UNIVERSITY OF FLORIDA

DEPARTMENT OF SURGERY

AMERICAN BOARD OF SURGERY IN-SERVICE TRAINING EXAM

(ABSITE)

BASIC SCIENCE 101

By

MATTHEW J. DELANO

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A BASIC SCIENCE REVIEW OF THE CORE TOPICS IN GENERAL SURGERY FOR THE AMERICAN BOARD

OF SURGERY IN-SERVICE TRAINING EXAM

© 2008 MATTHEW J. DELANO

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ACKNOWLEDGMENTS

RICHARD E. DEAN, M.D.JOHN ARMSTRONG, M.D.GEORGE SAROSI, M.D.KEVIN BEHRNS, M.D.MICHAEL E. MAHLIA, M.D.WILLIAM CANCE, M.D.LYLE L. MOLDAWER, Ph.D.

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CHAPTER 1COURSE DESCRIPTION AND SYLLABUS: BASIC SCIENCE 101

Goals:1. Understand the historical significance and current purpose of the ABSITE.2. Understand and comprehend the five fundamental areas of surgery related basic science

knowledge that the ABSITE test.3. Improve individual ABSITE scores by 10-20%.4. Promote personal lifelong habits of scientific surgical learning and self education.

Basic Science 101 will focus on building and reinforcing the fundamentals of surgical basic science knowledge which will serve as a foundation for further clinical and operative knowledge growth and ABSITE success.

AudienceAll categorical and preliminary surgical residents (PGY-1 - PGY-7+)

Course Directors:John H. Armstrong, M.D., F.A.C.S., john.armstrong@surgery.ufl.eduoffice: 273-5675, pager: 413-5666, cell: 786-255-4820George Sarosi, M.D., george.sarosi@surgery.ufl.edu

Course Schedule:

Review Session Date: Topics to be covered: Course materials:December 13, 2009 BODY AS A WHOLE Chapter 3December 20, 2008 BODY AS A WHOLE Chapter 4January 3, 2009 BODY AS A WHOLE Chapter 5January 10, 2009 GASTROINTESTINAL TRACT Chapters 6, 7January 17, 2009 CARDIOVASCULAR AND PULMONARY Chapter 8January 24, 2009 GU, HEAD AND NECK, SKIN, Chapter 9

MUSCULOSKELETAL, NERVOUS, ENDOCRINE,HEMATIC AND LYMPHATIC SYSTEMS ANDBREAST

The course is broken down by basic science knowledge category as tested by the ABSITE. The

course material has been concentrated from the past ten years of Michigan State Integrated

ABSITE Reviews, by Richard E. Dean.

Reference Material:

The Physiologic Basis of Surgery . 3rd Ed. by J. Patrick O’Leary, 2002, Lippincott Wiliams & Wilkins, ISBN 0-7817-3839-3.

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CHAPTER 2AMERICAN BOARD OF SURGERY IN-SERVICE TRAINING EXAM (ABSITE)

IntroductionThe American Board of Surgery offers annually to surgery residency programs the In-Training Examination (ABSITE), a written, multiple-choice examination designed to measure the progress attained by residents in their knowledge of basic science and the management of clinical problems related to general surgery. The ABSITE is furnished to program directors as an evaluation instrument to assess residents' progress. The results are released only to program directors. It is not available to individual residents and is not required as part of the certification process.

Reporting of ResultsABSITE results are made available to program directors in early March. The ABS provides program directors with various reports, including a resident's individual score report. Residents are strongly encouraged to keep copies of their score report for their records, as the ABS does not retain this information. The ABS will not provide residents with a score report or "transcript." Residents who request this information will be directed to contact their general surgery residency program.

If you have questions once you have received your individual score report, your program director can help with the interpretation of the results. The ABS will not discuss examination results with residents. The ABS also will not regenerate any report as a result of miscoding of information, such as PGY level, name, etc. Any inquiries regarding the ABSITE must come directly from the program.

Examination ContentSince 2006 the ABS offers the ABSITE as a junior level (PG-1 and -2) and senior level (PG-3 to -5) examination. Both the junior- and senior-level versions consist of 225 multiple-choice questions; examinees are given five hours to take the exam. For the junior-level exam, 60% of the examination focuses on basic science, while 40% centers on the management of clinical surgical problems. In the senior-level exam, 20% of the exam focuses on basic science and 80% on clinical management. The relative emphasis on clinical content categories in the two examinations is shown in the following tables.

Table 1. Junior and Senior ABSITE basic science and clinical medicine breakdown.

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Table 2. Knowledge categories comprising the Junior and Senior ABSITE

Table 3. Junior and Senior ABSITE basic science and clinical medicine breakdown by

knowledge category.

Adapted from the American Board of Surgery: http://home.absurgery.org/

Table 4. Breakdown of the 2007 Junior ABSITE.

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BODY AS A WHOLE: NUMBER OF QUESTIONSBasic Science 47Clinical Management 57

GASTROINTESTINAL:Basic Science 29Clinical Management 9

CARDIOVASCULAR AND RESPIRATORY:Basic Science 25Clinical Management 7

GU, HEAD AND NECK, SKIN,MUSCULOSKELETAL, NERVOUS, SYSTEMS:

Basic Science 11Clinical Management 7

ENDOCRINE, HEMATIC, LYMPHATIC, BREASTBasic Science 14Clinical Management 7

As you can see the Junior ABSITE is over 60% basic science while the Senior ABSITE is

predominantly clinical medicine.

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CHAPTER 3BODY AS A WHOLE: SESSION 1

Metabolism and Nutrition

Establishing Energy (Caloric) Requirements

The energy expenditure can be determined by the Harris-Benedict equation, which determines the basal energy expenditure. The formulas are based on body weight, height, age, and sex.

BEE = 66.5 + 13.7 x weight (kg) + 5.0 x height (cm) – 6.8 x age (yr) {Male}

BEE = 655.1 + 9.56 x weight (kg) + 1.85 x height (cm) – 4.7 x age (yr) {Female}

The metabolic cart measurement determines energy expenditure from oxygen utilization and CO2

generation.

The resting energy expenditure of most patients is at 25 calories per kilogram per day. Additional energy may be expended in patients sustaining multiple fractures, severe infection, or burns. In these circumstances, the energy expenditure may reach 35-40 kilocalories per kilogram.

Adequate calorie replacement can be determined with frequent measurements on the metabolic cart or by determining total nitrogen excretion, which represents gluconeogenesis of protein to meet energy requirements if adequate non-protein calories are unavailable.

Non-protein calories are provided as:

Glucose, which generates 4 calories/gm in the solid state. However, in solution only 3.4 cals/gm result. 60-70 % of the non-protein calories are usually provided from glucose or glucose substrates, i.e. starch

Lipids when metabolized generate 9 calories/gm. 30-40% of the non-protein calories are provided by lipids.

Protein is provided as amino acids, which generate 4 calories/gm. Under usual conditions, 1gm/kg/day is required to meet protein requirements.

Sabiston, Textbook of Surgery, 15th Edition, pp 140-2

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Normal Caloric Requirements in a Neonate

The neonate has a metabolic rate 2.5 times that of an adult and requires 120 calories/Kg per day for growth. Formulas for infants have 20 cal/oz. Thus, weight in Kg x 6 oz = volume of formula necessary to deliver 120 cal/Kg/day. Formula composition is 50% carbohydrate, 35% fat, and 15% protein with vitamins and minerals.

Sabiston, Textbook of Surgery, 16th Edition, p 1465

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Substrate of Gluconeogenesis in Starvation

In early starvation, caloric needs are met by fat and protein, sparing the glycogen reserve. During the first few days, the body uses 60-90 gm of protein daily. This is mostly converted to glucose in the liver by gluconeogenesis, and is used predominantly by brain tissue, leukocytes, and erythrocytes. If starvation progresses beyond several days, the obligatory nitrogen loss begins to decrease as the brain adapts to using fat as a fuel source. This is in the form of keto acids produced by the liver, as free fatty acids cannot cross the blood/brain barrier whereas keto acids can. As use of keto acids increases, the daily protein breakdown decreases to approximately 25 gm. This protein sparing allows an average individual with an average supply of fat and muscle to survive total starvation for several months or approximately 100 days.

Schwartz, 6th edition, p 81

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Characteristics of Glutamine

Glutamine, an amide of the acidic amino acid glutamate, is a key component in our biochemistry. It is absorbed in the gut, where it may be broken down to alanine and used in the process of gluconogenesis in the liver. It is also used by the kidney as a source of nitrogen in making ammonia.

Glutamine is the most abundant free amino acid in the body. When not in abundance in the diet, it is synthesized for the most part in muscle and is used as the primary source of fuel for enterocytes and neoplastic cells. It has been increasingly recognized as important for the maintenance of healthy intestinal mucosa and may even protect the mucosa from injury induced by chemotherapy, radiation, and other agents. In catabolic states glutamine is released from muscle and is used by GI mucosa. It has been proposed that this increase in Glutamine use may result in significant muscle wasting.

Shils, M.D., et al, Modern Nutrition in Health & Disease, 8th ed., pp 18-20, 1424-26

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Mechanisms of Gout (DNA Breakdown Products)

Nucleic acids are the primary components of DNA. Purines and pyrimidines represent the end points of nucleic acids synthesis. These products are predominately products of endogenous synthesis. Catabolism of the breakdown products of purines and pyrimidines is uric acid and beta-amino-isobutyric acid, which are excreted predominately in the urine. There is little recycling of these products.

Gout is characterized by elevated levels of urate in the blood and uric acid in the urine. The elevated levels or urates lead to deposit of the urate crystals in the joints, initiating an inflammatory arthritis. Elevated levels of urate may occur where there is an abnormally high turnover of nucleic acids as in polycythemia, myeloid metaplasia, chronic leukemia, and other hematopoietic diseases. Gouty arthritis resulting from these diseases is referred to as secondary metabolic gout. In primary gout, there is no evidence of increased destruction of nucleic acids and the hyperuricemia is due largely to inherited metabolic defect of purine metabolism leading to excessive rates of conversion of glycine to uric acid. The mechanisms of elimination of uric acid are normal. In some cases there may be a defect in the kidney where there is a faulty enzymatic transport of urates by the renal tubules resulting in lower rates of excretion of urate as uric acid.

Review of Physiologic Chemistry, 15th edition, pp 381-93

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Insulin Response IV vs. PO Glucose

An elevated blood glucose level is the most important regulator of insulin secretion. Other stimulants of insulin release include amino acids (arginine being the most potent), long-chain fatty acids, gastrointestinal hormones (namely gastrin and secretin), acetylcholine, sulfonylureas.

The threshold value for glucose-stimulated insulin secretion is 100mg/dL. An oral dose of glucose is a more potent stimulator of insulin than an equivalent IV dose. An oral glucose load has the added benefit of stimulating the secretion of gastrin and secretin .

Rhoades RA, Tanner GA, Medical Physiology, 1995, p 710

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Hormones in Satiety

Insulin is an anabolic hormone released in the mileau of elevated glucose levels. This hormone promotes fat storage and protein synthesis and inhibits lipolysis. Growth hormone is also an anabolic hormone. Glucagon, catacholamines, and steroids promote proteolysis and gluconeogenesis and are considered catabolic hormones.

Satiety usually follows intake of carbohydrates and fat. The anabolic hormones are liberated with these nutrients.

Sabiston, Textbook of Surgery, 16th edition, p 98

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Indications Parenteral vs. Enteral Nutrition

Enteral nutrition is the preferred method of providing nutritional support if the GI tract is functional.

Parenteral nutrition indications include:

1. Newborn infants with catastrophic gastrointestinal anomalies, such as tracheoesophageal fistula, gastroschisis, omphalocele, or massive intestinal atresia

2. Infants who fail to thrive due to gastrointestinal insufficiency associated with short-bowel syndrome, malabsorption, enzyme deficiency, meconium ileus, or idiopathic diarrhea

3. Adult patients with short-bowel syndrome secondary to massive small-bowel resection (<100 cm without colon or ileocecal valve, or <50 cm with intact ileocecal valve and colon)

4. Patients with enteroenteric, enterocolic, enterovesical, or high-output enterocutaneous fistulas (>500 mL/d)

5. Surgical patients with prolonged paralytic ileus after major operations (>7 to 10 days), multiple injuries, or blunt or open abdominal trauma, or patients with reflex ileus complicating various medical diseases

6. Patients with normal bowel length but with malabsorption secondary to sprue, hypoproteinemia, enzyme or pancreatic insufficiency, regional enteritis, or ulcerative colitis

7. Adult patients with functional gastrointestinal disorders such as esophageal dyskinesia after cerebrovascular accident, idiopathic diarrhea, psychogenic vomiting, or anorexia nervosa

8. Patients with granulomatous colitis, ulcerative colitis, or tuberculous enteritis in which major portions of the absorptive mucosa are diseased

9. Patients with malignancy, with or without cachexia, in whom malnutrition might jeopardize successful use of a therapeutic option

10. Patients in whom attempts to provide adequate calories by enteral tube feedings or high residuals have failed

11. Critically ill patients who are hypermetabolic for >5 days or for whom enteral nutrition is not feasible

Schwartz, Principles of Surgery, 9th Edition

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Protein Requirements in TPN

Basic Nutritional Needs

Determination of the patient’s protein requirement is the first critical step in formulating a nutritional support program. The requirements for a normal, active man are 1 gm protein/kg body weight daily (6.25 gm protein = 1 gm nitrogen). Requirements change with the clinical state, decreasing to 1 gm/kg/day early in re-feeding after starvation and increasing to 1-2 gm/kg/day in burned or severely septic patients. Total intake may have to be limited to 40-50 gm/day in hepatic failure.

Nitrogen/non-protein calories = 1:100-1:200 to obtain optimal nitrogen balance.

Example

1:100 = 1gm nitrogen to 100 calories

or

6.25gm protein to 25gm glucose

70Kg male will require:

non-protein calories

70Kg x 25 = 1750 cal/day

or

1800 cal 4 cal/gm glucose = 450gm glucose

450 25 = 18

Protein

6:25gms x 18 = 122.5gms protein

Lawrence, Essentials of General Surgery, p 72

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Etiology of Mortality with Enteral Feedings

Aspiration is a common problem associated with enteral feedings. Although vomiting and aspiration with asphexia are unusual, aspiration pneumonia is a significant risk factor. Nasogastric feedings should be reserved for those with intact mental status and protective laryngeal reflexes. Although nasojejunal feedings are associated with fewer pulmonary complications, passing the tube beyond the pylorus can be difficult to achieve and maintain. Nasoenteric feeding can further be complicated by tube clogging or kinking, displacement, or removal. Nasopharyngeal complications, i.e. sinusitis, bleeding, and inflammation may occur.

Enteral feeding extending beyond 30 days should be considered for PEG or jejunostomy.

Schwartz, Principles of Surgery, 8th Edition, pp 33-35

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Earliest Indicators of Nutritional Replenishment

Several methods of assessing appropriate nutritional support are available:

1) Clinical assessment of daily weights over several days acknowledging that fluid retention is a possibility. Improved lymphocyte count may also be helpful.

2) Indirect calorimetric measurements can provide information regarding caloric requirements and metabolic fuels being utilized.

3) Prealbumin measurements on a regular basis. The half-life of prealbumin is 2 days.4) Transferrin measurements on a regular basis determine the status of protein synthesis.

Transferrin is a short-acting protein with a turnover rate of 10 days. Inadequate amounts of protein and calories will be reflected in low transferrin levels.

5) Total nitrogen balance can be determined clinically using the urinary urea nitrogen (UUN) method and comparing it to daily nitrogen intake. The UUN method requires collecting the 24 hr urine, determining the nitrogen content, and then adding 2-4gms for nitrogen loss from stool and integument.

Sabiston, Textbook of Surgery, 16th Edition, p 100ACS Surgery, Principles and Practice, 2003, p 1568

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Characteristics of Respiratory Quotient

Substrate metabolism can be determined by the respiratory quotient (RQ). The respiratory quotient (RQ) is the ratio of the volume of CO2 produced to the volume of O2 consumed per unit of time. It can be calculated for reactions outside the body, for individual organs and tissues, and for the whole body. The RQ of carbohydrate is 1.00 and that of fat is about 0.70. This is because O2 and H are present in carbohydrate in the same proportions as in water, whereas in the various fats, extra O2 is necessary for the formation of H2O.

RQ > 1 indicates lipogenesis and overfeeding.RQ <0.7 indicates ketosis; fat oxidation and starvation

RQ = CO2 ConsumptionO2 Production

Carbohydrate:

C6H12O6 = 602 → 6CO2 + 6H2O(glucose)

RQ = 6/6 = 1.00

Fat:

2C51H98O6 + 145-02 →102-CO 2 + 98-H2O(tripalmitin)

RQ = 102/145 = 0.703

Determining the RQ of protein in the body is a complex process, but an average value of 0.82 has been calculated.

The O2 consumption and the CO2 production of an organ can be calculated by multiplying its blood flow per unit of time by the arteriovenous differences for O2 and CO2. Data on the RQ of individual organs are of considerable interest in drawing inferences about the metabolic processes occurring in them. For example, the RQ of the brain is regularly 0.97 to 0.99, indicating that its principal but not its only fuel is carbohydrate. During secretion of gastric juice, the stomach has a negative RQ because it takes up more CO2 from the arterial blood than it puts into the venous blood.

Ganong, Review of Medical Physiology, 12th Edition, pp 226-227

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Utilization of Carbohydrates

Injuries and infection alter metabolism from the non-stress state where glucose is a predominate fuel source for most tissues. During stress, insulin resistance occurs and glucose is shunted away from nonessential organs such as skeletal muscles and adipose tissue. Hepatic gluconogenesis arising from alanine and glutamine catabolism, and pyruvate and lactate from skeletal muscle, provide a ready source of fuel (glucose) for the nervous system, leukocytes and erythrocytes, which do not require insulin for glucose transport.

In starvation, glucose production occurs at the expense of protein stores (skeletal muscles). Exogenous glucose, (50gms), facilitates fat entry into the TCA cycle and reduces ketosis. It also reduces protein catabolism as noted with decreased nitrogen excretion.

Schwartz, Principles of Surgery, 8th Edition, pp 28-29

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Caloric Calculation in TPN

Multiply the patient’s ideal body weight by 25kcal/kg/day to determine the total number of calories needed per day.

The caloric values of the major substrates of TPN are as follows:Carbohydrates (dextrose) 3.4kcal/gLipids 9.3 kcal/gProteins 4 kcal/g

To calculate the total caloric content of TPN, the individual components are multiplied by their own caloric value and then summed. (Dextrose (g) x 3.4 + (Lipid (g) x 9.3) + Nitrogen (g) x 4) = Total Caloric Content

Lawrence P. Essentials of General Surgery. 4th Ed pp 71-86

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Etiology of Impaired Glucose Uptake in Type II Diabetes

A major role of insulin is in promoting glucose transport into the cells. This transport may be enhanced by regulation of membranebound glucose transport peptides. Insulin resistance may result from either a diminished number of receptors or a decreased receptor affinity. Type II Diabetes is caused at least in part by receptor defects leading to insulin resistance.

Type I Diabetes is an autoimmune disorder associated with Class II alleles DR3 and DR4, and the HLA-DQ β(beta) chain are primarily responsible for susceptibility (and resistance) to autoimmune destruction.

ACS Surgery, Principles and Practice, 2003, p 1090Sabiston, Textbook of Surgery, 16th Edition, pp 649-50

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Treatment Elevated Homocysteine Levels

Homocysteine ureas are seven biochemically and clinically distinct disorders each characterized by elevated levels of the sulfur-containing amino acid homocysteine in blood and urine. The most common form results from reduced activity of crystathionine β-synthase, which converts methionine to cystein.

ClinicalHallmarks of this enzyme deficiency include dislocation of the lenses, mental retardation, Marfanoid habitus, osteoporosis, and thrombotic vascular disease.

TreatmentSome patients show chemical and clinical improvement following administration of specific vitamin supplements (Pyridoxine, Folate, or Cobalamin).

Harrison’s Principles of Internal Medicine, 14th Edition, p 2199

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Etiology of Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is a codominant genetic disorder that occurs in the heterozygous form in approximately 1 in 500 individuals. FH is due to mutations in the gene for the LDL receptor and is genetically heterozygous with more than 200 different mutations identified. Plasma levels of total and LDL cholesterol are elevated at birth and remain so throughout life. In untreated adults, total cholesterol levels range from 275-500mg per dL. Plasma triglycerides are typically normal or reduced.

As would be expected from the reduced number of LDL receptors, the fractional clearance of LDL is decreased, and LDL production is increased due to conversion of unused intermediary products.

Harrison, Principles of Internal Medicine, 14th Edition, pp 2138-42

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Diagnosis of the Metabolic Syndrome

The metabolic syndrome is characterized by obesity, non-insulin dependent diabetes mellitus, hyperinsulinism, hyperlipidemia, and cardiovascular disease. Recognition of patients with the metabolic syndrome is important so that they may be treated.

Schwartz, Principles of Surgery, 8th Edition, p 729

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Cardiac Nutrient Extreme Exercise

In heavy exercise, muscle glycogen is mainly used with anaerobic glycolysis being particularly important at the onset, followed by aerobic glycolysis later. In moderate exercise of longer duration half the needs are met by oxidation of carbohydrates (40 percent from glycogen and 10 percent from glucose) and half by free fatty acids (40 percent from adipose stores and 10 percent from muscle fat). In exercise of several hours’ duration, free fatty acids are used to an increasing extent.

Anaerobic glycolysis leads to lactate production. Lactate in muscle does not increase significantly until an oxygen intake of about 50 percent of the maximum is exceeded. Lactate diffuses from muscle relatively slowly, and a concentration gradient between tissue and blood may be present during a period of active lactate production, with the muscle lactate concentration being as high as 1.5 times that in blood. At any power output sustained for longer than 5 minutes, lactate in both muscle and blood increases transiently and then falls to resting levels owing to reduced production of lactate and its metabolism in muscle, liver and heart. The oxygen uptake at which plasma lactate rises in a progressively increasing power output test is sometimes known as the “anaerobic threshold.”

Jones and Campbell, Clinical Exercise Testing, 1982, pp. 18 – 22

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Determination of Nitrogen Balance in the Critically Injured Patient

Nitrogen balance is an indicator of equilibrium of protein intake, its metabolism, and subsequent excretion. A net balance of zero is felt to demonstrate protein equilibrium. To be truly accurate one must take into account all losses of protein, including losses from urine, stool, bile, enteric, and wound secretions. 6.25g of protein contain 1g of nitrogen. The following formula may be used:

Nitrogen Balance = (Nirogen intake) – (Nitrogen loss) = (Protein in grams/6.25) – (UUN + 4 gms)

where UUN = urine urea nitrogen from a 24 hour urine specimennitrogen (g) = protein (g)/6.25

Barie and Shires. Surgical Intensive Care, pp 909

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Wounds

Sequence of the Appearance of Wound Healing Cells

Healing of a wound created by any mechanism usually follows a predictable pattern under normal circumstances, which can be divided into four phases. Although they are listed in sequential fashion, they really blend together without a “lag phase” in the healing process.

1. Coagulation – Platelets release coagulation factors and cytokines to initiate the healing process. Fibrin is produced

2. Inflammation – This phase is characterized by migration of neutrophils and macrophages that regulate the connective tissue matrix repair.

3. Fibroplasia – Fibroblasts are attracted by the movement of wound macrophages, and lay down the new connective tissue matrix.

4. Remodeling – During this phase the process slows down, collagen synthesis and degradation are in equilibrium, angiogenesis and epithelization cease.

Schwartz, 6th edition, pp 280-284

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Characteristics of Wound Contraction

Wound contraction represents the centripetal movement of the wound edges toward the center of the wound. Wound contraction begins on the 4th or 5th day after wounding, and maximal contraction occurs 12 to 15 days later. Wound edges move toward each other at the rate of 0.6 to 0.75mm per day. The rate of contraction depends on a number of factors including tissue laxity, the type of wound (i.e. primary closure vs. secondary closure), the shape of the wound, and the location of the wound (i.e. immobile area or a joint area).

Myofibroblasts mediate the process. They are derived from normal fibroblasts and are identified on the 3rd day after wounding and persist for approximately 21 days post wounding. They are found predominately in the periphery of the wound. Myofibroblasts are differentiated from fibroblasts by the inclusion of microfilaments in their cytoplasm and a multilobulated nucleus. .

Physiologic Basis of Surgery, 2nd Edition, pp 123-124

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Skin Grafts

Skin grafts may be either full thickness, including all epidermis and dermis, or partial thickness, in which the skin is harvested at some level within the dermis. Partial-thickness grafts are frequently harvested at a thickness of 1/1200 to 1/2000 of an inch. Harvesting skin at this level will leave some dermis as well epidermal appendages such as hair follicles and sweat glands in the donor site. These epidermal appendages than allow regeneration of new epidermis to close the donor site. A full-thickness graft, because it includes the entire epidermis and dermis at the donor site, requires that the donor site be closed primarily or left open to granulate and contract. In a full-thickness graft there are no epidermal or dermal remnants to allow epithelialization as in a partial-thickness graft. As a general rule, split-thickness grafts have a greater change of surviving but will contract up to 40 percent on average. Partial-thickness grafts are usually used to resurface burns, as the donor areas will rapidly close and can be reharvested. A full-thickness graft is usually selected to resurface relatively small and critical areas such as an eyelid so that contraction of the grafted tissue is minimal.

Factors resulting in graft failure are as follows:1. Hematoma/Seroma (#1 cause)2. Mechanical reasons/ Shearing3. Technical reasons (graft to thick, wrong surface applied to wound)4. Infection5. Ischemia resulting in failure of imbibition

Schwartz, 7th Edition, pp 2094-95

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Characteristics of Secondary Wound Healing

Secondary wound healing or spontaneous closure occurs when the wound is left open and the margins of the wound contract to achieve closure. Secondary wound closure is used in management of wounds where a delay of several hours has occurred before seeking surgical care, infected or potentially infected wounds, and in circumstances where the circulation to the wound is marginal.

The normal phases of healing occur, i.e. coagulation, inflammation, fibroplasias, and remodeling. The deposition of collagen with progressive contraction reduces the risk of abscess formation, cellulitis, and sepsis as the wound gradually closes.

Contraction, one of the key factors in secondary wound healing, is mediated by myofibroblasts, which are able to exert powerful forces causing tissue movement.

Schwartz, Principles of Surgery, 7th Edition, pp 264-72

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Bowel Layer with Most Tensile Strength

The wall of the small bowel consists of four distinct layers. The mucosa is organized into villi and crypts rich in lymphatics and blood vessels, and is responsible for absorption of nutrients. The submucosa consists of connective tissue including fibroblasts, leukocytes, nerve fibers and vessels, and is the layer with the most tensile strength when approximation with sutures is used. Other layers include the muscularis with an outer layer of longitudinal muscle, and an inner layer of curcular muscle. The serosa is a single layer of mesothelial cells.

Schwartz, Principles of Surgery, 8th Edition, p 1020

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Vitamin Promoting Wound Healing with Chronic Steroid Use

ACTH, cortisone, and other glucocorticoids can have profound effects on healing rate. Cortisone and its derivatives decrease the rate of protein synthesis, stabilize lysosomal membranes, and inhibit the normal inflammatory reaction. High doses of corticoids limit capillary budding, inhibit fibroblast proliferation, and decrease the rate of epithelialization. Steroids given prior to or immediately after wounding have the greatest effect. Generally, even with high doses of steroids, wound-healing reactions go to completion; only the time scale is altered. All aspects of steroid-induced healing impairment other than wound contraction can be reversed by supplemental vitamin A. The recommended dose is 25,000 IU per day. Topical vitamin A has been found to be effective for open wounds. Anabolic steroids and growth hormone-releasing factor have also reversed other steroid-induced healing impairments.

Sabiston, Textbook of Surgery, The Biological Basis of Modern Surgical Practice, W.B. Saunders, 1991

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Foreign Bodies (with a pediatric focus)

ASPIRATION

Aspiration of foreign bodies most commonly occurs in the toddler age group.

A solid foreign body often will cause air trapping, with hyperlucency of the affected lobe or lung seen especially on expiration.

Delay in diagnosis can lead to atelectasis and infection. The most common anatomic location for a foreign body is the right main stem bronchus or the right lower lobe.

Total respiratory obstruction may occur with a tracheal foreign body; however, respiratory distress is usually mild if present at all. A unilateral wheeze is often heard on auscultation.

A chest radiograph will show a radiopaque foreign body, but in the case of a nonradiopaque object, the only clue may be hyperexpansion of the affected lobe on an expiratory film or fluoroscopy.

Bronchoscopy confirms the diagnosis and allows removal of the foreign body. A rigid bronchoscope should be employed in all cases. Epinephrine may be injected into the mucosa when the object has been present for a long period of time to minimize bleeding.

Bronchiectasis may be seen as an extremely late phenomenon after repeated infections of the poorly aerated lung and may require partial or total resection of the affected lobe.

The differential diagnosis of a bronchial foreign body includes an intraluminal tumor (i.e., carcinoid, hemangioma, or neurofibroma).

INGESTION

The most common foreign body in the esophagus is a coin, followed by small toy parts. The coin is retained in the esophagus at one of three locations: the cricopharyngeus, the area of the aortic arch, or the gastroesophageal junction, all areas of normal anatomic narrowing.

Symptoms are variable depending on the anatomic position of the foreign body and the degree of obstruction. There is often a relatively asymptomatic period after ingestion. The initial symptoms are dysphagia, drooling, and vomiting. The longer the foreign body remains in the esophagus, the greater the incidence of respiratory symptoms, which include cough, stridor, and wheezing.

The chest radiograph is diagnostic in the case of an ingested coin.

A contrast swallow evaluation may be required for nonradiopaque foreign bodies.

Typically, the treatment is by esophagoscopy, rigid or flexible, for removal of the foreign body.

Rarely, esophagotomy is required for removal, particularly of sharp objects.

Diligent follow-up is required after removal of foreign bodies—especially batteries, which can cause liquefactive necrosis followed by strictures, and sharp objects, which can injure the underlying esophagus.

Schwartz

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Local Factors Involved in Impaired Wound Healing

Infection Infection exists when bacteria is >105 organisms per gram of tissue Foreign bodies, necrotic tissue, and hematomas can increase the likelihood that infection will

develop. Uremia, DM, CA and AIDS have been shown to increase susceptibility to wound infection. Radiation injury & impaired circulation increase the risk of infection.

Hypoxia & Smoking Oxygen is necessary for cellular respiration and for hydroxylation of proline and lysine

residues Adequate tissue oxygenation requires an adequate circulating blood volume, adequate

cardiac function, and adequate local vasculature Smoking can impair tissue oxygenation by acutely stimulating vasoconstriction Smokers have carboxyhemoglobin levels between 1% and 20%. Carboxyhemoglobin limits

the oxygen-carrying capacity of the blood and increases platelet adhesiveness.

Radiation Radiation produces inflammation and desquamation in a dose-dependent manner After radiation, surrounding cells must migrate into the injured area for adequate healing to

occur. Fibroblasts that migrate into the irradiated tissue are often abnormal because of radiation exposure.

Collagen is synthesized to an abnormal degree in irradiated tissue, causing fibrosis. The media of dermal blood vessels in irradiated areas thickens and some blood vessels

become occluded, resulting in a decrease in the total number of blood vessels. In previously irradiated tissue, abnormal healing occurs. The decreased vascularity and

increased fibrosis limits the ability of platelets and inflammatory cells to access the area. Damaged fibroblasts and keratinocytes may not respond normally to stimulants during the healing process. And because of the diminished blood supply, irradiated tissue is predisposed to infection.

Schwartz

Systemic Factors Involved in Impaired Wound Healing

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Malnutrition Hypoproteinemia inhibits proper wound healing by limiting the supply of critical amino acids

required for the synthesis of collagen and other proteins. Arginine and glutamine are important for healing. Cystine is essential for creating the collagen triple helix structure. Carbohydrate and fat provide an energy source for healing. Vitamin C is a required cofactor for hydroxylation of lysine and proline during collagen

synthesis. Vitamin A is important for epithelialization, proteoglycan synthesis, and immune function. Vitamin D is important for bone healing. Zinc is a required cofactor for DNA polymerase and reverse transcriptase – zinc deficiency

can result in deficient granulation tissue formation and healing.

Cancer Cachexia of cancer limits healing Anorexia associated with cancer contributes to poor nutrition Some cancers produce gastrin and VIP that can interfere with nutrient absorption Cancer may increase glucose turnover, leading to glucose intolerance Cancer may increase protein catabolism Vitamin C may be taken up by cancer, limiting its availability for collagen synthesis Cancer patients may be anergic because of abnormal inflammatory cell activity

Diabetes DM is associated with impaired neutrophil chemotaxis and phagocytic function Neuropathy is associated with increased risk of pressure ulcers

Steroids and Immunosuppression Adrenocortical steroids inhibit all phases of wound healing. There is a deficiency in inflammatory cell function. Steroids decrease macrophage migration, fibroblast proliferation, collagen accumulation, and

angiogenesis.

O’Leary, The Physiological Basis of Surgery

36

Fibronectin

Fibronectin is a noncollagenous glycoprotein Noncollagenous glycoproteins interact with cells and extracellular matrix (ECM)

components to promote adhesion, migration, proliferation, and gene expression Fibronectin is important for cell-cell attachment, clot stabilization, wound healing, nerve

regeneration, and phagocytosis

Fibronectin & Early Wound Healing

Fibrin and fibronectin form a lattice early on in wound healing Fibronectin is produced by fibroblasts and epithelial cells Fibronectin has lots of binding sites for cell surface integrins which aids the migration of

cells into the wound

O’Leary, The Physiologic Basis of Surgery

37

Wound Healing

Wound healing is a complex cellular and biochemical cascade that leads to restitution of integrity and function.

Although individual tissues may have unique healing characteristics, all tissues heal by similar mechanisms, and the process undergoes phases of inflammation, cellular migration, proliferation, matrix deposition, and remodeling.

Factors that impede normal healing include local, systemic, and technical conditions that the surgeon must take into account.

Optimal outcome of acute wounds relies on complete evaluation of the patient and of the wound, and application of best practices and techniques.

Clinically, excess healing can be as significant a problem as impaired healing; genetic, technical, and local factors play a major role.

Future advances in growth factor understanding, tissue engineering, and dressing design are expected to increase the armamentarium in improving wound outcomes.

Schwartz

38

Sequence of Events in Wound Healing (from The Physiologic Basis of Surgery)

The healing process can be broken down into early, intermediate, late and terminal phases.

1. The early phase is characterized by hemostasis and inflammation. Hemostasis must be the first event achieved in the healing process. Fibrin and fibronectin form a lattice that provides a scaffold for the migration of

inflammatory, endothelial, and mesenchymal cells into the wound. This lattice also binds cytokines released at the time of injury and serves as a reservoir for these factors as healing progresses.

Neutrophils (PMNs) are the first leukocytes found in wounded tissue. They phagocytose damaged tissue or bacteria and digest it using hydrolytic enzymes.

As monocytes migrate into the extravascular space, they transform into macrophages, and then chemotactic factors stimulate the migration of macrophages into the wounded area. Macrophages phagocytose bacteria and dead tissue and secrete matrix metalloproteinases (MMPs) that break down damaged matrix. Macrophages also produce cytokines that stimulate fibroblast proliferation and collagen production. *At 48 to 72 hours, macrophages begin to outnumber PMNs.

Lymphocytes produce factors that are essential for normal healing – critical lymphokines include EGF and FGF.

After 5 to 7 days, few inflammatory cells remain in normal healing wounds.

2. The intermediate phase is characterized by mesenchymal cell proliferation and migration/chemotaxis, epithelialization, and angiogenesis. The intermediate phase occurs 2 to 4 days after wounding & its processes are

mediated by cytokines. Fibroblasts are the primary mesenchymal cell involved in wound healing – smooth

muscle cells are also involved.

39

Fibroblasts can secrete matrix MMPs to break down matrix impeding their migration.

PDGF and TGF-beta are important stimulants of fibroblast proliferation. FGF-1 is the most potent angiogenic stimulant identified; heparin is an important

cofactor for this growth factor. Incisional wounds generally are re-epithelialized in 24 to 48 hours. The sequence of events in epithelialization includes basal cell detachment,

migration, proliferation, and differentiation. Regenerated epithelium does not retain all of the functional advantages of normal

epithelium. There are fewer basal cells in regenerated epidermis, and the interface between epidermis and dermis is abnormal. Rete pegs, undulating projections of epidermis that penetrate papillary dermis, are not found on re-epithelialized surfaces.

3. The late phase of healing is focused on the synthesis of collagen and other matrix proteins and wound contraction. Collagen is synthesized by fibroblasts beginning 3 to 5 days after injury. The rate of collagen synthesis increases rapidly and continues at an accelerated rate

for 2 to 4 weeks. Collagen gradually replaces fibrin in the wound. TGF-beta stimulates collagen synthesis. Glucocorticoids inhibit collagen synthesis. Type I collagen is the most common. Type III collagen is increased in early phases of wound healing. The extracellular connective tissue matrix contains collagen, proteoglycans,

attachment proteins (like fibronectin), and elastin.

4. The terminal phase of healing is characterized by wound remodeling. Approximately 21 days after injury, net accumulation of wound collagen becomes

stable. Although collagen content is maximal, the bursting strength of the wound is only 15% of normal skin.

The process of scar remodeling dramatically increases wound-bursting strength. By 6 weeks after wounding, the wound has reached 80% to 90% of its eventual

strength. The bursting strength of scar reaches a maximum of 80% to 90% of skin breaking

strength at 6 months – it never reaches 100% of its original strength. There is turnover of collagen and new collagen is synthesized in a denser, more

organized manner along stress lines. MMPs and hyaluronidase are involved in scar remodeling. The activity of collagenolytic enzymes is modulated by tissue inhibitors of

metalloprotenases (TIMPs). During remodeling there is an increase in cross-linking between collagen fibers that

contributes to the increase in wound-breaking strength. As collagen matures, type III collagen is replaced by type I collagen.

The Physiologic Basis of Surgery

40

Fracture Healing

Fracture healing can be divided into 4 stages:1. Hematoma formation (inflammation) and angiogenesis

TGF- induces mesenchymal cells and osteoblasts to produce type II collagen and proteoglycans.

PDGF recruits inflammatory cells at the fracture site. Bone morphogenetic proteins (BMPs) are osteoinductive mediators inducing metaplasia

of mesenchymal cells into osteoblasts. IL-1 (interleukin-1) and IL-6 recruit inflammatory cells to the fracture site. Cells ensheathe the fracture and differentiate into chondrocytes or osteoblasts. The initial callus acts as an internal splint against bending and rotational deformation.

2. Cartilage formation with subsequent calcification Cartilage in callus is replaced by woven bone.

3. Cartilage removal and bone formation Woven-bone mineralized callus has to be replaced by lamellar bone for the bone to

resume normal function. Before this can occur, the fracture site must be consolidated – this includes filling the gaps between ends of bone.

4. Bone remodeling Replacement of woven bone by lamellar bone.

Current Diagnosis and Treatment in Orthopedics

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Cancer

Radiation Therapy

Radiation causes breaks in DNA and generates free radicals from cell water that may damage cell membranes, proteins and organelles.

Radiation damage is dependent on oxygen; hypoxic cells are more resistant. Augmentation of oxygen is the basis for radiation sensitization. Sulfhydryl compounds interfere with free radical generation and may act as radiation

protectors. Radiation is quantitated on the basis of the amount of radiation absorbed in the patient; it is

not based on the amount of radiation generated by the machine. The rad (radiation absorbed dose) is defined as 100 erg of energy per gram of tissue. The International System (SI) unit for rad is the Gray (Gy); 1 Gy = 100 rad. Radiation dose is measured by placing detectors at the body surface or calculating the dose based on radiating phantoms that resemble human form and substance. Radiation dose has three determinants: total absorbed dose, number of fractions, and time.

Compounds that incorporate into DNA and alter its stereochemistry (e.g., halogenated pyrimidines, cisplatin) augment radiation effects. Hydroxyurea, another DNA synthesis inhibitor, also potentiates radiation effects. Compounds that deplete thiols (e.g., buthionine sulfoximine) can also augment radiation effects. Hypoxia is a major factor that interferes with radiation effects.

Tumors which are highly radiosensitive include seminomas, lymphomas, squamous cell carcinomas (head and neck, esophagus, anal).

Harrison’s

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Weight Loss in Cancer

Cancer and its treatment commonly reduce nutritional intake sufficient to cause weight loss and alteration of intermediary metabolism.

A variety of tumor derived factors (bombesin and ACTH) and host derived factors (i.e. tumor necrosis factor TNF, IL1 and IL6) contribute to the altered metabolism, and a cycle is established in which protein catabolism, glucose intolerance, and lipolysis cannot be reversed by the provision of calories.

The altered host metabolism is due to: 1. Increased glucose turnover with incomplete utilization of glucose 2. Protein catabolism is accelerated in an effort to meet the glucose needs 3. Inability to effectively use fat as an energy source.

Decreased intake and weight loss may also result from obstruction (i.e. esophagus or stomach) and/or pain.

Up to 70% of cancer patients die from the effects of starvation with infection the final common pathway.

The Physiologic Basis of Surgery

Characteristics of Angiogenesis

43

Angiogenesis is essential for tumor growth and metastasis.

Many of the common oncogenes and tumor-suppressor genes have been shown to play a role in inducing angiogenesis, including ras, HER2, and mutations in p53.

In angiogenesis the endothelium secretes basic fibroblast growth factor, platelet-derived growth factor (PDGF), and insulin-like growth factor. The basement membrane and stroma around the capillary are proteolytically degraded. The endothelium then migrates through the degraded matrix. And the sprouting tips anastomose to form a vascular network surrounded by a basement membrane.

Of the angiogenic stimulators, the best studied are the vascular endothelial growth factors (VEGFs). VEGF is induced by hypoxia and by different growth factors and cytokines. VEGF increases vascular permeability, induces endothelial cell proliferation and tube formation, and induces endothelial cell synthesis of proteolytic enzymes such as uPA, PAI-1, urokinase plasminogen activator receptor, and MMP-1. Furthermore, VEGF may mediate blood flow by its effects on the vasodilator nitric oxide.

Natural inhibitors of angiogenesis include thrombospondin 1 and angiostatin.

Angiogenesis is a prerequisite not only for primary tumor growth but also for metastasis. Angiogenesis in the primary tumor, as determined by microvessel density, has been demonstrated to be an independent predictor of distant metastatic disease and survival in several cancers.

Schwartz

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Soft Tissue Sarocoma

Presentation

Sarcomas most commonly present as an asymptomatic mass.

Approximately two thirds of soft tissue sarcomas arise in the extremities; the remaining one third are distributed between the retroperitoneum, trunk, abdomen, and head and neck.

Soft tissue sarcomas often grow in a centrifugal fashion and compress surrounding normal structures.

Assessment

Chest radiography should be performed for patients with primary sarcomas to assess for lung metastases. For patients with high-grade lesions or tumors >5 cm (T2), computed tomography (CT) of the chest should be considered.

CT is the preferred technique for evaluating retroperitoneal sarcomas.

MRI often is favored for soft tissue sarcomas of the extremities.

Fine-needle aspiration is an acceptable method of diagnosing most soft tissue sarcomas

Core needle biopsy is a safe, accurate, and economical procedure for diagnosing sarcomas

Incisional biopsies usually are performed as a last resort when fine-needle aspiration or core biopsy specimens are nondiagnostic

Excisional biopsy is not recommended

Histologic Grade

Histologic grade is the most important prognostic factor for patients with sarcomas.

The features that define grade are cellularity, differentiation, pleomorphism, necrosis, and the number of mitoses.

Tumor grade has been shown to predict the development of metastases and overall survival.

The metastatic potentials have been estimated at 5 to 10% for low-grade lesions, 25 to 30% for intermediate-grade lesions, and 50 to 60% for high-grade tumors.

Treatment

The treatment algorithm for soft tissue sarcomas depends on tumor stage, site, and histology.

Multimodality treatment including surgical resection, radiation therapy and, in selected cases, systemic chemotherapy, has been applied to patients with locally advanced, high-grade, extremity sarcomas.

Overall 5-year survival rate for patients with all stages of soft tissue sarcoma is 50 to 60%.

Of the patients who die of sarcoma, most will succumb to metastatic disease in the lungs, which 80% of the time occurs within 2 to 3 years of the initial diagnosis.

Schwartz

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Carcinoembryonic antigen (CEA)

Carcinoembryonic antigen (CEA) is a glycoprotein

Elevated CEA levels have been detected in patients with primary colorectal cancer as well as in patients with breast, lung, ovarian, prostate, liver, and pancreatic cancer.

CEA also may be elevated in benign conditions such as diverticulitis, peptic ulcer disease, bronchitis, liver abscess, and alcoholic cirrhosis, especially in smokers and in elderly persons.

CEA measurement is most commonly used in the management of colorectal cancer. Use of CEA level as a screening test for colorectal cancer is not recommended. CEA levels may be useful if obtained preoperatively and postoperatively in patients with a diagnosis of colorectal cancer. Preoperative elevation of CEA level is an indicator of poor prognosis. Data supports the use of CEA for monitoring for postoperative recurrence. CEA measurement is the most cost-effective approach for detecting metastasis, with 64% of recurrences being detected first by an elevation in CEA level. CEA is the marker of choice for monitoring metastatic colorectal cancer during systemic therapy.

Schwartz

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General Cancer Staging

Primary Tumor (T)TX Primary tumor cannot be evaluated

T0 No evidence of primary tumor

Tis Carcinoma in situ (early cancer that has not spread to neighboring tissue)

T1, T2, T3, T4 Size and/or extent of the primary tumor

Regional Lymph Nodes (N)

NX Regional lymph nodes cannot be evaluated

N0 No regional lymph node involvement (no cancer found in the lymph nodes)

N1, N2, N3 Involvement of regional lymph nodes (number and/or extent of spread)

Source: www.cancer.gov

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Distant Metastasis (M)

MX Distant metastasis cannot be evaluated

M0 No distant metastasis (cancer has not spread to other parts of the body)

M1 Distant metastasis (cancer has spread to distant parts of the body)

Lymphoproliferative disorders following solid organ transplantation

Lymphoproliferative disorders are the most common malignancies complicating organ transplantation (excluding nonmelanoma skin cancer and in situ cervical cancer), accounting for 21% of all malignancies versus 5% of malignancies in the general population

The lymphoproliferative disorders occurring after transplantation have different characteristics from those that occur in the general population. Non-Hodgkin lymphoma (NHL) accounts for 65% of lymphomas in the general population, compared to 93% in transplant recipients. These tumors are mostly large-cell lymphomas, the great majority of which are of the B-cell type. Extranodal involvement is common, occurring in approximately 30 to 70% of cases.

The pathogenesis of posttransplant NHL in most patients appears to be related to B cell proliferation induced by infection with Epstein-Barr virus (EBV) in the setting of chronic immunosuppression.

More than 50% of patients with PTLD present with extranodal masses. Involved organs include the gastrointestinal tract (stomach, intestine), lungs, skin, liver, central nervous system, and the allograft itself. More specifically, 20 to 25% have CNS disease (which is rare in the general population), and a similar proportion have infiltrative lesions in the allograft. Involvement of the allograft can lead to allograft dysfunction, including renal failure, heart failure, and respiratory dysfunction.

Three types of EBV-related lymphoproliferative disease occur in transplant recipients:

1. Benign polyclonal lymphoproliferation (55% cases): an infectious mononucleosis-type acute illness that develops 2 to 8 weeks after immunosuppressive therapy begins. This disorder is characterized by polyclonal B cell proliferation with normal cytogenetics and no evidence of immunoglobulin gene rearrangements to suggest malignant transformation. It accounts for approximately 55% of cases.

2. The second EBV-induced disorder (30% cases) is similar to the first in its clinical presentation, but is characterized by polyclonal B cell proliferation with evidence of early malignant transformation, such as clonal cytogenetic abnormalities and immunoglobulin gene rearrangements.

3. The last disorder (15%) is usually an extranodal condition presenting with localized solid tumors characterized by monoclonal B cell proliferation with malignant cytogenetic abnormalities and immunoglobulin gene rearrangements.

UpToDate

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Cell Cycle

The cell cycle involves two coordinated events: chromosomal DNA replication (S-phase) and then division into daughter cells (M-phase). These coordinated events are subdivided into four broad periods by gap periods (G-phases).

The G1 is the interval from the previous division to the beginning of DNA synthesis. Quiescent cells are recruited to G1 phase through mitogenic stimulation. At the restriction point, these cells either undergo cell cycle arrest or progress to S-phase.

G2 is the interval between DNA synthesis and nuclear division. The cell cycle is concluded with M phase.

Nondividing cells such as mature fibroblasts will exit the cell cycle after the M phase, stop further DNA synthesis and remain in the G0 phase.

The machinery that drives cell cycle progression is made up of a group of enzymes called cyclin-dependent kinases (CDK).

Cyclin expression fluctuates during the cell cycle, and cyclins are essential for CDK activities and form complexes with CDK.

There also are negative regulators for CDK termed CDK inhibitors, which inhibit the assembly or activity of the cyclin-CDK complex.

Schwartz

Harrison’s

The Physiologic Basis of Surgery

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Apoptosis

Apoptosis occurs through either an intrinsic pathway, in which activation of caspase 8 results in mitochondrial changes and ultimately cell death, or an extrinsic pathway in which the high production of caspase 8 leads directly to activation of caspase 3 and cell death.

The bcl-2 gene is characterized as a major repressor of apoptosis.

The p53, Bax, myc, and abl genes have been shown to induce apoptosis.

The Physiologic Basis of Surgery

50

Serum Tumor Markers in Testicular Cancer

Three serum tumor markers have established roles in testicular cancer:

1. Alpha fetoprotein (AFP)

2. Beta subunit of human chorionic gonadotropin (beta-hCG, since the alpha subunit is common to several pituitary hormones)

3. Lactate dehydrogenase (LDH)

Serum levels of AFP and/or beta-hCG are elevated in 80 to 85 percent of men with NSGCTs, even when nonmetastatic. In contrast, serum beta-hCG is elevated in fewer than 20 percent of testicular seminomas, and AFP is not elevated in pure seminomas

Neither serum beta-hCG nor AFP alone or in combination is sufficiently sensitive or specific to establish the diagnosis of testicular cancer in the absence of histologic confirmation.

Although serum tumor markers are helpful at the time of initial diagnosis of a testicular cancer and for prognostication, their main utility is for subsequent follow-up of disease status after primary treatment.

UpToDate

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Genetics

P53

The p53 protein may be the most frequently mutated protein in human cancer. P53 is a nonspecific suppressor of transcription and a specific transcriptional activator. The tumor suppression by p53 is linked to its ability to regulate transcription. Inherited germ line mutations in p53 (the Li-Fraumeni syndrome) result in a variety of

familial neoplasms including tumors of the breast, brain, adrenal gland, sarcoma, and leukemia

O’Leary, The Physiologic Basis of Surgery

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Colorectal Cancer Genetics

The mode of presentation of CRC follows one of three patterns: sporadic, inherited, and familial:

1. Sporadic disease (70%): there is no family history. It is most common over the age of 50, and dietary and environmental factors have been etiologically implicated.

2. Inherited predisposition to CRC (<10%): these cases are subdivided according to whether or not colonic polyps are a major disease manifestation. The diseases with polyposis include familial adenomatous polyposis (FAP) and the hamartomatous polyposis syndromes (eg, Peutz-Jeghers, juvenile polyposis [2]), while those without polyposis include hereditary nonpolyposis CRC (HNPCC, Lynch syndrome). These conditions are all associated with a high risk of developing CRC. In many cases, the causative genetic mutation has been identified and can be tested for.

3. “Familial” CRC (25%): affected patients have a family history of CRC, but the pattern is not consistent with one of the inherited syndromes described above. Individuals from these families are at increased risk of developing CRC, although the risk is not as high as with the inherited syndromes. Having a single affected first-degree relative (ie, parent, child, sibling) increases the risk of developing CRC 1.7-fold over that of the general population. The risk is further increased if two first-degree relatives have CRC or if the index case is diagnosed before age 5.

Syndrome/disease Responsible gene Mode of aquisition

FAP APC Germline (inherited)

HNPCC (Lynch syndrome) MMR

hMSH2hMLH1hPMS1hPMS2hMSH3hMSH6

Sporadic tumor Tumor suppressor genes Somatic (acquired)

p53DCCAPCOncogenesmycrassrcerbB2MMR genes (epigenetic change)

UpToDate

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Lynch Syndrome, Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

Lynch syndrome, also called hereditary nonpolyposis colorectal cancer (HNPCC), is the most common of the inherited colon cancer susceptibility syndromes.

Lynch syndrome is an autosomal dominant disorder that is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes. It accounts for 2 to 3% of all colon cancer cases and similarly is responsible for about 2% of uterine cancer. Lynch syndrome is characterized by significantly increased risk for colon cancer and endometrial cancer as well as a smaller risk of several other associated cancers.

As in most other familial cancer syndromes, early age of onset and multiplicity of cancers have been considered hallmarks of Lynch syndrome. In registry-based Lynch syndrome series, the mean age at initial colorectal cancer diagnosis is about 45 years, compared to around age 65 for sporadic colorectal cancer, and some Lynch syndrome patients present with colorectal cancer in their twenties.

Multiplicity of cancers is a hallmark of Lynch syndrome. About 7 to 10% of identified Lynch family members have had more than one cancer by the time of diagnosis. Approximately 20 to 40% of patients have been reported to develop metachronous colorectal cancer after initial resection if a subtotal colectomy is not performed. Similarly, clustering of more than one Lynch-associated cancer (colorectal and uterine) in an individual patient should raise suspicion of Lynch syndrome.

The colorectal cancers in Lynch syndrome differ from typical sporadic colorectal cancers in location, histology, and natural history. Like most sporadic colorectal cancers, Lynch cancers appear to evolve from adenomas, but when detected the adenomas tend to be larger, flatter, are more often proximal, and more commonly have high-grade dysplasia and/or villous histology than sporadic adenomas.

The adenoma-carcinoma sequence is thought to progress much more rapidly in Lynch syndrome and new cancers have occurred within two to three years after what appeared to be a negative colonoscopy. Like the adenomas, colorectal cancers in Lynch syndrome are also more commonly proximal; nearly 70% of first colorectal cancers in Lynch syndrome arise proximal to the splenic flexure whereas only about 40 to 50% of sporadic colorectal cancers are in this region.

The Amsterdam II criteria can be remembered by the "3-2-1 rule" (3 affected members, 2 generations, 1 under age 50)

Revised Amsterdam criteria by the International Collaborative Group on HNPCC

There should be at least three relatives with an HNPCC-associated cancer (colorectal cancer, cancer of

the endometrium, small bowel, ureter, or renal pelvis)

One should be a first degree relative of the other two

At least two successive generations should be affected

At least 1 should be diagnosed before age 50

Familial adenomatous polyposis should be excluded in the colorectal cancer case(s) if any

Tumors should be verified by pathological examination

Adapted from Vasen, HF, Watson, P, Mecklin, JP, et al. Gastroenterology 1999; 116:1453.

UpToDate

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Statistics

Definition of Statistical Power

Power is defined as 1-beta where beta is essentially the probability that your data shows no difference between two groups when in fact there is a difference. Incorrectly accepting the null hypothesis is known as a type II error. 1-beta is then the probability that you have correctly shown that there is a difference between the data. Larger sample sizes increase the power of a test.

Alpha level: the probability that your data shows a difference when there really isn’t one (type I error). You have incorrectly rejected the null hypothesis.

Sensitivity: a/(a+c) The probability that if a disease is present, the test will be positive.

Specificity: d/(b+d) The probability that if a disease is absent, the test will be negative.

Positive Predictive value: a/(a+b) The probability that if the test is positive, the disease is present.

Negative Predictive value: d/(d+c) The probability that if the test is negative, the disease is absent.

Accuracy: (a+d)/(a+b+c+d) The probability that the test results are correct (a combination of the PPV and the NPV).

Relative risk: (a/(a+b))/(c/(c+d)) The amount of increased chance of developing a disease if a risk factor is present.

Condition

a+ b+_c- d-

TestSensitivity = a/(a+c)Specificity = d(d+b)Accuracy = (a+d)/(a+b+c+d)Positive Predictive Value (PV+) = a/(a+b)Negative Predictive Value (PV-) = d/(d+c)

Calculations for sensitivity, specificity, accuracy, positive predictive value, and negative predictive value.

O’Leary, The Physiologic Basis of Surgery, 1993.

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P Value in Students T Test

The decision of which statistical test to utilize depends primarily upon what type of data you are going to analyze. Variables may be either quantitative or qualitative. Quantitative variables may be either continuous or discrete. A continuous variable is only limited by the accuracy of the instrument: e.g., weight. On the other hand, a discrete variable has only certain values (whole numbers): e.g., the number of residents of this program entering a plastics residency each year. Ratio variables are another form of quantitative variables. Qualitative variables can be either nominal or ordinal. A nominal variable is a named category (usually seen as a yes or no answer: e.g., survival of a patient) whereas an ordinal variable is usually seen in ranking scales: e.g., rate your diarrhea on a scale of 1 – 10.

Quantitative variables possess a normal distribution, following a bell-shaped curve, and are described by “parameters.” They are analyzed by parametric tests. These parametric tests are:

Student’s T test: used to determine potential differences between two (and only two) samples or quantitative data. Univariate (i.e., determines differences between treatments based upon a single outcome).

ANOVA or AOV: analysis of variance. Also univariate, used to compare more than two means or samples of data. Means compared by several methods:

Contrast analysis: Means decided upon prior to initiation of study.

Scheffe’s interval: low power. Used for multiple comparisons between pairs of means that were not elucidated prior to the study being designed.

Mutiple comparison tests: makes all possible comparisons between meansLeast Significant Difference (LSD)Fisher’s LSDDuncan’s Multiple RangeStudent-Neuman-Keuls (SNK)Turkey’s testWaller-Duncan Bayes LSD

Hotelling’s T2 and Multivariate analysis of variance (MAOV): when two or more outcome variables are to be measured. Multivariate.

Regression analysis: Looks at relationships or variables, not just differences.

Qualitative variables are not distributed normally and are analyzed by nonparametric statistics:

Chi-squared: for nominal variables—yes/no answers

Mann-Whitney U test: test differences between two unpaired treatments.

Wilcoxon Signed rank test: test differences between two paired treatments.

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Kruskal-Wallis ANOV: test differences between more than two treatments.

Spearman rank correlation: tests strength of relationship between two variables.

Davis AT. Biostatistics. In: O’Leary PJ ed. The Physiologic Basis of Surgery. Williams & Wilkins. Philadelphia. 1993:233-254.

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P Value in T-Test

The t-test (also known as Student’s t-test) is used to determine if differences exist between two (and no more than two) samples of normally distributed quantitative data. A paired t-test is used when the numbers of observations are paired and have equal variance. An unpaired t-test is used when the number of observations is not paired. A paired t-test has more statistical power than an unpaired, and requires less than half the sample size required for an unpaired analysis.

A statistically significant difference between groups occurs when the p-value is <0.05. In other words, there is a less than 5% chance that the differences between the groups are the result of random chance. In this context, 0.05 is also equal to alpha, the Type I error rate.

The Physiologic Basis of Surgery, 2nd Edition, pp 254, 257, and 267

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Definition of Adverse Event

An adverse effect is defined as an unintended injury caused by treatment that resulted in a prolonged hospital stay or a measurable disability at discharge. It is estimated that the annual incidence of adverse surgical events is approximately 3.0% and that 54% of these events were preventable. Nearly half of all adverse surgical events were accounted for by technique-related complications, wound infections, and postoperative bleeding.

Patient Safety in Surgical Care: A Systems Approach, ACS Surgery Principles and Practice, 2006, www.ascsurgery.com

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Mode of Data Set

The mode and the median are two commonly used descriptors of central tendency when considering a population (study group) with quantitative variable. The mode is the value that occurs most often, whereas the median is the value that divides the distribution in equal halves.

As an example, a study examining the height in feet of seven objects with data of 2, 3, 4, 5, 6, 6, 7 –

The median is 5The mode is 6

Physiologic Basis of Surgery, 2nd Edition, pp 352-3

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Interpretation of Odds Ratio

The odds ratio represents the odds that the outcome is associated with the treatment, relative to the control.

Two examples:

1. Case-control design, testing the risk factor cocaine use, where the cases are decreased motor vehicle accident (MVA) victims, and the controls are surviving MVA victims. If the odds ratio is 5 to 1, this means that cocaine users in an MVA are 5 to 1 times more likely to die than non-cocaine users.

2. Randomized controlled trial, with an odds ratio derived from logistic regression, where the treatment is the wonder drug Tilapanene, and the control (standard of care) is Averol, with the outcome being mortality. If the odds ratio is 5 to 1, this means that the group receiving Tilapanene was 5 to 1 times more likely to die than the group receiving Averol.

Alan Davis, Ph.D., Associate Professor, Michigan State University, Author Biostatistics, Physiologic Basis of Surgery

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Questions

Metabolism

1. A 70 Kg male minimally stressed patient is placed on TPN. What is the expected caloric requirement?

A) 1200B) 1500C) 2000D) 2500

2. The rationale for providing 2 – 3 grams of protein/kg in septic patients is based on the following rationale:

A) The extra protein provides a useable fuel sourceB) Protein is necessary for the protein turnoverC) The extra protein can be reserved and used in the anabolic phaseD) Extra protein is used as a metabolic fuel for brain and white blood cells

3. The respiratory quotient (RQ) of 0.7 in a recovering burn patient indicates which primary fuel source?

A) FatB) CarbohydrateC) ProteinD) Mixed protein/carbohydrate

4. A TPN prescription (order) is based on which of the following?

A) All caloric requirements from glucoseB) A 70 – 30 glucose to lipid ratio of non-protein caloriesC) 0.5-6m/Kg/24hr of proteinD) A 70 -30 lipid to glucose ratio of non-protein calories

5. The protein requirements for a resting adult are met by which of the following?

A) .24 grams of nitrogen/kgB) 2.5 grams of protein/kgC) 1.5 grams of glycine/kgD) .4 grams of egg albumin/kgE) .48 grams of nitrogen /kg

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6. A patient on TPN for malnutrition due to Crohn’s ileitis and fulminant diarrhea develops a periorbital pustular rash and darkening of the skin creases. What is the etiology?

A) Essential fatty acid deficiencyB) Zinc deficiencyC) Vitamin B deficiencyD) Vitamin C deficiency

7. Protein sparing in starvation is a result of:

A) LipogenesisB) Higher epinephrine levelsC) KetogenesisD) Trans-animation

8. Which of the following glucose substrates is the most potent stimulator of insulin release?

A) PO carbohydrate loadingB) IV glucoseC) PO glucoseD) Apoprotein bound glucose orally

9. Which of the following statements is TRUE concerning glucose absorption from the intestine?

A) Passively absorbed with waterB) Actively absorbed in association with sodium and chlorideC) Can be absorbed only as disaccharideD) Absorbed similar to fructose

10. The major fuel source in sepsis is which of the following?

A) GlucoseB) KetonesC) Branched chain amino acidsD) GlycerolE) Short chain fatty acids

11. An elderly patient presents with symptoms suggestive of sepsis. Which of the following would be most supportive of this diagnosis?

A) The patient fell and broke her hip yesterday and now is hypermetabolicB) The patient has abdominal findings and has a glucose of 400 with ketoacidosisC) BUN is 40, the creatinine is 1.7D) The patient has a temperature of 102° and the metabolic cart indicates that the primary

fuel used is fat

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E) The patient has become increasing somnolent and the serum calcium is 14 mg

12. Energy requirements following a major burn injury are reflected in:

A) Weight gainB) Increased excretion of urinary nitrogen C) Increased appetiteD) Elevated levels of catecholamines

13. The acute phase protein response from the liver during an inflammatory response to sepsis is characterized by which of the following?

A) Albumin synthesis is increasedB) Transferrin levels are increasedC) Complement levels are increasedD) Fibrinogen levels are decreased

14. The most abundant amino acid in the body is:

A) Alanine B) LeucineC) GlutamineD) Tryptophane

15. The primary fuel source of neoplastic cells is:

A) GlucoseB) KetonesC) TriglyceridesD) Glutamine

16. Characteristics of the micelle include:

A) The incorporation of triglyceridesB) Is the transport mechanism for lymphatic triglyceridesC) Intracellular lipid aggregationsD) Bile salts and monoglycerides

17. Following absorption of long chain fatty acids from the intestine, these fatty acids are then released in what form?

A) ChylomicronsB) Free triglyceridesC) PhospholipidsD) Short chain fatty acids that enter the bloodstream

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18. The final product of lipid metabolism in the liver is:

A) KetonesB) Acetyl CoAC) GlucoseD) Glycerol

19. The preferred energy source for the colonocyte is:

A) GlucoseB) GlutamineC) AlanineD) Short chain fatty acids

20. The cytochrome P-450 system is responsible for:

A) Conjugating bilirubinB) Metabolic breakdown of drugsC) Conversion of hem to bilirubinD) Activation of kallikreins

21. Risk of death due to enteral feeding is increased with:

A) IleusB) Hypertonic feedingC) Jejunal feedingsD) Diarrhea

22. Aspiration pneumonia is most likely in patients with:

A) Cardiac cachexiaB) Starvation induced cachexiaC) Pseudo bulbar paralysisD) Anoxic brain injury

23. The breakdown products of nucleic acids are:

A) Recycled to replenish DNAB) Purines and pyrimidinesC) Excreted as ureaD) Replaced from exogenous sources

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Wound

24. In the process of wound healing, fibroblasts arise from:

A) Migratory macrophagesB) Dermal fibroblastsC) Endothelial cellsD) Mast cells

25. Which of the following best characterizes the sequence of wound healing?

A) Remodeling, inflammation, coagulation, fibroplasiaB) Coagulation, fibroplasia, remodeling, inflammationC) Inflammation, fibroplasia, remodeling, coagulationD) Coagulation, inflammation, fibroplasia, remodeling

26. Collagen synthesis in the skin would plateau at the:

A) 3rd dayB) 7th dayC) 21st dayD) 42nd day

27. Which of the following is TRUE regarding fetal wound healing (FWH)?

A) FWH leads to more scar formationB) FWH has more collagen formationC) FWH has a higher hyaluronic acid contentD) FWH has a more pronounced inflammatory phase, primarily with lymphocytes

28. Which of the following is TRUE regarding skin grafts?

A) Full thickness grafts are used to cover large areas such as burns because there is less contractionB) Once a split thickness graft is harvested from a donor site, it (the donor sight) cannot be used againC) A partial thickness graft may be 1/1500 of an inchD) Split thickness grafts will survive less frequently than full thickness grafts

29. Escharotomy of a circumferential full thickness burn of an extremity is best managed by:

A) Immediate escharotomyB) Determining tissue pressures above 50cmC) Doppler monitoring the distal pulseD) Waiting for paresthesias and deep tissue pain

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30. Which of the following is TRUE regarding restrictive problems in ventilatory management of a burn patient?

A) The problem is usually manifest before fluid resuscitationB) The problem may occur when only 50% of the circumference of the thorax is burnedC) Early escharotomy should be performed to diminish the restrictive problemD) Local anesthesia injected into the eschar is necessary to diminish the pain of performing

the escharotomy

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Cancer

31. A Stage II breast malignancy consists of:

A) A single clone of malignant cellsB) Numerous sub clones from a single transformed cellC) Several apoptotic clonesD) Several transformed cells developing into diverse clones

32. Which of the following is TRUE regarding angiogenesis?

A) It is mediated only by soluble locally secreted factorsB) It is a relatively simple processC) Tumor cells release angiogenic factorsD) Tumors can grow and metastasize without support from angiogenic factors

33. Radiation resistance in large tumors is due to:

A) Decreased concentrations of glutamine within the tumorB) Decreased concentrations of oxygen in the tumorC) Radiation diffusion is limitedD) Tumor cells on the periphoria absorb the radiation

34. Which of the following statements regarding non-Hodgkin’s lymphoma is correct?

A) The nodular type often has an indolent courseB) The diffuse type is localized and does not spreadC) Splenectomy should be considered for all casesD) Chemotherapy and radiation therapy are rarely effective

35. Characteristics of a post-transplant lymphoma include:

A) Lymph node involvementB) Kidney involvement is rareC) Polyclonal T cellsD) Monoclonal B cells

36. An 18-year old patient has a 4cm hard mass in the quadriceps femoris. The mass has increased in size over the past 3 months. Appropriate treatment is:

A) Incisional biopsyB) Excisional biopsyC) AmputationD) Chemotherapy

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Genetics

37. What is the major difference between (1) apoptosis and (2) necrosis?

A) No differenceB) (1) has cystoplasmic shrinking and DNA fragmentationC) (2) is a natural phenomenonD) Defects in (1) cause premature aging

38. Which is TRUE regarding the P53 gene?

A) It is the least mutated gene in the human cancersB) Overstimulation of P53 leads to cancerC) Deletion of P53 allows unregulated growthD) Inactivation of P53 leads to increased apoptosis

39. The tumor marker most specific for cancer is:

A) CEAB) AFPC) PSAD) Calcitonin

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Statistics

40. Statistical power is defined as:

A) 1-Beta (you have shown a difference in data)B) Type II error (you have incorrectly rejected the null hypothesis)C) Power is unrelated to sample sizeD) Type I error (you have correctly rejected the null hypothesis)

41. Quantitative variables are best characterized as:

A) Uses ordinal dataB) Depends on accuracy of instrument usedC) Uses nominal dataD) Includes qualitative variables

42. Which of the following statements best defines the term “prevalence” which is used in epidemiologic studies?

A) It represents the frequency of new cases occurring within a defined populationB) It represents the number of individuals with a disease in a defined populationC) It represents the potential risk of a disease in a populationD) It represents the deaths associated with a specific disease

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ANSWER KEY: Chapter 3

METABOLISM GENETICS1. C 37. B2. A 38. C3. A 39. D4. B STATISTICS5. A 40. A6. B 41. B7. C 42. B8. C9. B10. C11. D12. B13. C14. C15. D16. D17. A18. A19. D20. B21. A22. C23. BWOUND24. B25. D26. B27. C28. D29. C30. CCANCER31 B32. C33. B34. A35. D36. A

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