as a case.
The selection of a valid control group is
important in case-control studies and has there-
1 Principles of Cancer Epidemiology
fore generated a fair amount of discussion in the
epidemiological literature. It is possible to select
population controls, hospital controls, friends or
relatives of patients, or any combination of these
[17]. Case-control studies have the advantage of
being relatively quick and inexpensive to conduct
and are especially appealing in rare diseases. A
disadvantage is the large potential for selection
bias, especially in the recruitment of controls. In
addition there is also a real danger for informa-
tion (recall) bias. Similar to cohort studies, bias
by confounding can never be totally ruled out.
Pilot Study
A pilot study is often performed before the start
of a large study. Its aim is to improve the method-
ological quality and evaluate the feasibility. The
estimate of the effect of an intervention in a pilot
study is determined to a large extent by chance
and therefore cannot be considered as conclusive.
However, inclusion of such results in a later
cumulative meta-analysis may lead to sufficient
power so as to assess the efficacy of an experi-
mental intervention [18].
Systematic Review
In a systematic review, all available evidence (lit-
erature) on a certain topic is reviewed in a sys-
tematic, transparent, and reproducible manner.
These studies can be especially useful when
results from single studies are contradictory and/
or have large confidence intervals due to small
sample size. When the studies in a systematic
review are reasonably homogenous, their results
can be pooled in meta-analyses. This results in
one effect size for all the studies together, with a
much smaller confidence interval than the indi-
vidual studies. An example is a systematic review
on the survival of patients with uveal melanoma
treated with brachytherapy. The result of this
meta-analysis showed that the 5-year melanoma-­
related mortality rate was 6% for small and
medium tumors and 26% for large tumors [19].
9
Conclusions
In general, ophthalmic tumors are rare compared
to other ophthalmic diseases. Therefore, it is dif-
ficult to conduct large studies with enough power
to get statistically significant and clinically rele-
vant results. A large number of studies are pub-
lished each year, most of which are descriptive,
concerning retrospective patient series. To con-
duct randomized clinical trials, international col-
laboration is necessary to include enough patients
in the different treatment arms of the study.
Furthermore, uniform definitions and study
methodology are very important to compare the
different studies in the literature and to be able to
perform systematic reviews and meta-analyses.
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2. Guyatt GH, Haynes RB, Jaeschke RZ, et al. Users’
guides to the medical literature: XXV. Evidence-­
based medicine: principles for applying the users’
guides to patient care. Evidence-based medicine
working group. JAMA. 2000;284:1290–6.
3. Moll AC, Imhof SM, Cruysberg JR, et al. Incidence of
retinoblastoma in children born after in-vitro fertilisa-
tion. Lancet. 2003;361:309–10.
4. Singh AD, De Potter P, Fijal BA, et al. Lifetime
prevalence of uveal melanoma in white patients
with oculo(dermal) melanocytosis. Ophthalmology.
1998;105:195–8.
5. Moll AC, Imhof SM, Bouter LM, et al. Second primary
tumors in patients with hereditary r­ etinoblastoma: a reg-
ister-based follow-up study, 1945–1994. Int J Cancer.
1996;67:515–9.
6. U.S. Department of Health and Human Services.
Centers for Disease Control and Prevention (CDC).
Principles of epidemiology in public health practice:
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tistics. Atlanta, GA: Office of Workforce and Career
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7. Kaplan EL, Meier P. Nonparametric estimation
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8. Cohn JN. Introduction to surrogate markers.
Circulation. 2004;109(25):IV–20-IV-21.
9. Foss AJ, Lamping DL, Schroter S, et al. Development
and validation of a patient based measure of outcome in
ocular melanoma. Br J Ophthalmol. 2000;84:347–51.
10. Moll AC, Imhof SM, Kuik DJ, et al. High parental age
is associated with sporadic hereditary retinoblastoma:
10 A. C. Moll et al.

the Dutch retinoblastoma register 1862–1994. Hum
Genet. 1996;98:109–12.
11. Fletcher O, Easton D, Anderson K, et al. Lifetime
risks of common cancers among retinoblastoma sur-
vivors. J Natl Cancer Inst. 2004;96:357–63.
12. Moll AC, Imhof SM, Schouten-van Meeteren AYN,
et al. Screening for pineoblastoma in patients with
retinoblastoma. Arch Ophthalmol. 2001;120:1774.
13. Harbour JW. What is the best treatment for retinoblas-
toma? Am J Ophthalmol. 2004;138:471–3.
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Association between choroidal pigmentation and
posterior uveal melanoma in a white population. Br J
Ophthalmol. 2004;88:39–43.
15. Abel U, Koch A. The role of randomization in clini-
cal studies: myths and beliefs. J Clin Epidemiol.
1999;52:487–97.
16. Oxman AD, Guyatt GH. A consumer’s guide to sub-
group analyses. Ann Intern Med. 1992;116:78–84.
17. Lasky T, Stolley PD. Selection of cases and controls.
Epidemiol Rev. 1994;16:6–17.
18. Friedman LM, Furberg CD, De Mets
DL. Fundamentals of clinical trials. St. Louis: Mosby;
1996.
19. Seregard S. Long-term survival after ruthenium
plaque radiotherapy for uveal melanoma. A meta-­
analysis of studies including 1,066 patients. Acta
Ophthalmol Scand. 1999;77:414–7.
Further Readings
Bouter LM, Zielhuis GA, Zeegers MP. Textbook of epi-
demiology. Houten: Bohn Stafleu van Loghum; 2018.
Fletcher RH, Fletcher SW, Wagner EH. Clinical epidemi-
ology: the essentials. Baltimore: Williams & Wilkins;
1996.
Guyatt G, Rennie D, editors. Users’ guide to the medical
literature: a manual for evidence-based clinical prac-
tice. Chicago: AMA Press; 2002.
Rothman KJ. Epidemiology: an introduction. New York:
Oxford University Press; 2002.
Sackett DL, Strauss SE, Richardson WS, et al. Evidence-
based medicine. Edinburgh: Churchill Livingstone;
2000.
User’s guide to evidence-based practice. Educative series
of articles from the JAMA. www.cche.net/users-
guides/main.asp.
Website of the centre for evidence-based medicine,
Oxford, United Kingdom. www.cebm.net.
 Etiology of Cancer
Brian T. Hill
Introduction
Cancer is a pathologic accumulation of clonally
expanded cells derived from a common precur-
sor. The fundamental cause of all cancers is
genetic damage, which is usually acquired but is
sometimes congenital. In general, the genetic
dysregulation that gives rise to uncontrolled cell
proliferation results from activation of growth-­
promoting oncogenes and/or deletion/inactiva-
tion of growth-inhibiting tumor suppressor genes.
Additional contributions to carcinogenesis come
from genes that regulate programmed cell death
(apoptosis) and genes involved in DNA repair.
The most widely accepted theory of cancer devel-
opment is the Knudson “2-hit” hypothesis, which
posits that a mutation in one predisposing gene is
necessary but not sufficient for malignancy and
that only after development of a second mutation
will invasive cancer develop (Fig. 2.1) [1]. In
addition, it has become increasingly apparent that
cancer cells must evade host immune responses
and this can sometimes be exploited to treat can-
cer. In this chapter, we discuss the major catego-
ries of carcinogens and their role in the etiology
of cancers, with an emphasis on common oph-
thalmic cancers.
B. T. Hill (*)
Department of Taussig Cancer Institute, Cleveland
Clinic, Cleveland, OH, USA
e-mail: hillb2@ccf.org
© Springer Nature Switzerland AG 2019
A. D. Singh, B. E. Damato (eds.), Clinical Ophthalmic Oncology,
https://doi.org/10.1007/978-3-030-04489-3_2
2
Carcinogenic Agents
Although a clearly defined cause is not apparent
in the majority of de novo malignancies, it is well
documented that carcinogenic agents contribute
to many human cancers. These fall into several
broad groups, which can be categorized as infec-
tive (e.g., viruses), chemical (including occupa-
tional, environmental, and therapeutic),
electromagnetic radiation (i.e., ultraviolet [UV],
X-ray, gamma ray), and immunosuppressive
(HIV, immunosuppressive medications). These
are shown in Table 2.1.
Chemical Carcinogens
Several hundred chemicals have been shown to
be carcinogenic in humans. Harm from these
chemical carcinogens can be a result of occupa-
tional (asbestos, aniline dyes), environmental
(alcohol, tobacco), or iatrogenic (chemotherapy)
exposure. While many carcinogens are directly
mutagenic to DNA, most carcinogens undergo
activation after exposure to reactive metabolites
that are responsible for genetic damage.
Environmental Exposure
Of the known environmental carcinogens, per-
haps the most well-documented agent known to
11
12 B. T. Hill

Fig. 2.1 Schematic

representation of
Knudson 2-hit Sporadic cancer
hypothesis in which (2 sequential mutations acquired) Cancer
normal cell require two * * *
successive mutations to
delete both functional
copies of a given gene to
develop cancer. In
contrast, cells with
germline mutations only
* *
require a single genetic Hereditary cancer
event to develop (1 inherited mutation, 1 acquired mutation) Cancer
malignancy (*mutation)

Table 2.1 Various types of carcinogens

Chemicals Radiation Infectious Dietary Iatrogenic
Occupational UV light Virus Fat Radiation
 Arsenic X-ray  HPV Calorie Immunosuppression
 Asbestos Gamma ray  EBV Low fiber Chemotherapy
 Coal tars Nuclear radiation  KSHV
 Soot  HTLV-1
 Benzene  HEP B/C
 Vinyl chloride
Behavioral Bacteria
 H. pylori
 C. psittaci
 Tobacco Fungus
 A. flavus
 Alcohol Parasite
 Schistosoma
 Clonorchis

cause cancer is asbestos. This is a naturally
occurring mineral that has a broad range of
industrial and commercial applications, but aero-
solized fibers of asbestos are known to lodge in
small airways, causing tissue damage and signifi-
cantly predisposing exposed individuals to both
lung cancer as well as mesothelioma [2].
A number of other agents have been associ-
ated with elevated risks of various cancers
through epidemiologic studies. For example, sev-
eral agents have been implicated in lung cancer,
including heavy metals [arsenic, cadmium, chro-
mium, and nickel, as well as BCME (bischloro-
methl ether)] [3]. Aromatic amines such as
4-AMP, 4-aminobiphenyl, naphthylamine, and
benzidine are associated with an increased risk of
bladder cancer [3]. Aflatoxin and vinyl chloride
are associated with liver cancers. An exhaustive
list of known environmental carcinogens is
beyond the scope of this text but should be con-
sidered when obtaining the occupational and
social history of patients with newly diagnosed
cancer.
Behavioral Exposure
Tobacco
Tobacco is responsible for over 30% of the cancer
deaths and represents the single most common
cause of preventable cancer. Cigarettes as well as
smokeless tobacco are associated with cancers of
2 Etiology of Cancer
multiple organs, including the oral cavity, phar-
ynx, larynx, lung, esophagus, stomach, pancreas,
colon, rectum, kidney, bladder, ureter, and cervix.
Over 60 carcinogens have been identified in
tobacco, with the highest carcinogenic potency
attributed to polycyclic aromatic hydrocarbons,
nitrosamines, and aromatic amines [4]. The risk of
tobacco-associated cancer is proportional to total
lifetime cigarette smoke exposure. The risk of lung
cancer among long-term heavy smokers is approx-
imately 10–20 times greater than non-smokers.
Alcohol
Excessive and repeated alcohol intake is associ-
ated with liver, rectal, and breast cancers.
Interestingly, simultaneous exposure to alcohol
and cigarette smoke results in a synergistic
increase in the risk of oral cancer, with a relative
risk relative to non-smoking, those who abstain
from alcohol of over 35-fold for the heaviest con-
sumers. Similar tobacco-alcohol interactions are
also known for esophageal cancer.
Electromagnetic Radiation
Ultraviolet Light
Ultraviolet light B (UV-B) has a wavelength
between 280 nm and 320 nm and is the primary
oncogenic form of UV light, whereas ultraviolet
A (UV-A, wavelength 320–400 nm) has insuffi-
cient energy to induce DNA damage, and ultra-
violet light C (UV-C, 200–280 nm) is absorbed
by the atmospheric ozone and therefore not a sig-
nificant cause of environmental cancer.
UV light induces cancer by the formation of
pyrimidine dimers in affected DNA, which can
result in inactivation of tumor suppressor genes
such as p53. Patients with the autosomal recessive
disorder, xeroderma pigmentosum (XP), lack the
ability to repair DNA damage caused by UV light,
owing to a defect in the nucleotide excision repair
pathway (NER), thereby resulting in an increased
risk of skin cancer that is at least 2000-fold rela-
tive to unaffected individuals [5, 6].
UV light from sun exposure is associated with
increased incidence of several types of skin can-
13
cer, including squamous cell carcinoma, basal
cell carcinoma, and melanoma [7]. In the eye,
UV exposure increases the risk of ocular surface
squamous neoplasia (OSSN), which includes
dysplasia, carcinoma in situ, and squamous cell
carcinoma of the conjunctiva or cornea.
In the case of uveal melanoma, sunlight expo-
sure has not been implicated as a cause of this con-
dition, known risk factors including Caucasian
race, light skin color, blond hair, and blue eyes [8].
I onizing Radiation (X-Rays
and Gamma Rays)
In the early twentieth century, it was recognized
that radiation can cause tissue damage and vari-
ous cancers, such as acute leukemia and skin can-
cer. Ionizing radiation causes cell death by DNA
damage, leading to the induction of apoptosis and
cell cycle arrest. In general, a dose-response rela-
tionship is well described, with both duration and
intensity of radiation affecting the relative risk of
developing cancer.
Sources of ionizing radiation include occupa-
tional exposure (e.g., X-rays) and exposure to
nuclear power or atomic weapons. Iatrogenic
sources of radiation for cancer treatment also
cause secondary malignancies. The best-­described
data documenting radiation-induced cancers
comes from the study of the survivors of the
Chernobyl nuclear power plant disaster as well as
the Hiroshima and Nagasaki atomic bomb events
of World War II [9, 10]. In the latter case, the rela-
tive risk of all cancers was 1.53 and included mul-
tiple solid tumors arising in the breast, lung,
esophagus, stomach, and GU tract. All these solid
tumors had a relative risk of between 1.2 and 2.4.
In this population, a notable outlier was leukemia,
which had a relative risk of 5.6 [9].
Infections Agents
A number of infectious agents are carcinogenic.
The mechanisms by which each pathogen causes
cancer are diverse and include induction of
genomic instability as a result of chronic
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