·
Lead-time bias, length-time bias, selection
bias, overdiagnosis bias, and avoidance bias can make a screening test appear
to improve outcomes when it does not. When lead-time
bias occurs, survival appears increased, but life is not truly prolonged. The test only lengthens the time
that the patient, the physician, or the investigator is aware of the disease.
When length-time bias occurs,
aggressive cancers are not detected during screening, presumably due to the
higher mortality from these cancers and the length of the screening interval. Selection bias can occur when the test
population is either healthier or at higher risk for developing the condition
than the general public. Overdiagnosis bias,
such as with some indolent forms of prostate cancer, detects conditions that
will never cause significant mortality or morbidity during a person’s
lifetime. The goal of screening is to detect disease at an earlier and more
curable stage.
·
Testing of the
APC gene has been shown to be cost-effective
when used to identify carriers of the disease-causing APC gene mutation among
at-risk relatives of individuals with FAP. Early diagnosis via presymptomatic
testing reduces morbidity and increases life expectancy through improved
surveillance and timely prophylactic colectomy. FAP is an example of a
condition in which presymptomatic testing may be lifesaving.
·
Long-term exposure to environmental tobacco
smoke (passive smoking) has been associated with a 30% increase in the risk of
lung cancer in nonsmokers. β-Carotene has been
associated with an increase in the risk of lung cancer.
·
Hereditary prostate
cancer, which accounts for 5% to 10% of all cases, is primarily
associated with disease of early onset. Major susceptibility loci for
hereditary prostate cancer were recently mapped to chromosome
1 and the X chromosome.
·
The Knudson model
predicts that children with familial tumors
have inherited an initial genetic hit (i.e., a distinct genetic alteration) and
require only one additional, rate-limiting genetic hit to initiate
tumorigenesis. In contrast, children with sporadic
tumors need to acquire two independent genetic hits
within the same cell, an unlikely event that explains the less frequent,
unilateral presentation and later onset of sporadic cancers.
Knudson model also explains the paradox that tumor
suppressor gene mutations are loss-of-function or recessive mutations, yet
familial cancer presents as an autosomal dominant trait.
·
p53
functions as a transcription factor, directing expression of p21, an inhibitor of the cyclin-dependent
kinases that regulate the cell cycle. Activation of p53 leads to arrest in the G1 phase of the cell cycle,
enabling cells to repair DNA damage before proceeding into S phase and DNA
replication. In other cells, activation of p53 causes activation of multiple
effectors, leading to apoptosis—a suicide program in cells whose DNA may have
been irreparably damaged.
·
SMAD genes,
active in signaling by transforming growth factor–α (TGF-α), are
mutated in pancreatic tumors.
·
P-glycoprotein
is a member of the adenosine triphosphate
(ATP)-binding cassette family. P-glycoprotein spans the plasma membrane
and recognizes a broad spectrum of anticancer drugs. In the presence of ATP,
P-glycoprotein pumps the drugs to the extracellular space, so that effective
concentration at the intracellular target is never achieved.
·
The Goldie-Coldman
model predicts drug resistance by use of
cell number and the spontaneous cancer cell mutation rate. Even a tumor
that is too small to be detected clinically has a significant chance of
containing a cell with a resistance-conferring mutation. Although combination
chemotherapy allows for reduction of the dosage of any one agent, it does not
inherently reduce side effects or the risk of mutation-induced secondary
malignancy or eliminate the need for radiation therapy (which reduces the risk
of local recurrence). Finally, combination therapy does not allow for higher
dosages. If anything, combination chemotherapy necessitates lower dosages of agents that have common toxicities.
Combination chemotherapy attempts to address possible cross-resistance by
employing different mechanisms, and nonoverlapping
toxicities allow for effective dosing.
·
Coffee and
alcohol consumption do not seem to increase the risk of pancreatic cancer.
·
Breast
conservation therapy that involves lumpectomy with radiotherapy and
modified radical mastectomy that involves removal of the breast and axillary
nodes provide identical survival rates for women
with stage I or II breast cancer.
·
Data from large cohort studies and case-control
studies support the contentions that red meat,
animal fat, and total fat consumption increase the risk of prostate cancer.
·
Both normal and malignant prostatic epithelial
cells produce PSA; production may
actually be higher in normal cells than in malignant
cells. A problem with PSA-based screening is that an elevated PSA level
lacks specificity. Despite the increased likelihood of prostate cancer in men
with a moderately elevated serum PSA level (i.e., a level 4 to 10 ng/ml),
biopsy usually reveals benign prostatic hyperplasia (BPH) rather than prostate
cancer. Determination of the free PSA level
(i.e., the percentage of PSA that is unbound to serum proteins) is also a
potential means of distinguishing malignancy from benign hyperplasia. PSA
derived from malignant epithelial cells tends to bind
more avidly to serum proteins. Thus, in men with an elevated serum PSA
level, cancer is more likely when the percentage
of free PSA is low.
·
The mainstay of treatment for advanced-stage ovarian cancer is total
abdominal hysterectomy with bilateral oophorectomy
plus debulking and partial omentectomy, followed by a combination
chemotherapy regimen containing a taxane and a
platinum analogue.
·
Part of the success
of Pap smear screening is due to the fact that this approach
typically detects premalignant lesions, as opposed to invasive cancer. This
unique feature makes it possible to eradicate
precursor lesions before the development of frankly invasive cancers. In
addition, the interval of time between the development of a precursor lesion
and the occurrence of invasive disease may be several years, thus allowing many
opportunities for the detection and eradication of premalignant disease.
·
Extracellular volume
deficits exist in all patients with symptomatic hyercalcemia of malignancy. The single most
important and urgent treatment is the infusion of normal saline to correct the
extracellular volume deficit, increase the glomerular filtration rate, and,
secondarily, increase renal calcium excretion.
Glucocorticoids may be useful in patients with lymphoid
malignancies as the mechanism of hypercalcemia in those
conditions is often related to excess hydroxylation of vitamin D. However, in
HHM due to other causes, dexamethasone will have little effect on the calcium
level and may exacerbate the altered mental status.
·
Epidural spinal
cord compression should be suspected on the basis of the symptoms
reported by the patient and the signs elicited by the physician on physical
examination. The current recommendation for the radiographic evaluation of
patients with suspected epidural compression is gadolinium-enhanced
MRI of the entire spinal axis.
·
SVC syndrome
is most commonly caused by extrinsic compression of the thin-walled,
low-pressure SVC by a malignant mediastinal mass such as bronchogenic carcinoma (especially small cell
lung cancer) and non-Hodgkin lymphoma.
Before a histologic diagnosis is established, emergency treatment with
mediastinal irradiation is only warranted in children and occasionally in
adults who have mental status alteration, other life-threatening manifestations
of increased intracranial pressure, cardiovascular collapse, or evidence of
upper airway obstruction. In the absence of such conditions, as with this
patient, the next step in the management of SVC syndrome should focus on
efforts to obtain a histologic diagnosis of the underlying condition so
that appropriate therapy may be initiated. Obtaining further radiologic studies
will not assist in making a histologic diagnosis and are therefore not the most
appropriate next step in the management of this patient. Recent experience in adults suggests that SVC syndrome is
not a true emergency and that histologic diagnosis should be quickly
established and treatment promptly initiated.
·
GISTs
occur predominantly in middle-aged patients. Approximately 70% occur in the
stomach, 20% occur in the small intestine, and less than 10% occur in the
colon, esophagus, and rectum. Survival
correlates with tumor location. The best prognoses are associated
with tumors of the esophagus and stomach; the worst prognoses are associated
with tumors occurring in the small intestine. GISTs frequently lack muscle and Schwann cell markers that are typical of
leiomyosarcomas found in other anatomic sites. The protooncogene c-kit
encodes a transmembrane tyrosine kinase receptor located on the long arm of
chromosome 4. Mutations of c-kit cause the receptor to be activated
constitutively without its ligand. Imatinib
is an oral, relatively specific inhibitor of three tyrosine kinase receptors.
It is used in the treatment of GISTs.
·
Side effects of
intravesical BCG include dysuria,
urinary frequency, hematuria, and a flulike syndrome. More
significantly, because BCG is an attenuated mycobacterium, it can produce
local, regional, and systemic infections. Granulomatous
infections can occur at extravesical sites, including the prostate,
epididymis, testes, kidney, liver, and lungs. BCG
sepsis is the most serious complication and can be life-threatening.
Systemic involvement is treated with triple-antibiotic antituberculous therapy
for 6 months.
·
In some patients with CLL, the clinical course is complicated by progressive
conditions, secondary malignancies, immune abnormalities, and infections.
Progressive conditions include Richter syndrome,
in which patients develop worsening
lymphadenopathy, hepatosplenomegaly, fever, abdominal pain, weight loss, and
anemia. Patients who develop Richter syndrome do not respond well to
therapy, and survival is short. PLL
is the second most common transformation in CLL; however, most cases of PLL
arise de novo. Compared with patients with de novo disease, patients with PLL
that arises through transformation tend to be younger, and they have less
marked lymphocytosis. Other transformations in CLL include acute lymphoblastic
leukemia, multiple myeloma, and Hodgkin lymphoma. CML is not a known
complication of CLL.
·
The current treatment
of choice for HCL is either cladribine or the purine analogue
pentostatin; both of these agents have been shown to induce remission in
80% of patients, and the choice is based on physician preference.
·
Chemotherapy with melphalan and prednisone
is a reasonable therapeutic option for MM
because this combination has been shown to have a higher response rate than
monotherapy with either drug. In patients who have bone disease, pamidronate
is added to provide protection against skeletal complications; this approach
appears to improve quality of life and possibly provides a survival advantage.
Therefore, current recommendations are to add bisphosphonates such as
pamidronate to the regimens for all patients with evidence of bone involvement.
·
Considerable data suggest that MDS results from combined defects of both
stroma and hematopoietic stem cells. Several clinical syndromes that may have a
more predictable natural history can now be defined. For example, a deletion of the long arm of chromosome 5 can be
detected in some older patients, especially women, with a macrocytic, refractory
anemia (RA). The platelet count is typically normal or elevated. The bone
marrow picture in the RA with 5q– syndrome is characterized by the presence of monolobulated
and bilobulated micromegakaryocytes. Two thirds of these patients have
RA or RA with ringed sideroblasts (RARS), and the remainder have RAEB
(RA with excess of blasts). In those patients who have a del(5q) as their sole
cytogenetic abnormality, MDS tends to follow a more benign
course, although progression to acute myeloid leukemia (AML) may
occur.
·
The term complete
remission is reserved for patients who have full
recovery of normal peripheral blood counts and bone marrow cellularity with
less than 5% residual blast cells.
·
The treatment for
Ph+ ALL should include an intensive remission-induction chemotherapy
program, followed by allogeneic stem cell transplantation in the first CR if a
donor is available. Considerable interest exists in investigating new agents,
especially the tyrosine kinase inhibitor imatinib
mesylate, in this high-risk group of patients.
·
AML accounts for
about 80% of acute leukemias in adults and is most likely to present
with hemorrhage or infection. Standard induction therapy with cytarabine and
daunorubicin (7 + 3 regimen) is followed by consolidation chemotherapy but
generally no long-term maintenance regimen.
·
Up to 95% of
patients with CML express Ph, which results from a reciprocal
translocation between the long arms of chromosomes 9 and 22. Patients with CML
who do not have Ph translocation have a significantly worse prognosis than do
patients who test positive for the bcr-abl gene.
·
ET is
diagnosed after secondary causes of elevated platelet counts (e.g., iron
deficiency, malignancies, inflammatory conditions, and infections) have been
excluded. Major thrombotic complications occur in 20%
to 30% of patients. Thrombotic complications frequently manifest as DVT and
pulmonary embolism. Thrombosis of hepatic veins leads to Budd-Chiari syndrome;
thrombosis of renal veins can cause nephrotic syndrome. Erythromelalgia and
digital ischemia constitute microvascular forms of arterial thrombosis in ET. Hemorrhagic events occur in up to 40% of patients,
with the gastrointestinal tract, urinary tract, skin, eyes, and brain being
possible bleeding sites. Individual patients can suffer from both thrombotic
and hemorrhagic episodes. Unlike PV, ET rarely
progresses, and leukemia develops in only 3% to 4% of patients.
·
Concomitant
chemoradiotherapy involves sensitizing
tumor cells to radiation by administering chemotherapy, usually
cisplatin and fluorouracil, during radiation therapy. Use of concomitant
chemoradiotherapy has led to improvements in the control of locoregional
disease, & increased overall survival with concomitant
chemoradiotherapy.
Induction chemotherapy leads to tumor shrinkage, laryngeal preservation, and decreased
disease in areas other than the head and neck, presumably by eradicating
micrometastases. However, survival is not improved with
this modality because the locoregional control achieved is not better than that
achieved with surgery and radiation therapy.
·
The half-lives of
AFP and β-hCG are 6 days and 1 day, respectively. After
treatment of NSGCT testicular tumor,
unequal reduction of β-hCG and AFP may occur, suggesting that the two
markers are synthesized by heterogeneous clones of cells within the tumor;
thus, both markers should be followed.
β-hCG is similar to luteinizing hormone except for its distinctive beta
subunit.
·
Hyperleukocytosis
is a potentially fatal complication of acute leukemia when the blast count is
>100,000/µL. Complications of the syndrome are mediated by hyperviscosity, tumor aggregates causing slow blood
flow, and invasion of the primitive leukemic cells, which cause
hemorrhage. The brain and lungs are most commonly involved. The
pulmonary syndrome may lead to respiratory distress and progressive respiratory
failure. Chest radiographs may show either alveolar or interstitial
infiltrates. A common finding in patients with markedly elevated
immature white blood cell counts is low arterial oxygen tension on arterial
blood gas with a normal pulse oximetry. This may actually be due to pseudohypoxemia, because white blood cells
rapidly consume plasma oxygen during the delay between collecting arterial
blood and measuring oxygen tension, causing a spuriously low measured oxygen tension.
Placing the arterial blood gas immediately in ice will prevent the
pseudohypoxemia.
·
Mutation control
genes: Genes such as hMSH2 and hMLH1 are responsible for
ensuring the fidelity of the DNA duplication process. Microsatellite
instability results from the faulty DNA editing process. Subsequently, the
mutation rate increases and cancers occur.
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