Prof. Anna Vašků1
LF MU
aVL- 2020/2021
Cancer as a complex disease
Pathophysiology of oncologic emergencies
General medicine
January 5, 2021
prof. Anna Vašků2
„Read and Write genome“ concept
̶ Genomes are DNA databases containing coding and formatting
sequences that permit heritable transmission of the capacity to
synthesize biologically adaptive RNA and protein molecules. In
the course of evolution, the coding sequences and formatting
signals change to encode novel adaptations. Traditionally, these
genome changes have been attributed to accidental causes. But
research on the mechanisms of DNA mutability has led to a
different picture of active biologically mediated genome
restructuring (Shapiro, 2011 and Shapiro, 2013).
̶ The fluid read–write (RW) genome replaces the constant readonly
memory (ROM) genome.
prof. Anna Vašků3
„Read and Write (RW) genome“
concept
̶ The basic idea of the RW genome is that cells use DNA
as a modificable data storage medium to encode the RNA
and protein molecules they need to deal with changing
circumstances.
̶ Change is continual for living organisms. Alterations occur
as cells progress through the cell cycle, as environmental
conditions vary, as cells experience damage, as
multicellular morphogenesis proceeds, and as they
interact with other cells and organisms.
prof. Anna Vašků4
„Read and Write (RW) genome“
concept
̶ To manage recurring short-term variations, cells primarily deploy transient
nucleoprotein complexes to regulate expression of genome data and carry
out the necessary tasks of cell growth and replication.
̶ For longer-term changes, such as cellular differentiation and multicellular
morphogenesis, heritable epigenetic modifications of the genome come into
play over a number of cell generations.
̶ For the longest-term changes that create new biological functions in
evolution, cells engage their natural genetic engineering (NGE) capabilities to
acquire and alter DNA sequences and reconfigure genome organization.
Sometimes, NGE functions also alter DNA structure to meet shorter-term
needs, such as rapid generation of diversity among adaptive immune system
receptors and countervailing variation of surface antigens on microbial
invaders.
prof. Anna Vašků5
„Natural genetic engineering
systems“
̶ The phrase “natural genetic engineering” (NGE)
reflects the reality that living cells possess all the
biochemical tools necessary for cutting, splicing,
polymerizing and modifying DNA (i.e., writing on their
genomes).
̶ NGE functions are analogous to the tools we use in
artificial genetic engineering. In addition, there are
certain complexes of biochemical activities and DNA
sequences that constitute specialized genome change
cassettes, summarized under the title “mobile
DNA”(Craig et al., 2015).
prof. Anna Vašků6
NGE
Endo- and exo-nucleases
Ligases
Error-free and mutator DNA polymerases
Site-specific recombinases
Homologous recombination complexes
Non-homologous end-joining (NHEJ) complexes
Reverse transcriptases (RTs)
Transposons and transposases
Retroviruses / retrotransposons and cDNA integrases
RNA chaperones / endonucleases and RTs for target-primed reverse transcription
(TPRT) and genome insertion of cDNA copies of retroelement or cellular RNAs
DNA secretion and uptake systems
RNA secretion and uptake systems
Viruses
prof. Anna Vašků7
RW concept and cancer
̶ Cancer occurs when cells decouple from an
organismʼs normal regulatory apparatus and
proliferate uncontrollably to form a neoplasm,
which may spread around the body to colonize
remote organs (metastasis).
̶ Cancer remains deeply mysterious.
prof. Anna Vašků8
RW concept and cancer
̶ Cancer comes in many varieties (it is, for example, specific to the
organ of origin), but its progression generally follows a pattern.
̶ Clinicians have identified a dozen or so “hallmarks” of cancer,
such as genome instability and heterogeneity, a shift in
metabolism from oxidation–phosphorylation to fermentation
(glycolysis), disabling of apoptotic pathways, transition to a motile
state, evasion of the immune system, and a degree of cell–cell
cooperation including the recruitment of normal cells in the vicinity
of the primary tumor and in metastatic niches.
prof. Anna Vašků9
RW concept and cancer
̶ In spite of the focus on cancer as a human disorder, it is found to
be widespread in biology, occurring among mammals, fish, reptiles
and even plants. This suggests ancient evolutionary roots.
̶ Multicellular organisms outsource their heritability to specialized
germ cells, and in return somatic cells are subject to strict controls
over their proliferation, such as apoptosis and tumor suppressor
mechanisms.
̶ Cancer represents a breakdown in these controls, and thus an
abrogation of an ancient covenant that dates back to the dawn of
multicellularity over 1 billion years ago. Even “primitive” organisms
such as sponges, with lineages hundreds of millions of years old,
possess tumor suppressor genes.
prof. Anna Vašků10
Cancer
̶ Cancer does not seem to be a series of genetic accidents,
but a deeply pre-programmed, ancient, systematic
response to an insult or stress!
̶ The “cancer subroutine” is unlikely to be as simple as a
cassette of genes activated in an orderly sequence but a
gene regulatory network with a pre-defined dynamical
trajectory.
prof. Anna Vašků11
Tumorigenesis is a multistep evolutionary process involving myriad, genetic,
and epigenetics alterations. Epigenetic alterations during cancer initiation
and progression provide an abundant source of variability that not only
promotes rapid tumor adaptation but also provides a rich source of labile
biomarkers to complement genetic analysis.
Tumour Biol. 2016 Jul 28. Biomarkers of genome instability
and cancer epigenetics. Reis AH, Vargas FR, Lemos B.
prof. Anna Vašků12
Genome stability
̶ Since our genomes are constantly exposed to
exogenously-derived (e.g. UV radiation) and
endogenously-derived (e.g. metabolically
generated reactive oxygen species) DNA
damaging agents, an impaired ability to
detect and/or respond appropriately to these
efects can impact on the maintenance of
genetic stability.
O´Driscoll M: Curr Genomics. 2008 May; 9(3): 137–146
prof. Anna Vašků13
prof. Anna Vašků14
Tumor-supresor protein p53 (TP53)
̶ Is a nuclear protein with key role between G0 and G1
phase of the cell cycle.
̶ Mutant variants of the p53 gene can be found in many
cancer types.
̶ Somatic mutations-usually
̶ Germ mutations (syndrome Li-Fraumeni).
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p53-germ cell mutation
̶ Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition
syndrome that is commonly associated with a germline mutation in
the tumor suppressor gene p53.
̶ Loss of p53 results in increased expression of CD44, a cancer
stem cell (CSC) marker, which is involved in the scavenging of
reactive oxygen species (ROS).
prof. Anna Vašků16
Genome stability
̶ There are many examples of human Mendelian
disorders defective in the repair of or response to
DNA damage.
̶ The importance of these pathways is demonstrated
by the increase in cancer predisposition and
developmental abnormalities associated with these
conditions.
O´Driscoll M: Curr Genomics. 2008 May; 9(3): 137–146
prof. Anna Vašků17
Copy number variants
̶ The changes in gene copy number are associated with
different phenotypes in humans. Perhaps, the most well
known example of this is the trisomy 21 causative of Down
syndrome.
̶ An increased expression of the genes on chromosome 21
results directly or indirectly in a clinically heterogeneous
disorder incorporating cognitive impairment, facial
dismorphology, growth retardation, cancer predisposition,
microcephaly, heart and skeletal abnormalities
O´Driscoll M: Curr Genomics. 2008 May; 9(3): 137–146
prof. Anna Vašků18
Gene mutations as a cause
of variability in genes
̶ Rare alleles - prevalence less than 1% in
population as a result of selection pressure
and/or „recent“ mutation. These mutations
represent „great genetic factors“ causing
monogenic diseases
̶ Polymorphisms - prevalence more than 1% in
population, smaller genetic factors in
interactions with environmental factors
conditioning complex diseases (including most
of sporadic cancers).
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Gene mutations as a cause of variability in genes
̶ Mutations in somatic cells
✓are generating in somatic cells during the lifetime
✓are cell and/or tissue specific, without transfer to
offspring
̶ Mutations in germ cells
✓they become components of genetic predisposition
✓they are present in all cells of the individual
✓they are transfered to offspring
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MR Stratton et al. Nature 458, 719-724 (2009)
The lineage of mitotic cell divisions from the
fertilized egg to a single cell within a cancer showing
the timing of the somatic mutations acquired by the
cancer cell and the processes that contribute to
them.
Somatic cell mutations: an example
Sporadic colorectal cancer
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MR Stratton et al. Nature 458, 719-724 (2009)
Figurative depiction of the landscape of
somatic mutations present in a single cancer genome.
Somatic cell mutations: an example
Sporadic colorectal cancer
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Tumor epigenetics
̶ It is now generally accepted that human cancer cells harbor global
epigenetic abnormalities and that epigenetic alterations may be
the key to initiating tumorigenesis(Baylin and Jones, 2011;
Sandoval and Esteller, 2012; Sharma et al., 2010).
̶ The cancer epigenome is characterized by substantial changes in
various epigenetic regulatory layers.
̶ Differences in DNA and histon methylation and acetylation state of
histones in cancer DNA have been found.
prof. Anna Vašků23
DNA methylation
̶ Human malignant tumors are characterized by pervasive changes in the patterns of DNA
methylation. These changes include a globally hypomethylated tumor cell genome and
the focal hypermethylation of numerous 5'-cytosine-phosphate-guanine-3' (CpG) islands,
many of them associated with gene promoters.
̶ Specific DNA methylation changes were linked with tumorigenesis in a cause-and-effect
relationship.
̶ Cancer-associated DNA hypomethylation may increase genomic instability.
̶ Promoter hypermethylation events can lead to silencing of genes functioning in
pathways reflecting hallmarks of cancer, including DNA repair, cell cycle regulation,
promotion of apoptosis or control of key tumor-relevant signaling networks.
̶ Many of the most commonly hypermethylated genes encode developmental
transcription factors, the methylation of which may lead to permanent gene silencing.
Inactivation of such genes will deprive the cells in which the tumor may initiate from the
option of undergoing or maintaining lineage differentiation and will lock them into a
perpetuated stem cell-like state thus providing an additional window for cell
transformation.
Int J Mol Sci. 2018 Apr 12;19(4)
prof. Anna Vašků24
Tumor phenotype
Is characterised by the process of malignant
transformation of the cell with
- loss of control of cell division (alterations in cell
cycle, antiapoptotic state, „immortality „ of tumor
cell, alteration in signal transduction),
- loss of cell-cell contant inhibition,
- invasivity,
- changes in metabolism
- proangiogenetic activation
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Malignant transformed cells
➢Continue their division.
➢Needs for presence of hormones and
growth factors decreased.
➢Production of own growth factors
(autocrinnal stimulation).
➢Decrement of ability to stop the growth.
➢Decreased ability to stop the growth in
worse nutrition conditions
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Tumors and immortality of cells
̶ Increased activity of telomerase.
̶ Telomers are key stabilisation factors of terminal part of
the chromosome.
̶ Telomeres have repetitive sequence TAGGG.
̶ The length of telomers is decreased after multiple
divisions of the cell (1 cell cycle is shortening of 1
telomere).
̶ Their renewal is catalysed by telomerase.
Two mechanisms during tumorigenesis:
mechanisms TERT („telomerase reverse transcriptase“)
„alternative lengthening of telomere (ALT) pathway“),
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Metastatic phenotype
➢Increased motility, invasion and ability to form metastases.
➢Increased production of receptors (adhesive molecules)
➢Increased production of hydrolytic enzymes
➢Function of chemokines
➢Loss of dependence to adhere to substrates (tumor cells
are able to divide even in tissue culture)
➢Loss of gap junctions.
➢Changes in cell membrane (glycolipids and glycoproteins
modifications).
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Phenomenon of tumor suport
➢Chemical cancerogenes:
➢Initiators: compounds with cancerogenic
potential after their metabolisation (P450).
➢Promoters: effects possible after initiators
(phorbolester).
prof. Anna Vašků29
Inflammation and tumorigenesis
̶ Epigenetic switches play an important role in cancer development.
̶ Most of the currently discovered switches are induced by
inflammation or involve inflammatory signaling.
̶ Chronic infections and inflammation contribute to about 25 % of all
cancers.
̶ In many examples, the same inflammatory trigger (e.g., IL-6) that
induced the switch is constitutively activated in cancer cells to
maintain the new (tumor) phenotype.
prof. Anna Vašků30
Apoptosis and tumorigenesis
̶ Overexpression of Bcl2 (B-cell lymphoma 2) gene was
found to be related to inhibition of apoptosis during
tumorigenesis.
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Tumor neoangiogenesis
̶ Dysequilibrium between antiangiogenetic and proangiogenetic
factors („angiogenetic switch“).
̶ Without neoangiogenetic switch, the tumor growth is possible
only to 1 – 2 mm3, when O2 and nutrients support is possible
by difussion from surrounding tissue.
̶ Hypoxia of tumor cells
̶ HIF- alpha induced transcription angiogenetic factors
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Hypoxia and tumor angiogenesis
➢Hypoxia occurs in chronic and acute vascular
diseases and tumor formation.
➢Human tumors grew like cords around blood vessels,
and tumor cells located > 180 µm from the blood
vessels were observed to become necrotic.
➢Hypoxia induces angiogenesis during tumor growth;
when tumor growth progresses, HIF-1 program is
switched iiun the tissue. As a result, also angiogenesis
occurs and the tumor develops its own vasculature.
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prof. Anna Vašků35
Oncologic emergencies
̶ can occur at any time during the course of a malignancy,
from the presenting symptom to end-stage disease.
̶ Although some of these conditions are related to cancer
therapy, they are by no means confined to the period of
initial diagnosis and active treatment.
̶ Prompt identification of and intervention in these
emergencies can prolong survival and improve quality of
life, even in the setting of terminal illness.
prof. Anna Vašků36
Hypercalcemia
̶ Hypercalcemia will be experienced by up to one-third of cancer
patients at some point in their disease course. Among patients
hospitalized for hypercalcemia, malignancy is the most common
cause
̶ Breast, lung, and renal cell carcinomas; multiple myeloma; and
adult T-cell leukemia/lymphoma are the prevailing causes of
hypercalcemia.
prof. Anna Vašků37
Hypercalcemia
̶ Bone metastases may cause a local paracrine effect by producing several factors that
stimulate osteoclasts, leading to bone resorption with resultant hypercalcemia and bone
destruction.This is most commonly seen in metastatic breast cancer and multiple myeloma.
Prostate cancer, despite the frequency with which it metastasizes to bone, only rarely causes
hypercalcemia, underscoring that it is not just osseous involvement but the specific tumorbone
interaction that determines calcium liberation from bone.
̶ Very rarely, a tumor will manufacture PTH itself.
̶ Tumor production of vitamin D analogues is a less common etiology of malignant
hypercalcemia.
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Hypercalcemia
̶ Up to 80% of malignant hypercalcemia is caused by PTHrP released by the tumor into
the systemic circulation. Given its homology to parathyroid hormone (PTH), PTHrP can
mimic the action of PTH on the bones and kidneys but, unlike PTH, PTHrP does not
influence intestinal absorption of calcium.
̶ The effects of PTHrP represent a true paraneoplastic syndrome (ie, systemic signs and
symptoms caused by a tumor), with circulating PTHrP causing bone resorption and renal
retention of calcium. Squamous cell carcinomas from the aerodigestive and genitourinary
tracts commonly cause this type of “humoral” hypercalcemia but this can also be seen in
breast, kidney, cervical, endometrial, and ovarian cancer.
prof. Anna Vašků39
Parathyroid Hormone Relation Peptide (PTHrP)
̶ PTHrP was discoverde as mediator of syndrome "humoral
hypercalcemia of malignancy" (HHM).
̶ During the syndrome inn different type of cancer (in absebce of
metastases) similar compounds to PTH are produceds which is
related to:
̶ Hypercalcemia
̶ Hypophosphatemia
̶ Increased cAMP exctretion by urine
̶ The effects are similar to those caused by PTH; no PTH levels are
detected.
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OPG/RANK/RANKL as a common effector in bone immune system and a vascular
system
̶ OPG, RANK and RANKL are selectively produced by many cell
types in diferent tissue: lymphocytes, osteoblasts and endothelial
cells.
̶ RANKL is functioning as a survival factor for dendritic cells and as a
osteoclastogenic factor after RANK ligation.
̶ OPG inhibits activation of osteoclasts by blocking RANKL/RANK
interaction.
̶ OPG/RANKL/RANK triad is considered a osteoimmunomodulating
complex.
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Genetic families of PTH and PTHrP: PTHrP, PTH and TIP39 are
probably members of the same genetic family. Their receptors
PTH1R and PTH2R are 7 transmembrane G protein-coupled
receptors.
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Production of PTHrP regulated by growth factor (GF) in tumor states. Tumor cells
are able to be stimulated at a distance (outside the bone) by autocrine
growth factors to an increased production of PTHrP. It reaches via circulation
the bone tissue and supports bone resorption. Metastatic tumor cells in the
bone are able to secrete PTHrP supporting bone resorption and paracrine
growth factors which further support PTHrP production.
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Oncogenic osteomalacia
̶ Oncogenic osteomalacia is a paraneoplastic syndrome in which a bone or soft tissue
tumor or tumor-like lesion induces hypophosphatemia and low vitamin D levels that
reverse when the inciting lesion is resected.
̶ In the past 15 or so years, a humoral factor, phosphotonin, has been identified in
clinical and experimental studies as being responsible for the serum biochemical
changes.
̶ Phosphotonin causes hyperphosphaturia by inhibiting the reabsorption of phosphate
by the proximal renal tubules.
̶ Fibroblast growth factor 23, phosphate-regulating gene with homologies to
endopeptides located on the ‘x’ chromosome (PHEX) and matrix extracellular
phosphoglycoprotein (MEPE) are candidates proposed for the production of
phosphatonin and the altered pathophysiology in oncogenic osteomalacia.
prof. Anna Vašků45
Symptoms of hypercalcemia
̶ The symptoms of hypercalcemia are
nonspecific, and delayed recognition of
this metabolic derrangement can worsen
morbidity and mortality. The mnemonic
“bones, stones, moans, and groans” is
used to emphasize
̶ skeletal pain,
̶ nephrolithiasis,
̶ abdominal discomfort, and
̶ altered mentation
prof. Anna Vašků46
Symptoms of hypercalcemia
̶ Bone pain is usually related to discrete metastases
̶ Even in the setting of profound hypercalciuria, not all patients
will form kidney stones, which may be due to differences in the
urine mineral concentration needed to precipitate calculi.
̶ Abdominal pain can arise from dysregulated intestinal motility,
pancreatitis, or severe constipation.
̶ Changes in sensorium can occur along a spectrum from
lethargy to coma.
̶ In addition, hypercalcemia shortens the QT interval and can
produce arrhythmias.
prof. Anna Vašků47
Hyponatremia
̶ The assessment of hyponatremia in cancer patients, as in all
patients, requires a critical determination of volume status.
̶ The sodium concentration is the largest contributor to plasma
osmolarity and reflects how much water is present in the blood
relative to the cells, in which the majority of the body's water is
stored. Laboratory measurement of the sodium concentration thus
reveals the distribution of water among the body's fluid
compartments, and hyponatremia means that intravascular water
is present in excess relative to sodium, either through water
retention and/or sodium loss.
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Hyponatremia
̶ The amount of sodium in the body, not the plasma sodium concentration,
determines the volume of fluid outside the cells, and this volume can be
readily measured by physical examination.
̶ If the total body sodium is high, then the extracellular fluid volume is large and
the patient will appear edematous.
̶ If the total body sodium is low, then the extracellular space (including the
circulatory volume) will contract and the patient will progressively develop
hypotension and tachycardia.
̶ A low plasma sodium concentration can thereby be associated with clinical
hypervolemia, hypovolemia, or euvolemia, depending upon total sodium
content. The physician must correctly evaluate the hyponatremic patient's
volume to understand both their sodium and water balance and then select
the appropriate treatment.
prof. Anna Vašků49
SIADH
̶ Euvolemic hyponatremic patients with cancer have normal
extracellular fluid volume, reflecting appropriate total sodium
content, but excessive water in the intravascular space can be
observed, most commonly mediated through the syndrome of
inappropriate antidiuretic hormone (SIADH).
̶ Antidiuretic hormone promotes free water uptake in the distal
tubules by binding to the vasopressin 2 (V2) receptor.
Compounding the problem is continued free water intake because
the thirst mechanism is not sufficiently inhibited.
prof. Anna Vašků50
SIADH
̶ SIADH should be suspected based upon the location of primary and
metastatic tumors because SIADH is more commonly encountered in
diseases originating in or involving the lungs, pleura, thymus, and brain.
Between 10% to 45% of patients with small cell lung cancer will show
evidence of SIADH.
̶ Iatrogenic causes of hyponatremia include cisplatin, cyclophosphamide,
ifosfamide, the vinca alkaloids, and imatinib. Each of these drugs can cause
SIADH, but all can also produce hyponatremia through a variety of other
mechanisms (eg, platinum-induced salt-wasting nephropathy), and therefore
careful evaluation is required to determine the underlying etiology of
hyponatremia in patients receiving these medications.
̶ Drugs with high emetogenic potential can stimulate ADH release through
nausea, an appropriate physiologic response that may be confused with
SIADH.
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Hyponatremia
̶ Hyponatremia can be classified as mild (131-135 mmol/L),
moderate (126-130 mmol/L), or severe (<125 mmol/L). Serum
glucose should be measured to ensure that hyperglycemia is not
creating a spurious finding of hyponatremia.
̶ SIADH is diagnosed when, after exclusion of adrenal insufficiency
and hypothyroidism, the effective osmolality (calculated by
subtracting [blood urea nitrogen (BUN)/2.8] from the measured
osmolality) is less than 275 milliosmoles (mOsm)/kg of water, and
the urine osmolality exceeds 100 mOsm/kg of water.
̶ Urine sodium greater than 40 mmol/L in the absence of excessive
dietary sodium intake, hypouricemia less than 4 mg/dL, and BUN
less than 10 mg/dL all support the diagnosis of SIADH.
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Hypoglycemia
̶ Hypoglycemia can arise in the patient with cancer through several
etiologies. Some tumors are capable of ectopic production of
substances that affect glucose metabolism. Insulin is made in
excess by insulinomas and nesidioblastosis.
̶ Mesenchymal tumors like sarcoma, including gastrointestinal
stromal tumor and solitary fibrous tumor, can produce insulin-like
growth factors (IGFs) such as IGF-2, which increases glucose
utilization by tissues and blunts the secretion of growth hormone.
̶ Levels of a related protein, IGF-1, have been reported to be
elevated in rare cases of lung cancer. Rapidly proliferating
neoplasms can consume glucose prodigiously. Overexpression of
the mitochondrial enzyme hexokinase II allows some cancer cells
to maintain glycolysis even in the presence of oxygen.
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Hypoglycemia
̶ In fact, this disproportionate uptake through the Warburg effect is exploited in
fluorodeoxyglucose positron emission tomography imaging to visualize
tumors against a background of normal tissue. Given the anabolic and
biosynthetic demands of dividing cells, tumors with high mitotic rates may
consume glucose with sufficient briskness as to induce hypoglycemia; this is
most often seen in aggressive lymphomas (eg, Burkitt lymphoma) but has
also been described in small cell lung cancer. The swift proliferation may be
associated with increased lactic acid, even in the absence of hypoxemia.
Tumors can infiltrate organs that play crucial roles in normal glucose
metabolism, such as hepatocellular carcinoma replacing the liver parenchyma
or pheochromocytoma overtaking the adrenal gland.
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Signs and symptoms
̶ of hypoglycemia arise both from neuroglycopenia and adrenergic
counterregulation.
̶ Neurologic manifestations range from confusion and blurred vision to
seizures and coma.
̶ The catecholamine response to hypoglycemia can result in diaphoresis,
palpitations, and dilation of the pupils.
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Tumor Lysis Syndrome (TLS)
̶ Tumor lysis occurs when cancer cells release their contents into
the bloodstream, either spontaneously or following antineoplastic
therapy, leading to an influx of electrolytes and nucleic acids into
the circulation.
̶ The sudden development of hyperkalemia, ammonia,
hyperuricemia, and hyperphosphatemia can have life-threatening
end-organ effects on the myocardium, kidneys, and central
nervous system (CNS).
̶ Hypocalcemia, a consequence of hyperphosphatemia, is included
in the constellation of metabolic disturbances known as tumor lysis
syndrome (TLS).
prof. Anna Vašků56
TLS
̶ Patients are variably symptomatic from the metabolic derangements of TLS.
Clinical TLS is diagnosed when one or more of 3 conditions arise:
̶ acute renal failure (defined as a rise in creatinine to 1.5 times or more the
upper limit of normal that is not attributable to medications),
̶ arrhythmias (including sudden cardiac death), and
̶ seizures
̶ Acute renal failure can manifest as a decrease in urine output, uremia-related
altered sensorium, or crystalline obstructive uropathy.
̶ Arthralgias can arise from gout flare.
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TLS
̶ TLS is more common in the rapidly proliferative hematologic malignancies
such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML),
and Burkitt lymphoma, but has been documented in solid tumors, notably
small cell lung cancer, germ cell tumors, inflammatory breast cancer, and
melanoma. Liver metastases may increase TLS risk.
̶ Treatment-provoked TLS can occur following chemotherapy, treatment with
single-agent corticosteroids in patients with sensitive tumors, radiation,
surgery, or ablation procedures.
The onset of TLS can be delayed by days to weeks in a patient with a solid
malignancy.
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̶ The pericardial sac is distensible up to a volume of 2 l, if stretching
occurs over a slow time period.
̶ Rising intrapericardial pressure affects all 4 cardiac chambers, but the
right ventricular wall is much thinner and more susceptible to extrinsic
compression. Diastolic pressures throughout the chambers begin to
equalize and adversely affect cardiac output by compromising filling.
̶ At this point, tamponade pathophysiology emerges.
Cardiovascular Emergencies
Pericardial Effusion and Cardiac Tamponade
prof. Anna Vašků59
̶ Malignant pericardial effusions develop through direct or
metastatic involvement of the pericardial sac. Direct
extension is most common in those tumors with sites of
origin adjacent to the heart: lung cancer, breast cancer,
and mediastinal lymphoma.
̶ Metastases to the epicardium are seen in noncontiguous
breast and lung cancer, as well as in melanoma.
̶ Primary neoplasms of the pericardium are exceedingly
rare, but include mesothelioma.
̶ Cancer treatment, especially thoracic irradiation, can
cause transudative effusions. Immunosuppression can
also allow suppurative infections to develop in the
pericardial space.
Cardiovascular Emergencies
Pericardial Effusion and Cardiac Tamponade
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Pericardial Effusion and Cardiac Tamponade
̶ Pericardial effusions can be asymptomatic, although their presence portends
a poor prognosis, especially if larger than 350 mls.
̶ Pericarditis symptoms may precede the emergence of tamponade.
Tamponade classically presents with the Beck triad: hypotension, elevated
jugular venous pressure, and a muffled precordium. However, only a minority
of patients actually demonstrate all 3 signs. Most patients complain of
dyspnea and chest discomfort, which may begin abruptly.
̶ Tamponade pathophysiology can arise from volumes of as little as 100 ml if
they accumulate rapidly. Even if the effusion forms over a longer period of
time, the “last drop” phenomenon describes the critical point of
pathophysiologic collapse at which intrapericardial pressure finally overcomes
the compensatory mechanisms of the heart and causes cardiac output to
drop precipitously. In this manner, a chronic effusion can cause hyperacute
symptomatology.
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Diagnosis
̶ The diagnostic utility of the physical examination should not be discounted
but should be coupled with appropriate studies. Tachycardia is nearly
universal, and pulsus paradoxus is an ominous finding, with a value greater
than 10 mm Hg having been arbitrarily defined as abnormal.
̶ Chest x-rays may show cardiomegaly and the classic “water bottle” cardiac
silhouette.
̶ Electrocardiography can show low voltage and electrical alternans from the
shifting axis of the heart as it moves like a pendulum within the fluid-filled sac.
̶ Echocardiography is the definitive test, demonstrating right ventricular
collapse during early diastole.
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Superior Vena Cava Syndrome
̶ The thin-walled superior vena cava (SVC) returns all blood from
the cranial, neck, and upper extremity vasculature to the right side
of the heart.
̶ Primary or metastatic tumors can cause compression.
̶ Nononcologic etiologies include syphilitic aortic aneurysms
(vanishingly rare since the advent of penicillin), fibrosing
mediastinitis (classically associated with histoplasmosis),
substernal hypertrophy of the thyroid, granulomatous disease
(such as tuberculosis and sarcoidosis), and thrombosis,
particularly that due to an underlying hypercoagulable state or
endothelial damage from an indwelling vascular device.
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Superior Vena Cava Syndrome
̶ The extent of SVC obstruction and acuity of development dictate the patient's
presentation. Blockage is better tolerated when there has been time for
collateral veins to develop in adjacent venous systems like the azygos and
internal mammary, a process that usually takes weeks.
̶ The veins on the patient's chest wall may be visibly distended.
̶ Edema in the arms, facial plethora (not necessarily unilateral), chemosis, and
periorbital edema may also occur. Stridor is an alarming sign that edema is
narrowing the luminal diameter of the pharynx and larynx.
̶ Hoarseness and dysphagia can result from edema around the aerodigestive
tracts.
̶ Presyncope or syncope is more common early on, when cardiac output
declines without compensation.
̶ Headaches stem from distention of cerebral vessels against the dura, but
confusion may indicate cerebral edema.
̶ All of these symptoms may be more noticeable when the patient is supine.
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Diagnosis
̶ Cancers classically associated with SVC syndrome include lung cancer
(particularly right-sided), breast cancer, primary mediastinal lymphoma,
lymphoblastic lymphoma, thymoma, and germ cell tumors (either
primary or metastatic to the mediastinum).
̶ Radiographic imaging is crucial to diagnosis and treatment planning,
especially if radiation and endovascular stents are potential
interventions.
prof. Anna Vašků65
Infectious Emergencies
Neutropenic Fever
̶ A patient's absolute neutrophil count (ANC) can decline through a cancer's
direct interference with hematopoiesis, as in leukemia or metastatic
replacement of the bone marrow, but neutropenia is most commonly seen as
an effect of cytotoxic therapy.
̶ Other risk factors include the rapidity of the ANC decline; exposure to prior
chemotherapy or current immunosuppression; pretreatment elevations in
alkaline phosphatase, bilirubin, or aspartate aminotransferase levels; reduced
glomerular filtration rate; and cardiovascular comorbidities. T
̶ The classes of chemotherapy with the highest risk of inducing neutropenia
are the anthracyclines, taxanes, topoisomerase inhibitors, platinums,
gemcitabine, vinorelbine, and certain alkylators like cyclophosphamide and
ifosfamide.
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Neutropenic fever
̶ Infection is responsible for at least half of the cases of neutropenic
fever. Fever is a single oral temperature of 38.3°C (101°F) or
higher, or temperatures of 38.0°C (100.4°F) or higher measured 1
hour apart.
̶ A patient's reduced ability to mount an inflammatory response can
limit localizing signs and symptoms, and therefore fever may be
the only abnormal finding at presentation. Skin and soft tissue
infections may not be associated with erythema or induration, and
abscesses will not accumulate in the absence of pus-generating
neutrophils. Pulmonary infections may not result in audible or
radiographically visible.
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Infectious Emergencies
̶ A minority of cases of febrile neutropenia will have an offending infectious
agent identified. Of those that do have a documented infectious source, a
variety of organisms can be responsible.
̶ Gram-positive cocci, which are now responsible for the majority of culturepositive
cases of neutropenic fever, include Staphylococcus aureus,
Staphylococcus epidermidis (especially in patients with indwelling devices),
Streptococcus pneumoniae, Streptococcus pyogenes, the Streptococci
viridans, and Enterococcus faecalis and faecium. Corynebacterium is the
most likely gram-positive bacillus.
̶ Gram-negative bacilli include Escherichia coli, Klebsiella species, and
Pseudomonas aeruginosa.
̶ Candida is the most common fungal infection, but Aspergillus and
Zygomycetes are more feared for their angioinvasive predilection.
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Neurologic Emergencies
̶ Malignant spinal cord compression (MSCC) was first described in
1925 by Spiller and remains a common oncologic emergency that
requires prompt treatment to relieve pain and preserve
neurological function.
̶ Although all tumor types have the potential to cause MSCC,
breast, prostate, and lung cancer each account for approximately
15% to 20% of the cases, with non-Hodgkin lymphoma, renal cell
carcinoma, and myeloma each causing 5% to 10% of cases.
̶ Although most cases of MSCC occur in patients with a known
diagnosis of malignancy, 5% to 25% of MSCC cases occur as the
initial presentation of malignancy.
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Neurologic Emergencies
̶ MSCC is defined as the compressive indentation, displacement, or
encasement of the thecal sac that surrounds the spinal cord or
cauda equina by cancer.
̶ Compression can occur by posterior extension of a vertebral body
mass, by anterior extension of a mass arising from the dorsal
elements, or by growth of a mass invading the vertebral foramen.
̶ The majority of the cases occur when metastatic tumor reaches
the vertebral bodies via hematogenous spread, with secondary
erosion into the epidural space.
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Neurologic Emergencies
̶ Early detection is critical because the single most important prognostic factor for regaining
ambulation after treatment of MSCC is pretreatment neurologic status.
̶ The clinical presentation of MSCC can vary significantly depending on severity, location, and
duration of the compression.
̶ The most common initial symptom is back pain, which occurs in approximately 90% of the
cases. Because back pain is a common symptom and has multiple causes, clinicians must
always keep MSCC in their differential diagnosis. It is also important to remember that MSCC
can be the initial presentation of malignancy. In a retrospective series of 337 patients with
MSCC at the Mayo Clinic, compression was the first sign of malignancy in 20% of the cases,
with lung cancer, multiple myeloma, and non-Hodgkin lymphoma accounting for
approximately 75% of these initial presentations manifested by spinal epidural metastases.
̶ The back pain associated with MSCC may gradually worsen over time and usually precedes
neurologic symptoms by weeks to months. Referred pain is common and varies according to
the location of the offending lesion. Cervical compression can present as subscapular pain,
thoracic compression as lumbosacral or hip pain, and lumbosacral compression as thoracic
pain.6
prof. Anna Vašků71
Neurologic Emergencies
̶ Once symptoms other than pain are present, the progression can be quite
rapid. These symptoms include motor weakness, sensory impairment, and
autonomic dysfunction. Cauda equina syndrome may present as urinary
retention and overflow incontinence (90% sensitivity and 95% specificity).
Other symptoms include decreased sensation over the buttocks, posterior
superior thighs, and perineal region.
̶ Physical examination findings depend on the location of the lesion(s) as well
as the degree and duration of impingement.
̶ Most patients have tenderness to percussion over the affected spinal region.
̶ The Valsalva maneuver may worsen their back pain.
̶ Hyperreflexia, spasticity, and loss of sensation (position, temperature,
pinprick, and vibratory) can occur early.
̶ Deep tendon reflexes may then become hypoactive or absent.
̶ Late signs include weakness, Babinski sign, and decreased anal sphincter
tone.
prof. Anna Vašků72
Malignant spinal cord compression (MSCC)
Because there is no clinical model to rule out MSCC in
cancer patients with back pain, all reports of new-onset
back pain should prompt an immediate assessment. For
those patients with only back pain and a normal
neurologic examination, imaging of the spinal axis
should be completed within the next 48 to 72 hours.
Those with neurologic deficits need emergent
evaluation before nerve damage becomes permanent.
The gold standard for the diagnosis of MSCC is MRI,
with a sensitivity of 93%, a specificity of 97%, and an
overall accuracy of 95%.
prof. Anna Vašků73
Increased Intracranial Pressure
̶ Elevated intracranial pressure (ICP) secondary to malignancy in
the brain can cause devastating neurologic injury. Successful
management requires prompt recognition and therapy. The vast
majority of all intracranial neoplasms are metastatic, with lung
cancer (20%), breast cancer (5%), melanoma (7%), renal cancer
(10%), and colorectal cancer (1%) being the most common tumors
of origin.
̶ Untreated patients have a median survival of approximately 4
weeks.
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Increased Intracranial Pressure
̶ The majority of metastases travel to the brain via hematogenous
spread.
̶ Tumor microemboli tend to lodge in the distal arteries and small
capillaries of the “watershed” areas and the gray-white matter
junctions. The distribution of metastases also follows the relative
blood flow volume of the brain, with most occurring in the
cerebrum, then the cerebellum, followed by the brainstem.
̶ Increased ICP is due to both the mass effect of the tumor as well
as cerebral edema caused by neoplastic disruption of the bloodbrain
barrier, which is caused in part by local production of
vascular endothelial growth factor (VEGF).
prof. Anna Vašků75
The clinical presentation of brain metastases
̶ will vary depending on the location, size, and rate of growth of the tumor. In a series of 111 patients with
brain metastases, the most common presentation was headache, seen in 48% of patients and most
often described as tension (in 77%).
̶ In contrast to benign tension headaches, however, these headaches tended to worsen with bending
over or with Valsalva maneuvers, and in many cases were also accompanied by nausea or emesis.
̶ The “classic” tumor-associated headache pattern, consisting of an early morning headache that
improves during the day, occurred in only 36% of the cases.
̶ Seizures range from 10% to 20% in incidence and are almost exclusively caused by supratentorial
lesions.
̶ Strokes occur if the tumor embolizes, bleeds, or compresses an artery. Melanoma, choriocarcinoma,
thyroid cancer, and renal cell carcinoma are more likely to cause hemorrhagic strokes.
̶ Focal neurologic dysfunction is dependent on the location of the lesion. Clinicians must consider brain
metastases in patients with cancer who report new or changing headaches, focal neurologic changes,
or cognitive changes. A physical examination should be performed to evaluate for focal neurologic
deficits and papilledema.
̶ The triad of signs referred to as the Cushing response (hypertension with wide pulse pressure,
bradycardia, and an irregular respiratory rate) is a late effect and indicates impending herniation.
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Diagnosis
̶ Once an intracranial malignancy is suspected, contrast-enhanced MRI
is the preferred method of diagnosis.
̶ Contrast-enhanced MRI is more sensitive than either nonenhanced
MRI or CT scanning in differentiating metastases from other CNS
lesions.
̶ Noncontrast CT scan is the preferred scanning technique, however, in
an acute situation when hemorrhage or hydrocephalus is suspected.
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Seizures
̶ Seizures are the presenting symptom of intracranial metastases in
10% to 20% of patients with intracranial involvement.
̶ Seizures may or may not be associated with ICP.
̶ Status epilepticus requires emergent treatment.
prof. Anna Vašků78
Hematologic Emergencies
Hyperviscosity Syndrome
̶ Hyperviscosity syndrome (HVS) refers to the clinical sequelae
caused by increased blood viscosity. Increased serum viscosity
(SV) is a result of excess proteins, usually immunoglobulins (Igs),
most commonly arising from Waldenström macroglobulinemia
(WM) (85%) and multiple myeloma (MM).
̶ Increased blood viscosity can result from elevated cellular
components seen in hyperproliferative states such as leukemia
and myeloproliferative diseases such as polycythemia vera (PV).
prof. Anna Vašků79
Hematologic Emergencies
Hyperviscosity Syndrome
̶ Similarly, polycythemia vera (PV) can cause elevated blood viscosity
due to increased red blood cell mass.
̶ PV can cause vascular symptoms and complications secondary to
thrombocytosis with platelet hyperaggregability, leukocytosis, and/or
high hematocrit, causing elevated blood viscosity. A decrease in
cerebral blood flow and a high incidence of thrombotic complications
are seen in these patients.
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Hyperviscosity Syndrome
̶ In normal healthy subjects, hematocrit is the main determinant of blood viscosity, with
fibrinogen being the main determinant of plasma viscosity due to a combination of its large
size, asymmetric shape, charge, and concentration, even though albumin is the most
abundant protein in the blood.
̶ In paraproteinemias, such as WM and MM, excessive amounts of circulating Igs are
produced. IgM is the largest Ig (molecular weight, 1,000,000) and is the most likely
paraprotein to cause hyperviscosity, but HVS has also been documented in cases of MM or
kappa light chain disease.
̶ As the concentration of Igs increases, they form aggregates and bind water via their
carbohydrate content, which causes a rise in oncotic pressure and increases the resistance
to blood flow. Igs are positively charged and therefore decrease the repellant forces between
the negatively charged red blood cells. When present in excess, these proteins
electrostatically bind to the red blood cells, causing rouleaux formation as well as decreasing
the red blood cell malleability. Eventually, this leads to impaired transit of blood cells,
microvascular congestion, decreased tissue perfusion, and subsequent tissue damage.
prof. Anna Vašků81
HVS
̶ The “classic triad” of HVS includes neurologic abnormalities, visual changes,
and bleeding, although all 3 need not be present to make the diagnosis.
̶ Hyperviscosity causes impaired microcirculation in the brain that manifests
itself in the form of headache, altered mental status, nystagmus, vertigo,
ataxia, paresthesias, seizures, or even coma.
̶ Ophthalmologic examination can detect hyperviscosity, revealing dilated,
engorged veins that resemble “sausage links,” a finding known as fundus
paraproteinaemicus. If untreated, this will progress to complete retinal vein
occlusion and flame-shaped hemorrhages.
̶ Mucosal bleeding and purpura are also common clinical manifestations of
HVS, with proteins coating the platelets and hindering their function.
̶ Other clinical consequences of HVS include congestive heart failure,
ischemic acute tubular necrosis, and pulmonary edema, with multiorgan
system failure and death occurring if treatment is not promptly initiated.
prof. Anna Vašků82
Leukostasis
̶ Leukostasis is a hematologic emergency that is associated with respiratory
failure, intracranial hemorrhage, and early death. If it is not recognized and
treated promptly, the mortality rate can be as high as 40%.
̶ Risk for leukostasis increases with a white blood cell count (WBC) greater
than 100,000/mm3. The incidence ranges from 5% to 13% in patients with
AML and 10% to 30% in adult patients with ALL.
̶ Other risk factors include younger age (with presentation in infants being
most common); ALL with 11q23 rearrangement or the Philadelphia
chromosome; and AML subtypes M3, M4, and M5.
̶ Hyperleukocytosis portends a poor prognosis, with a higher risk of early
mortality, especially in patients with ALL. The WBC count is the most
important prognostic factor in ALL, and patients who present with a WBC
greater than 50,000/m3 have a particularly poor prognosis; very few children
with hyperleukocytosis become long-term survivors
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Leukostasis
̶ The pathophysiology of leukostasis is not completely understood. There is believed to be a
component of “sludging” by the leukemic blasts in the microvasculature secondary to
increased whole blood viscosity.
̶ On average, the leukemic myeloblasts have a mean cell volume that is almost twice that of
the leukemic lymphoblasts and therefore the manifestations are more common in patients
with AML than those with ALL. There is also differential expression of adhesion molecules on
the lymphoblast and myeloblast cells that has been implicated in the higher incidence of
leukostasis noted in patients with AML versus patients with ALL.
̶ Evidence also suggests that there are leukemic blast/endothelial cell interactions that lead to
vascular wall disruption as well as complement-induced granulocyte aggregation.
̶ In general, whole blood viscosity is not dramatically increased in leukostasis because the rise
in the WBC is often counterbalanced by a decrease in the erythrocyte count. This is important
to recognize because packed red blood cell transfusions in patients with asymptomatic
hyperleukocytosis can rapidly lead to leukostasis.
prof. Anna Vašků84
Leukostasis
̶ can involve any organ system, but the initial symptoms most commonly are related to the respiratory
system and the CNS.
̶ Pulmonary symptoms can range from exertional dyspnea to severe respiratory distress, with diffuse
interstitial or alveolar infiltrates often present on chest x-ray, although these are not required for the
diagnosis.
̶ Neurologic manifestations span the spectrum from mild confusion to somnolence. Patients commonly
report headache, dizziness, tinnitus, blurred vision, or visual field defects. Physical examination can
reveal papilledema, retinal vein bulging, and retinal hemorrhage. Intracranial hemorrhage can present
with focal neurologic deficits.
̶ Other symptoms include myocardial infarction, limb ischemia, renal vein thrombosis, and disseminated
intravascular coagulation.
̶ Fever is almost always seen and can be greater than 39°C. Although infection is found in only a few
cases, it does need to be ruled out because this syndrome can mimic sepsis.
̶ Thrombocytopenia is also usually present and underestimated because WBC fragments can be
counted as platelets in some automated cell counters.
̶ Disseminated intravascular coagulation is often seen in association with this syndrome, most commonly
in the M3 subtype of AML, although it can occur in all types of leukemia.
prof. Anna Vašků85
Respiratory Emergencies
̶ Malignant Airway Obstruction
̶ Airway obstruction can be caused by virtually any malignancy, but the most
common culprits include tumors of the tongue, oropharynx, thyroid, trachea,
bronchi, and lungs.
̶ Mediastinal tumors such as lymphomas and germ cell tumors can also cause
airway obstruction, more commonly in the pediatric population.
̶ Primary bronchogenic carcinomas are the most common cause of malignant
airway obstructions, and up to 30% of patients with primary lung tumors will
develop airway obstruction. Airway obstruction does not appear to adversely
affect overall survival, with a median survival of 8.2 months versus 8.4
months when comparing patients with airway obstruction with those without.
̶ Prompt recognition and treatment can lead to a markedly improved quality of
life, with up to 95% of patients reporting a decrease in dyspnea and a
significant increase in quality of life after treatment.
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Malignant Airway Obstruction
̶ Airway obstruction may result from external compression of the trachea or bronchi by the
tumor, or by an involved lymph node.
̶ The obstruction can also occur by infiltration of the tumor within the oropharynx, trachea, and
bronchi, causing severe narrowing.
̶ The clinical manifestations of malignant airway obstruction depend on the severity and
location of the obstruction. The symptoms are nonspecific and can be mistaken for more
common conditions including chronic obstructive pulmonary disease exacerbations, asthma,
or bronchitis.
̶ The most common presentation of malignant airway obstruction is dyspnea. The symptoms
usually worsen at night and while lying supine.
̶ Patients will often have a productive cough and wheezing, and may also present with stridor,
especially if the obstruction is located in the trachea or carina. In these cases, the symptoms
may be quite minimal until the airway is critically narrow, but then appear rapidly and pose a
life-threatening situation.
prof. Anna Vašků87
Chemotherapeutic Emergencies
Extravasation of Chemotherapy
̶ Extravasation, defined as the unintended leakage of the chemotherapy drug into the
extravascular space, is a dreaded complication of chemotherapy administration
̶ Vesicants are chemotherapy agents that have the ability to induce tissue necrosis, resulting
in functional impairment and disfigurement. Vesicants include the anthracyclines, vinca
alkaloids, and mitomycin C.
̶ Irritants such as the platinum compounds, taxanes, and topoisomerase I inhibitors cause an
inflammatory reaction but not tissue necrosis. This classification is not absolute because the
severity of tissue injury is dependent on drug concentration and volume. For example,
platinums or taxanes can behave like vesicants and induce ulcerations at high concentrations
or at large volumes.
̶ Nonaggressive agents are drugs that rarely cause any reaction when extravasation occurs.
̶ The frequency of extravasation in adults is estimated to be between 0.1% to 6% of peripheral
iv infusions and somewhat less in implanted venous access port infusions.
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Chemotherapeutic Emergencies
Extravasation of Chemotherapy
̶ Extravasations vary in their clinical presentation and severity. Symptoms may occur
immediately after the incident or develop in subsequent days or weeks.
̶ In most cases, initial symptoms include pain, blistering, induration, and discoloration.
̶ Ulceration may not appear for several days and may continue to worsen for months, as the
drug diffuses into the adjacent tissue. In severe cases, necrosis of the skin and the
underlying tissues may develop, leading to infection, scars, treatment delay, functional
deficits, amputation, and, rarely, death.
̶ In the case of irritant extravasation, symptoms include erythema, swelling, and tenderness.
Phlebitis, hyperpigmentation, and sclerosis can subsequently develop along the vein. These
symptoms usually resolve within weeks and long-term sequelae are extremely rare.
̶ Patients with small, deep veins or those with damaged veins secondary to multiple
venipunctures are at higher risk, as are patients with neurologic deficits because of an
inability to follow instructions or secondary to an impaired ability to detect changes in
sensation. Obesity and movement during chemotherapy administration also increase the risk
of extravasation.
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Chemotherapeutic Emergencies
Extravasation of Chemotherapy
̶ Diagnosis
̶ Extravasation is usually diagnosed by local symptoms of pain,
erythema, and swelling, or by leakage of fluid around the iv site, but a
change in the rate of infusion or absence of blood return from the
vascular access may be the initial sign.
̶ Once suspected, even if asymptomatic, the infusion needs to be
discontinued and treatment initiated immediately.
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Anaphylactic Reactions to Chemotherapy
̶ Essentially any chemotherapeutic agent has the potential to cause
an infusion reaction, which can range significantly in severity.
These are often called hypersensitivity reactions; however,
because some do not have a hypersensitivity component, they are
more properly termed infusion reactions.
̶ Anaphylaxis is defined as a serious allergic reaction that is rapid in
onset and may cause death. It is rare with most conventional
cytotoxic agents, although it is well established with platinum
drugs and the taxanes. Other agents known to commonly cause
infusion reactions include cyclophosphamide, ixabepilone,
bleomycin, L-asparaginase, and monoclonal antibodies such as
rituximab.
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