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Prevention and Management
of Acute and Late Toxicities
in Radiation Oncology

Management of Toxicities in
Radiation Oncology
Gokhan Ozyigit
Ugur Selek
Editors

123
Prevention and Management of Acute
and Late Toxicities in Radiation Oncology
Gokhan Ozyigit • Ugur Selek
Editors

Prevention and
Management of Acute
and Late Toxicities
in Radiation Oncology
Management of Toxicities in Radiation
Oncology
Editors
Gokhan Ozyigit Ugur Selek
Chair and Professor Chair and Professor
Department of Radiation Oncology Department of Radiation Oncology
Hacettepe University, Faculty of Medicine Koc University, Faculty of Medicine
Ankara Istanbul
Turkey Turkey

ISBN 978-3-030-37797-7    ISBN 978-3-030-37798-4 (eBook)

https://doi.org/10.1007/978-3-030-37798-4

© Springer Nature Switzerland AG 2020

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 illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, expressed or implied, with respect to the material contained herein or for any
errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
To our patients from whom we have learned
to excel.
Preface

The role of radiation oncologists in multidisciplinary care is gradually becoming

essential and more involved in patient care in the current era of improving technol-
ogy and individualized management. As the patients’ awareness and their participa-
tion in treatment decisions increase, the clinicians have been discussing more and
more about the quality of life issues in addition to outcome matters. Therefore,
acute and late toxicity management is more crucial than ever in our clinical practice
in comparison to a decade ago. We have planned to provide a structured and com-
prehensive book to deliver a current evidence-based and/or practice-proven man-
agement tool to feel confident in prescribing the innovative treatments with a goal
of functionally unimpaired patient during and after radiotherapy.
In this context, our book covers prevention and current management of acute and
late toxicities of radiation therapy in a wide range of malignancies, while each chap-
ter focuses on a particular anatomic site with information on normal sectional anat-
omy, contouring of target volumes and organs at risk, dose constraints, the
pathophysiology of radiation toxicity, and treatment approaches for each potential
toxicity; given under the variability of planning and delivery of intensity-modulated
radiation therapy, volumetric modulated arc therapy, stereotactic radiosurgery, and
stereotactic body radiotherapy.
Overall, this book will enable the selection of appropriate, evidence-based man-
agement options in individual patients who experience radiation toxicities, taking
into account the organ-specific pathophysiology of radiation injury, for practicing
clinical and radiation oncologists, radiotherapists, fellows, residents, and nurses.
We hope to encourage the clinicians through practical and theoretical aspects of
acute and late toxicity management in modern radiation oncology, and we extend
our most sincere gratitude to our patients, who stand side by side with us to fight
with their cancer, and who teach us invaluable lessons to brace our faith to
succeed.

Ankara, Turkey Gokhan Ozyigit

Istanbul, Turkey  Ugur Selek

vii
Acknowledgments

The editors are indebted to Gesa Frese and Wilma McHugh from Springer DE and
Niveka Somasundaram and Mariesha Justin from SPi Global/Springer Nature for
their assistance in preparing Prevention and Management of Acute and Late
Toxicities in Radiation Oncology. We extend our most sincere gratitude to our col-
leagues and friends at Hacettepe University, Koç University, and Baskent University
as well as our families.

ix
Contents

1 Toxicity Management for Central Nervous System Tumors

in Radiation Oncology ��������������������������������������������������������������������������������   1
Guler Yavas and Gozde Yazici
2 Toxicity Management for Head and Neck Tumors
in Radiation Oncology-I������������������������������������������������������������������������������ 59
Sezin Yuce Sari
3 Toxicity Management for Head and Neck Tumors in Radiation
Oncology-II�������������������������������������������������������������������������������������������������� 85
Pervin Hurmuz
4 Toxicity Management for Thorax Tumors in Radiation Oncology �������� 107
Teuta Zoto Mustafayev and Banu Atalar
5 Toxicity Management for Upper Abdomen Tumors
in Radiation Oncology �������������������������������������������������������������������������������� 171
Zumre Arican Alicikus and Barbaros Aydin
6 Toxicity Management for Pelvic Tumors in Radiation Oncology������������ 231
Nilufer Kılıc Durankus, Duygu Sezen, Ugur Selek, and Yasemin
Bolukbasi
7 Toxicity Management for Other Sites in Radiation Oncology���������������� 267
Cagdas Yavas and Melis Gultekin

xi
Toxicity Management for Central
Nervous System Tumors in Radiation 1
Oncology

Guler Yavas and Gozde Yazici

1.1 Anatomy

The central nervous system (CNS) consists of the brain and the spinal cord (SC).
The spinal cord is a single structure, whereas the adult brain can be defined by four
major regions: the cerebrum, the diencephalon, the brain stem, and the cerebellum.
The main functions of the CNS include receiving, processing, and responding to
sensory information.

1.1.1 Brain

Embryologically, the brain is composed of the prosencephalon (forebrain), the

mesencephalon (midbrain), and the rhombencephalon (hind brain). The prosen-
cephalon forms the two hemispheres (telencephalon) and the diencephalon (inter-
brain) during the later stages of embryogenic life [1]. The weight of the brain
changes from birth through adulthood. At birth the brain weighs less than 400 g,
but by the beginning of the second year of life it weighs around 900 g, and the adult
brain weighs between 1250 and 1450 g [2]. The cerebrum is the largest region of
the human brain and the two hemispheres together account for 85% of the brain
mass. The interbrain (diencephalon) is the part that links the two hemispheres of
the brain. The diencephalon has four regions: the epithalamus, thalamus,

G. Yavas
Faculty of Medicine, Department of Radiation Oncology, Selcuk Meram University,
Konya, Turkey
G. Yazici (*)
Hacettepe University, Faculty of Medicine, Department of Radiation Oncology,
Ankara, Turkey
e-mail: yazicig@hacettepe.edu.tr

© Springer Nature Switzerland AG 2020 1

G. Ozyigit, U. Selek (eds.), Prevention and Management of Acute and Late
Toxicities in Radiation Oncology, https://doi.org/10.1007/978-3-030-37798-4_1
2 G. Yavas and G. Yazici

hypothalamus, and subthalamus. Each cerebral hemisphere is divided into five

lobes entitled as: the frontal, parietal, temporal and occipital lobes, and the insula.
The surfaces of the cerebral hemispheres are formed by highly folded collection of
gray matter, few millimeters in width, named as the cerebral cortex. Although it is
only 2–4 mm in thickness, the gray matter accounts for 40% of total brain mass.
The inner region of the cortex is a central core of white matter that consists solely
of neuronal pathways. Deep within the cerebral white matter is an important region
of the cerebrum, a group of sub-cortical gray matter known as “basal nuclei.” The
basal nuclei are composed of the caudate nucleus, putamen, and globus pallidus
which are important regulators of skeletal muscle movements [3].
The cavities within the cerebral hemispheres are called as the right and the left
lateral ventricles, which communicate with the third ventricle via interventricular
foramen (foramen of Monro). The first and the second ventricles lie within the
hemispheres of the brain, and the third ventricle is located in the interbrain. The
space between the pons, bulbus, and the cerebellum is called as the fourth ventricle.
These ventricles are continuous with one another and with the central canal of the
spinal cord. The inner surface of the ventricles is lined by ependymal cells, and
protruding into each ventricle is a choroid plexus which functions in the production
of cerebrospinal fluid (CSF). About 300–400 mL of CSF is produced daily. The
CSF forms a liquid cushion for the brain, and helps to nourish the brain.
The brain and spinal cord is covered by three membranes which are called the
meninges. The dura mater is the outermost layer of the meninges, lying directly
underneath the bones of the skull and vertebral column. Inside the dura mater there
is the arachnoid mater. Arachnoid mater consists of layers of connective tissue. It is
avascular, and does not receive any innervation. Underneath the arachnoid mater is
the sub-arachnoid space which contains CSF. The pia mater is located underneath
the sub-arachnoid space. It is very thin, and is tightly adhered to the surface of the
brain and spinal cord. It follows the contours of the brain. Like the dura mater, pia
mater is highly vascularized with blood vessels perforating through the membrane
to supply the underlying neural tissue. Therefore the dura mater and pia mater are
very sensitive to pain.

1.1.2 Brain Stem

The brain stem (BS) is composed of the mesencephalon, the pons, and the medulla
oblongata. The BS begins inferior to the thalamus and is positioned between the
cerebrum and the spinal cord. The mesencephalon is a relatively narrow band of the
BS surrounding the cerebral aqueduct (of Sylvius), extending from the diencepha-
lon to pons. The pons is thicker portion of the brainstem, and is about 25–30 mm in
length. The pons bulges from the midbrain and medulla and is separated from them
by the superior and inferior pontine sulci. Posteriorly it is surrounded by the cere-
bellum, and they unite through the middle cerebellar peduncles. The medulla oblon-
gata is the caudal portion of the BS [2].
1 Toxicity Management for Central Nervous System Tumors in Radiation Oncology 3

1.1.3 Spinal Cord

The spinal cord runs through the spinal canal from the cranial top portion of the
atlas down to the L1–2 intervertebral disc in adults. It may extend below to L3 ver-
tebral body in children. The spinal cord ends at the level of the L1 vertebral body,
and the roots extend caudally in the cauda equina to exit in the appropriate interver-
tebral foramina. It is 45 cm long, 30 g in weight, and approximately 1 cm in diam-
eter [2, 4]. The spinal cord in the spinal canal is surrounded by meninges. Dorsal
and ventral roots course through the intervertebral foramina.

1.1.4 Orbita (Eye, Retina, Lens)

The orbits are conical structures surrounding the organs of vision. The shape of the
orbit resembles a four-sided pyramid. Orbit supports the eye and it protects this vital
structure. The volume of the orbital cavity in an adult is roughly about 30 cc.
The globe of the eye, or bulbus oculi, is a bulb-like structure consisting of a wall
enclosing a fluid-filled cavity. The adult eyeball is spherical in shape, and is 24 mm
in length antero-posteriorly. The anterior segment of the eyeball consists of the
structures ventral to the vitreous humor, including the cornea, iris, ciliary body, and
lens (crystalline lens). The pupil serves as an aperture which is adjusted by the sur-
rounding iris, acting as a diaphragm that regulates the amount of light entering the
eye. Both the iris and the pupil are covered by the convex transparent cornea. The
cornea is the major refractive component of the eye due to the huge difference in
refractive index across the air-cornea interface. The lens is a transparent, biconvex
structure. Lens and the cornea refract light to focus on the retina. The lens is made
of transparent proteins called “crystallins.” It is approximately 5 mm thick and has
a diameter of about 9 mm for an adult [5].
The posterior segment of the eyeball is located posteriorly to the lens, and it
includes the anterior hyaloid membrane, the vitreous humor, the retina, and the
choroid. The retina is the light-sensitive tissue that lines thinner surface of the eye.
In embryogenesis both the retina and the optic nerves originate from the diencepha-
lon and should therefore be considered as part of the CNS.

1.1.5 Optic Pathway

The optic pathway consists of the series of cells and synapses that carry visual infor-
mation from the environment to the brain for processing. It includes the retina, optic
nerve, optic chiasm, optic tract, lateral geniculate nucleus, optic radiations, and stri-
ate cortex.
The optic nerve is the second cranial nerve, responsible for transmitting the
sensory information for vision. The optic nerves are surrounded by the cranial
meninges. The optic nerves progress from the posterior aspect of the globe,
4 G. Yavas and G. Yazici

angle up through the optic canals, and unite to form the optic chiasm. At the
chiasm, fibers from the nasal (medial) half of each retina cross over to the con-
tralateral optic tract, while fibers from the temporal (lateral) halves remain ipsi-
lateral. Each optic tract travels to its corresponding cerebral hemisphere to reach
the lateral geniculate nucleus. From the lateral geniculate nucleus, the signals
continue to the primary visual cortex, where further visual processing takes
place [6].

1.1.6 Hippocampus

The hippocampus has a distinctive, curved shape that has been likened to the
sea-­
horse monster of Greek mythology and the ram’s horns of Amun in
Egyptian mythology. The literature describes considerable age and disease-
specific variability in hippocampal size (range 2.8–4.0 cm3) and location. The
hippocampus is located in the medial temporal lobe of the brain. It is a paired
structure, with mirror-­image halves in the left and right sides of the brain. It
consists of ventral and dorsal portions, both of which share similar composi-
tion but are parts of different neural circuits. It belongs to the limbic system
(Latin limbus = border) which includes the hippocampus, cingulate cortex,
olfactory cortex, and amygdala. It plays important roles in long-term memory
and spatial navigation [7].

1.1.7 Pituitary Gland

The pituitary gland (hypophysis cerebri) is a small organ situated in a depression

of the sphenoid bone at the base of the skull called the “sella turcica.” Anatomically,
the pituitary gland is related superiorly to the optic chiasm, inferiorly to the sphe-
noid sinus, and laterally, on either side, to the cavernous sinus and the structures
contained within. The pituitary gland measures approximately 10 × 13 × 6 mm,
weighs about 500 mg, and occupies most of the volume of the sella turcica. The
gland consists of two anatomically and functionally distinct regions, the anterior
lobe (adenohypophysis) and the posterior lobe (neurohypophysis). Between these
lobes lies a small sliver of tissue called the intermediate lobe. The adenohypophy-
sis is originated from the Rathke’s pouch, an ectodermal diverticulum from the
roof of the stomodeum, whereas the neurohypophysis is derived from the dien-
cephalon. The adenohypophysis is divided into the pars anterior (anterior lobe)
and the pars intermedia (intermediate lobe). The neurohypophysis consists mainly
of the “pars posterior” (posterior lobe), part of the infundibular stem and the
median eminence. The adenohypophysis secretes several hormones (somatotro-
pin, gonadotropins, thyrotropin, adrenocorticotropin, prolactin, lipotropic hor-
mones, and endorphins), whereas the posterior pituitary essentially stores
vasopressin and oxytocin, secreted by the supraoptic and paraventricular nuclei of
the hypothalamus [8].
1 Toxicity Management for Central Nervous System Tumors in Radiation Oncology 5

1.2 Contouring

Over the past decades a great deal of progress has been made in the field of radiation
oncology as the profession has switched from 2-dimensional to 3-dimensional to
intensity modulated and stereotactic techniques. Radiation-related side effects can
be improved by avoiding critical structures called organs at risk (OARs) with the
help of these technical developments. The comprehensive identification and delin-
eation of OARs are vital to the quality of radiation therapy treatment planning and
the safety of treatment delivery. The delineation of intracranial OARs is one of the
most crucial points in the planning of brain tumors since RT to the brain may cause
serious side effects. Moreover, accurate delineation of OARs is essential for the
inverse-planning process of intensity modulate radiotherapy (IMRT).
In some situations changes in anatomy because of the possible tumor extension
necessitates a basic understanding of normal anatomy. During the delineation of
intracranial OAR using contrast-enhanced computed tomography (CT) scans
together with magnetic resonance imaging (MRI) allows better visualization and
definition when compared to using CT alone. For example, in order to delineate
spinal cord accurately, especially for stereotactic planning, a high-resolution
T2-weighted MRI is recommended. Moreover during the delineation of optic chi-
asm and optic nerves using a high-resolution T1- or T2-weighted MRI rather than
planning CT helps better and easier delineation. It is very important to contour on
appropriate density windows for each tissue. The structures should be reviewed in
the coronal and sagittal planes when contouring on axial slices to verify complete-
ness of coverage in all dimensions [9].

1.2.1 Brain

The delineation of the brain consists of the small brain vessels, cerebellum, CSF and
excludes the brainstem and large cerebellar vessels, including the sigmoid sinus,
transverse sinus, and superior sagittal sinus (Figs. 1.1 and 1.2). CT bone settings in
addition to brain soft tissue 350/40 WW/WL-settings are recommended. The carotid
canal and cavernous sinus which are located in the middle cranial fossa are not rec-
ommended to be included [9–11].

1.2.2 Brain Stem

The cranial boarder of the brainstem (BS) is defined as bottom of optic tract or the
disappearance of posterior cerebral artery which is the bottom of the lateral ventri-
cles, and the caudal border is defined as the tip of the dens of C2 (cranial border of
the spinal cord). For delineation of BS, MRI is recommended; however, the bottom
section of the lateral ventricles is easily visible on both MRI and CT (Fig. 1.3).
Visualization of sagittal plane may be helpful when defining the BS. From cranial
to caudal, BS may be divided into three parts during contouring: the midbrain, pons,
6 G. Yavas and G. Yazici

Fig. 1.1 Delineation of the brain as normal structure

and medulla oblongata [10–12]. Cochlea should also be delineated in pontocerebel-

lar region (Fig. 1.4).

1.2.3 Spinal Cord

For delineation of the spinal cord accurately, especially for stereotactic planning, a
high-resolution T2-weighted MRI or CT myelogram is recommended. The spinal
cord should be delineated instead of whole spinal canal. For CNS tumors, the cra-
nial border of the spinal cord is defined at the tip of the dens of C2, which is the
caudal border of the BS, and the caudal border at the upper edge of T3 [11].
1 Toxicity Management for Central Nervous System Tumors in Radiation Oncology 7

Fig. 1.2 Delineation of the cerebellum as normal structure

8 G. Yavas and G. Yazici

Fig. 1.3 Delineation of the brain stem as normal structure

1 Toxicity Management for Central Nervous System Tumors in Radiation Oncology 9

Fig. 1.4 Delineation of the cochlea as normal structure

10 G. Yavas and G. Yazici

1.2.4 Orbita (Eye, Retina, Lens)

Cornea can be easily delineated using 2–3 mm brush on both MRI and CT scans
(Fig. 1.5). Lens, which is up to 10 mm in diameter, is a biconvex, avascular, non-­
innervated, encapsulated body composed entirely of epithelial cells and fibers. The
lens can be easily delineated on CT [10, 11].
The posterior segment of the eyeball includes the anterior hyaloid membrane,
vitreous humor, retina, and choroid [10, 11]. The retina is approximately 0.25 mm
thick, and covers the posterior 5/6 of the globe, extending nearly as far as the ciliary
body. The retina can be delineated on both MRI and CT using a 3 mm brush. The
anterior border of the retina is between the insertion of the medial rectus muscle and
the lateral rectus muscle, posterior to the ciliary body. The optic nerve is excluded
from this contour. On axial images the anterior limit of the retina is between the
insertion of the medial rectus muscle and the insertion of the lateral rectus muscle,
posteriorly to the ciliary body [10, 11, 13]. Lacrimal glands should also be delin-
eated (Fig. 1.6).

Fig. 1.5 Delineation of the orbita

1 Toxicity Management for Central Nervous System Tumors in Radiation Oncology 11

Fig. 1.6 Delineation of the lacrimal glands

1.2.5 Optic Pathway

The optic nerve is thin, usually 2–5 mm thick, and is clearly identifiable on CT. Using
both CT and T1- and T2-weighted imaging/fast fluid-attenuated inversion recovery
imaging of MRI is recommended for the accurate delineation of the optic nerve.
Depending on the orientation of the scan plane relative to the brain, the optic nerve
and chiasm can appear on multiple images (Fig. 1.7). The optic nerves should be
delineated all the way from the posterior edge of the eyeball, through the bony optic
canal to the optic chiasm. It is crucial to delineate the optic apparatus in continuity,
since gaps in the structures will result in omission of the dose from the missing
volume for that structure’s dose–volume histogram.
The optic chiasm is usually 2–5 mm thick, and is located in the sub-arachnoid
space of the supracellar cistern 1 cm superior to pituitary gland. Internal carotid
artery forms the lateral boarder of the optic chiasm. It is demarcated inferiorly by
the third ventricle. The pituitary stalk is the most important landmark since it is
located just behind the crossing of the fibers. Pituitary gland is easily visible in
T1-weighted MRI images because it shows hyperintense signals. Although it can
be visible on both CT and MRI scans, a T1-weighted MRI with axial, sagittal, and
coronal sections is recommended for better delineation [10, 11, 13].
12 G. Yavas and G. Yazici

Fig. 1.7 Delineation of optic pathway

1 Toxicity Management for Central Nervous System Tumors in Radiation Oncology 13

1.2.6 Hippocampus

During the recent years, the accurate delineation of the hippocampus (dentate gyrus)
has been increasingly important since both the clinical and preclinical evidence sug-
gest that irradiation to hippocampal dentate gyrus can cause neurocognitive impair-
ment. The hippocampus is delineated as the gray matter medial to the medial
boundary of the temporal horn of the lateral ventricle bordered medially by the
quadrigeminal cistern as described by Gondi et al. [14] (Fig. 1.8). At the level of the
curve of the temporal horn which is also called as uncal recess, the hippocampus is
easily visible because it is the gray matter included in the curve and is bounded
anteriorly, laterally, and medially by the CSF in the temporal horn. Amygdala,
which is a gray matter located medially to the temporal horn of the lateral ventricle
is easily distinguished from the hippocampus at this level. The amygdala should be
excluded from the contour of the hippocampus [13]. The boundary between the hip-
pocampus and the amygdala is not clearly visible in the more caudal slices. The
hippocampus is mainly composed of gray matter therefore for the delineation of

Fig. 1.8 Delineation of the hippocampus

14 G. Yavas and G. Yazici

hippocampus T1-weighted MRI scan is recommended. Very thin slice-thickness

(1–2 mm) is necessary to visualize the hippocampus. In sagittal view it is easy to
visualize “banana” shape hippocampus.

1.2.7 Pituitary Gland

The pituitary gland is oval-shaped structure which is craniocaudally up to 12 mm,

and is located in the sella turcica. The pituitary gland is one of the smallest OARs;
therefore, it is difficult to visualize it on CT images (Fig. 1.9). The lateral border of
the pituitary gland is formed by the cavernous sinuses. The inner part of the sella
turcica can be used as surrogate anatomical bony structure. It is better to define the
pituitary gland in the sagittal images [11, 13].

1.3 Pathophysiology

Despite the significant advances in limiting overt neurotoxicity, cognitive dysfunc-

tion is still a major problem particularly for childhood CNS tumors. During the last
decades the researchers focused on identifying the primary cause of tissue damage.
However, the data indicates that the response of the CNS to RT is a continuous and
interacting process. Although the exact mechanism is not clear, the clinical and
scientific evidence helps us to understand the pathophysiology of radiation-induced
brain injury. The CNS is particularly more vulnerable to ionizing irradiation when
compared to other tissue types. The ionizing irradiation may cause direct or indirect
DNA damage, but it may also cause a metabolic stress, which is very harmful for the
CNS [15]. Understanding the mechanisms of radiation-induced CNS toxicity may
help to develop strategies to either increase the radiation tolerance or treat CNS
alterations caused by ionizing radiation.
The etiology of radiation-induced CNS toxicity is a multifactorial process that
is influenced by patient-related factors including age, medical comorbidities, psy-
chological and genetic predispositions, characteristics of the underlying malig-
nancy, and any additional injuries caused by other treatment modalities such as
surgery and chemotherapy [16]. The radiation-induced CNS injury is described in
three phases from the radiobiological perspective: acute (within days to weeks
after irradiation), early delayed (within 1–6 months post-irradiation), and late or
late delayed (>6 months post-irradiation). The Radiation Therapy Oncology Group
(RTOG) describes acute injury based on the clinical time expression as the injury
occurring during or within 90 days of RT. Acute injury includes seizure, coma, and
paralysis which are considered to be secondary to edema and disruption of the
blood–brain barrier (BBB). The corticosteroid treatment improves the acute neuro-
logic changes. Late toxicities include headache, lethargy, and severe CNS dysfunc-
tions such as partial loss of power and dyskinesia, and coma, and occur after
1 Toxicity Management for Central Nervous System Tumors in Radiation Oncology 15

Fig. 1.9 Delineation of the pituitary gland

16 G. Yavas and G. Yazici

90 days of RT. Radiation-induced late toxicities are probably associated with

increased intracranial pressure caused by the persistent vasogenic edema resulting
from BBB damage [17].
Larger fraction sizes and compressed fractionation schedules are known to con-
tribute negatively to the CNS toxicity. RTOG prospectively compared different
whole brain RT fractionation schedules in patients with symptomatic brain metasta-
ses with respect to the impact on overall survival [18]. Multiple fractionation sched-
ules ranging from 10 Gy in a single fraction to up to 40 Gy delivered over 20
fractions were delivered. Most fractionation schedules were not significantly differ-
ent in terms of overall survival times, except the delivery of 10 Gy in a single frac-
tion. 10 Gy to the entire brain in single fraction was determined to be significantly
detrimental. It can be interpreted from these data that, above a certain threshold,
larger fractionation sizes has detrimental impact on radiation-induced brain injury
when the treatment volumes are equivalent.
Among the varieties of radiation-induced CNS toxicities, it is the late delayed
effects that cause severe and irreversible neurological consequences. After the expo-
sure of ionizing radiation, late delayed effects within the CNS have been attribut-
able to both the parenchymal and vascular injury involving the oligodendroglial
cells, neuronal progenitors, and vascular endothelial cells [19]. Late delayed toxic-
ity of CNS irradiation may be presented with different scenarios including demye-
lination, proliferative and degenerative glial reactions, endothelial cell loss, and
capillary occlusion. Therefore a single mechanism cannot explain these complex
alterations. At least four factors contribute to the development of CNS toxicity: (1)
damage to vessel structures; (2) deletion of oligodendrocyte-2 astrocyte progenitors
(O-2A) and mature oligodendrocytes; (3) deletion of neural stem cell populations in
the hippocampus, cerebellum, and cortex; (4) generalized alterations of cytokine
expression [20]. These four contributing factors can be explained with (1) the vas-
cular hypothesis, (2) parenchymal hypothesis, (3) the dynamic interactions between
multiple cell type’s hypothesis, and (4) molecular mechanisms.

1.3.1 Vascular Hypothesis

The vascular hypothesis argues that vascular damage leads to ischemia with second-
ary white matter necrosis. Death of endothelial cells is an early event in small ves-
sels which may be responsible for the initial edema [21, 22]. After the early changes
of the vascular wall there is progressive loss of endothelia. Thrombocytes adhere to
exposed matrix which leads to the formation of thrombi. Thrombi occur within
weeks and months after RT. After this, abnormal endothelial proliferation is
observed. In the acute and subacute phases of vascular damage the most prominent
findings are altered permeability of the vascular wall and BBB breakdown, and in
the late phase the important findings are telangiectasia, hyalinosis, and fibrinoid
deposits in the vessel wall.
1 Toxicity Management for Central Nervous System Tumors in Radiation Oncology 17

1.3.2 Parenchymal Hypothesis

1.3.2.1 Oligodendrocytes
Since the white matter necrosis after RT is associated with demyelination, the
parenchymal hypothesis initially focused on the oligodendrocytes as they are
required for the formation of myelin sheaths. The progenitor cells of oligodendro-
cytes, known as O-2A cells, give rise to mature oligodendrocytes. It has been pro-
posed that the radiation-induced loss of O-2A progenitor cells leads to failure to
replace oligodendrocytes that eventually results in demyelination and white matter
necrosis. It has been shown that the oligodendrocytes are the most radiosensitive
type of glial cells, with cell death occurring rather early after relatively low doses of
irradiation. Therefore, the data seemed to be consistent with the white matter selec-
tivity of radiation-induced brain injury. However, the time course of oligodendro-
cyte depletion after irradiation was not consistent with that of white matter necrosis
during the development of late delayed effects [19, 20].

1.3.2.2 Astrocytes
Astrocytes have many functions besides their supportive role, including modula-
tion of synaptic transmission and secretion of neurotrophic factors such as basic
fibroblast growth factor to promote neurogenesis. Astrocytes are vital for the
protection of endothelial cells oligodendrocytes, and neurons from oxidative
stress. It has been suggested that hippocampal astrocytes are capable of regulat-
ing neurogenesis by instructing the stem cells to adopt a neuronal fate [23]. In
response to injury, astrocytes exhibit two common reactions: in acute phase cel-
lular swelling (radiation-­induced edema), and in chronic phase hyperplasia and
hypertrophy. In chronic phase astrocytes undergo proliferation, exhibit hypertro-
phic nuclei/cell bodies, and show increased expression of glial fibrillary acidic
protein (GFAP) [24–26]. These reactive astrocytes secrete a host of pro-inflam-
matory mediators such as cyclooxygenase (Cox)-2 and the intercellular adhesion
molecule (ICAM)-1, which lead to the infiltration of leukocytes into the brain via
BBB breakdown [25–27].

1.3.2.3 Microglia
Microglia are the immune cells of the brain. After injury, microglia become acti-
vated. Activated microglia can proliferate, phagocytose, and exacerbate the injury
by the production of reactive oxygen species (ROS), lipid metabolites, and hydro-
lytic enzymes. Although microglial activation plays an important role in phagocyto-
sis of dead cells, sustained activation is believed to contribute to a chronic
inflammatory state. In-vitro studies suggested that activated microglia leads to a
remarkable increase in expression of pro-inflammatory genes TNFα, IL-1β, IL-6
and Cox-2, and the chemokines. In particular, excessive generation of ROS from the
injured and/or pro-inflammatory cells has been implicated in the development of
late delayed effects of the ionizing radiation [27–29].
18 G. Yavas and G. Yazici

1.3.2.4 Neurons
The neurons, which are located in the gray matter, were initially thought to be a
radioresistant. Therefore the neurons were believed to play no role in radiation-­
induced CNS injury. However, studies have demonstrated radiation-induced changes
in hippocampal cellular activity, synaptic efficiency/spike generation, and neuronal
gene expression [30–32]. In addition, the chronic and progressive cognitive dys-
function following cranial irradiation was shown in both children and adult patients
in clinical studies; therefore, the neurons should be sensitive to radiation.

1.3.3 Neuronal Stem Cells/Neurogenesis

The hippocampus plays important roles in the consolidation of information from

short-term memory to long-term memory, and in spatial memory. The dentate gyrus,
which is a part of hippocampus is a highly dynamic structure and a major site of
postnatal/adult neurogenesis. Residents in the hippocampus are neuronal stem cells,
self-renewing cells capable of generating neurons, astrocytes, and oligodendroglio-
cytes. High doses of radiation produce overt histopathological changes such as
demyelination and vasculopathies within the brain parenchyma, but lower doses
produce cognitive dysfunction without inducing obvious morphological changes.
Although the pathogenesis of radiation-induced cognitive dysfunction is unknown,
recent studies suggest that it may involve impaired neurogenesis within the sub-
granular zone (SGZ) of the dentate gyrus [19, 33, 34].

1.3.4  ynamic Interactions Between Multiple Cell Types

D
Hypothesis

The radiation-induced late CNS injury is a dynamic process between the multiple
cell types of the CNS. Oligodendrocytes, astrocytes, microglia, neurons, and vas-
cular endothelial cells are not only passive bystanders that merely die from radia-
tion damage but rather act as participants in an orchestrated response to radiation
injury [28, 35].

1.3.5 Molecular Mechanisms

There are many suggested molecular mechanisms involved in the radiation-induced

CNS toxicity including: (a) apoptosis and neurogenesis inhibition, (b) excessive
production of cytokines and chemokines, (c) VEGF, hypoxia and blood–brain bar-
rier disruption, (d) radiation-induced ROS generation.

1.3.5.1 Apoptosis and Neurogenesis Inhibition

Radiation-induced apoptosis is primarily related to mitochondrial damage followed
by caspase activation. In addition, ATM gene is required for the regulation of
1 Toxicity Management for Central Nervous System Tumors in Radiation Oncology 19

apoptosis in some part of the brain including hippocampal dentate gyrus, external
granular layer of the cerebellum and retina. In preclinical studies it has been dem-
onstrated that apoptosis occurs in the young adult rat brain after ionizing radiation,
and leads to damage in hippocampal neurons which eventually is associated with
cognitive decline [20, 36, 37].

1.3.5.2 Excessive Production of Cytokines and Chemokines

Among the numerous pro-inflammatory cytokines and chemokines IL-1, IL-6,
TNF-α, and TGF-β are the ones that are excessively produced immediately after
radiation exposure to brain tissue [20]. Although there are many studies providing
the evidence that the expression of TNF- α is directly activated by ionizing radia-
tion, limited evidence is available with respect to the pathways describing the
TNF-α gene induction in response to radiation [38]. All of these cytokines and che-
mokines in the irradiated tissue perpetuate and augment the inflammatory response
for long periods of time, causing to possible chronic inflammation and radiation-­
induced CNS injury.

1.3.5.3 VEGF, Hypoxia, and Blood–Brain Barrier Disruption

The endothelial cell density after RT is reduced which gradually diminishes the
integrity of BBB. This causes vasogenic edema, inflammation, and tissue hypoxia.
Hypoxia causes induction of HIF-1α and VEGF. VEGF augments the vascular per-
meability which eventually causes disruption of BBB, worsening vasogenic edema,
inflammation, and tissue hypoxia. All of these cascades further increase the VEGF
concentrations. Eventually VEGF concentrations become sufficient to increase
endothelial proliferation and angiogenesis which leads to a dramatic increase in
endothelial cells. This situation is referred as “conditional renewal.” All of these
cascades end with white matter necrosis. Reports suggesting that anti-VEGF ther-
apy can normalize BBB function in microvessels damaged during radiosurgery in
the human brain and suggest that manipulating the VEGF signaling cascade may be
a useful strategy for mitigating late delayed injuries resulting from brain radiation
as well [19, 39].

1.3.5.4 Radiation-Induced ROS Generation

Reactive oxygen species (ROS) include free radicals, oxygen ions, and both inor-
ganic and organic peroxides. ROS are highly reactive since they have unpaired
electrons in their shells. In normal situation, the antioxidant systems protect cells
against oxidative damage. However, under stress, ROS levels can increase dramati-
cally, overwhelming antioxidant systems and resulting in significant injury to tis-
sues. This condition is called as “oxidative stress.” Increased levels of ROS might
arise from macrophages, infiltrating activated leukocytes, and neurons. Tissue
hypoxia resulting from vascular damage is another source of ROS generation.
Moreover pro-­inflammatory cytokines and growth factors increase intracellular
ROS generation [19].
The brain is very vulnerable to oxidative stress. When compared to other cells,
neurons and glial cells contain relatively low levels of antioxidant enzymes
20 G. Yavas and G. Yazici

including catalase, glutathione peroxidase, and superoxide dismutase (SOD).

Additionally, myelin membranes contain relatively high levels of peroxidizable
fatty acids which make them highly susceptible to ROS. Strategies to block effector
molecules or to reduce oxidative stress are attractive approaches for mitigating
radiation-­induced toxicity [19, 39].

1.3.5.5 Brain
Radiation-induced brain toxicity has been classified into three phases: acute, early
delayed (subacute), and late delayed injury. These phases were first described by
Sheline [40]. Acute brain injury occurs during and/or in days to weeks after irradia-
tion. Early delayed brain injury is seen 1–6 months post-irradiation; however, some
other researchers consider this time course as 6–12 weeks. Late delayed injury,
which is the most severe, often irreversible and progressive form of the injury usu-
ally develops >6 months after irradiation.
The most common acute reactions associated with brain irradiation include
headache, nausea, drowsiness, and sometimes worsening of neurologic symptoms,
fatigue, hair loss (alopecia), skin erythema (radiation dermatitis). Acute side effects
are usually transient and self-limiting [41–43]. The initial vascular injury causes
platelet aggregation and thrombus formation in microvessels within weeks to
months. Furthermore early vascular injury causes degenerative structural changes in
white matter.
General neurologic deterioration during early delayed period (2–6 months after
RT) is probably due to transient, diffuse demyelination. Many focal neurologic
signs following irradiation of intracranial tumor have been attributed to intralesional
reactions, probably indicative of tumor response or perilesional reactions including
edema and demyelination. Periventricular white matter lesions start to appear on
conventional MR imaging or CT during this interval, even with standard fraction-
ated partial brain RT [41]. Similar to acute toxicities, early delayed side effects are
usually reversible and resolve spontaneously.
Late delayed side effects are of the most concern when discussing radiation-­
induced brain toxicity. Unlike acute and early delayed side effects, late delayed
toxicity is largely progressive and irreversible. Due to the limited lifespan of many
adult brain tumor patients receiving irradiation to the brain, it is largely unknown
what the long-term consequences of most treatments would be after many years.
The classical late effect following brain irradiation is either localized or multifocal
necrosis, often associated with high-dose and large brain-volume treatment.
Complications include worsening neurologic signs and symptoms, seizures, and
increased intracranial pressure [41]. Both conventional and more precise treatments
including stereotactic radiotherapy (SRT) and stereotactic radiosurgery (SRS) have
the potential to produce late delayed side effects such as cognitive alterations in
short-term memory and concentration, and in rare cases dementia. Radiation-­
induced neuropsychological function and cognition deficits evolve in a biphasic
pattern with a subacute transient decline corresponding to more common symp-
toms, followed by a late delayed irreversible impairment several months or years
later in a much smaller proportion of surviving patients [44].
1 Toxicity Management for Central Nervous System Tumors in Radiation Oncology 21

1.3.5.6 Brain Stem

Brainstem injury patients may exhibit III-XII cranial nerve palsy as well as long-­
beam (cone and sensory system) and cerebellar injury symptoms. The pathophysi-
ology of the brain stem injury is similar to brain injury [45].
Patients have no clinical symptoms in mild cases; serious complaints vary and
include limb weakness, hemiplegia, gait instability, temperature sensory distur-
bance, diplopia, dysarthria, tongue, and facial paralysis. One severe clinical mani-
festation of brain stem injury is syncope. Damage to descending sympathetic
nerve fibers, which anatomically run along the brain stem, may result in syncope
or Horner syndrome. Some patients may recover from the disease after their
brainstem suffers mild radiation injury, while others may need earlier medical
intervention to alleviate their symptoms. However, patients who develop severe
radiation brainstem injuries have a poor prognosis due to the lack of effective
medical therapies [46].

1.3.5.7 Spinal Cord

The most common early delayed side effect of the spinal cord is transient myelopa-
thy, particularly in the cervical and thoracic spine. The most common pathophysiol-
ogy of the transient myelopathy is believed to be demyelination on the posterior
columns. Lhermitte’s sign, or “transient radiation myelopathy,” which is character-
ized by an electric shock sensation that radiates down the spine and extremities on
flexion of the neck, is a relatively infrequent sequela of irradiation of the cervical
spinal cord. It is a self-limiting condition and most patients improve during the
course of several months to a year. Although Lhermitte’s sign is rarely a precursor
of myelitis, there have been some reports of patients who developed radiation
myelopathy after experiencing Lhermitte’s sign. In general, the Lhermitte’s sign
that predated true radiation myelitis is later in onset than the usual latency period of
2–4 months [46].
Late effects to spinal cord are less common and highly severe. A progressive
myelopathy syndrome can be seen, initially presenting with a partial cord
involvement and progressing to a total transverse myelopathy. Irreversible radi-
ation myelopathy usually is not seen earlier than 6–12 months after the comple-
tion of treatment. Typically, half of the patients who develop radiation-induced
myelopathy in the cervical or thoracic cord region will do so within 20 months
of treatment and 75% of cases will occur within 30 months. The signs and
symptoms are typically progressive over several months, but acute onset of ple-
gia over several hours or a few days is also possible. The diagnosis of radiation
myelopathy is one of exclusion; a history of radiation therapy in doses sufficient
to result in injury must be present. The region of the irradiated cord must lie
slightly above the dermatome level of expression of the lesion; the latent period
from the completion of treatment to the onset of injury must be consistent with
that observed in radiation myelopathy; and local tumor progression must be
ruled out. Radiation myelopathy is a diagnosis of exclusion, and patients must
be evaluated for tumor progression and paraneoplastic syndromes with MRI of
the cord [47, 48].
Another random document with
no related content on Scribd:
The Project Gutenberg eBook of Pyramids of snow
This ebook is for the use of anyone anywhere in the United States
and most other parts of the world at no cost and with almost no
restrictions whatsoever. You may copy it, give it away or re-use it
under the terms of the Project Gutenberg License included with this
ebook or online at www.gutenberg.org. If you are not located in the
United States, you will have to check the laws of the country where
you are located before using this eBook.

Title: Pyramids of snow

Author: Edith Metcalfe

Release date: December 16, 2023 [eBook #72428]

Language: English

Original publication: London: Ward, Lock & Co., Limited, 1903

Credits: Al Haines

*** START OF THE PROJECT GUTENBERG EBOOK PYRAMIDS

OF SNOW ***
"'Go out and stop out, or I'll have you put out.'" (Page 83.)
 PYRAMIDS OF SNOW.

BY

EDITH METCALFE.

"I can tell you without the help of an augur what will be your fate you become a
gambler. Either the vice will end by swallowing you up alive as a quicksand does, or if you
are a winner, your gains will disappear more quickly than they came, melting like pyramids
of snow."

WILLIAM DE BRITAINE.

LONDON:
WARD, LOCK & CO., LIMITED.
NEW YORK AND MELBOURNE.
1903

CONTENTS.
CHAPTER I
The Viaticum

CHAPTER II.
The Best Thing in the World

CHAPTER III.
Fraud

CHAPTER IV.
Mediation

CHAPTER V.
Kindred and Affinity

CHAPTER VI.
Bravado

CHAPTER VII.
Melville leads Trumps

CHAPTER VIII.
Rivals

CHAPTER IX.
Bigamy

CHAPTER X.
Light come, Light go

CHAPTER XI.
Mrs. Sinclair pays a Visit

CHAPTER XII.
A Pic-nic
CHAPTER XIII.
Murder

CHAPTER XIV.
The Finding of the Body

CHAPTER XV.
Flight

CHAPTER XVI.
An Unexpected Will

CHAPTER XVII.
An Arrest

CHAPTER XVIII.
A Faithful Servant

CHAPTER XIX.
In the Park

CHAPTER XX.
Money makes a Difference

CHAPTER XXI.
The Result of the Trial

CHAPTER XXII.
Mr. Tracy becomes Active

CHAPTER XXIII.
Sir Ross is Quits

CHAPTER XXIV.
Mrs. Sinclair Resolves to Go Away

CHAPTER XXV.
Mrs. Sinclair Goes away
CHAPTER XXVI.
Fate takes the Odd Trick

CHAPTER XXVII.
The Place of Peace

PYRAMIDS OF SNOW.

CHAPTER I.

THE VIATICUM.

Upon most of the people who thronged the rooms the incident was lost.
Of those who saw it many did not understand its meaning, and the rest were
too much absorbed in their own affairs to give it any attention. The scene
was the Casino at Monto Carlo; every chair was occupied, and behind every
chair men and women were standing, all intent upon the play, all consumed
by the feverish thirst of winning money born of the atmosphere of the place.
The brilliant light flashed in jewels and gleamed in eager eyes, heightened
the colour of flushed cheeks and emphasised the pallor of haggard faces;
against the black evening coat of one man sitting down was outlined the
bare arm of a woman, who laid her stake upon the table, and when the hand
was withdrawn it still hesitated over the black coat until the fortune of the
stake should be declared. Dominating everything was the monotonous
sound of the croupiers' voices and the noise of the money as it was raked to
and fro upon the tables.
 The incident which took place in this scene was a not uncommon one. It
was a little procession of three men, one a dark, good-looking man in well-
cut evening dress, who walked nonchalantly through the rooms, pausing
almost imperceptibly while his two companions shot a glance of
interrogation at each of the croupiers; when the croupiers, in reply, had shot
a glance of assent at his companions, the dark man moved on again until he
had almost completed his tour of the rooms. It was Melville Ashley
undergoing the process of identification as a well-known frequenter of the
rooms before receiving the viaticum which should enable him to return to
London.

It is the habit of the Englishman to conceal his feelings, and no one

could have guessed from Melville's demeanour whether he experienced
relief at having come to the end of his tether, regret at knowing that he
could play no more that season, mortification at his somewhat humiliating
position, or any other emotion which one may suppose natural to a gambler
who is suddenly baulked in his pursuits. He seemed entirely unconcerned,
perhaps a little bored, but certainly in complete possession of himself. To
the few people who, knowing him, found time to vouchsafe him a nod of
greeting, he bowed pleasantly enough. Of the existence of the others he
appeared unaware, though, in point of fact, his senses were so alert that he
could have supplied a remarkably close description of everyone had he been
asked to do so. For the time the gambling fever had left him, and with the
vanishing of his last coin there awoke in his mind an intense disgust at the
heavy scent in the air and the grotesque sight of the many pairs of white
gloves. He was only anxious for the great baize doors to swing behind him
and exclude him from what was generally the one desire of his heart.

Only once did he betray any interest. A woman leaning back in her
chair put out her hand to detain him. She understood the significance of his
escort, and there was some commiseration in her eyes.

"Are you going home, Mr. Ashley?" she asked, in a low tone.

"Yes," he answered, with a little smile; "I leave to-night."

In those conventional words was conveyed a perfectly frank confession

of the state of his finances. No need to invent any explanation of so sudden
a departure. His questioner was well enough acquainted with the language
of the place to know that he had pledged his word to return at once to
London, in consideration of value received.

"I'm sorry," she said, and looked as if she meant it; "but I daresay I shall
be following you soon, and then, perhaps, we may meet again. London is a
tiny little place."

"Yes," Melville assented politely; "but wouldn't it be as well if you gave

me one of your cards?"

"I haven't any," said Mrs. Sinclair, smiling lightly, for she liked a
sportsmanlike loser. "Men always carry cards—in case of duels, I suppose,
but women have no room in their purses for anything but money, and
nowhere but their purses to put anything else. Give me one of yours, and I
will write to you."

"That is too good of you," he replied, as he gave her one; "but of course
you will forget all about it. Good-night, good-bye."

"Auf wiedersehen," she answered prettily, and turned to her companion

on her left, who had watched the little comedy with a scowl upon his face.
Melville noted the scowl and bowed sardonically as he moved away. To be
conscious of superiority to anyone is satisfactory in one's hour of
discomfiture, and Melville derived a complacent satisfaction from this little
man's evident annoyance.

"The little bounder doesn't like me," he thought, "but he's a little ass to
show it. He must be very rich for Mrs. Sinclair to be willing to lay aside her
weeds for him."

The doors swung behind him, and in another moment Melville was in
the open air. He stretched out his arms in pure enjoyment of the lovely
night.

"I am infinitely obliged to you," he said to his escort; "the other trifling
formalities will, doubtless, be completed in due course;" and in what
seemed an incredibly short time Melville was on his way to London.
 Inside the Casino, the little bounder turned to his companion.

"Since you have no room in your purse for visiting cards," he said, "may
I not keep that one in safe custody for you?"

"Thanks, no," the woman answered, and slipped it inside her dress; "I
haven't finished playing yet, and my luck is in to-night."

"Would you be as kind to me," he pursued, "if I had to have recourse to

the charity of the bank to pay my fare to London? Or would you drop me
when my money went?"

Mrs. Sinclair looked at him coolly.

"Don't ask leading questions, and please don't make yourself ridiculous.
Civility costs nothing, and it amused me to be civil to that—gentleman."

"It is rare for you to be amused with anything that costs nothing," he
retorted, but Mrs. Sinclair would not be drawn. She began to play again,
and, when at last she stopped, the little man's carrying capacity was taxed to
take her winnings back to her hotel.

It would be a vain task to try to record all Melville Ashley's thoughts as

the train bore him across France; in the aggregate they amounted to little
less than a comprehensive cursing of everything and everybody, including
himself. For his position was desperate.

The younger son of his parents, both of whom had died while he was
still an infant, he had been brought up with his brother Ralph under the
guardianship of his uncle, Sir Geoffrey Holt, lord of the manor of
Fairbridge, in Surrey, whose co-heir, at any rate, he hoped some day to be.
Sir Geoffrey had played his part well, placing every advantage in the way of
both his nephews, but as the years slipped by he found it difficult to be quite
impartial in his personal treatment of the two lads, though he never failed to
be impartial in his dealings with them so far as they affected the education
and up-bringing of the boys.
 It was Ralph, however, who engrossed his uncle's affection, and
something in Melville's nature rose in rebellion at the thought that he came
second in the estimation of any person. Both boys were handsome, Melville
especially so; both were well endowed with intelligence, and both took
advantage of their opportunities. But whereas Ralph developed into a frank
and unaffected man, fond of athletics and outdoor pursuits, Melville became
more and more self-centred and reserved, devoting all his time to his one
absorbing love of music. Manhood brought liberty, and liberty in Melville's
case brought lack of self-restraint. His finer qualities led him into a certain
sort of temptation, and the men with whom his rare musical talents brought
him into contact were of a free and easy Bohemian type that did not afford
the most healthy companionship for a young fellow of his particular
temperament. Musical evenings led to smoking concerts, and the concerts
to late nights of which other and less innocent amusements were the
principal feature; billiards and cards became first a habit and then a passion,
and Melville was still in his early twenties when it was obvious that he was
a confirmed gambler.

Sir Geoffrey was patient and he was rich, but detestation of the gambler
was added to his dislike of his younger nephew, and more than one violent
quarrel had taken place between the two. It says much for the elder man that
he never referred to the position of absolute dependence occupied by the
younger one; but when, a few weeks before, Melville came to him with the
oft-repeated tale, Sir Geoffrey spoke his mind in the vernacular.

"Let me know the sum total of your accursed debts," he said, "if you
have the honesty or the wit to remember them, and I will clean the slate.
Then I will give you a final two hundred and fifty for yourself, and that
shall be the end."

When Melville gave him the damning list of debts, Sir Geoffrey bit his
lips until they bled. Livery stables, and wine and cigar merchants told a tale
of luxurious living which Sir Geoffrey himself had never been able to
afford in his younger days, and there were other items not precisely
specified, into which the elder man thought it better not to enquire too
curiously. But he kept his word. He drew crossed cheques payable to every
person named in the list for the full amount, and demanded a receipt from
each in full discharge of his nephew's liability. When the last receipt came
in, after a miserable week of waiting, he sent for Melville to his library.

"Is that the last?" he enquired grimly, and Melville assented. Then Sir
Geoffrey sat down at his table and drew one cheque more. "There is the two
hundred and fifty I promised you," he said; "make the best use of it you can,
for it is the last you ever have from me. The dog-cart will take you to the
station in half-an-hour." Then he turned on his heel and left him, and
Melville returned to town.

Five weeks before! And now the whole of the money was gone. With all
his ingenuity it would be difficult to invent a story which his uncle would
be likely to accept as a valid explanation of so surprising a fact.

Melville lighted a cigar and cursed his luck again.

Then the gambler's spirit re-asserted itself. He had had a glorious time at
Monte Carlo while it lasted. One night he had won more than five thousand
pounds, and another night the bank had to send out twice for fresh supplies
of money. That was the time of triumph. People had crowded round him,
some to follow his play, some to envy, some to congratulate him, and
among them he had seen Lavender Sinclair for the first time: a magnificent
woman truly, with splendid colouring and grandly moulded limbs; she wore
turquoise velvet, he remembered, and round her neck a barbaric collar of
turquoise bosses linked together on red gold; even in that room, where
jewels were as common as morals were rare, her jewels were conspicuous,
and she wore them perfectly. Some acquaintance introduced him to her, and
she seemed interested in hearing his name—had met people who knew him,
or some distant kinsmen, but there was no indication of any desire on her
part to press the acquaintance. She was in the ripest glory of her beauty, the
sort that is at its best when it is mature. He wondered idly how old she was,
over thirty certainly; but, after all, it did not matter. Rumour had it that she
was going to marry Sir Ross Buchanan, and Melville was contemptuous of
her choice of a second husband; he knew the man by sight, an undersized,
rather weakly fellow, who inherited an old title from his father and, it was
said, two millions sterling from his mother. Sir Ross was a pill that required
an unusual amount of gilding, and Melville's first admiration of the woman
was replaced by scorn of her venality. She was sympathetic though when he
bade her good-bye, and Melville appreciated sympathy.

The journey was very tedious, so Melville opened his dressing-case and
took out a packet of letters which had reached him at the hotel, but to which
he had not troubled to attend. Several he tore up and threw away, but there
was one which he carefully replaced in its envelope in his bag. It was from
his brother, and ran as follows:

"DEAR MELVILLE,—Why didn't you tell me you were going to

Monte Carlo? However, I hope you are enjoying yourself and having good
luck. By the way, I am going to ask you to do me a great favour. Can you
lend me a hundred for a fortnight? I will repay you then. My solicitors are
selling some capital for me, but they are so slow, and I am in immediate
want of the money. Do write soon.—Yours ever, RALPH ASHLEY. P.S.—
Have you heard of my engagement to Gwendolen Austen?"

"So he is hard up, too," Melville muttered. "No, I wouldn't lend him
fifty pounds if I had fifty thousand to-morrow. And engaged to Gwendolen
is he? I wonder if I can put an end to that. If she were my wife I might even
win the old man round again."

Then his mind reverted to his immediate difficulties, and he went over
the old useless ground of trying to think of some way to raise the wind,
failing once more to see any light at all, as indeed he was bound to fail,
since honest work did not come into his most casual consideration.

It was not, however, until he found himself in his chambers in Jermyn

Street that he fully realised how he had come to the end of all things. There
were invitations awaiting him which he could not accept for lack of ready
money; little accounts which he would have been only too glad to hand over
to his uncle if he had remembered their existence; all insignificant enough
individually, but totalling up to a considerable sum; private tips from
hangers-on at stables, which were certain to be good since he could not
avail himself of them; letters from women suggesting trips up the river or
supper after the play; even letters from friends saying they were hard up,
and reminding him of small obligations under which he lay to them.
Melville felt as if he were at last at bay, with all his worries like so many
starving wolves tearing him down to his destruction. And worse than all
was the extreme physical reaction from the unwholesome life of excitement
he had lately been leading at Monte Carlo. While that life lasted no fatigue
oppressed him. A tumbler of champagne or a stiff pick-me-up from a
chemist always availed to keep him going. But now the excitement was
over. The curtain was rung down, the lights were all turned out, he was
alone with his troubles, and had no pluck left to face them. In sheer
weariness he turned into bed and slept the sleep of deep exhaustion.

CHAPTER II.

THE BEST THING IN THE WORLD.

Even while Melville, with despair gnawing at his heart, was speeding on
his journey back to England, Sir Geoffrey Holt was keeping festival at
Fairbridge Manor. That very evening he had given a final dinner party to
celebrate the betrothal of his god-child, Gwendolen Austen, to his favourite
nephew, Ralph Ashley.

In the whole of a land which is proud to claim as its children so many

fair women and brave men, it would be difficult to find a fairer woman or a
braver man than now engrossed Sir Geoffrey's thoughts, and in their
approaching union he looked to see the culmination of his own happiness. It
was infinitely pleasant to know that the two, over whose lives he had
watched so tenderly, would never leave him now, but hand-in-hand would
walk in quiet contentment by his side, lightening the burden of his
increasing years, and giving him fresh pleasure in their own unfolding joys.
No man could ever hope to win richer reward for his unfailing goodness to
others than Sir Geoffrey was reaping now for his long care of this boy and
girl.

So he threw wide his hospitable doors, and asked the county to come
and shower congratulations upon the happy couple. For a week he kept
open house, and his pleasure was so apparent, his high spirits so contagious,
that he made himself loved the more by his unaffected delight and his
manner of displaying it. To his succession of dinner parties practically the
entire county came, until both Ralph and Gwendolen were at a loss to find
fresh ways of saying, "Thank you," for so many expressions of goodwill.

But this evening had brought the entertainments to a close, and when Sir
Geoffrey, standing by his open door, had bade the latest guest good-bye, he
turned with a sigh of satisfaction into the great hall where his children, as he
called them, were laughing over some incident which had amused them
during the day.

Sir Geoffrey pulled his god-daughter towards him and held her face
between his hands.

"The last guest gone," he said, smiling at her; "now, Gwen, confess you
are not sorry."

"I didn't know there was so much kindness in the world," she answered,
smiling back at him, and her eyes were shining; "but I confess I am glad we
are all by ourselves again."

"Tired?" he asked.

"Not a bit," she answered brightly; "unless it be of seeming to occupy so

much attention."

"And you don't want to go to bed?"

"Indeed, no," she said indignantly. "When one is as happy as I am it

would be a shame to spend a single hour asleep."
 "Then let us go down to the house-boat," Sir Geoffrey said. "I daresay
Ralph can manage to amuse you somehow, and I want to talk to your
mother."

"Do you want to talk to me, Ralph?" said Gwendolen, turning to her
lover, who was looking at her with affectionate pride.

"I don't seem to have had a chance of talking to you for a week," Ralph
answered promptly. "Let's go at once and—and get a deck chair ready for
your mother."

Sir Geoffrey chuckled.

"An admirable reason for both of you hurrying away. Ralph is too weak
to move one by himself; you must help him, Gwendolen."

Ralph put a wrap round Gwendolen, and, linking her arm in his, went
through the French window across the garden.

It was a glorious night. A full moon shed a mellow splendour across the
lawns, throwing the masses of the cedars into bold relief against the sky,
and glinting in all the diamond panes of the heavy-leaded windows. Over
the phloxes and tobacco plants that adorned the borders great moths were
wheeling, and bats were flickering in and out of the plantation that screened
the stables from the house. As the garden sloped towards the river the turf
was more closely shaven, and along the water's edge were sunk pots in
which magnificent geraniums and sweet heliotrope were growing.

Moored by the extreme boundary of the garden Ralph's house-boat lay;

it contained a little bedroom and two sitting-rooms, fragrant with flowers
and light with mirrors and thin curtains, and the upper part, covered in with
a pale green awning, was a mass of flowers and palms. Here were deck
chairs, and little tables, and Japanese lanterns.

Ralph put two chairs ready for Mrs. Austen and Sir Geoffrey, and then
looked at Gwendolen.
 "Shall we wait here for them, or would you like me to punt you up the
stream?"

"Let us stay here," she answered; "somehow——"

"Yes?" he said enquiringly.

"Somehow I fancy the others will not come," she said, rippling with
laughter. "Sir Geoffrey is always so thoughtful."

Ralph took her in his arms and kissed her passionately.

"I love you—I love you," he said, between set teeth, and Gwendolen
drew a sigh of perfect content. "If it could always be like this," he went on.
"Just you and I in the peace, with the river and the moonlight to reflect our
happiness."

But Gwendolen shook her head.

"You would soon tire of that," she said, and when he would have
demurred laid her hand upon his lips. "I hope you would, at any rate, for I
would not like you to be a lotos-eater dreaming your days away. There is so
much to do in the world, Ralph, and surely we, to whom so much has been
given, would not wish to give nothing in return."

He kissed the hand that caressed him.

"Tell me what I am to do."

Gwendolen considered.

"It is not easy to see just at first," she admitted, "but work, like charity,
begins at home. You will be a good master to your household, and will take
an active interest in the estate. You will be so anxious to make the tenants
happier in their respective stations that you will be surprised to find how
many things go to make up their lives. Life is a big bundle of little things,
you know, not a little bundle of big ones. If you really set your heart upon
doing good you will never stop for lack of something to do. That is a
wonderful thought, Ralph: there is no end to the good you can do in the
world."

"Go on," he said tenderly; "go on, dear, good little woman!"

"That is only thinking of your life at home," said Gwendolen; "but there
are wider interests outside. I should like you to make a name for yourself in
the great world; it might be in philanthropy, it might be in politics. I'm often
sorry you have no profession, but the world has always need of good men,
and I won't let you hold wool for me while the world wants one pair of
honest hands. Oh! Ralph, wouldn't that be more worth while than idling
your life away, even if it could always be like this?"

"Much more worth while," he answered gravely. "You have made me

happy; you will make me good; you may make me famous. That is a great
deal for one little woman to do for a man. What am I to do in return for
you?"

"Only love me," she said. "Love me always as you do now; never any
less tenderly or truly, even when the other interests are nearer than they are
to-night. What more can you do than give me love—the best thing in the
world?"

"I think I may safely promise that," Ralph said, and his deep voice
quivered. What had he done that Providence should heap blessings on him
so lavishly? For what had already been bestowed upon him he could never
show sufficient gratitude, and now there was the crowning gift of all—the
love of a pure and beautiful girl, whom he knew he had loved all his life.

Gwendolen lay back in one of the deck chairs, and Ralph, leaning
against the wooden railing, feasted his eyes upon the picture that she made.
In a dress of white mousseline-de-soie, trimmed with rare point lace, she
looked ethereally beautiful in this setting of coloured lamps and lovely
flowers. Her hands were clasped upon her lap, and the moonlight caught the
diamonds in the ring that he had given her, and even sought out the little
diamond drop that did duty as an earring. Against the scarlet cushions on
which she reclined her fair skin showed like ivory, and Ralph was filled
with something akin to amazement that this incarnation of all that was