Hypomania (literally "under mania" or "less than mania") is a mood state characterized by persistent disinhibition and mood elevation (euphoria), with behavior that is noticeably different from the person's typical behavior when in a non-depressed state. It may involve irritability, but less severely than full mania. According to DSM-5
criteria, hypomania is distinct from mania in that there is no
significant functional impairment; mania, by DSM-5 definition, does
include significant functional impairment and may have psychotic features.
Characteristic behaviors of persons experiencing hypomania are a
notable decrease in the need for sleep, an overall increase in energy,
unusual behaviors and actions, and a markedly distinctive increase in
talkativeness and confidence, commonly exhibited with a flight of
creative ideas. Other symptoms related to this may include feelings of grandiosity, distractibility, and hypersexuality.
While hypomanic behavior often generates productivity and excitement,
it can become troublesome if the subject engages in risky or otherwise
inadvisable behaviors, and/or the symptoms manifest themselves in
trouble with everyday life events.
When manic episodes are separated into stages of a progression
according to symptomatic severity and associated features, hypomania
constitutes the first stage of the syndrome, wherein the cardinal
features (euphoria or heightened irritability, pressure of speech and activity, increased energy, decreased need for sleep, and flight of ideas) are most plainly evident.
Signs and symptoms
Individuals in a hypomanic state have a decreased need for sleep, are extremely gregarious and competitive, and have a great deal of energy. They are, otherwise, often fully functioning (unlike individuals suffering from a full manic episode).
Distinctive markers
Specifically, hypomania is distinguished from mania by the absence of psychotic symptoms and grandiosity, and by its lesser degree of impact on functioning.
Hypomania is a feature of bipolar II disorder and cyclothymia, but can also occur in schizoaffective disorder. Hypomania is also a feature of bipolar I disorder;
it arises in sequential procession as the mood disorder fluctuates
between normal mood (euthymia) and mania. Some individuals with bipolar I
disorder have hypomanic as well as manic episodes. Hypomania can also
occur when moods progress downwards from a manic mood state to a normal
mood. Hypomania is sometimes credited with increasing creativity and
productive energy. Numerous people with bipolar disorder have credited hypomania with giving them an edge in their theater of work.
People who experience hyperthymia, or "chronic hypomania", encounter the same symptoms as hypomania but on a longer-term basis.
Associated disorders
Cyclothymia, a condition of continuous mood fluctuations, is characterized by oscillating experiences of hypomania and depression
that fail to meet the diagnostic criteria for either manic or major
depressive episodes. These periods are often interspersed with periods
of relatively normal (euthymic) functioning.
When a patient presents with a history of at least one episode of
both hypomania and major depression, each of which meet the diagnostic
criteria, bipolar II disorder is diagnosed. In some cases, depressive
episodes routinely occur during the fall or winter and hypomanic ones in
the spring or summer. In such cases, one speaks of a "seasonal
pattern".
If left untreated, and in those so predisposed, hypomania may transition into mania, which may be psychotic, in which case bipolar I disorder is the correct diagnosis.
Causes
Often in
those who have experienced their first episode of hypomania – generally
without psychotic features – there may be a long or recent history of
depression or a mix of hypomania combined with depression (known as
mixed-state) prior to the emergence of manic symptoms. This commonly
surfaces in the mid to late teens. Because the teenage years are
typically an emotionally charged time of life, it is not unusual for
mood swings to be passed off as normal hormonal teen behavior and for a
diagnosis of bipolar disorder to be missed until there is evidence of an
obvious manic or hypomanic phase.
In cases of drug-induced hypomanic episodes in unipolar
depressives, the hypomania can almost invariably be eliminated by
lowering medication dosage, withdrawing the drug entirely, or changing
to a different medication if discontinuation of treatment is not
possible.
Mania
and hypomania are usually studied together as components of bipolar
disorders, and the pathophysiology is usually assumed to be the same.
Given that norepinephrine and dopaminergic
drugs are capable of triggering hypomania, theories relating to
monoamine hyperactivity have been proposed. A theory unifying
depression and mania in bipolar individuals proposes that decreased
serotonergic regulation of other monoamines can result in either
depressive or manic symptoms. Lesions on the right side frontal and
temporal lobes have further been associated with mania.
Diagnosis
The DSM-IV-TR
defines a hypomanic episode as including, over the course of at least
four days, elevated mood plus three of the following symptoms OR
irritable mood plus four of the following symptoms, when the behaviors
are clearly different from how the person typically acts when not
depressed:
involvement in pleasurable activities that may have a high potential
for negative psycho-social or physical consequences (e.g., the person
engages in unrestrained buying sprees, sexual indiscretions, reckless
driving, physical and verbal conflicts, foolish business investments,
quitting a job to pursue some grandiose goal, etc).
Medications
Antimanic
drugs are used to control acute attacks and prevent recurring episodes
of hypomania combined with a range of psychological therapies.
The recommended length of treatment ranges from 2 years to 5 years.
Anti-Depressants may also be required for existing treatments but are
avoided in patients who have had a recent history with hypomania. Sertraline has often been debated to have side effects that can trigger hypomania.
The Ancient Greek physician Hippocrates called one personality type 'hypomanic' (Greek: ὑπομαινόμενοι, hypomainómenoi).
In 19th century psychiatry, when mania had a broad meaning of insanity,
hypomania was equated by some to concepts of 'partial insanity' or monomania. A more specific usage was advanced by the German neuro-psychiatrist Emanuel Ernst Mendel
in 1881, who wrote, "I recommend, taking into consideration the word
used by Hippocrates, to name those types of mania that show a less
severe phenomenological picture, 'hypomania'". Narrower operational definitions of hypomania were developed in the 1960s and 1970s.
Conscious
perception of visceral sensations map to specific regions of the body,
as shown in this chart. Some sensations are felt locally, whereas others
are perceived as affecting areas that are quite distant from the
involved organ.
Referred pain, also called reflective pain, is pain perceived at a location other than the site of the painful stimulus. An example is the case of angina pectoris brought on by a myocardial infarction (heart attack), where pain is often felt in the neck, shoulders, and back rather than in the thorax (chest), the site of the injury. The International Association for the Study of Pain has not officially defined the term; hence several authors have defined it differently.
Radiating pain is slightly different from referred pain;
for example, the pain related to a myocardial infarction could either be
referred or radiating pain from the chest. Referred pain is when the
pain is located away from or adjacent to the organ involved; for
instance, when a person has pain only in their jaw or left arm,
but not in the chest. Referred pain has been described since the late
1880s. Despite an increasing amount of literature on the subject, the biological mechanism of referred pain is unknown, although there are several hypotheses.
Characteristics
The size of referred pain is related to the intensity and duration of ongoing/evoked pain.
Temporal summation is a potent mechanism for generation of referred muscle pain.
Central hyperexcitability is important for the extent of referred pain.
Patients with chronic musculoskeletal pains have enlarged referred pain areas to experimental stimuli. The proximal
spread of referred muscle pain is seen in patients with chronic
musculoskeletal pain and very seldom is it seen in healthy individuals.
Modality-specific somatosensory changes occur in referred areas,
which emphasize the importance of using a multimodal sensory test regime
for assessment.
Referred pain is often experienced on the same side of the body as the source, but not always.
Mechanism
There
are several proposed mechanisms for referred pain. Currently there is
no definitive consensus regarding which is correct. The cardiac general
visceral sensory pain fibers follow the sympathetics back to the spinal
cord and have their cell bodies located in thoracic dorsal root ganglia
1-4(5).
As a general rule, in the thorax and abdomen, general visceral afferent
(GVA) pain fibers follow sympathetic fibers back to the same spinal cord
segments that gave rise to the preganglionic sympathetic fibers.
The central nervous system (CNS) perceives pain from the heart as coming
from the somatic portion of the body supplied by the thoracic spinal
cord segments 1-4(5). Classically the pain associated with a myocardial
infarction is located in the mid or left side of the chest where the
heart is actually located. The pain can radiate to the left side of the
jaw and into the left arm. Myocardial infarction can rarely present as
referred pain and this usually occurs in people with diabetes or older age. Also, the dermatomes
of this region of the body wall and upper limb have their neuronal cell
bodies in the same dorsal root ganglia (T1-5) and synapse in the same
second order neurons in the spinal cord segments (T1-5) as the general
visceral sensory fibers from the heart. The CNS does not clearly discern
whether the pain is coming from the body wall or from the viscera, but
it perceives the pain as coming from somewhere on the body wall, i.e.
substernal pain, left arm/hand pain, jaw pain.
Convergent-projection
This
represents one of the earliest theories on the subject of referred
pain. It is based on the work of W.A. Sturge and J. Ross from 1888 and
later TC Ruch in 1961. Convergent projection proposes that afferent
nerve fibers from tissues converge onto the same spinal neuron, and
explains why referred pain is believed to be segmented in much the same
way as the spinal cord. Additionally, experimental evidence shows that
when local pain (pain at the site of stimulation) is intensified the
referred pain is intensified as well.
Criticism of this model arises from its inability to explain why
there is a delay between the onset of referred pain after local pain
stimulation. Experimental evidence also shows that referred pain is
often unidirectional. For example, stimulated local pain in the anterior
tibial muscle causes referred pain in the ventral portion of the ankle;
however referred pain moving in the opposite direction has not been
shown experimentally. Lastly, the threshold for the local pain
stimulation and the referred pain stimulation are different, but
according to this model they should both be the same.
Convergence-facilitation
Convergence
facilitation was conceived in 1893 by J MacKenzie based on the ideas of
Sturge and Ross. He believed that the internal organs were insensitive
to stimuli. Furthermore, he believed that non-nociceptive afferent
inputs to the spinal cord
created what he termed "an irritable focus". This focus caused some
stimuli to be perceived as referred pain. However, his ideas did not
gain widespread acceptance from critics due to its dismissal of visceral
pain.
Recently this idea has regained some credibility under a new term, central sensitization.
Central sensitization occurs when neurons in the spinal cord's dorsal
horn or brainstem become more responsive after repeated stimulation by
peripheral neurons, so that weaker signals can trigger them. The delay
in appearance of referred pain shown in laboratory experiments can be
explained due to the time required to create the central sensitization.
Axon-reflex
Axon reflex suggests that the afferent fiber is bifurcated before connecting to the dorsal horn.
Bifurcated fibers do exist in muscle, skin, and intervertebral discs.
Yet these particular neurons are rare and are not representative of the
whole body. Axon-Reflex also does not explain the time delay before the
appearance of referred pain, threshold differences for stimulating local
and referred pain, and somatosensory sensibility changes in the area of
referred pain.
Hyperexcitability
Hyperexcitability
hypothesizes that referred pain has no central mechanism. However, it
does say that there is one central characteristic that predominates.
Experiments involving noxious stimuli and recordings from the dorsal
horn of animals revealed that referred pain sensations began minutes
after muscle stimulation. Pain was felt in a receptive field that was
some distance away from the original receptive field. According to
hyperexcitability, new receptive fields are created as a result of the
opening of latent convergent afferent fibers in the dorsal horn. This
signal could then be perceived as referred pain.
Several characteristics are in line with this mechanism of
referred pain, such as dependency on stimulus and the time delay in the
appearance of referred pain as compared to local pain. However, the
appearance of new receptive fields, which is interpreted to be referred
pain, conflicts with the majority of experimental evidence from studies
including studies of healthy individuals. Furthermore, referred pain
generally appears within seconds in humans as opposed to minutes in
animal models. Some scientists attribute this to a mechanism or
influence downstream in the supraspinal pathways. Neuroimaging
techniques such as PET scans or fMRI may visualize the underlying neural processing pathways responsible in future testing.
Thalamic-convergence
Thalamic
convergence suggests that referred pain is perceived as such due to the
summation of neural inputs in the brain, as opposed to the spinal cord,
from the injured area and the referred area. Experimental evidence on
thalamic convergence is lacking. However, pain studies performed on
monkeys revealed convergence of several pathways upon separate cortical
and subcortical neurons.
Examples
Location
Description
Upper chest/left limb
Myocardial ischaemia
(the loss of blood flow to a part of the heart muscle tissue) is
possibly the best known example of referred pain; the sensation can
occur in the upper chest as a restricted feeling, or as an ache in the
left shoulder, arm or even hand.
Head
"Ice-cream headache" or "brain freeze" is another example of referred pain, in which the vagus nerve or the trigeminal nerve
in the throat and the palate, respectively, transmit pain signals,
because of the rapid cooling and rewarming of the capillaries in the
sinuses.[4]
General
Phantom limb pain,
a type of referred pain, is the sensation of pain from a limb that has
been lost or from which a person no longer receives physical signals. It
is an experience almost universally reported by amputees and
quadriplegics.
Palmaris longus A problem originating in the forearm might be felt in the palm, and not in the forearm.
Laboratory testing methods
Pain
is studied in a laboratory setting due to the greater amount of control
that can be exerted. For example, the modality, intensity, and timing
of painful stimuli can be controlled with much more precision. Within
this setting there are two main ways that referred pain is studied.
Algogenic substances
In recent years several different chemicals have been used to induce referred pain including bradykinin, substance P, capsaicin, and serotonin. However, before any of these substances became widespread in their use a solution of hypertonic saline
was used instead. Through various experiments it was determined that
there were multiple factors that correlated with saline administration
such as infusion rate, saline concentration, pressure, and amount of
saline used. The mechanism by which the saline induces a local and
referred pain pair is unknown. Some researchers have commented that it
could be due to osmotic differences, however that is not verified.
Using electrical stimulation
Intramuscular
electrical stimulation (IMES) of muscle tissue has been used in various
experimental and clinical settings. The advantage to using an IMES
system over a standard such as hypertonic saline is that IMES can be
turned on and off. This allows the researcher to exert a much higher
degree of control and precision in terms of the stimulus and the
measurement of the response. The method is easier to carry out than the
injection method as it does not require special training in how it
should be used. The frequency of the electrical pulse can also be
controlled. For most studies a frequency of about 10 Hz is needed to
stimulate both local and referred pain.
Using this method it has been observed that significantly higher
stimulus strength is needed to obtain referred pain relative to the
local pain. There is also a strong correlation between the stimulus
intensity and the intensity of referred and local pain. It is also
believed that this method causes a larger recruitment of nociceptor
units resulting in a spatial summation. This spatial summation results
in a much larger barrage of signals to the dorsal horn and brainstem neurons.
Use in clinical diagnosis and treatments
Referred
pain can be indicative of nerve damage. A case study done on a
63-year-old man with an injury sustained during his childhood developed
referred pain symptoms after his face or back was touched. After even a
light touch, there was a shooting pain in his arm. The study concluded
that his pain was possibly due to a neural reorganization which
sensitized regions of his face and back after the nerve damage occurred.
It is mentioned that this case is very similar to what phantom limb
syndrome patients suffer. This conclusion was based on experimental
evidence gathered by V. Ramachandran in 1993, with the difference being
that the arm that is in pain is still attached to the body.
Orthopedic diagnosis
From
the above examples one can see why understanding of referred pain can
lead to better diagnoses of various conditions and diseases. In 1981
physiotherapist Robin McKenzie described what he termed centralization.
He concluded that centralization occurs when referred pain moves from a
distal to a more proximal location. Observations in support of this
idea were seen when patients would bend backward and forward during an
examination.
Studies have reported that the majority of patients that
experienced centralization were able to avoid spinal surgery through
isolating the area of local pain. However, the patients who did not
experience centralization had to undergo surgery to diagnose and correct
the problems. As a result of this study there has been a further
research into the elimination of referred pain through certain body
movements.
One example of this is referred pain in the calf. McKenzie showed
that the referred pain would move closer to the spine when the patient
bent backwards in full extension a few times. More importantly, the
referred pain would dissipate even after the movements were stopped.
General diagnosis
As with myocardial ischaemia
referred pain in a certain portion of the body can lead to a diagnosis
of the correct local center. Somatic mapping of referred pain and the
corresponding local centers has led to various topographic maps being
produced to aid in pinpointing the location of pain based on the
referred areas. For example, local pain stimulated in the esophagus is
capable of producing referred pain in the upper abdomen, the oblique
muscles, and the throat. Local pain in the prostate can radiate referred
pain to the abdomen, lower back, and calf muscles. Kidney stones
can cause visceral pain in the ureter as the stone is slowly passed
into the excretory system. This can cause immense referred pain in the
lower abdominal wall.
Further, recent research has found that ketamine, a sedative, is capable of blocking referred pain. The study was conducted on patients suffering from fibromyalgia,
a disease characterized by joint and muscle pain and fatigue. These
patients were looked at specifically due to their increased sensitivity
to nociceptive stimuli. Furthermore, referred pain appears in a
different pattern in fibromyalgic patients than non-fibromyalgic
patients. Often this difference manifests as a difference in terms of
the area that the referred pain is found (distal vs. proximal) as
compared to the local pain. The area is also much more exaggerated owing
to the increased sensitivity.
Neutron capture therapy (NCT) is a noninvasive therapeutic modality for treating locally invasive malignant tumors such as primary brain tumors, recurrent head and neck cancer, and cutaneous and extracutaneous melanomas. It is a two-step procedure: first, the patient is injected with a tumor-localizing drug containing the non-radioactive isotope boron-10 (10B), which has a high propensity to capture thermal neutrons. The cross section of the 10B (3,837 barns) is many times greater than that of the other elements present in tissues such as hydrogen, oxygen, and nitrogen. In the second step, the patient is radiated with epithermal neutrons,
the source of which is either a nuclear reactor or, more recently, an
accelerator. After losing energy as they penetrate tissue, the neutrons
are captured by the 10B, which subsequently emits high-energy
alpha particles that can selectively kill those tumor cells that have
taken up sufficient quantities of 10B. All of the clinical experience to date with NCT is with the non-radioactive isotope boron-10, and this is known as boron neutron capture therapy (BNCT). At this time, the use of other non-radioactive isotopes, such as gadolinium,
has been limited to experimental studies, and to date, it has not been
used clinically. BNCT has been evaluated clinically as an alternative to
conventional radiation therapy for the treatment of high-grade gliomas, meningiomas, and recurrent, locally advanced cancers of the head and neck region and superficial cutaneous and extracutaneous melanomas.
Boron neutron capture therapy
History
After
the initial discovery of the neutron in 1932 by Sir James Chadwick, H.
J. Taylor in 1935 showed that boron-10 nuclei had a propensity to
capture thermal neutrons. This results in nuclear fission of the
boron-11 nuclei into stripped down helium-4 nuclei (alpha particles) and
lithium-7 ions. In 1936, G.L. Locher, a scientist at the Franklin
Institute in Philadelphia, Pennsylvania, recognized the therapeutic
potential of this discovery and suggested that neutron capture could be
used to treat cancer. W. H. Sweet, from Massachusetts General Hospital,
first suggested the technique for treating malignant brain tumors and a
trial of BNCT against the most malignant of all brain tumors,
glioblastoma multiforme, using borax as the boron delivery agent in
1951. A clinical trial was initiated in a collaboration with Brookhaven National Laboratory in Long Island, New York, U.S.A. and the Massachusetts General Hospital in Boston in 1954.
A number of research groups throughout the world have continued
the early groundbreaking work of William Sweet and Ralph Fairchild, and
in particular, the pioneering clinical studies of Hiroshi Hatanaka (畠中洋)
in Japan. This was followed by clinical trials in a number of other
countries including Japan, the United States, Sweden, Finland, Czech
Republic, Argentina, and the European Union (centered in the
Netherlands). Currently, the program in Japan has transitioned from a
reactor neutron source to accelerators, and now a Phase I/II trial is
underway to evaluate the safety and therapeutic efficacy of the
accelerator neutron sources.
Basic principles
Neutron capture therapy is a binary system that consists of two separate
components to achieve its therapeutic effect. Each component in itself
is non-tumoricidal, but when combined together they are highly lethal to
cancer cells.
1)
Boron compound (b) is selectively absorbed by cancer cell(s). 2)
Neutron beam (n) is aimed at cancer site. 3) Boron absorbs neutron. 4)
Boron disintegrates emitting cancer-killing radiation.
BNCT is based on the nuclear capture and fission reactions that occur when non-radioactive boron-10,
which makes up approximately 20% of natural elemental boron, is
irradiated with neutrons of the appropriate energy to yield excited
boron-11 (11B*). This undergoes instantaneous nuclear fission to produce high-energy alpha particles (4He nuclei) and high-energy lithium-7 (7Li) nuclei. The nuclear reaction is:
Both the alpha particles and the lithium nuclei produce closely
spaced ionizations in the immediate vicinity of the reaction, with a
range of 5–9 µm,
which is approximately the diameter of the target cell. The lethality
of the capture reaction is limited to boron containing cells. BNCT,
therefore, can be regarded as both a biologically and a physically
targeted type of radiation therapy. The success of BNCT is dependent
upon the selective delivery of sufficient amounts of 10B to the tumor with only small amounts localized in the surrounding normal tissues.
Thus, normal tissues, if they have not taken up sufficient amounts of
boron-10, can be spared from the nuclear capture and fission reactions.
Normal tissue tolerance is determined by the nuclear capture reactions
that occur with normal tissue hydrogen and nitrogen.
A wide variety of boron delivery agents have been synthesized,
but only two of these currently are being used in clinical trials. The
first, which has been used primarily in Japan, is a polyhedral borane
anion, sodium borocaptate or BSH (Na2B12H11SH), and the second is a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine
or BPA. The latter has been used in clinical trials in the United
States, Finland, Japan, and, more recently, Argentina and Taiwan.
Following administration of either BPA or BSH by intravenous infusion,
the tumor site is irradiated with neutrons, the source of which until
recently has been specially designed nuclear reactors, but now specially
designed accelerators are being used. Until 1994, low-energy (< 0.5 eV) thermal neutron beams were used in Japan and the United States, but since they have a limited depth of penetration in tissues, higher energy (>.5eV<10 a="" class="mw-redirect" href="https://en.wikipedia.org/wiki/KeV" title="KeV">keV
) epithermal neutron beams, which have a greater depth of penetration, have been used in clinical trials in the United States, Europe, Japan, Argentina, Taiwan, and China. In theory BNCT is a highly selective type of radiation therapy that can target tumor cells without causing radiation damage to the adjacent normal cells and tissues. Doses up to 60–70 grays (Gy)
can be delivered to the tumor cells in one or two applications compared
to 6–7 weeks for conventional fractionated external beam photon
irradiation. However, the effectiveness of BNCT is dependent upon a
relatively homogeneous cellular distribution of 10B within the tumor, and this is still one of the main unsolved problems that have limited its success.
Radiobiological considerations
The
radiation doses delivered to tumor and normal tissues during BNCT are
due to energy deposition from three types of directly ionizing radiation
that differ in their linear energy transfer (LET), which is the rate of energy loss along the path of an ionizing particle:
low-LET gamma rays, resulting primarily from the capture of thermal neutrons by normal tissue hydrogen atoms [1H(n,γ)2H];
high-LET protons, produced by the scattering of fast neutrons and from the capture of thermal neutrons by nitrogen atoms [14N(n,p)14C]; and
high-LET, heavier charged alpha particles (stripped down helium [4He] nuclei) and lithium-7 ions, released as products of the thermal neutron capture and fission reactions with 10B [10B(n,α)7Li].
Since both tumor and surrounding normal tissues are present in
the radiation field, even with an ideal epithermal neutron beam, there
will be an unavoidable, nonspecific background dose, consisting of both
high- and low-LET radiation. However, a higher concentration of 10B
in the tumor will result in it receiving a higher total dose than that
of adjacent normal tissues, which is the basis for the therapeutic gain
in BNCT.
The total radiation dose in Gy delivered to any tissue can be expressed
in photon-equivalent units as the sum of each of the high-LET dose
components multiplied by weighting factors (Gyw), which depend on the increased radiobiological effectiveness of each of these components.
Clinical dosimetry
Biological
weighting factors have been used in all of the recent clinical trials
in patients with high-grade gliomas, using boronophenylalanine (BPA) in
combination with an epithermal neutron beam. The 10B(n,α)7Li
component of the radiation dose to the scalp has been based on the
measured boron concentration in the blood at the time of BNCT, assuming a
blood: scalp boron concentration ratio of 1.5:1 and a compound
biological effectiveness (CBE) factor for BPA in skin of 2.5. A relative biological effectiveness
(RBE) or CBE factor of 3.2 has been used in all tissues for the
high-LET components of the beam, such as alpha particles. The RBE factor
is used to compare the biologic effectiveness of different types of
ionizing radiation. The high-LET components include protons resulting
from the capture reaction with normal tissue nitrogen, and recoil
protons resulting from the collision of fast neutrons with hydrogen.
It must be emphasized that the tissue distribution of the boron
delivery agent in humans should be similar to that in the experimental
animal model in order to use the experimentally derived values for
estimation of the radiation doses for clinical radiations. For more detailed information relating to computational dosimetry and treatment planning, interested readers are referred to a comprehensive review on this subject.
Boron delivery agents
The development of boron delivery agents for BNCT began in the early 1960s and is an ongoing and difficult task. A number of boron-10 containing delivery agents have been prepared for potential use in BNCT. The most important requirements for a successful boron delivery agent are:
low systemic toxicity and normal tissue uptake with high tumor
uptake and concomitantly high tumor: to brain (T:Br) and tumor: to blood
(T:Bl) concentration ratios (> 3–4:1);
tumor concentrations in the range of ~20 µg 10B/g tumor;
rapid clearance from blood and normal tissues and persistence in tumor during BNCT.
However, as of 2019 no single boron delivery agent fulfills all of
these criteria. With the development of new chemical synthetic
techniques and increased knowledge of the biological and biochemical
requirements needed for an effective agent and their modes of delivery, a
wide variety of new boron agents has emerged (see examples in Table 1),
but only two of these, boronophenylalanine (BPA) and sodium borocaptate
(BSH) have been used clinically.
Table 1. Examples of new low- and high-molecular-weight boron delivery agents currently under evaluationa,b
Boric acid
Boronated unnatural amino acids
Boron nitride nanotubes
Boronated VEGF
Boron-containing immunoliposomes and liposomes
Carboranyl nucleosides
Boron-containing Lipiodol
Carboranyl porphyrazines
Boron-containing nanoparticles
Carboranyl thymidine analogues
Boronated co-polymers
Decaborone (GB10)
Boronated cyclic peptides
Dodecaborate cluster lipids and cholesterol derivatives
Boronated DNAc intercalators
Dodecahydro-closo-dodecaborate clusters
Boronated EGF and anti-EGFR MoAbs
Linear and cyclic peptides
Boronated polyamines
Polyanionic polymers
Boronated porphyrins
Transferrin-polyethylene glycol liposomes
Boronated sugars
aThe delivery agents are not listed in any order
that indicates their potential usefulness for BNCT. None of these agents
have been evaluated clinically. bSee Barth, R.F., Mi, P., and Yang, W., Boron delivery
agents for neutron capture therapy of cancer, Cancer Communications,
38:35 (doi: 10.1186/s40880-018-0299-7), 2018 for an updated review. cThe abbreviations used in this table are defined as
follows: BNCT, boron neutron capture therapy; DNA, deoxyribonucleic
acid; EGF, epidermal growth factor; EGFR, epidermal growth factor
receptor; MoAbs, monoclonal antibodies; VEGF, vascular endothelial
growth factor.
The major challenge in the development of boron delivery agents
has been the requirement for selective tumor targeting in order to
achieve boron concentrations (20-50 µg/g tumor) sufficient to produce
therapeutic doses of radiation at the site of the tumor with minimal
radiation delivered to normal tissues. The selective destruction of
brain tumor (glioma) cells in the presence of normal cells represents an
even greater challenge compared to malignancies at other sites in the
body, since malignant gliomas are highly infiltrative of normal brain,
histologically diverse and heterogeneous in their genomic profile. In
principle, NCT is a radiation therapy that could selectively deliver
lethal doses of radiation to tumor cells while sparing adjacent normal
cells.
Gadolinium neutron capture therapy (Gd NCT)
There also has been interest in the possible use of gadolinium-157 (157Gd) as a capture agent for NCT for the following reasons: First, and foremost, has been its very high neutron capture cross section of 254,000 barns. Second, gadolinium compounds, such as Gd-DTPA (gadopentetate dimeglumine Magnevist®), have been used routinely as contrast agents for magnetic resonance imaging (MRI) of brain tumors and have shown high uptake by brain tumor cells in tissue culture (in vitro). Third, gamma rays and internal conversion and Auger electrons are products of the 157Gd (n,γ)158Gd capture reaction (157Gd + nth (0.025eV) → [158Gd] → 158Gd
+ γ + 7.94 MeV). Although the gamma rays have longer pathlengths,
orders of magnitude greater depths of penetration compared with alpha
particles, the other radiation products (internal conversion and Auger electrons) have pathlengths of approximately one cell diameter and can directly damage DNA. Therefore, it would be highly advantageous for the production of DNA damage if the 157Gd
were localized within the cell nucleus. However, the possibility of
incorporating gadolinium into biologically active molecules is very
limited and only a small number of potential delivery agents for Gd NCT
have been evaluated.
Relatively few studies with Gd have been carried out in experimental
animals compared to the large number with boron containing compounds
(Table 1), which have been synthesized and evaluated in experimental
animals (in vivo). Although in vitro activity has been demonstrated using the Gd-containing MRI contrast agent Magnevist® as the Gd delivery agent, there are very few studies demonstrating the efficacy of Gd NCT in experimental animal tumor models, and, as evidenced by a lack of citations in the literature, Gd NCT has not, as of 2019, been used clinically in humans.
Neutron sources
Nuclear reactors
Until recently neutron sources for NCT have been limited to nuclear reactors and in the present section we only will summarize information that is described in more detail in a 2009 review. Reactor-derived neutrons are classified according to their energies as thermal (En <0 .5="" epithermal="" ev="" sub="">n
<10 fast="" kev="" or="" sub="">n >10 keV). Thermal neutrons are the most important for BNCT since they usually initiate the 10B(n,α)7Li
capture reaction. However, because they have a limited depth of
penetration, epithermal neutrons, which lose energy and fall into the
thermal range as they penetrate tissues, are not used for clinical
therapy other than for skin tumors such as melanoma.
A number of nuclear reactors with very good neutron beam quality have been developed and used clinically. These include:
Kyoto University Research Reactor Institute (KURRI) in Kumatori, Japan;
the FiR1 (Triga Mk II) research reactor at VTT Technical Research Centre, Espoo, Finland;
the RA-6 CNEA reactor in Bariloche, Argentina;
the High Flux Reactor (HFR) at Petten in the Netherlands; and
Tsing Hua Open-pool Reactor (THOR) at the National Tsing Hua University, Hsinchu, Taiwan.
JRR-4 at Japan Atomic Energy Agency, Tokai, JAPAN
However, as of April 2019, only the RA-6 reactor in Argentina and the
THOR reactor in Taiwan currently are being used for clinical studies.
Although not currently being used for BNCT, the neutron
irradiation facility at the MITR represented the state of the art in
epithermal beams for NCT with the capability of completing a radiation
field in 10–15 minutes with close to the theoretically maximum ratio of
tumor to normal tissue dose. Unfortunately, however, no clinical studies
currently are being carried out at the HFR and the MITR. The operation
of the BNCT facility at the Finnish FiR1 research reactor (Triga Mk II),
treating patients since 1999, was terminated in 2012 due to a variety
of reasons, one of which was financial.
It is anticipated that future clinical studies in Finland will utilize
an accelerator neutron source designed and fabricated in the United
States by Neutron Therapeutics, Danvers, Massachusetts. Finally, a
low-power "in-hospital" compact nuclear reactor has been designed and
built in Beijing, China, and at this time has only been used to treat a
small number of patients with cutaneous melanomas.
Accelerators
Accelerators also can be used to produce epithermal neutrons and
accelerator-based neutron sources (ABNS) are being developed in a number
of countries. Interested readers are referred to two recently published
reviews relating to accelerator neutron sources and abstracts of the 17th and 18th International Congresses
on Neutron Capture Therapy for more information on this subject. For
ABNS, one of the more promising nuclear reactions involves bombarding a 7Li
target with high-energy protons. An experimental BNCT facility, using a
thick lithium solid target, was developed in the early 1990s at the
University of Birmingham in the UK, but to date no clinical or
experimental animal studies have been carried out at this facility,
which makes use of a high-current Dynamitron accelerator originally supplied by Radiation Dynamics.
Recently, a cyclotron-based neutron source (C-BENS) has been developed by Sumitomo Heavy Industries (SHI) in Japan.
It has been installed at the Particle Radiation Oncology Research
Center of Kyoto University in Kumatori, Japan. It now is being used in a
Phase I clinical trial to evaluate its safety for treating patients
with high-grade gliomas. A second one has been constructed by High
Energy Accelerator Organization (KEK) with Mitsubishi Heavy Industrial,
and Toshiba, for use at University of Tsukuba in Japan. A third one is
being built by CICS with Hitachi for use in Tokyo. A fourth accelerator,
manufactured by SHI, is located at the Southern Tohoku BNCT Research
Center in Fukushima prefecture in Japan and is being used in a Phase II
clinical trial for BNCT of recurrent brain tumors and head and neck
cancer. Finally, a fifth one, which as of Spring 2019 has been installed
at Helsinki University Hospital in Finland.
This accelerator was designed and fabricated by Neutron Therapeutics in
Danvers, Massachusetts and it is anticipated that clinical use will
begin in the latter half of 2019. It will be important to determine how
these ABNS compare to BNCT that has been carried out in the past using
nuclear reactors as the neutron source.
Clinical studies of BNCT for brain tumors
Early studies in the US and Japan
It
was not until the 1950s that the first clinical trials were initiated
by Farr at the Brookhaven National Laboratory (BNL) in New York
and by Sweet and Brownell at the Massachusetts General Hospital (MGH)
using the Massachusetts Institute of Technology (MIT) nuclear reactor
(MITR)
and several different low molecular weight boron compounds as the boron
delivery agent. However, the results of these studies were
disappointing, and no further clinical trials were carried out in the
United States until the 1990s.
Following a two-year Fulbright fellowship in Sweet's laboratory
at the MGH, clinical studies were initiated by Hiroshi Hatanaka in Japan
in 1967. He used a low-energy thermal neutron beam, which had low
tissue penetrating properties, and sodium borocaptate (BSH) as the boron
delivery agent, which had been evaluated as a boron delivery agent by
Albert Soloway at the MGH. In Hatanaka's procedure,
as much as possible of the tumor was surgically resected ("debulking"),
and at some time thereafter, BSH was administered by a slow infusion,
usually intra-arterially, but later intravenously. Twelve to 14 hours
later, BNCT was carried out at one or another of several different
nuclear reactors using low-energy thermal neutron beams. The poor
tissue-penetrating properties of the thermal neutron beams necessitated
reflecting the skin and raising a bone flap in order to directly
irradiate the exposed brain, a procedure first used by Sweet and his
collaborators.
Approximately 200+ patients were treated by Hatanaka, and subsequently by his associate, Nakagawa. Due to the heterogeneity of the patient population, in terms of the microscopic diagnosis of the tumor and its grade, size, and the ability of the patients to carry out normal daily activities (Karnofsky performance status),
it was not possible to come up with definitive conclusions about
therapeutic efficacy. However, the survival data were no worse than
those obtained by standard therapy at the time, and there were several
patients who were long-term survivors, and most probably they were cured
of their brain tumors.
More recent clinical studies in the US and Japan
BNCT of patients with brain tumors was resumed in the United States in the mid-1990s by Chanana, Diaz, and Coderre
and their co-workers at the Brookhaven National Laboratory Medical
Research Reactor (BMRR) and at Harvard/Massachusetts Institute of
Technology (MIT) using the MIT Research Reactor (MITR).
For the first time, BPA was used as the boron delivery agent, and
patients were irradiated with a collimated beam of higher energy
epithermal neutrons, which had greater tissue-penetrating properties
than thermal neutrons. A research group headed up by Zamenhof at the
Beth Israel Deaconess Medical Center/Harvard Medical School and MIT was
the first to use an epithermal neutron beam for clinical trials.
Initially patients with cutaneous melanomas were treated and this was
expanded to include patients with brain tumors, specifically melanoma
metastatic to the brain and primary glioblastomas (GBMs). Included in
the research team were Otto Harling at MIT and the Radiation Oncologist
Paul Busse at the Beth Israel Deaconess Medical Center in Boston. A
total of 22 patients were treated by the Harvard-MIT research group.
Five patients with cutaneous melanomas were treated using an epithermal
neutron beam at the MIT research reactor (MITR-II) and subsequently
patients with brain tumors were treated using a redesigned beam at the
MIT reactor which possessed far superior characteristics to the original
MITR-II beam, and BPA as the capture agent. The clinical outcome of the
cases treated at Harvard-MIT has been summarized by Busse.
Although the treatment was well tolerated, there were no significant
differences in the mean survival times of patients that had received
BNCT compared to those who received conventional external beam
X-irradiation.
Miyatake and Kawabata at Osaka Medical College in Japan
have carried out extensive clinical studies employing BPA (500 mg/kg)
either alone or in combination with BSH (100 mg/kg), infused
intravenously (i.v.) over 2 h, followed by neutron irradiation at Kyoto
University Research Reactor Institute (KURRI). The Mean Survival Time
(MST) of 10 patients in the first of their trials was 15.6 months, with
one long-term survivor (>5 years). Based on experimental animal data,
which showed that BNCT in combination with X-irradiation produced
enhanced survival compared to BNCT alone, Miyatake and Kawabata combined
BNCT, as described above, with an X-ray boost.
A total dose of 20 to 30 Gy was administered, divided into 2 Gy daily
fractions. The MST of this group of patients was 23.5 months and no
significant toxicity was observed, other than hair loss (alopecia).
However, a significant subset of these patients, a high proportion of
which had small cell variant glioblastomas, developed cerebrospinal
fluid dissemination of their tumors.
In another Japanese trial, carried out by Yamamoto et al., BPA and BSH
were infused over 1 h, followed by BNCT at the Japan Research Reactor
(JRR)-4 reactor.
Patients subsequently received an X-ray boost after completion of BNCT.
The overall median survival time (MeST) was 27.1 months, and the 1 year
and 2-year survival rates were 87.5 and 62.5%, respectively. Based on
the reports of Miyatake, Kawabata, and Yamamoto, it appears that
combining BNCT with an X-ray boost can produce a significant therapeutic
gain. However, further studies are needed to optimize this combined
therapy alone or in combination with other approaches including chemo-
and immunotherapy, and to evaluate it using a larger patient population.
Clinical studies in Finland
A
team of clinicians led by Heikki Joensuu and Leena Kankaanranta and
nuclear engineers led by Iro Auterinen and Hanna Koivunoro at the
Helsinki University Central Hospital and VTT Technical Research Center
of Finland have treated approximately 200+ patients with recurrent
malignant gliomas (glioblastomas)
and head and neck cancer who had undergone standard therapy, recurred,
and subsequently received BNCT at the time of their recurrence using BPA
as the boron delivery agent.
The median time to progression in patients with gliomas was 3 months,
and the overall MeST was 7 months. It is difficult to compare these
results with other reported results in patients with recurrent malignant
gliomas, but they are a starting point for future studies using BNCT as
salvage therapy in patients with recurrent tumors. Due to a variety of
reasons, including financial,
no further studies have been carried out at this facility, which is
scheduled for decommissioning. However, a new facility for BNCT
treatment will be opened at Meilahti Tower Hospital
in 2019 using an accelerator designed and fabricated by Neutron
Therapeutics. This is the first BNCT accelerator specifically designed
to be used in a hospital, and the BNCT treatment and clinical studies
will be continued there. Both Finnish and foreign patients are expected
to be treated at the facility.
Table 2. Past BNCT clinical trials using an epithermal neutron beams for BNCT of patients with gliomas*
Reactor Facility*
No. of patients & duration of trial
Delivery agent
Median survival time (months)
BMRR, U.S.A
53 (1994–1999)
BPA 250–330 mg/kg
12.8
MITR, MIT, U.S.A.
20 (1996–1999)
BPA 250 or 350 mg/kg
11.1
KURRI, Japan
40 (1998–2008)
BPA 500 mg/kg
23.5 (primary + X-ray)
JRR4, Japan
15 (1998–2007)
BPA 250 mg/kg + BSH 5 g
10.8 (recurrent), 27.1 (+ X-ray)
R2-0, Studsvik Medical AB, Sweden
30 (2001–2007)
BPA 900 mg/kg
17.7 (primary)
FiR1, Finland
50 (1999–2012)
BPA 290–400 mg/kg
11.0 – 21.9 (primary), 7.0 (recurrent)
HFR, Netherlands
26 (1997–2002)
BSH 100 mg/kg
10.4 – 13.2
* A more comprehensive compilation of data relating to BNCT clinical trials can be found in Radiation Oncology 7:146–167, 2012
Clinical studies in Sweden
Finally,
to conclude this section, the following is a brief summary of a
clinical trial that was carried out by Stenstam, Sköld, Capala and their
co-workers in Sweden using BPA and an epithermal neutron beam at the
Studsvik nuclear reactor, which had greater tissue penetration
properties than the thermal beams originally used in Japan. This study
differed significantly from all previous clinical trials in that the
total amount of BPA administered was increased (900 mg/kg), and it was
infused i.v. over 6 hours. This was based on experimental animal studies
in glioma bearing rats demonstrating enhanced uptake of BPA by
infiltrating tumor cells following a 6-hour infusion.
The longer infusion time of the BPA was well tolerated by the 30
patients who were enrolled in this study. All were treated with 2
fields, and the average whole brain dose was 3.2–6.1 Gy (weighted), and
the minimum dose to the tumor ranged from 15.4 to 54.3 Gy (w). There has
been some disagreement among the Swedish investigators regarding the
evaluation of the results. Based on incomplete survival data, the MeST
was reported as 14.2 months and the time to tumor progression was 5.8
months. However, more careful examination
of the complete survival data revealed that the MeST was 17.7 months
compared to 15.5 months that has been reported for patients who received
standard therapy of surgery, followed by radiotherapy (RT) and the drug
temozolomide (TMZ).
Furthermore, the frequency of adverse events was lower after BNCT (14%)
than after radiation therapy (RT) alone (21%) and both of these were
lower than those seen following RT in combination with TMZ. If this
improved survival data, obtained using the higher dose of BPA and a
6-hour infusion time, can be confirmed by others, preferably in a randomized clinical trial, it could represent a significant step forward in BNCT of brain tumors, especially if combined with a photon boost.
Clinical Studies of BNCT for extracranial tumors
Head and neck cancers
The single most important clinical advance over the past 15 years
has been the application of BNCT to treat patients with recurrent
tumors of the head and neck region who had failed all other therapy.
These studies were first initiated by Kato et al. in Japan
and subsequently followed by several other Japanese groups and by
Kankaanranta, Joensuu, Auterinen, Koivunoro and their co-workers in
Finland.
All of these studies employed BPA as the boron delivery agent, usually
alone but occasionally in combination with BSH. A very heterogeneous
group of patients with a variety of histopathologic types of tumors have
been treated, the largest number of which had recurrent squamous cell
carcinomas. Kato et al. have reported on a series of 26 patients with
far-advanced cancer for whom there were no further treatment options.
Either BPA + BSH or BPA alone were administered by a 1 or 2 h i.v.
infusion, and this was followed by BNCT using an epithermal beam. In
this series, there were complete regressions in 12 cases, 10 partial
regressions, and progression in 3 cases. The MST was 13.6 months, and
the 6-year survival was 24%. Significant treatment related complications
("adverse" events) included transient mucositis, alopecia and, rarely,
brain necrosis and osteomyelitis.
Kankaanranta et al. have reported their results in a prospective
Phase I/II study of 30 patients with inoperable, locally recurrent
squamous cell carcinomas of the head and neck region.
Patients received either two or, in a few instances, one BNCT treatment
using BPA (400 mg/kg), administered i.v. over 2 hours, followed by
neutron irradiation. Of 29 evaluated patients, there were 13 complete
and 9 partial remissions, with an overall response rate of 76%. The most
common adverse event was oral mucositis, oral pain, and fatigue. Based
on the clinical results, it was concluded that BNCT was effective for
the treatment of inoperable, previously irradiated patients with head
and neck cancer. Some responses were durable but progression was common,
usually at the site of the previously recurrent tumor. As previously
indicated in the section on neutron sources, all clinical studies have
ended in Finland, based on a variety of reasons including economic
difficulties of the two companies directly involved, VTT and Boneca.
However, there are plans to resume clinical studies using an accelerator
neutron source designed and fabricated by Neutron Therapeutics.
Finally, a group in Taiwan,
led by Ling-Wei Wang and his co-workers at the Taipei Veterans General
Hospital, have treated 17 patients with locally recurrent head and neck
cancers at the Tsing Hua Open-pool Reactor (THOR) of the National Tsing Hua University.
Two-year overall survival was 47% and two-year loco-regional control
was 28%. Further studies are in progress to further optimize their
treatment regimen.
Other types of tumors
Melanoma and extramammary Paget's disease
Other extracranial tumors that have been treated include malignant melanomas,
which originally was carried out in Japan by the late Yutaka Mishima
and his clinical team in the Department of Dermatology at Kobe
University
using BPA and a thermal neutron beam. It is important to point out that
it was Mishima who first used BPA as a boron delivery agent and this
subsequently was extended to other types of tumors based on the
experimental studies of Coderre et al. at the Brookhaven National
Laboratory.
Local control was achieved in almost all patients, and some were cured
of their melanomas. More recently, Junichi Hiratsuka and his colleagues
at Kawasaki Medical School Hospital have treated patients with melanoma
of the head and neck region, vulva, and extramammary Paget's disease of
the genital region with impressive clinical results. The first clinical trial of BNCT in Argentina for the treatment of melanomas was performed in October 2003
and since then several patients with cutaneous melanomas have been
treated as part of a Phase II clinical trial at the RA-6 nuclear reactor
in Bariloche. The neutron beam has a mixed thermal-hyperthermal neutron
spectrum that can be use to treat superficial tumors. Finally, as recently reported,
the in-hospital neutron irradiator (IHNI) in Beijing has been used to
treat three patients with cutaneous melanomas with a complete response
of the primary lesion and no evidence of late radiation injury during a
24+-month follow-up period. The ultimate aim of the group in Beijing is
to initiate a multi-institutional randomized clinical trial to evaluate
BNCT of melanomas.
Colorectal cancer
Two
patients with colon cancer, which had spread to the liver, have been
treated by Zonta and his co-workers at the University of Pavia in Italy.
The first was treated in 2001 and the second in mid-2003. The patients
received an i.v. infusion of BPA, followed by removal of the liver
(hepatectomy), which was irradiated outside of the body (extracorporeal
BNCT) and then re-transplanted into the patient. The first patient did
remarkably well and survived for over 4 years after treatment, but the
second died within a month of cardiac complications.
Clearly, this is a very challenging approach for the treatment of
hepatic metastases, and it is unlikely that it will ever be widely used.
Nevertheless, the good clinical results in the first patient
established proof of principle. Finally, Yanagie and his
colleagues at Meiji Pharmaceutical University in Japan have treated
several patients with recurrent rectal cancer using BNCT. Although no
long-term results have been reported, there was evidence of short-term
clinical responses.
Conclusions
BNCT
represents a joining together of nuclear technology, chemistry,
biology, and medicine to treat brain tumors, recurrent head and neck
cancers, and cutaneous and extracutaneous melanomas. Sadly, the lack of
progress in developing more effective treatments for these tumors has
been part of the driving force that continues to propel research in this
field. BNCT may be best suited as an adjunctive treatment, used in
combination with other modalities, including surgery, chemotherapy,
immunotherapy, and external beam radiation therapy for those
malignancies, whether primary or recurrent, for which there are no
effective therapies. Clinical studies have demonstrated the safety of
BNCT. The challenge facing clinicians and researchers is how to move
forward. A significant advantage of BNCT is the potential ability to
selectively deliver a radiation dose to the tumor with a much lower dose
to surrounding normal tissues. This is an important feature that makes
BNCT particularly attractive for salvage therapy of patients with a
variety of malignancies who already have been heavily irradiated.
Although it may be only palliative, BNCT can produce striking clinical
responses, as evidenced by the experiences of several groups treating
patients with recurrent, therapeutically refractory head and neck
cancers.
Challenges that need to be addressed include:
Optimizing the dosing and delivery paradigms and administration of BPA and BSH.
The development of more tumor-selective boron delivery agents for BNCT.
Accurate, real time dosimetry to better estimate the radiation doses delivered to the tumor and normal tissues.
Evaluation of recently constructed accelerator-based neutron sources as an alternative to nuclear reactors.
For a more detailed discussion of these challenges and their
solutions in BNCT, readers are referred to the published abstracts of
the 17th and 18th International Congresses on Neutron Capture Therapy, two reviews on the current status of BNCT,
and a recent Commentary that provides a realistic appraisal of the
future of BNCT. If the problems enumerated above can be solved BNCT
could have an important role in twenty-first century cancer treatment of
those malignancies that are loco-regional and that are presently
incurable by other therapeutic modalities.
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