CBI 1: 56 y.o. woman with chills, lightheadedness, and weakness

1. Differentiate among types of shock

-Hypovolemic shock - This is the most common type of shock and based on insufficient circulating volume. Its primary cause is loss of fluid from the circulation (most often "hemorrhagic shock"). Causes may include internal bleeding, traumatic bleeding, high output fistulae or severe burns.

-Cardiogenic shock - This type of shock is caused by the failure of the heart to pump effectively. This can be due to damage to the heart muscle, most often from a large myocardial infarction. Other causes of cardiogenic shock include arrhythmias, cardiomyopathy, congestive heart failure (CHF), contusiocordis, or cardiac valve problems.

-Distributive shock - As in hypovolemic shock there is an insufficient intravascular volume of blood. This form of "relative" hypovolemia is the result of dilation of blood vessels which diminishes systemic vascular resistance. Examples of this form of shock are:

-Septic shock - Caused by an overwhelming systemic infection resulting in vasodilation leading to hypotension. Septic shock can be caused by Gram negative bacteria such as (among others) Escherichia coli, Proteus species, Klebsiella pneumoniae which release an endotoxin which produces adverse biochemical, immunological and occasionally neurological effects which are harmful to the body, and other Gram-positive cocci, such as pneumococci and streptococci, and certain fungi as well as Gram-positive bacterial toxins. Septic shock also includes some elements of cardiogenic shock.

%% -Anaphylactic shock - Caused by a severe anaphylactic reaction to an

allergen, antigen, drug or foreign protein causing the release of histamine which causes widespread vasodilation, leading to hypotension and increased capillary permeability.

%% -Neurogenic shock - Neurogenic shock is the rarest form of shock. It is

caused by trauma to the spinal cord resulting in the sudden loss of autonomic and motor reflexes below the injury level. Without stimulation by sympathetic nervous system the vessel walls relax uncontrollably, resulting in a sudden decrease in peripheral vascular resistance, leading to vasodilation and hypotension. (This term can be confused with Spinal

shock which is a recoverable loss of function of the spinal cord after injury and does not refer to the haemodynamic instability per se.)

-Obstructive shock - In this situation the flow of blood is obstructed which impedes circulation and can result in circulatory arrest. Several conditions result in this form of shock.

%% -Cardiac tamponade - in which fluid in the pericardium prevents inflow of

blood into the heart (venous return). %% -Tension pneumothorax - through increased intrathoracic pressure,

bloodflow to the heart is prevented (venous return).%% -Massive pulmonary embolism - is the result of a thromboembolic incident

in the blood vessels of the lungs and hinders the return of blood to the heart.

%% -Aortic stenosis - hinders circulation by obstructing the ventricular outflow

tract

2. Define sepsis and septic shock

Sepsis is a serious medical condition that is characterized by a whole-body inflammatory state (called a systemic inflammatory response syndrome or SIRS) and the presence of a known or suspected infection. The body may develop this inflammatory response to microbes in the blood, urine, lungs, skin, or other tissues.

In 1992, the ACCP/SCCM Consensus Conference Committee defined septic shock: ". . .sepsis-induced hypotension (systolic blood pressure <90 mm Hg or a reduction of 40 mm Hg from baseline) despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are receiving inotropic or vasopressor agents may have a normalized blood pressure at the time that perfusion abnormalities are identified."

To diagnose septic shock the following two criteria must be met:

% -Evidence of infection, through a positive blood culture.% -Refractory hypotension - hypotension despite adequate fluid resuscitation and

cardiac output.-In adults it is defined as a systolic blood pressure < 90 mmHg, or a

mean arterial pressure < 60 mmHg, without the requirement for inotropic support, or a reduction of 40 mmHg in the systolic blood pressure from baseline.

-In children it is BP < 2 standard deviation of the normal blood pressure.

In addition to the two criteria above, two or more of the following must be present:

-Tachypnea (high respiratory rate) > 20 breaths per minute or, on blood gas, a less than 32 mmHg of PCO2

-White blood cell count < 4000 cells/mm³ or > 12000 cells/mm³

3. Identify the physiologic disturbances that underlie septic shock and the key components of resuscitation for these disturbances

-Initial - During this stage, the hypoperfusional state causes hypoxia, leading to the mitochondria being unable to produce adenosine triphosphate (ATP). Due to this lack of oxygen, the cell membranes become damaged, they become leaky to extra-cellular fluid, and the cells perform anaerobic respiration. This causes a build-up of lactic and pyruvic acid which results in systemic metabolic acidosis. The process of removing these compounds from the cells by the liver requires oxygen, which is absent.

-Compensatory (Compensating) - This stage is characterized by the body employing physiological mechanisms, including neural, hormonal and bio-chemical mechanisms in an attempt to reverse the condition. As a result of the acidosis, the person will begin to hyperventilate in order to rid the body of carbon dioxide (CO2). CO2 indirectly acts to acidify the blood and by removing it the body is attempting to raise the pH of the blood. The baroreceptors in the arteries detect the resulting hypotension, and cause the release of adrenaline and noradrenaline. Noradrenaline causes predominately vasoconstriction with a mild increase in heart rate, whereas adrenaline predominately causes an increase in heart rate with a small effect on the vascular tone; the combined effect results in an increase in blood pressure. This is known as Cushing reflex and its triad is the subjective identifying characteristic of this stage. Renin-angiotensin axis is activated and arginine vasopressin (Anti-diuretic hormone; ADH) is released to conserve fluid via the kidneys. Also, these hormones cause the vasoconstriction of the kidneys, gastrointestinal tract, and other organs to divert blood to the heart, lungs and brain. The lack of blood to the renal system causes the characteristic low urine production. However the effects of the Renin-angiotensin axis take time and are of little importance to the immediate homeostatic mediation of shock

-Progressive (Decompensating) - Should the cause of the crisis not be successfully treated, the shock will proceed to the progressive stage and the compensatory mechanisms begin to fail. Due to the decreased perfusion of the cells, sodium ions build up within while potassium ions leak out. As anaerobic metabolism continues, increasing the body's metabolic acidosis, the arteriolar smooth muscle and precapillary sphincters relax such that blood remains in the capillaries. Due to this, the hydrostatic pressure will increase and, combined with histamine release, this will lead to leakage of fluid and protein into the surrounding tissues. As this fluid is lost, the blood concentration and viscosity increase, causing sludging of the micro-circulation. The prolonged

vasoconstriction will also cause the vital organs to be compromised due to reduced perfusion. If the bowel becomes sufficiently ischemic, bacteria may enter the blood stream, resulting in the increased complication of endotoxic shock.

-Refractory (Irreversible) - At this stage, the vital organs have failed and the shock can no longer be reversed. Brain damage and cell death have occurred. Death will occur imminently.

Treatment consists of:% -Stabilization of airway: Intubation, mechanical ventilation, chest xray, ABG’s% -Fluids/Meds/Monitoring/Infusions: Central venous catheter% -Want to reach 70% central venous oxygen saturation and CVP 8-12 mmHg% -Volume infusion with 500mL IV isotonic saline bolus.% -Vasopressors: NE, dopamine, vasopressin

-IV Antibiotics

4. Define the health risks for splenectimized patients or those with impaired splenic function

Asplenia increases the risk of sepsis from polysaccharide encapsulated bacteria, and can result in overwhelming post splenectomy infection (OPSI), often fatal within a few hours. In particular, patients are at risk from Pneumococcus, Haemophilus influenzae, and meningococcus. The risk is elevated as much as 350–fold. These bacteria often cause a sore throat under normal circumstances but after splenectomy, when infecting bacteria cannot be adequately opsonized, the infection becomes more severe.

An increase in blood leukocytes can occur following a splenectomy. The post-splenectomy platelet count may rise to abnomormally high levels, leading to an increased risk of potentially fatal clot formation. There also is some conjecture that post-splenectomy patients may be at elevated risk of subsequently developing diabetes. Splenectomy may also lead to chronic neutrophilia. Splenectomy patients typically have Howell-Jolly bodies in their blood smears.

CBI 2: 3 year old female with pallor (Sonia Armenta)

1. Integrate pathophysiologic and morphologic approaches to the classification of anemia in children.

See “Introduction to Hematopoietic Neoplasms and Pathology of Acute Lymphoid Leukemia” and “Acute Myelogenous Leukemia and Myelodysplastic Syndromes” Lecture Notes

2. Identify the 2 most common types of leukemia in children and explain the specific diagnostic procedures needed to make a correct diagnosis.

-ALL

Diagnosing ALL begins with a medical history and physical examination, complete blood count, and blood smears. Because the symptoms are so general, many other diseases with similar symptoms must be excluded. Typically, the higher the white blood cell count, the worse the prognosis. Blast cells are seen on blood smear in 90% of cases. A bone marrow biopsy is conclusive proof of ALL. A lumbar puncture (also known as a spinal tap) will tell if the spinal column and brain has been invaded.

Pathological examination, cytogenetics (particularly the presence of Philadelphia chromosome) and immunophenotyping, establish whether the "blast" cells began from the B lymphocytes or T lymphocytes. DNA testing can establish how aggressive the disease is; different mutations have been associated with shorter or longer survival.

Medical imaging (such as ultrasound or CT scanning) can find invasion of other organs commonly the lung, liver, spleen, lymph nodes, brain, kidneys and reproductive organs.

-AML

The first clue to a diagnosis of AML is typically an abnormal result on a complete blood count. While an excess of abnormal white blood cells (leukocytosis) is a common finding, and leukemic blasts are sometimes seen, AML can also present with isolated decreases in platelets, red blood cells, or even with a low white blood cell count (leukopenia). While a presumptive diagnosis of AML can be made via examination of the peripheral blood smear when there are circulating leukemic blasts, a definitive diagnosis usually requires an adequate bone marrow aspiration and biopsy.

Marrow or blood is examined via light microscopy as well as flow cytometry to diagnose the presence of leukemia, to differentiate AML from other types of leukemia (e.g. acute lymphoblastic leukemia), and to classify the subtype of disease (see below). A sample of marrow or blood is typically also tested for chromosomal translocations by routine cytogenetics or fluorescent in situ hybridization. Genetic studies may also be performed to look for specific mutations in genes such as FLT3, nucleophosmin, and KIT, which may influence the outcome of the disease.

Cytochemical stains on blood and bone marrow smears are helpful in the distinction of AML from ALL and in subclassification of AML. The combination of a myeloperoxidase or Sudan black stain and a non specific esterase stain will provide the desired information in most cases. The myeloperoxidase or Sudan black reactions are most useful in establishing the identity of AML and distinguishing from ALL. The non-specific esterase stain is used to identify a

monocytic component in AMLs and to distinguish a poorly differentiated monoblastic leukemia from ALL.

The diagnosis and classification of AML can be challenging, and should be performed by a qualified hematopathologist or hematologist. In straightforward cases, the presence of certain morphologic features (such as Auer rods) or specific flow cytometry results can distinguish AML from other leukemias; however, in the absence of such features, diagnosis may be more difficult.

According to the widely used WHO criteria, the diagnosis of AML is established by demonstrating involvement of more than 20% of the blood and/or bone marrow by leukemic myeloblasts. AML must be carefully differentiated from "pre-leukemic" conditions such as myelodysplastic or myeloproliferative syndromes, which are treated differently.

Because acute promyelocytic leukemia (APL) has the highest curability and requires a unique form of treatment, it is important to quickly establish or exclude the diagnosis of this subtype of leukemia. Fluorescent in situ hybridization performed on blood or bone marrow is often used for this purpose, as it readily identifies the chromosomal translocation (t[15;17]) that characterizes APL.

3. Analyze the concept of risk stratification in pediatric leukemia and identify the key determinants of risk in childhood.

ALL

-Low risk: 1-10yr, WBC < 50 x 109/L, TEL-AML-1, hyperdiploid trisomy 4,10, or 17

-High-risk: <1yr, >10yr, WBC > 50 x 109/L, MLL t(4:11), BCR-ABL t(9:22), E2A-PBX1 t(1:19), hypodiploid induction failure, CNS disease

AML

• “good cytogenetics”: t(15;17)(q22;q12) seen in APL (M3) t(8;21)(q22;q22) seen mainly in M1, M2 , inv(16)(p13;q22) seen mainly in M4 • “intermediate cytogenetics”: patients with normal cytogenetics, involvement of the MLL gene 11 (11q23)

• “bad cytogenetics”: monosomy 7 (7q-), monosomy 5 (5q-), mutations in the FLT3, c-KIT and c-fms genes • other unfavorable factors: WBC > 100 x 109/L, secondary AML failed induction FAB M4, M5

4. Define the term “remission” and identify major components of therapy used to induce and sustain remission in children with leukemia.

Remission is the state of absence of disease activity in patients with known chronic illness that cannot be cured. It is commonly used to refer to absence of active cancer or inflammatory bowel disease when these diseases are expected to manifest again in the future. A partial remission may be defined for cancer as 50% or greater reduction in the measurable parameters of tumor growth as may be found on physical examination, radiologic study, or by biomarker levels from a blood or urine test. A complete remission is defined as complete disappearance of all such manifestations of disease. Each disease or even clinical trial can have its own definition of a partial remission.

Successful treatment of children with ALL involves administration of a multidrug regimen that is divided into several phases (induction, consolidation, and maintenance) and includes therapy directed to the central nervous system. Most treatment protocols take two to three years to complete, although the specific regimen varies depending upon immunophenotype and risk category.

Induction therapy is the initial phase of treatment and is designed to place the patient in remission. More than 90 percent of children and adolescents with ALL enter complete remission (CR) at the end of induction therapy regardless of their initial risk grouping. Induction therapy usually involves weekly administration of vincristine for three to four weeks, daily corticosteroids, and asparaginase. A fourth agent such as an anthracycline may be added to the three-dose regimen, particularly for high-risk patients.

Consolidation or intensification therapy is the second phase of ALL treatment and is initiated soon after attainment of CR. Ongoing treatment is required because small numbers of leukemic lymphoblasts remain in the bone marrow despite histologic evidence of CR after induction therapy. The goal of post-induction chemotherapy is to prevent leukemic regrowth, reduce residual tumor burden, and prevent the emergence of drug-resistance in the remaining leukemic cells.

Consolidation therapy usually lasts from four to six months. It commonly involves the use of several different drug combinations and drugs with mechanisms of action that differ from those used during the induction phase. Regimens often include the following drugs administered according to a variety of schedules to maximize drug synergy and minimize the development of drug resistance: Cytarabine, Methotrexate, Anthracyclines, Alkylating agents, and an Epipodophyllotoxin.

The overall treatment duration for most children with ALL is 2 to 3 years so the maintenance phase of therapy typically lasts about 2-2.5 years. After completion of the consolidation phase of therapy, patients often receive a less intensive continuation regimen using daily oral 6-mercaptopurine and weekly methotrexate with periodic intrathecal therapy. Survival rates: low risk > 85%, high risk > 75%

5. Explain the concept of “late effects” of therapy in the context of curable malignancies and connect late effects to specific therapies.

Agents thought to be associated with long-term neurocognitive impairment are methotrexate, corticosteroids, and possibly cytarabine. Two thirds of the studies of patients who received chemotherapy alone for ALL have indicated that survivors experience some degree of neurocognitive decline. It has been postulated that CNS prophylaxis with intrathecal chemotherapy may contribute to neurocognitive sequelae, but studies to date have not been conclusive. Learning issues are often multifactorial, and many children with ALL (like S. A.) are diagnosed during their preschool and early primary years. Therefore, in addition to having been exposed to both systemic and intrathecal chemotherapy, these children have also been absent from preschool, kindergarten, and the early grades to a greater extent than most of their peers. Whether effects of therapy are based on pharmacology or early educational experiences, it does appear that young children surviving ALL therapy face specific challenges that require attention from parents, health care providers, and educators.

See 5th release from CBI Case

CBI 3: 52 year old man with hemoptysis (Martin Smith)1. Identify categories of diseases that result in hemoptysis and specific disease processes in each category

Infectious –TB, Cocci, Pneumonia, bronchitis, bronchiectasis Neoplastic - Lung Cancer, Laryngeal cancer, MesotheliomaVascular – PE, Vasculitis (Wegener’s Granulomatosis), CHF, thrombocytopenia Autoimmune - Goodpasture’s, Lupus 2. Explain the utility of urinalysis in the diagnosis of renal disease and the particular significance of red blood cell casts.

The presence of red blood cells within the cast is always pathologic, and is strongly indicative of glomerular damage, which can occur in glomerulonephritis from various causes or vasculitis, including Wegener's granulomatosis, systemic lupus erythematosus, post-streptococcal glomerulonephritis or Goodpasture’s syndrome. They can also be

associated with renal infarction and subacute bacterial endocarditis. They are usually associated with nephritic syndromes.

3. Explain potential pathogenic mechanisms underlying disease processes that produce the syndrome of pulmonary alveolar hemorrhage and acute glomerulonephritis (red cell casts, and renal insufficiency)

Wegener’s Granulomatosis - Anti-neutrophil cytoplasmic antibodies (ANCAs) are responsible for inflammation, granuloma formation, and damage of endothelial cells causing end organ damage associated with the wide variety of symptoms seen.

Goodpasture’s Syndrome - Type II hypersensitivity due to antibodies that cause destruction of the basement membrane in areas with small capillary beds such as the lung and the glomerulus

Lupus - Type III hypersensitivity due to immune complex deposition in the tissues with activation of complement

CBI 4: 23-year-old man with abdominal pain (Josh)

1. Develop a differential diagnosis for right-sided abdominal pain based on anatomical and patho-physiological considerations

-IBD (Crohn’s, ulcerative colitis)-Appendicitis-Pancreatitis -Colon Cancer-GI Tract Lymphoma -IBS-Diverticulitis (most frequently left lower quadrant) -Biliary Tract Disease-Hepatitis

2. Outline the epidemiology of colorectal cancer in the United States

-3rd most common cancer, 3rd most deadly♂ Cancer-related deaths: Lung > Prostate > Colorectal♀ Cancer-related deaths: Lung > Breast > Colorectal

-Cause:65-85% are sporadic10-30% Family Hx5% HNPCC1% FAP<0.1% Rare syndromes

-Average age = 70-M:F ~ 1:1-150,000 new cases in 2006 -Incidence is decreasing due to screening-Location:

50% rectosigmoid15% ascending and descending (each)10% transverse and cecum (each)

3. List the risk factors for colorectal cancer

-Age - The risk of developing colorectal cancer increases with age. Most cases occur in the 60s and 70s, while cases before age 50 are uncommon unless a family history of early colon cancer is present.

% -Polyps of the colon - particularly adenomatous polyps, are a risk factor for colon cancer. The removal of colon polyps at the time of colonoscopy reduces the subsequent risk of colon cancer.

% -History of cancer - Individuals who have previously been diagnosed and treated for colon cancer are at risk for developing colon cancer in the future. Women who have had cancer of the ovary, uterus, or breast are at higher risk of developing colorectal cancer.

% -Heredity:-Family history of colon cancer, especially in a close relative before the age of

55 or multiple relatives. -Familial adenomatous polyposis (FAP) carries a near 100% risk of developing

colorectal cancer by the age of 40 if untreated-Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome

% -Smoking - Smokers are more likely to die of colorectal cancer than non-smokers. An American Cancer Society study found that "Women who smoked were more than 40% more likely to die from colorectal cancer than women who never had smoked. Male smokers had more than a 30% increase in risk of dying from the disease compared to men who never had smoked."

% -Diet - Studies show that a diet high in red meat and low in fresh fruit, vegetables, poultry and fish increases the risk of colorectal cancer. In June 2005, a study by the European Prospective Investigation into Cancer and Nutrition suggested that diets high in red and processed meat, as well as those low in fiber, are associated with an increased risk of colorectal cancer. Individuals who frequently eat fish showed a decreased risk. Physical inactivity. People who are physically active are at lower risk of developing colorectal cancer.

% -Virus - Exposure to some viruses (such as particular strains of human papilloma virus) may be associated with colorectal cancer.

% -Primary sclerosing cholangitis offers a risk independent to ulcerative colitis% -Low levels of selenium. % -Inflammatory bowel disease - About one percent of colorectal cancer patients have a

history of chronic ulcerative colitis. The risk of developing colorectal cancer varies inversely with the age of onset of the colitis and directly with the extent of colonic involvement and the duration of active disease. Patients with colorectal Crohn's disease have a more than average risk of colorectal cancer, but less than that of patients with ulcerative colitis.

% -Environmental factors - Industrialized countries are at a relatively increased risk compared to less developed countries that traditionally had high-fiber/low-fat diets. Studies of migrant populations have revealed a role for environmental factors, particularly dietary, in the etiology of colorectal cancers.

% -Exogenous hormones - The differences in the time trends in colorectal cancer in males and females could be explained by cohort effects in exposure to some gender-specific risk factor; one possibility that has been suggested is exposure to estrogens. There is, however, little evidence of an influence of endogenous hormones on the risk of colorectal cancer. In contrast, there is evidence that exogenous estrogens such as hormone replacement therapy (HRT), tamoxifen, or oral contraceptives might be associated with colorectal tumors.

-Alcohol - Drinking, especially heavily, may be a risk factor.

4. Compare and contrast the familial syndromes associated with an increased risk of colorectal cancer

FAP -FAP is due to a heritable mutation in the APC tumor suppressor gene -Characterized by the appearance of large numbers (sometimes thousands) of adenomatous polyps in the colon. -Although the polyps are benign one or several will invariably turn cancerous. This typically occurs in the 3rd or 4th decade of life. The risk of developing a malignancy is 100% for these individuals. -Syndrome is also characterized by development of tumors in other organs including the rectum, duodenum and stomach.

HNPCC -Syndrome is characterized by early onset colon cancer. However, the etiology differs from FAP in that there is no development of multiple polyps (hence the term NONPOLYPOSIS in the name) -Spectrum of tumors that occur in other organs is also distinct from FAP -HNPCC is caused by a heritable mutation in one of several DNA mismatch repair genes including MSH2, MLH1 and PMS2.

5. Discuss the clinical presentation of colorectal cancer

-If in proximal/ right colon:Tends to BLEED (à iron deficiency anemia)Blood is mixed in with stoolDull pain, fatigue

-If in distal or left colon:-Tends to OBSTRUCT (bowel diameter is smaller)-Change in bowel habits – constipation/ diarrhea; +/- blood-Hematochezia (bright red blood coats or maroon w/ clots in stool)-Colicky pain

6. Discuss the clinical work up for suspected colorectal cancer

% Digital rectal exam (DRE): The doctor inserts a lubricated, gloved finger into the rectum to feel for abnormal areas. It only detects tumors large enough to be felt in the distal part of the rectum but is useful as an initial screening test.

% Fecal occult blood test (FOBT): a test for blood in the stool. Two types of tests can be used for detecting occult blood in stools i.e. guaiac based (chemical test) and immunochemical. The sensitivity of immunochemical testing is superior to that of chemical testing without an unacceptable reduction in specifity.

% Endoscopy:Sigmoidoscopy: A lighted probe (sigmoidoscope) is inserted into the rectum

and lower colon to check for polyps and other abnormalities.

Colonoscopy: A lighted probe called a colonoscope is inserted into the rectum and the entire colon to look for polyps and other abnormalities that may

be caused by cancer. A colonoscopy has the advantage that if polyps are found during the procedure they can be immediately removed. Tissue can also be taken for biopsy.

7. Discuss the pathology of colorectal cancer and correlate stage with survival outcomes

The pathology of the tumor is usually reported from the analysis of tissue taken from a biopsy or surgery. A pathology report will usually contain a description of cell type and grade. The most common colon cancer cell type is adenocarcinoma which accounts for 95% of cases. Other, rarer types include lymphoma and squamous cell carcinoma.

Cancers on the right side (ascending colon and cecum) tend to be exophytic, that is, the tumour grows outwards from one location in the bowel wall. This very rarely causes obstruction of feces, and presents with symptoms such as anemia. Left-sided tumours tend to be circumferential, and can obstruct the bowel much like a napkin ring.

Adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the colorectal mucosa. It invades the wall, infiltrating the muscularis mucosae, the submucosa and thence the muscularis propria. Tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, reduced stroma ("back to back" aspect). Sometimes, tumor cells are discohesive and secrete mucus, which invades the interstitium producing large pools of mucus/colloid (optically "empty" spaces) - mucinous (colloid) adenocarcinoma, poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery - "signet-ring cell." Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present three degrees of differentiation: well, moderately, and poorly differentiated.

STAGE TNM GROUP GROUP DUKE’S PrognosisStage I T1 N0 M0 Duke’s A 5 year survival >90%  T2 N0 M0               Stage II T3 N0 M0 Duke’s B 5 year survival 70-85%  T4 N0 M0   5 year survival 55-65%           

Stage III any T N1 M0 Duke’s C 5 year survival 45-55%

  any T N2, N3 M0   5 year survival 20-30%

           

Stage IV any T any N M1 (distant) Duke’s D 5 year survival

< 5%

8. Present the treatment options for colorectal cancer and the follow-up plan

The treatment depends on the staging of the cancer. When colorectal cancer is caught at early stages (with little spread) it can be curable. However, when it is detected at later stages (when distant metastases are present) it is less likely to be curable.

Surgery remains the primary treatment while chemotherapy and/or radiotherapy may be recommended depending on the individual patient's staging and other medical factors.

The aims of follow-up are to diagnose in the earliest possible stage any metastasis or tumors that develop later but did not originate from the original cancer (metachronous lesions).

The U.S. National Comprehensive Cancer Network and American Society of Clinical Oncology provide guidelines for the follow-up of colon cancer.[73][74] A medical history and physical examination are recommended every 3 to 6 months for 2 years, then every 6 months for 5 years. Carcinoembryonic antigen blood level measurements follow the same timing, but are only advised for patients with T2 or greater lesions who are candidates for intervention. A CT-scan of the chest, abdomen and pelvis can be considered annually for the first 3 years for patients who are at high risk of recurrence (for example, patients who had poorly differentiated tumors or venous or lymphatic invasion) and are candidates for curative surgery (with the aim to cure). A colonoscopy can be done after 1 year, except if it could not be done during the initial staging because of an obstructing mass, in which case it should be performed after 3 to 6 months. If a villous polyp, polyp >1 centimeter or high grade dysplasia is found, it can be repeated after 3 years, then every 5 years. For other abnormalities, the colonoscopy can be repeated after 1 year.

CBI 5: 39 year old man with paralysis [Takeshi Takamatsu]

1. Explain how thyrotoxicosis/hyperthyroidism causes weight loss, tachycardia and memory loss.

Thyroid hormone functions as a stimulus to metabolism and is critical to normal function of the cell. In excess, it both overstimulates metabolism and exacerbates the effect of the sympathetic nervous system (by causing an increase in beta adrenergic receptors), causing "speeding up" of various body systems and symptoms resembling an overdose of epinephrine (adrenaline). These include fast heartbeat and symptoms of palpitations, nervous system tremor and anxiety symptoms, digestive system hypermotility (diarrhea), and weight loss.

2. Discuss the expected results of a thyroid function test in a hyperthyroid patient.

Decreased TSHIncreased T4 (total and free) Increased T3

3. Explain why hypokalemia and paralysis can be a complication of thyrotoxicosis.

Increased T4 leads to increased activity of Na +/K +-ATPase, which causes an INTRAcellular shift of K+. This results in hyperpolarization of the cell and inability to generate another action potential leading to paralysis.

4. Discuss the long term treatment for a patient with hypokalemic thyrotoxicosis

Treatment to prevent recurrent attacks – avoid precipitating factors e.g. CHO, EtOH and exercise

Definitive Therapy – Beta blockers, anti-thyroid drugs, radioactive iodine, thyroidectomy

Propranolol (non selective beta blocker) 

Block beta stimulation of NKATPase -> stop K intake -> normalize K serum levels -> help with muscle weakness

Also has effects on thyroid hormone. Decreases conversion of T4 to the more potent T3

5. Compare the biochemical and physiological consequences of hyperthyroidism and hypothyroidism.

Hypothyroidism Cold intolerance (decreased heat production)Weight gain, decreased appetiteHypoactivity, lethargy, fatigue, weaknessConstipationDecreased reflexesMyxedema (facial/periorbital)Dry, cool skin; coarse, brittle hair

HyperthyroidismHeat intolerance (increased heat production)

Weight loss, increased appetiteHyperactivityDiarrheaIncreased reflexesChest pain, palpitations, arrhythmiasWarm, moist skin; fine hair

CBI 6: 39 year-old woman (Karen Smith) with breast cancer

1. Discuss the 6 documented prognostic indicators for breast cancer and identify the most significant adverse prognostic sign

Prognostic factors include staging, (i.e., tumor size, location, grade, whether disease has traveled to other parts of the body), recurrence of the disease, and age of patient.

Stage is the most important, as it takes into consideration size, local involvement, lymph node status and whether metastatic disease is present. The higher the stage at diagnosis, the worse the prognosis. The stage is raised by the invasiveness of disease to lymph nodes, chest wall, skin or beyond, and the aggressiveness of the cancer cells. The stage is lowered by the presence of cancer-free zones and close-to-normal cell behavior (grading). Size is not a factor in staging unless the cancer is invasive. For example, Ductal Carcinoma In Situ (DCIS) involving the entire breast will still be stage zero and consequently an excellent prognosis with a 10yr disease free survival of about 98%.

Grading is based on how biopsied, cultured cells behave. The closer to normal cancer cells are, the slower their growth and the better the prognosis. If cells are not well differentiated, they will appear immature, will divide more rapidly, and will tend to spread. Well differentiated is given a grade of 1, moderate is grade 2, while poor or undifferentiated is given a higher grade of 3 or 4 (depending upon the scale used).

Younger women tend to have a poorer prognosis than post-menopausal women due to several factors. Their breasts are active with their cycles, they may be nursing infants, and may be unaware of changes in their breasts. Therefore, younger women are usually at a more advanced stage when diagnosed. There may also be biologic factors contributing to a higher risk of disease recurrence for younger women with breast cancer.

The presence of estrogen and progesterone receptors in the cancer cell is important in guiding treatment. Those who do not test positive for these specific receptors will not be able to respond to hormone therapy, and this can affect their chance of survival depending upon what treatment options remain, the exact type of the cancer, and how advanced the disease is.

In addition to hormone receptors, there are other cell surface proteins that may affect prognosis and treatment. HER2 status directs the course of treatment. Patients whose cancer cells are positive for HER2 have more aggressive disease and may be treated with

the 'targeted therapy', trastuzumab (Herceptin), a monoclonal antibody that targets this protein and improves the prognosis significantly. Tumors overexpressing the Wnt signaling pathway co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) may represent a distinct subtype of breast cancer and a potential treatment target.

2. Describe the three main treatment modalities for breast cancer and the goal of treatment for each

Breast cancer is treated first with surgery, and then with drugs, radiation, or both. Treatments are given with increasing aggressiveness according to the prognosis and risk of recurrence.Stage 1 cancers (and DCIS) have an excellent prognosis and are generally treated with lumpectomy with or without radiation. Although the aggressive HER2+ cancers should also be treated with the trastuzumab (Herceptin) regime. Stage 2 and 3 cancers with a progressively poorer prognosis and greater risk of recurrence are generally treated with surgery (lumpectomy or mastectomy with or without lymph node removal), radiation (sometimes) and chemotherapy (plus trastuzumab for HER2+ cancers). Stage 4, metastatic cancer, (i.e. spread to distant sites) is not curable and is managed by various combinations of all treatments from surgery, radiation, chemotherapy and targeted therapies. These treatments increase the median survival time of stage 4 breast cancer by about 6 months.

Drugs used in addition to surgery are called adjuvant therapy. There are currently 3 main groups of medications used for adjuvant breast cancer treatment:

% Hormone Blocking Therapy% Chemotherapy% Monoclonal Antibodies

One or all of these groups can be used.

Hormone Blocking Therapy: Some breast cancers require estrogen to continue growing. They can be identified by the presence of estrogen receptors (ER+) and progesterone receptors (PR+) on their surface (sometimes referred to together as hormone receptors, HR+). These ER+ cancers can be treated with drugs that block the production of estrogen or block the receptors, such as tamoxifen or an aromatase inhibitor.

Chemotherapy: Usually used for stage 2-4 disease. They are given in combinations. One of the most common treatments is cyclophosphamide plus doxorubicin (Adriamycin), known as CA; these drugs damage DNA in the cancer, but also in fast-growing normal cells where they cause serious side effects. Damage to the heart muscle is the most dangerous complication of doxorubicin. Sometimes a taxane drug, such as docetaxel, is added, and the regime is then known as CAT; taxane attacks the microtubules in cancer cells. Another common

treatment, which produces equivalent results, is cyclophosphamide, methotrexate, and fluorouracil (CMF). (Chemotherapy can literally refer to any drug, but it is usually used to refer to traditional non-hormone treatments for cancer.)

Monoclonal antibodies: A relatively recent and very exciting development in HER2+ breast cancer treatment. Cancer cells have a receptor called HER2 on their surface. This receptor is normally stimulated by a growth factor which causes the cell to divide, however in the absence of the growth factor, the cell will normally stop growing. In approx 20% of invasive breast cancers, the HER2 receptor is stuck in the "on" position. The cell divides without stopping, producing an aggressive form of cancer. Trastuzumab (Herceptin), a monoclonal antibody to HER2, has dramatically improved the 5yr disease free survival of 'early' (stages 1–3) HER2+ breast cancers to about 87%. Trastuzumab, however, is expensive, and approx 2% of patients suffer significant heart damage; it is otherwise well tolerated with far milder side effects than conventional chemotherapy. Other monoclonal antibodies are also being trialed.

Radiotherapy is given after surgery to the region of the tumor bed, to destroy microscopic tumors that may have escaped surgery. Radiation therapy can be delivered as external beam radiotherapy or as brachytherapy (internal radiotherapy). Radiation can reduce the risk of recurrence by 50-66% (1/2 - 2/3rds reduction of risk) when delivered in the correct dose.

3. Explain the mechanism of action for targeted therapy for breast cancer.

Targeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells (e.g. with traditional chemotherapy). Targeted cancer therapies may be more effective than current treatments and less harmful to normal cells.

Cancer cells have a receptor called HER2 on their surface. This receptor is normally stimulated by a growth factor which causes the cell to divide, however in the absence of the growth factor, the cell will normally stop growing. In approx 20% of invasive breast cancers, the HER2 receptor is stuck in the "on" position. The cell divides without stopping, producing an aggressive form of cancer. Trastuzumab (Herceptin), a monoclonal antibody to HER2, has dramatically improved the 5yr disease free survival of 'early' (stages 1–3) HER2+ breast cancers to about 87%. Trastuzumab, however, is expensive, and approx 2% of patients suffer significant heart damage; it is otherwise well tolerated with far milder side effects than conventional chemotherapy. Other monoclonal antibodies are also being trialed.

4. Relate prognostic indicators to treatment choice.

Breast cancer is treated first with surgery, and then with drugs, radiation, or both. Treatments are given with increasing aggressiveness according to the prognosis and risk of recurrence.Stage 1 cancers (and DCIS) have an excellent prognosis and are generally treated with lumpectomy with or without radiation. Although the aggressive HER2+ cancers should also be treated with the trastuzumab (Herceptin) regime. Stage 2 and 3 cancers with a progressively poorer prognosis and greater risk of recurrence are generally treated with surgery (lumpectomy or mastectomy with or without lymph node removal), radiation (sometimes) and chemotherapy (plus trastuzumab for HER2+ cancers). Stage 4, metastatic cancer, (i.e. spread to distant sites) is not curable and is managed by various combinations of all treatments from surgery, radiation, chemotherapy and targeted therapies. These treatments increase the median survival time of stage 4 breast cancer by about 6 months.

5. Outline the staging system for breast cancer and correlate the staging system for breast cancer with the prognostic indicators

Stage 0Stage 0 is used to describe non-invasive breast cancers, such as DCIS and LCIS. In stage 0, there is no evidence of cancer cells or non-cancerous abnormal cells breaking out of the part of the breast in which they started, or of getting through to or invading neighboring normal tissue.

Stage IStage I describes invasive breast cancer (cancer cells are breaking through to or invading neighboring normal tissue) in which:

% the tumor measures up to 2 centimeters, AND

% no lymph nodes are involved

Stage IIStage II is divided into subcategories known as IIA and IIB.

Stage IIA describes invasive breast cancer in which:

% no tumor can be found in the breast, but cancer cells are found in the axillary lymph nodes (the lymph nodes under the arm), OR

% the tumor measures 2 centimeters or less and has spread to the axillary lymph nodes, OR

% the tumor is larger than 2 centimeters but not larger than 5 centimeters and has not spread to the axillary lymph nodes

Stage IIB describes invasive breast cancer in which:

% the tumor is larger than 2 but no larger than 5 centimeters and has spread to the axillary lymph nodes, OR

% the tumor is larger than 5 centimeters but has not spread to the axillary lymph nodes

Stage IIIStage III is divided into subcategories known as IIIA, IIIB, and IIIC.

Stage IIIA describes invasive breast cancer in which either:

% no tumor is found in the breast. Cancer is found in axillary lymph nodes that are clumped together or sticking to other structures, or cancer may have spread to lymph nodes near the breastbone, OR

% the tumor is 5 centimeters or smaller and has spread to axillary lymph nodes that are clumped together or sticking to other structures, OR

% the tumor is larger than 5 centimeters and has spread to axillary lymph nodes that are clumped together or sticking to other structures

Stage IIIB describes invasive breast cancer in which:

% the tumor may be any size and has spread to the chest wall and/or skin of the breast AND

% may have spread to axillary lymph nodes that are clumped together or

sticking to other structures, or cancer may have spread to lymph nodes near the

breastbone

% Inflammatory breast cancer is considered at least stage IIIB.

Stage IIIC describes invasive breast cancer in which:

% there may be no sign of cancer in the breast or, if there is a tumor, it may

be any size and may have spread to the chest wall and/or the skin of the breast,

AND

% the cancer has spread to lymph nodes above or below the collarbone, AND

% the cancer may have spread to axillary lymph nodes or to lymph nodes

near the breastbone

Stage IV

Stage IV describes invasive breast cancer in which:

the cancer has spread to other organs of the body -- usually the lungs, liver, bone, or brain

6. Delineate the main side effects of each treatment modality, including the life threatening side effects, along with options for self-care.

Chemotherapy% -Short-term toxic effects:

-Alopecia and fatigue-Some develop premature ovarian failure

-5-FU-Skin, cardiac (MI & angina), CNS, ocular issues -Cyclophosphamide-Hemorrhagic cystitis, SIADH, hyperpigmentation

Hormonal Therapy Agents -Tamoxifen-hot flashes, DVT, PE -Anastrazole- athralgias, hot flashes, flu-like -Leuprolide- hot flashes, decreased libido, tumor flare (increased bone pain, urinary retention, back pain

Monoclonal Antibody Therapy -Trastuzimab- Cardiac toxicity (due to interaction with receptors in the heart) with

increasing potential for arrhythmias