Pbl Exam 6 Case 4

Front 1

1. What is transcription?

Back 1

Transcription is the transfer of the genetic message from DNA to RNA

Front 2

2. What is translation?

Back 2

Translation is the transfer of the genetic message form the nucleotide language of nucleic acids to the AA language of proteins.

Front 3

3. What makes ups the nucleic acid alphabet?

Back 3

There are only four characters, corresponding to the four nucleotide of mRNA (A, G, C, and U).

We have 20 amino acids. We need three bases to make up one amino acid, because 4^2=16 whereas 4^3=64 combinations. The 64 combinations or "codons" are more than required, but not overly excessive.

Front 4

4. What are tRNA molecules?

Back 4

Each tRNA molecule contains an anticodon and binds covalently a specific AA at its 3'-end.

Front 5

5. What are anticodons of tRNA?

Back 5

The anticodon of a tRNA molecule is a set of three nucleotides that can interact w/a codon on mRNA.

To interact, the codon and anticodon must be complimentary (i.e. they must be able to form base pairs in an antiparallel orientation.

Thus, the anticodon of a tRNA serves as the link between an mRNA codon and the AA that the codon specifies.

Front 6

6. What are the three codons that terminate protein synthesis and are known as "stop" codons?

Back 6

UGA, UAG, UAA

Front 7

7. Which two amino acids only have one codon?

Back 7

AUG = methionine

UGG = tryptophan

Front 8

8. What does it mean when the genetic code is described as degenerate?

Back 8

Degenerate means that an AA may have more than one codon.

However, each codon specifies only one amino acid, and the genetic code is thus unambiguous.

Front 9

9. What is the "wobble" hypothesis?

Back 9

Watson and Crick noted that the pairing between the 3' base of the codon and the 5' base of the anticodon does not always follow the strict base pairing rules that he and Watson has previously discovered.

At the third base of the codon (the 3'position of the codon and the 5' position of the anticodon), the base pairs can "wobble"; for example, G can pair with U, and A, C, or U can pair w/the unusual base hypoxanthine (I) found in tRNA.

B/c of "wobble" between the codon and anticodon, fewer than 61 tRNAs are required to translate the genetic code.

Front 10

10. How is the genetic code almost universal?

Back 10

All organissm studied so far sue the same genetic code, with some rare exceptions in human mitochondrial mRNA:

1. UGA codes for tryptophan instead of serving as a stop codon
2. AUA codes for methionine instead of isoleucine
3. CUA codes for threonine instead of leucine

Front 11

11. How is the the genetic code nonoverlapping and w/o punctuation?

Back 11

mRNA does not contain punctuation to separate one codon from the next, and the codons do not overlap. Each nucleotide is read only once.

Beginning with a start codon (AUG) near the 5' end of the mRNA, the codons are read sequentially, ending w/a stop codon (UGA, UAG, or UAA) near the 3' end of the mRNA.

Front 12

12. What is the relationship between mRNA and the protein product?

Back 12

The start codon (AUG) sets the reading frame -the order in which the sequence of bases in the mRNA is sorted into codons.

The order of the codons in the mRNA determines the sequence in which AAs are added to the growing polypeptide chain.

Thus the order of the codons in the mRNA determines the linear sequence of AAs in the protein.

Front 13

13. What are the mutations in genetic code?

Back 13

Mutations that result from damage to the nucleotides of DNA molecules or from unrepaired errors during replication can be transcribed into mRNA and therefore can result in the translation of a protein w/an abnormal AA sequence.

Front 14

14. What are the four different types of mutations?

Back 14

1. Point mutations
2. Insertions
3. Deletions
4. Frameshift

Front 15

15. What are point mutations?

What are the three types?

Back 15

Point mutations occur when only one base in DNA is altered, producing a change in a single base of an mRNA codon.

The three basic types of point mutations are:
1. Silent
-said to be silent when they do not effect the AA sequence of the protein.

2. Missense
-one AA in the protein is replaced by a different AA

3. Nonsense
-a codon change causes a codon to be replaced by a stop codon, so synthesis of the mutant protein terminates at this point.

Front 16

16. What are insertion and deletion mutations?

Back 16

An insertion occurs when one or more nucleotides are added to DNA. If the insertion does not generate a stop codon, a protein with more AAs than normal could be produced.

When one or more nucleotides are removed form the DNA, the mutation is known as a deletion. If the deletion does not affect the normal start and stop codons, a protein w/fewer than the normal number of AAs could be produced.

Front 17

17. What are frame-shift mutations?

Back 17

A frame-shift mutation occurs when the number of inserted or deleted nucleotides is not a multiple of three. The reading frame shifts at the point where the insertion or deletion begins. It usually leads to premature termination by new stop codons in the new reading frame.

Beyond that point, the AA sequence of the protein translated from the mRNA differs from the normal protein.

Front 18

18. What are splice site mutations?

Back 18

Splice site mutations-

May decrease splicing efficiency.
May alter splicing, inserting sequence from intron into mRNA or cause exon skipping, loss of one or more exons

Significant alterations in amount of protein made or production of substantially altered protein

Front 19

19. What are triplet repeat expansion?

Back 19

Triplet repeat expansion-

Proteins with long run of same codon, may increase number of repeats with time.

At some length, the repeat interferes with protein function and/or production

Front 20

20. What is an aminoacyl-tRNA?

Back 20

A tRNA that contains an AA attached covalently to its 3'-end is called an aminoacyl-tRNA and is said to be "charged."

Aminoacyl-tRNAs are named both for the AA and the tRNA that carries the AA.

Front 21

21. What do tRNAs recognize?

Back 21

A particular tRNA recognizes only the AUG start codon that initiates protein synthesis and not other AUG codons that specify insertion of mehtionine within the polypeptide chain.

Front 22

22. What attaches AAs to their tRNAs?

Back 22

Amino acids are attached to their tRNAs by highly specific enzymes known as aminoacyl-tRNA synthetases.

20 different synthetases exist, one for each AA. Each synthestase recognizes a particular AA and all of the tRNAs that carry that AA.

Front 23

23. How is the ester bond formed that links the AA to the tRNA by aminoacyl-tRNA synthetase?

Back 23

It is an energy-requiring process that occurs in two steps:

1. the AA is activated by ATP to form an enzyme/aminoacyl-AMP complex and pyrophosphate
2. the activated AA is transferred to the 2' or 3' hydroxyl group of the 3' terminal A residue of the tRNA, and AMP is released.

The energy in the aminoacyl-tRNA ester bond is subsequently used in the formation of a peptide bond during the process of protein synthesis.

Front 24

24. So, the insertion of the AA into a growing polypeptide chain depends on what?

Back 24

Depends solely on the bases of the anticodon, through complimentary base pairing w/the mRNA codon.

Front 25

25. What are the three steps of translation?

Back 25

1. Initiation
2. Elongation
3. Termination

Front 26

26. Translation steps summary

Back 26

It begins with the formation of the initiation complex.

Subsequently, synthesis of the polypeptide occurs be a series of elongation steps that are repeated as each AA is added to the growing chain.

Termination occurs where the mRNA contains an in-frame stop codon and the completed polypeptide chain is released.

Front 27

27. What occurs in the initiation of translation?

Back 27

1. In eukaryotes, translation begins w/formation of complex of met-tRNA , mRNA, and a ribosome.

2. Next, the mRNA must associate with a small ribosomal subunit (30S/40S)
-uses 5' cap and cap binding protein (CBP) in eukaryotes
- uses Shine-Dalgarno sequence in prokaryotes

3. The charged Met-tRNA binds to an initiation factor and large subunit (50S/60S)
-Met is formylated in prokaryotes ONLY

4. These components plus other initiation factors associate producing functional ribosomes
-requires ATP and GTP hydrolysis for energy.

Front 28

28. The functional ribosome is now complete and consists of what...?

During initiation, where does Met-tRNA bind?

Back 28

1. One small subunit
2. One large subunit
3. Two binding sites for tRNA
-P (peptidyl) site
-A (aminoacyl) site

During initiation, Met-tRNA binds to the ribosome at the P site.

Front 29

29. How does the initiation process differ for prokaryotes and eukaryotes?

Back 29

1. In bacteria, the initiating met-tRNA is formylated, producing a formyl-mehtionyl-tRNA that participates in formation of the initiation complex.

2. Only three initiation factors are required to generate this complex in prokaryotes, compared with the dozen or more required by eukaryotes.

3. The ribosomes also differ in size:
-Prokaryotes have 70S ribosomes, composed of 30S and 50S subunits
-Eukaryotes have 80S ribosomes, composed of 40S and 60S subunits.

4, Unlike eukaryotic mRNA, bacterial mRNA is not capped. It uses the Shine-Dalgarno sequence to identify the initiating AUG triplet.

Front 30

30. How is the initiation of translation regulated?

Give an example...

Back 30

Regulated at the level of initiation factors.

For example, insulin, an anabolic hormone, stimulates general protein synthesis by activating the initiation factor eIF4E.

Normally, eIF4E is bound to an inhibitor protein, designated 4E-binding protein (4E-BP). When insulin binds to its cell surface receptor, it initiates an intracellular sequence of events resulting in phosphorylation of 4E-BP.

Phosphorylated 4E-BP no longer binds to eIF4E, and eIF4E is now free to participate in the initiation of protein synthesis.

Front 31

31. How is eIF2 a regulator of the initiation step in protein synthesis?

Back 31

When eIF2 is phosphorylated, it is inactive, and protein synthesis cannot begin.

Conditions such as starvation, heat shock, and viral infection result in phosphorylation of eIF2 by a specific kinase.

Front 32

32. What does eIF2 have to do with globin synthesis?

Back 32

The regulation of globin synthesis by heme in reticulocytes illustrates the role of eIF2 in the regulation of translation.

Reticulocytes, which arethe precursors of RBCs, synthesize the oxygen carrying hemoglobin molecules from the globin polypeptide chains and Fe binding pigment, heme.

In the absence of heme, the rate of initiation of globin synthesis decreases. Heme acts by inhibiting the phosphorylation of the initiation factor eIF2. Thus, eIF2 is active in the presence of heme and globin synthesis is initiated.

Front 33

32. What does eIF2 and EF1 have in common?

Back 33

Both eukaryotic initiation factor 2 (eIF2) and elongation factor 1 (EF1) are types of heterotrimeric G proteins.

The dramatically change their conformation and actively form complexes when they bind GTP but become inactive and dissociate when they hydrolyze this GTP to GDP.

GTP can then displace the bound GDP to reactivate the initiation factor eIF2 or the elongation factor EF1.

Front 34

33. What is translation elongation?

Back 34

Elongation: amino acids are added to the carboxyl end of the growing polypeptide

After the initiation complex is formed, addition of each amino acid to the growing polypeptide chain involves binding of an aminoacyl-tRNA to the A site on the ribosome, formation of a peptide bond, and translocation of the peptidyl-tRNA to the P site.

The peptidyl-tRNA contains the growing polypeptide chain.

Front 35

34. How is the aminoacyl-tRNA bound to the A site?

Back 35

When Met-tRNA is bound to the P site, the mRNA codon in the A site determines which aminoacyl-tRNA will bind to that site.

An aminoacyl-tRNA binds when its anticodon is antiparallel and complimentary to the mRNA codon.

In eukaryotes, the incoming aminoacyl-tRNA first combines w/elongation factor EF1α containing bound GTP before binding to the mRNA-ribosome complex.

When the aminoacyl-tRNA-EF1α-GTP complex binds to the A site, GTP is hydrolyzed to GDP.

This prompts dissociation of EF1α-GDP from the aminoacyl-tRNA ribosomal complex, thereby allowing protein synthesis to continue.

Front 36

35. What happens to the free EF1α-GDP?

Back 36

The free EF1α-GDP reassociates w/the EF1βγ subunits, and GDP is released.

Subsequently, GTP binds and the βγ subunits dissociate.

Thus, EF1α-GDP is ready to bind another aminoacyl-tRNA molecule.

Front 37

36. How is the process of elongation different in prokaryotes?

Back 37

The process is very similar in prokaryotes, except that the corresponding factor for EF1α is named EF-Tu and the associating elongation factors are called EF-Ts instead of EF1βγ

Front 38

37. During elongation, how is the formation of a peptide bond accomplished?

Back 38

The amino acid on the tRNA in the A site forms a peptide bond with the methionine on the tRNA in the P site.

In subsequent rounds of elongation, the AA on the tRNA in the A site forms a peptide bond with the peptide on the tRNA in the P site.

The tRNA in the A site now contains the growing polypeptide chain, and the tRNA in the P site is uncharged.

Front 39

38. What catalyzes the formation of the peptide bonds?

Back 39

Peptidyltransferase, which is not a protein but the rRNA of the large ribosomal subunit, catalyzes the formation of the peptide bond.

Front 40

39. How is translocation accomplished?

Back 40

Translocation in eukaryotes involves another G-protein, elongation factor EF2 (EF-G in prokaryotes) that complexes w/GTP and binds to the ribosome, causing a conformational change that moves the mRNA and its base-paired tRNAs with respect to the ribosome.

The uncharged tRNA moves from the P site and is released from the ribosome.

The peptidyl-tRNA moves into the P site, and the next codon of the mRNA occupies the A site.

During translocation, GTP is hydrolyzed to GDP, which is released from the ribosome along w/the elongation factor.

Front 41

40. What terminates translation?

Back 41

The three elongation steps are repeated until the FIRST termination (stop) codon moves into the A site on the ribosome.

B/c no tRNAs w/anticodons that can pair w/stop codons normally exist in cells, release factors bind to the ribosome instead, causing peptidyltransferase to hydrolyze the bond between the peptide chains and tRNA,

The newly synthesized polypeptide is released from the ribosome, which dissociates into its individual subunits, releasing the mRNA.

Front 42

41. In sum, what are the four steps of translation?

Back 42

1. Polypeptide starts at amino terminus with methionine

2. Charged tRNAs aligned on mRNA by ribosome

3. Amino acids transferred from tRNA to growing polypeptide chain

4. Uncharged tRNA exits and can be attached to amino acid and be used again

Front 43

42. Energy requirements of protein synthesis

How many high-energy bonds are cleaved for each AA of a polypeptide?

Back 43

Formation of each aminoacyl-tRNA requires the equivalent of 2 high-energy phosphate bonds b/c ATP is converted to AMP and pyrophosphate, which is cleaved to form two inorganic phosphates.

As each AA is addded to the growing peptide chain, two GTPs are hydrolyzed, one at the step involving EF1 and the second at the translocation step.

Thus, 4 high-energy bonds are cleaved for each AA of the polypeptide.

Front 44

43. What are polysomes?

Back 44

As one ribosome moves along the mRNA, producing a polypeptide chain, a second ribosome can bind to the vacant 5' end of the mRNA.

Many ribosome can simultaneously translate a single mRNA, forming a complex known as a polysome.

Front 45

44. Ribosomes and polysomes

Back 45

A single ribosome covers approx 80 nucleotides of mRNA.

Therefore, ribosomes are positioned on mRNA at intervals of approx 100 nucleotides.

The growing polypeptide chains attached to the ribosomes become longer as each ribosome moves from the 5' end toward the 3' end of the mRNA.

Front 46

45. How are proteins processed?

Back 46

Nascent polypeptide chains (i.e. polypeptides that are in the process of being synthesized) are processed.

As they are produced, they travel through a tunnel in the ribosome, which can hold about 30 AA residues.

As polymerization of the chain progress, the AA residues at the N-terminal end begin to emerge from this protected region w/in the ribosome and to fold and refold into the 3-D conformation of the polypeptide.

Front 47

46. What mediates and helps the folding process?

What catalyzes disulfide bond formation?

Back 47

Proteins bind to the nascent polypeptide and mediate the folding process. These mediators are called chaperones b/c they prevent improper interactions from occurring.

Disulfide bond formation between cysteine residues is catalyzed by disulfide isomerases and may also be involved in producing the 3D structure of the polypeptide.

Front 48

47. What are the post-translational modifications?

Back 48

The initial methionine is removed by specific proteases; methionine is not the N-terminal AA of all proteins.

Subsequently, other specific cleavages also may occur that convert proteins to more active forms.

In addition, AA residues w/in the peptide chain can be modified enzymatically to alter the activity or stability of the proteins, direct it to a subcellular compartment, or prepare it for secretion from the cell.

Front 49

48. . What are the 9 posttranslational modifications and what are the purpose of them?

Back 49

1. Carboxylation - (Glu) coagulation cascade
2. Hydroxylation (Pro, Lys) collagen stability
3. Phosphorylation (Ser, Thr, Tyr) enzyme activity
4. Glycosylation (Ser, Asn) secretion, membrane
5. Fatty acylation - membrane anchor
6. Prenylation - membrane anchor
7. ADP-ribosylation - enzyme activity
8. Methylation
9. Acetylation

Front 50

49. Targeting of proteins to subcellular and extracellular locations

Back 50

Proteins for secretion, membranes, organelles are often modified in ER and Golgi

Synthesized by ribosomes of rough ER:
-Signal peptide of nascent protein binds signal recognition particle (SRP)
-Docks with receptor on ER
-Protein enters ER lumen via pore, can be modified and enter secretion pathway

Front 51

50. What occurs in the Golgi and the ER?

Back 51

The Golgi complex serves to process the proteins it receives from the rER and to sort them so that they are delivered to their appropriate destinations.

Processing, which can be initiated in the ER, involves glycosylation, the addition of carbohydrate groups, and modification of existing carbohydrate chains.

Sorting signals permit delivery of proteins to their target locations.

Front 52

51. What is the KDEL sequence?

Back 52

Proteins containing the KDEL (lys-asp-glu-leu) sequence at their carboxyl terminal are returned to the ER from the Golgi.

Front 53

52. Mannose-6-phosphate

Back 53

Glycosylation fo enzymes destined to become lysosomal enzymes results in the presence of a mannose 6-phosphate residue on an oligosaccharide attached to the enzyme.

This residue is recognized by the mannose 6-phosphate receptor protein, which incorporates the enzyme into a clathrin-coated vesicle.

The vesicle travels to endosomes and is eventually incorporated into lysosome.

Front 54

53. Tay-sachs disease

Back 54

An insertion in exon 11 of the α-chain of the hexosaminidase A gene is the most common mutation found in Jews who have Tay-sachs disease.

Hexosaminidases are lysosomal enzymes that are necessary for the normal degradation of glycosphingolipids, such as the gangliosides.

Asa result, gangliosides are found in high concentrations in the nervous system, causing a wide array of neurologic disorders known as gangliosidoses. Eventually, symptoms include UMN and LMN deficits, visual difficulties, seizures, and increasing cognitive dysfunction.

Front 55

54. What is the cause of sickle cell anemia?

Back 55

Sickle cell anemia is caused by a missense mutation. In the sickle cell gene, GTG replaces the normal GAG.

Thus, in the mRNA, the codon GUG replaces GAG and a valine residue replaces a glutamate residue in the protein.

Front 56

55. Is it possible that people with thalassemia have either a nonsense mutation in codon 17 or a large deletion in the β-globin gene?

Back 56

A nonsense mutation at codon 17 would cause a premature termination of translation.

A nonofunctional peptide containing only 16 AAs would result, producing a β⁰-thalassemia if the mutation occurred in both alleles.

A large deletion in the coding region of the gene could also produce a truncated protein.

Front 57

56. How do antibiotics work?

What about streptomycin?

Back 57

Many antibiotics are protein synthesis inhibitors.

These drugs take advantage of the differences between the mechanisms for proteins synthesis in prokaryotes and eukaryotes.

For example, streptomycin binds to the 16S rRNA of the 30S ribosomal subunit of prokaryotes. It interferes w/initiation of protein synthesis and causes misreading of mRNA.

Front 58

57. How does tetracycline work?

Back 58

Tetracycline binds to the 30S subunit of prokaryotes and inhibits binding of aminoacyl-tRNA to the A site of the ribosome.

Many bacteria are resistant.

Front 59

58. How do the macrolide antibiotics work?

Back 59

The macrolide antibiotics (e.g., erythromycin, clarithromycin) bind to the 50S subunit of bacteria and inhibit translocation.

Front 60

59. How does chloramphenicol work?

Back 60

Chloramphenicol is an antibiotic that interferes w/the peptidyltransferase activity of the 50S subunit of bacteria.

Can inhibit mitochondrial activity (this explains its toxicity)

Only used under SERIOUS conditions

Front 61

60. What is diphtheria?

Back 61

Diphtheria is a highly contagious disease caused by a toxin secreted by the bacterium Corynebacterium diphtheriae. Although the toxin is a protein, it is not produced by a bacterial gene, but by a gene brought into the bacterial cell by an infecting bacteriophage.

Front 62

61. What is the composition of the diphtheria toxin?

Back 62

The diphtheria toxin is composed of two protein subunits. The B subunit binds to a cell surface receptor, facilitating the entry of the A subunit into the cell. In the cell, the A subunit catalyzes a reaction in which the ADP ribose portion (ADPR) of NAD is transferred to EF2.

In this reaction, the ADPR is attached covalently to a posttranslationally modified histidine residue, known as diphthamide.

ADP-ribosylation of EF2 inhibits protein synthesis, leading to cell death.

Front 63

62. What is I-cell disease?

Back 63

I-cell disease (mucolipidosis II) is a disorder of protein targeting. Lysosomal proteins are not sorted properly form the Golgi to the lysososmes, and lysosomal enzymes end up being secreted from the cell.

This is b/c of a mutation in the enzyme N-acetylglucosamine phosphotransferase, which is a required first step for attaching the lysosomal targeting signal, mannose 6-phosphate, to lysosomal proteins.

Thus, lysosomal proteins cannot be targets to the lysosomes, and these organelles become clogged w/materials that cannot e digested, destroying overall lysosomal function.

This leads to a lysosomal storage disease of severe consequence.

Front 64

63. β-thalassemiass

Back 64

In β⁰-thalassemia, little or none of the Hgb β-chain is produced.

β-thalassemia intermedia is usually the result of two different mutations, or, less frequently, homozygosity for a mild mutation in the rate of synthesis, or a complex combo of mutations

Front 65

64. What are topoisomerases?

Back 65

These enzymes catalyze DNA replication and segregation by breaking, rotating, and religating DNA strands.

The enzymes that have been most successfully targeted by antibiotics are topoisomerases.

Front 66

65. What are the two types of topoisomerases?

Back 66

1. Type 1
-form and reseal single-stranded breaks in DNA to decrease positive supercoiling.

2. Type 2
-performs nuclease and ligase operations on both strands of DNA.

Front 67

66. What are the similarities/differences between types 1 and 2 topoisomerases?

Back 67

Both types of topoisomerases can remove excess DNA supercoils during DNA replication.

However, only type 2 topoisomerases can resolve intertwined copies of double-stranded DNA to permit segregation of the DNA to daughter cells.

Type 2 enzymes are both more complex and more versatile than type 1 topoisomerases, and the type 2 enzyme serves as a more frequent molecular target for chemotherapeutic agents.

Front 68

67. What is the MOA of a type 2 topoisomerase?

Back 68

1. The enzyme binds to a segment of DNA and forms covalent bonds w/phosphates form each strand, thereby nicking both strands.

2. The enzyme causes a second stretch of DNA from the same molecule to pass through the break, relieving supercoilding.

This passage of double-stranded DNA through a double stranded break is what permits separation of intertwined copies of DNA following replication, and thereby, segregation of DNA into progeny cells.

Front 69

68. What are the two main bacterial type 2 topoisomerases?

Back 69

1. DNA gyrase
2. Topoisomerase IV

DNA gyrase is particularly crucial for segregation in some bacteria, while topoisomerase IV is the critical enzyme in other bacteria.

Front 70

69. What enzyme catalyzes transcription?

How is this different in prokaryotes/eukaryotes?

Back 70

RNA polymerase.

In bacteria, one RNA polymerase synthesizes all the RNA in the cell. Furthermore, bacterial RNA polymerase is composed of only five subunits.

In contrast, eukaryotes express three different RNA polymerases, and each enzyme is considerably more complex in its subunit structure than the bacterial counterpart.

Front 71

70. What are inhibitors of toposiomerases called?

Back 71

Quinolones.

Quinolones are a major class of bactericidal antibiotics that act by inhibiting bacterial type II topoisomerases.

Front 72

71. MOA of quinolones

Back 72

Quinolones act by inhibiting one or both fo the two prokaryotic type 2 topoisomerases in sensitive bacteria, DNA gyrase and topoisomerase IV.

Quinolones primarily inhibit DNA gyrase in Gram-negative organisms, and they inhibit topoisomerase IV in Gram-positive organisms such as S. aureus.

Front 73

72. Quinolone activity at low vs. high concentrations

Back 73

At low concentrations, quinolones inhibit type II topoisomerases reversibly, and their action is bacteriostatic.

At higher concentrations, however, quinolone convert the topoisomerases into DNA-damaging agents by stimulating dissociation of the enzyme subunits form the broken DNA.

Doubly-nicked DNA cannot be replicated, and transcription cannot proceed through such breaks. Topoisomerase dissociation from the DNA and/or the bacterial response to the double stranded break lead ultimately to cell death.

Thus, at therapeutic doses, the quinolone antibiotics are bactericidal.

Front 74

73. What are the names of the quinolones?

Back 74

1. Ciprofloxacin
2. Gatifloxacin
3. Levofloxacin
4. Moxifloxacin
5. Norfloxacin
6. Ofloxacin

Front 75

74. What are the quinolones used to treat?

Back 75

They are widely used to treat common urogenital, respiratory, and GI infections caused by E. coli, Klebsiella pneumoniae, Campylobacter jejuni, Pseudomonas aeruginosa, Neisseria gonorrhoeae, and Enterobacter, Salmonella, and Shigella species.

Front 76

75. Ciprofloxacin

Back 76

MOA: Inhibits prokaryotic type 2 topoisomerases. At therapeutic doses, it has a bactericidal effect by causing double-stranded DNA breaks and cell death.

PURPOSE: Gram-negative infections

ADVERSE: *Cartilage damage, tendon rupture, peripheral neuropathy, increased ICP, seizure, severe hypersensitivity reaction, rash, GI disturbance

CONTRA: Concomitant tizanidine administration and hypersensitivity to quinolones

NOTES: Avoid coadministration of thioridazine due to increased risk of cardiotoxicity.

Front 77

76. Gatofloxacin, Levofloxacin, Moxifloxacin, Norfloxacin, Ofloxacin

Back 77

MOA: Inhibits prokaryotic type 2 topoisomerases. At therapeutic doses, it has a bactericidal effect by causing double-stranded DNA breaks and cell death.

PURPOSE: Gram-negative infections

ADVERSE: Cartilage damage, tendon rupture, peripheral neuropathy, increased ICP, seizure, severe hypersensitivity reaction, rash, GI disturbance

CONTRA: Hypersensitivity to quinolones

NOTES: Avoid coadministration of thioridazine due to increased risk of cardiotoxicity.

Front 78

77. How do bacteria evolve resistance to the quinolones?

Back 78

Bacteria evolve resistance through chromosomal mutations in the genes that encode type 2 topoisomerases, or through alterations in the expression of membrane porins and efflux pumps that determine drug levels inside the bacteria.

Front 79

78. What are the inhibitors of transcription called?

Back 79

Rifamycin derivatives, such as:

1. Rifabutin
2. Rifampin

These are semisynthetic derivatives of the naturally occurring antibiotic rifamycin B.

Front 80

79. Rifampin

Back 80

MOA: Form a stable complex w/bacterial DNA-dependent RNA polymerase, thereby inhibiting RNA synthesis. It targets the β-subunit of bacterial RNA polymerase.

PURPOSE: Prophylaxis of meningococcal disease and for mycobacterial infections, including tuberculosis

ADVERSE: Thrombocytopenia, hepatotoxicity, *saliva, tear, sweat and urine discoloration, influenza like illness, elevated LFTs, GI disturbance

CONTRA: Active Neisseria meningitidis infection

Front 81

80. Rifampin NOTES

Back 81

NOTES: Particularly effective against phagosome-dwelling mycobaceria b/c it is bactericidal for intracellular as well as extracellular bacteria.

Rifampin increases the in vitro activity of isoniazid

Displays high selectivity for bacteria, so it is generally well tolerated, and the incidence of adverse effects is low.

Rifampin is not used as a single angent b/c of rapid development of resistance

May reduce cyclosporine concentration and efficacy

Front 82

81. Rifabutin

Back 82

MOA: Form a stable complex w/bacterial DNA-dependent RNA polymerase, thereby inhibiting RNA synthesis. It targets the β-subunit of bacterial RNA polymerase.

PURPOSE: Mycobacterial infections, including tuberculosis

ADVERSE: Thrombocytopenia, hepatotoxicity, saliva, tear, sweat and urine discoloration, influenza like illness, elevated LFTs, GI disturbance

CONTRA: Active Neisseria meningitidis infection

NOTES: Avoid concurrent administration of clarithromycin w/rifabutin, b/c clarithromycin increases plasma concentration of rifabutin and rifabutin reduces plasma concentration of clarithromycin

Front 83

82. What are three general consideration that apply to inhibitors of bacterial translation?

Back 83

1. Translation inhibitors target either the 30S or 50S subunit of the bacterial ribosome.

2. In addition to their inhibitor effects on bacterial ribosomes, protein synthesis inhibitors can affect mammalian mitochondrial ribosomes, cytosolic ribosomes, or both.

3. Complete inhibition of protein synthesis is not sufficient to kill a bacterium.

Front 84

83. What is the most common mechanism by which inhibitors of translation cause adverse effects?

Back 84

Through inhibition of host ribosomes.

Front 85

84. What are the three categories of drugs that target the 30S ribosomal subunit?

Back 85

1. Aminoglycosides
2. Spectinomycin
3. Tetracyclines

Front 86

85. What are aminoglycosides?

What are the names of the aminoglycosides?

Back 86

Aminoglycosides are used mainly to treat infections caused by Gram-negative bacteria. These agents are charged molecules that are not orally bioavailable so they must be administered parenterally.

They include:
1. Streptomycin
2. Amikacin
3. Gentamicin
4. Kanamycin
5. Neomycin
6. Netilmicin
7. Paromomycin
8. Tobramycin

Front 87

86. Aminoglycosides

Back 87

MOA: Bind to 16S rRNA of the 30S subunit and elicit concentration-dependent effects on protein synthesis. Aminoglycosides are bactericidal due to induction of mRNA misreading; misread mRNA causes synthesis of aberrant proteins that insert into membrane, forming pores that eventually lead to cell death.

PURPOSE: Serious Gram-negative infections

ADVERSE: *Ototoxicity, acute renal failure, neuromuscular blockage, respiratory paralysis

CONTRA: Hypersensitivity to aminoglycosides

NOTES: Act synergistically w/β-lactam antibiotics

Front 88

87. What are the three mechanisms by which bacteria can become resistant to aminoglycosides?

Back 88

1. Plasmid-encoded production of a transferase enzyme or enzymes that inactivate aminoglycosides.

2. Impaired drug entry, possibly by alteration or elimination of porins or other proteins involved in drug transport.

3. Mutation of the drug target on the 30S ribosomal subunit.

Front 89

88. What is the David model?

Back 89

The David model frames the story of cell death in terms of the concentration dependent effects of aminoglycosides.

When drug first enters the cell, it is poorly transported across bacterial membranes. At these initial low concentrations, misreading occurs, leading to synthesis of aberrant proteins. Some of these proteins insert into membranes and cause the formation of membrane pores, which allow aminoglycosides to flood the cell and halt protein synthesis completely.

As a result, the damage to the membrane cannot be repaired, and leakage of ions and, later, larger molecules leads to cell death.

Front 90

89. What is the single most important factor restricting aminoglycoside use?

Back 90

Ototoxicity (manifesting as either auditory or vestibular damage).

The aminoglycosides are known to accumulate in the perilymph and endolymph of the inner ear and at high concentrations, to damage highly sensitive hair cells.

Aminoglycosides can also cause acute renal failure, apparently as a result of drug accumulation in proximal tubular cells.

Front 91

90. Spectinomycin

Back 91

MOA: Structural relative of the aminoglycosides that also binds to the 16S rRNA of the 30S ribosomal subunit. Spectinomycin permits formation of the 70S complex but inhibits translocation. It is not bactericidal but is bacteriostatic.

PURPOSE: Alternative therapy for gonorrheal infections

ADVERSE: Injection site pain, nausea, dizziness, insomnia

CONTRA: Hypersensitivity to spectinomycin

Front 92

91. What are tetracyclines and what are their names?

Back 92

Tetracyclines are broad-spectrum, bacteriostatic antibiotics that are used widely.

They are:
1. Chlortetracycline
2. Demeclocycline
3. Doxycycline
4. Methacycline
5. Minocycline
6. Oxytetracycline
7. Tetracycline

Front 93

92. MOA of tetracyclines

Back 93

Tetracyclines bind reversibly to the 16S rRNA of the 30S subunit and inhibit protein synthesis by blocking the binding of aminoacyl tRNA to the A site on the mRNA ribosome complex.

This action prevents the addition of further AAs to the nascent peptide.

Front 94

93. What is the reason for the high selectivity of tetracyclines in bacteria?

Back 94

The high selectivity derives from active accumulation of these drugs in bacteria but not in mammalian cells.

Tetracyclines enter Gram-negative bacteria by passive diffusion through porin protein in the outer membrane, followed by active transport across the inner cytoplasmic membrane.

In contrast, mammalian cells lack the active transport system found in susceptible bacteria.

Front 95

94. Tetracyclines

Back 95

MOA: Bind reversibly to the 16S rRNA of the 30S subunit and inhibit protein synthesis by blocking the binding of aminoacyl tRNA to the A site on the mRNA ribosome complex.

PURPOSE: Used to treat a variety fo infections, including Corynebacterium acnes, Haemophilus influenze, Vibrio cholerae, spirochetes, Mycoplasma pneumoniae, Chlamydia species, and rickettsial species. Also used for malaria prophylaxis (doxycycline).

ADVERSE: Bulging fontanelle, *discoloration and hypoplasia of teeth and temporary stunting of growth, hepatotoxicity, pseudotumor cerebri, *photosensitivity, rash, GI disturbance, vestibular disturbance (minocycline), candidal infection.

CONTRA: Last half of pregnancy, infancy, < 8 y/o; patients with sever renal impairment should not be treated w/any tetracyclines except for doxycycline.

Front 96

95. How does tetracycline resistance occur?

Back 96

Tetracycline resistance occurs by plasmid-encoded efflux pumps, production of proteins that interfere w/binding of tetracyclines to the ribosome, or enzymatic inactivation of tetracyclines.

Front 97

96. Important pharmacokinetic feature of tetracyclines

What do tetracyclines have to do with acitretin?

Back 97

Interaction of these drugs w/foods high in calcium.

B/c these products and medicines impair the absorption of tetracyclines, the tetracyclines are generally taken on an empty stomach.

Once they are in the circulation, however, the same interaction w/cations, can cause sequestration of the drugs in bone and teeth.

*Also, avoid coadministration with acitretin due to increased risk of elevated ICP

Front 98

97. What are the two most problematic adverse effects of the tetracyclines?

Back 98

Kidney toxicity and GI distress.

Nausea and vomiting are the most common reasons for premature discontinuation of a course of tetracycline.

Front 99

98. What's so special about doxycycline?

Back 99

Compared w/other tetracyclines, a lower fraction of doxycycline is eliminated via the kidney, making this drug safer for use in patients w/renal failure.

Also, doxycycline is excreted in the feces largely in an inactive form, so this agent has the added advantage of minimally altering intestinal flora.

Hence, doxycline use is associated w/a lower incidence of nausea, vomiting, and superinfection w/pathogenic organisms than the other tetracyclines, especially in an immunocompromised patient.

Front 100

99. What are the glycylcyclines?

Back 100

They are a new class of antibiotics.

It includes Tigecycline, which has a broad spectrum of activity and has been approved for IV administration in the treatment of serious skin and abdominal infections.

Front 101

100. Tigecycline

Back 101

MOA: Resembles that of the tetracyclines; Bind reversibly to the 16S rRNA of the 30S subunit and inhibit protein synthesis by blocking the binding of aminoacyl tRNA to the A site on the mRNA ribosome complex. It is bacteriostatic.

PURPOSE: Skin or subcutaneous infection, complicated abdominal infection

ADVERSE: GI disturbance

CONTRA: Hypersensitivity to tigecycine

Front 102

101. What are the five categories of antibiotics that target the 50S ribosomal subunit?

Back 102

1. Macrolides and ketolides
2. Chloramphenicol
3. Lincosamides
4. Streptogramins
5. Oxazolidinones

Front 103

102. What are macrolides?

What is their MOA?

Back 103

Macrolides are named for their large lactone rings. They are especially important in the treatment of pulmonary infections, including Legionnaire's disease.

They are bacteriostatic antibiotics that block the translocation step of protein synthesis by targeting the 23S rRNA of the 50S subunit. Macrolides bind to a specific segment of 23S rRNA and block the exit tunnel form which nascent peptides emerge.

Front 104

103. What are the names of the macrolides and ketolides?

Back 104

1. Azithromycin
2. Clarithromycin
3. Erythromycin
4. Telithromycin

Front 105

104. What is erythromycin used to treat?

Back 105

Erythromycin is used to treat a variety fo infections, notably those due to Corynebacterium acnes, Legionella pneumophila, Treponema pallidum (syphilis), Mycoplasma pneumoniae, and Chlamydia species

Front 106

105. What is clarithromycin used to treat?

Back 106

Clarithromycin has increased activity against H.. influenzae.

Front 107

106. What is azithromycin used to treat?

Back 107

Azithromycin has increased activity against H. influenzae and Moraxella catarrhalis.

Front 108

107. Adverse effects and contraindications of macrolides and ketolides

Back 108

ADVERSE: *Acute cholestatic hepatitis, *ototoxicity, fulminant hepatic necrosis (rare, telithromycin), and GI disturbance

CONTRA: Hepatic dysfunction

Front 109

108. How is resistance accomplished by bacteria against macrolides?

Back 109

Resistance can be onferred by chromosomal mutations leading to alteration of the 50S ribosomal binding site, production of methylases that alter the 50S binding site, or production of esterases that degrade macrolides.

Front 110

109. What is the most frequent reason for discontinuing erythromycin?

Back 110

GI intolerance, as the drug can directly stimulate gut motility and cause nausea, vomiting, diarrhea, and sometimes anorexia.

Azithromycin and clarithromycin are generally well tolerated, although these drugs can also cause liver impairment.

Front 111

110. What are the pharmacological interactions with macrolide use?

Back 111

Macrolides and ketolides inhibit hepatic metabolism of cyclosporine, carbamazepine, warfarin, and theophylline, and can lead to toxic levels of these drugs.

Macrolides eliminate certain species of intestinal flora that inactivate digoxin, thereby leading to greater oral absorption of digoxin in some patients.

Front 112

111. Telithromycin

Back 112

This is the ketolide that has a MOA similar to that of the macrolides, but w/a higher affinity for the 50S ribosomal subunit due to its ability to bind an additional site on 23S rRNA.

This higher affinity allows the use of telithromycin in treating infections due to certain bacterial strains that are resistant to macrolides.

Front 113

112. Chloramphenicol

Back 113

MOA: Binds to 23S rRNA and inhibits peptide bond formation, apparently by occupying a site that interferes w/proper positioning of the aminoacyl moiety of tRNA in the A site.

PURPOSE: Bacteriostatic broad-spectrum antibiotic that is effective against Gram+ and Gram- bacteria (especially anaerobes), and rickettsiae.

ADVERSE: *Hemolytic anemia in patients with low levels of G6PD, aplastic anemia, **gray baby syndrome

CONTRA: Hypersensitivity to chloramphenicol

NOTES: Most adverse effects are due to inhibition of mitochondrial function.

Front 114

113. What are the organisms most highly susceptible to chloramphenicol treatment?

Back 114

1. Haemophilus influenzae
2. Neisseria meningitidis
3. Some strains of Bacteriodes

This drug is still used occasionally in the treatment of typhoid fever, bacterial meningitis, and rickettsial diseases, but only when safer alternatives are not available.

Front 115

114. How have microbes developed resistance to chloramphenicol?

Which two mechanisms are at work here...?

Back 115

1. Low level resistance has emerged by the selection of mutants w/decreased permeability to the drug.

2. More clinically significant is the type of resistance that has arisen from the spread of specific plasmid-encoded acetyltransferases that inactivate the drug.

Front 116

115. What is the gray baby syndrome?

Back 116

Occurs when chloramphenicol is administered at high doses to newborn infants.

B/c newborns lack an effective glucuronic acid conjugation mechanism for the degradation and detox of chloramphenicol, the drug can accumulate to toxic levels and cause vomiting, hypothermia, gray color, respiratory distress, and metabolic acidosis.

Front 117

116. What are the pharmacologic interactions with chloramphenicol?

Back 117

Cloramphenicol antagonizes the bactericidal effects of penicillins and aminoglycosides

Like the macrolides, it also inhibits hepatic metabolism of warfarin, phenytoin, tolbutamide, and chlorpropamide, and thereby potentiates their effects.

Front 118

117. Lincosamides: clindamycin

Back 118

MOA: Clindamycin blocks peptide bond formation, apparently through interactions with both the A site (like chloramphenicol) and the P site.

PURPOSE: Bacterial infections due to anaerobic organisms

ADVERSE: **Psuedomembranous colitis, increased liver function tests, jaundice, GI disturbance, rash

CONTRA: Hypersensitivity to clindamycin

*NOTES: Clindamycin is associated w/overgrowth of C. difficile, which can result in pseudomembranous colitis.

Front 119

118. What are the drugs that are mixed in streoptogramins?

Back 119

1. Dalfopristin, a group A steptogramin

2. Quinupristin, a group B streptogramin

Front 120

119. Streptogramins

Back 120

MOA: Inhibit protein synthesis by binding to the peptidyl transferase center of bacterial 23S rRNA.

PURPOSE: Vancomycin-resistant enterococcus (VRE) infection, skin and subcutaneous infection caused by staphylococcal or streptococcal species.

ADVERSE: Injection site inflammation, GI disturbance, hyperbilirubinemia, arthralgia, myalgia, headache

NOTES: Should not be coadministered w/SSRIs, due to risk of serotonin syndrome. Coadministration with pimozide should be avoided due to increased risk fo cardiotoxicity

Front 121

120. How are streptogramins unusual among the 50S antibiotics?

Back 121

They are bactericidal against many, but not all, susceptible bacterial species.

Current hypothesis is that, unlike other 50S antibiotics, the streptogramins induce a conformational change in the ribosome that is reversible only after subunit dissociation.

Front 122

121. Oxazolidinones: Linezolid

Back 122

MOA: Linezolid appears to act at the 50S ribosomal subunit b/c mutations in 23S rRNA can confer drug resistance.

PURPOSE: Gram+ bacterial infections, especially VRE, MRSA, S. agalactiae, S. pneumoniae (including multi-drug resistant strains) and S. pyogenes, nosocomial pneumonia, complicated diabetic foot infections

ADVERSE: *Myelosuppression, peripheral neuropathy, optic neuropathy

CONTRA: Hypersensitivity to linezolid

NOTES: Available in both oral and IV formulation; precise mechanism of action remains uncertain.

Front 123

122. What is the log cell kill model?

Back 123

The log cell kill model states that the cell destruction caused by cancer chemotherapy is first-order; that is, that each does of chemo kills a constant fraction of cells.

If the tumor starts with 10^12 cells and 99.99% are killed, then 10⁸ malignant cells will remain. The next dose of chemo will then kill 99.99% of the remaining cells, and so on.

Front 124

123. What is vertical transmission?

What is horizontal transmission?

Back 124

Veritcal transmission is when chromosomal mutations are transferred to daughter cells to create drug-resistant organisms.

Alternatively, bacteria can acquire resistance by gaining genetic material from other bacteria (horizontal transmission).

Front 125

124. What are the three ways in which bacteria acquire genetic material?

Back 125

1. Conjugation; chromosomal or plasmid DNA is transferred directly between bacteria.

2. Transduction; DNA can also be transferred from one cell to another by a bacterial virus or bacteriophage.

3. Transformation; naked DNA in the environment is taken up by the bacteria.

Front 126

125. What are the inhibitors of folate metabolism used for?

Back 126

Folic acid is a vitamin that participates in a number of enzymatic reactions involving the transfer of one-carbon units. These reactions are essential for the biosynthesis of DNA and RNA precursors.

Thus, it is not surprising that inhibition of folate biosynthesis and interference w/the folate cycle have been used widely in the treatment of bacterial infections, parasitic infections, and cancer.

Front 127

126. What are antimicrobial dihydropteroate synthase inhibitors?

Back 127

Bacteria are unable to take up folic acid from the environment and therefore must synthesize the vitamin de novo from PABA, pteridine, and glutamate. Mammalian cells, on the other hand, use folate receptors and folate carriers in the plasma membrane to scavenge the intact vitamin.

Using this metabolic difference, dihydropteroate synthase is an ideal target from antibacterial therapy.

Front 128

127. What are the names of the antimicrobial dihydropteroate synthase inhibitors?

Back 128

Sulfonamides:
1. Sulfanilamide
2. Sulfadiazine
3. Sulfamethoxazole
4. Sulfadoxine
5. Sulfalene

Sulfones:
6. Dapsone

Front 129

128. What are sulfonamides?

Back 129

Sulfonamides were the first modern agents to be employed in the treatment of bacterial infections. They have a similar structure to PABA. They are highly selective drugs b/c bacterial growth requires activity of the enzymes that is inhibited by the sufonamides. Therefore, mammallian cells are unaffected by these drugs.

However, sulfonamide resistance is quite common and has results in their diminished use.

Front 130

129.

Sulfanilamide
Sulfadiazine
Sulfamethoxazole
Sulfadoxine
Sulfalene

Back 130

MOA: PABA analogues that competitively inhibit microbial dihydropteroate synthase and thereby prevent the synthesis of folic acid.

PURPOSE: Susceptible vaginal infections (sulfanilamide), toxoplasmosis (sulfadiazine), P. carinii pneuomonia, shigellosis, traveler's diarrhea, UTI, granuloma inguinale, acute otitis media (SMT)

ADVERSE: Kernicterus in newborns, crystalluria, Stevens-Johnson syndrome, agranulocytosis, aplastic anemia, hepatic failure, GI disturbance, rash

CONTRA: Infants < 2 mos; pregnant women at term; breastfeeding; megaloblastic anemia.

Front 131

130. Sulfonamides therapeutic considerations

Back 131

1. Sulfonamides compete w/bilirubin for binding sites on serum albumin and can cause kernicterus in newborns.
2. Avoid coadministration w/PABA, which is the natural substrate for dihydropteroate synthase.
3. B/c of the high incidence of sulfonamide resistance, sulfonamides are commonly administered in combo with a synergistic drug such as trimethoprim or pyrimethamine.

Front 132

131. What is dapsone?

What is a rare, adverse effect?

Back 132

Dapsone, a member of the sulfone class of dihydropteroate synthase inhibitors, is used in the treatment of leprosy and P. carinii pneumonia.

5% of patients develop methemoglobinemia after administration of the drug.

Front 133

132. Dapsone

Back 133

MOA: PABA analogue that competetively inhibits microbial dihydropteroate synthase and therefore prevents the synthesis of folic acid.

PURPOSE: Leprosy, dermatitis herpetiformis, P. carinii pneumonia

ADVERSE: Hemolytic anemia, methemoglobinemia, toxic epidermal necrolysis, erythema nodosum, pancreatitis, toxic hepatitis, peripheral neuropathy, abdominal pain

CONTRA: G6PD deficiency

Front 134

133. What are some therapeutic considerations for dapsone?

Back 134

1. Dapsone and trimethoprim or pyrimethamine can be used as a synergistic drug combo.

2. Patients susceptible to hemolytic anemia and methemobloginemia are typically deficient in the erythrocyte enzyme G6PD.

Front 135

134. What are antimicrobial dihydropteroate reductase inhibitors?

Back 135

Dihydropteroate reductase (DHFR) is the enzyme that reduces DHF to tetrahydrofolate (THF). These drugs are folate analogues that competitively inhibit DHFR and prevent the regeneration of THF from DHF.

By doing so, these drugs prevent the synthesis of dUMP to dTMP. These drugs are used both in the treatment of infection and in cancer chemotherapy.

Front 136

135. What are the names of the antimicrobial dihydropteroate reductase inhibitors?

Back 136

1. Trimethoprim
2. Pyrimethamine
3. Methotrexate

Front 137

136. Trimethoprim

Back 137

MOA: Folate analogue that selectively inhibits bacterial DHFR and thereby prevents the conversion of DHF to THF; it is bacteriostatic.

PURPOSE: UTI, combo therapy with sulfamethoxazole

ADVERSE: Stevens-Johnson syndrome, leukopenia, megaloblastic anemia, rash, pruritus

CONTRA: Megaloblastic anemia due to folate deficiency

NOTES: It is bacteriostatic and can be used as a single agents to treat uncomplicated UTI.

Front 138

137. Pyrimethamine

Back 138

MOA: Folate analogue that selectively inhibits parasitic DHFR

PURPOSE: Toxoplasmosis and Malaria

ADVERSE: Stevens-Johnson syndrome, leukopenia, megaloblastic anemia, rash

CONTRA: Megaloblastic anemia due to folate deficiency

NOTES: Typically used in combo with sulfadiazine for treatment of toxoplasmosis; folic acid may interfere with the efficacy of pyrimethamine.

Front 139

138. What is methotrexate?

Back 139

Methotrexate is a folate analogue that reversibly inhibits DHFR. In mammalian cells, DHFR inhibition causes a critical shortage of intracellular supplies of THF, resulting in cessation of DNA and RNA synthesis. Thus, mammalian cells treated w/methotrexate are arrested in the S phase of the cell cycle.

Front 140

139. Why is methotrexate relatively selective for cancer cells compared to normal cells?

Back 140

Rapidly growing cancer cells have an increased requirement for the various compounds that depend on folate intermediates required for DNA synthesis. In addition, malignant cells may be more susceptible to the apoptosis-induced effects of methotrexate.

Front 141

140. What is leukovorin (folinic acid rescue)?

Back 141

The use of high dose methotrexate in cancer chemo has been broadened by the application of folinic acid rescue. In this technique, folinic acid is administered to the patient several hours after an otherwise lethal dose of methotrexate. The rationale is that the malignant cells are killed selectively, while the normal cells are rescued by folinic acid.

A hypothesis for this suggests that normal cells are able to concentrate the folinic acid whereas malignant cells have a reduced rate of folinic acid transport.

Front 142

141. Methotrexate

Back 142

MOA: Folate analogue that reversibly inhibits DHFR and thereby prevents the regeneration of THF from DHF.

PURPOSE: Many tumor types, including CA of the breast, lung, head and neck; acute lymphoblastic leukemia, choriocarcinoma, autoimmune diseases including psoriasis, RA, *Early stages of ectopic pregnancy

ADVERSE: Myelosuppresion, liver failure, GI hemorrhage, mucous membrane inflammation, hepatic cirrhosis, kidney disease, interstitial pulmonary disease, hyperuricemia, GI disturbance, stomatitis, alopecia, photosensitivity, rash.

CONTRA: Pregnancy, breastfeeding, patients w/psoriasis/RA who have alcoholism, alcoholic liver disease, chronic liver disease, or preexisting blood dyscrasia.

Front 143

142. What are (nine!) therapeutic considerations for methotrexate?

Back 143

1. Its use has been broadened by folinic acid rescue
2. MTX toxicity to the GI mucosa and bone marrow is generally reversible after therapy is discontinued
3. Extremely toxic to the fetus b/c folinic acid is essential for differentiation of fetal cells and for neural tube closure
4. Under investigation as an abortion inducing agent either alone or in combo with misoprostol
5. Avoid coadministration of polio vaccine in immunosuppressed patients taking MTX as a component of chemo
6. Avoid EtOH intake
7. Use extreme caution with coadministration of naproxen and phenylbutazone
8. ***Coadministration with trimethoprim may result in severe MTX toxicity
9. Oral absorption of MTX can be decreased by 50% in patients receiving oral antibiotics

Front 144

143. What is ischemic bowel disease?

Back 144

Acute occlusion of one of the three major supply trunks of the intestines, celiac, SMA, and IMA, may lead to infarction of several meters of intestine.

Severity of injury ranges from:
1. Transmural infarction (most severe)
2. Mural infarction
3. Mucosal infarction

*Almost always, transmural infarction is caused by mechanical compromise of the major mesenteric blood vessels.

Front 145

144. What are the five predisposing condition for bowel ischemia?

Back 145

1. Arterial thrombosis
2. Arterial embolism
3. Venous thrombosis
4. Nonocclusive ischemia
5. Misc

Front 146

145. An embolic arterial occlusion most often involves which of the three major vessels?

Why?

Back 146

Embolic arterial occlusion most often involves the branches of the SMA.

The origin of the IMA from the artery is more oblique and this may contribute to the relative sparing of this arterial axis from embolism.

Front 147

146. What are the two phases of ischemic injury?

Which is more harmful?

Back 147

1. Initial hypoxic injury
2. Secondary reperfusion

Most of the intestinal injury in ischemic bowel disease is actually caused by reperfusion.

Among the most important factors in this process are the generation of oxygen free radicals, neutrophil infiltration, and the production of inflammatory mediators in tissue that has insufficient metabolic reserve to detox injurious free radicals and other mediators.

Front 148

147. What ares of the bowel are at greatest risk of bowel infarction?

Back 148

Small intestinal infarction following sudden and total occlusion of mesenteric arterial blood flow may involve only a short segment, but more often involves a substantial portion.

The splenic flexure of the colon is at greatest risk of ischemic injury b/c it is the watershed between the distribution of the SMA and IMA.

Front 149

148. What is the morphology of "transmural" infarction?

1/2

Back 149

Regardless of whether the arterial or venous side is occluded, the infarction appears hemorrhagic b/c of blood reflow into the damaged area. In the early stages, the infarcted bowel appears intensely congested and dusky to purple-red, with foci of subserosal and submucosal ecchymotic discoloration. With time,t he wall becomes edematous, thickened, rubbery, and hemorrhagic.

Front 150

149. What is the morphology of "transmural" infarction?

2/2

Back 150

Histologically, there is obvious edema, interstitial hemorrhage, and sloughing necrosis of the mucosa. Normal features of the mural musculature, particularly cellular nuclei, become indistinct. Within 1-4 days, intestinal bacterial produce gangrene and sometimes perforation of the bowel.

Front 151

150. How do arterial occlusions appear morphologically compared to venous occlusions?

Back 151

In arterial occlusions the demarcation from normal bowel is usually sharply defined.

In venous occlusions the area of dusky cyanosis fades gradually into the adjacent normal bowel, having no clear-cut definition between viable and nonviable bowel.

Front 152

151. What is the morphology of "mucosal and mural" infarction?

1/2

Back 152

Mucosal and mural infarction may inolve any level of the gut from the stomach to the anus. THe lesions may be multifocal or continuous and widely distributed. Affected areas may appear dark red or purple.

On opening the bowel, there is hemorrhagic, edematous thickening of the mucosa, which may penetrate more deeply into the submucosa and muscle wall. Superficial ulceration may be present.

Front 153

152. What is the morphology of "mucosal and mural" infarction?

2/2

Back 153

In the mildest form of ischemic injury, the superficial epithelium of the colon or the tips of the small intestinal villi may be necrotic or sloughed. Inflammation is absent.

With complete mucosal necrosis, epithelial sloughing leaves behind only the acellular scaffolding of the lamina propria. When severe, there is extensive hemorrhage and necrosis of multiple tissue layers. Bacterial infections may induce superimposed pseudomembranous inflammation, particularly in the colon.

Front 154

153. What is the morphology of chronic bowel ischemia?

Back 154

With chronic vascular insufficiency to a region of intestine, mucosal inflammation and ulceration may develop, mimicking both acute enterocolitis from other causes and idiopathic IBD. Submucosal chronic inflammation and fibrosis may lead to stricture.

Although colonic structures typically occur in the watershed area of the splenic flexure, both acute and chronic mucosal ischemia are notoriously segmental and patchy.

Front 155

153. What are the clinical features of bowel ischemia?

Back 155

Total bowel infarction has a 50-75% mortality rate. It tends to occur in older individuals, when cardiac and vascular diseases are most prevalent. Typically occurring in severely ill patients, it presents as severe abdominal pain, bloody diarrhea, or gross medlema, nausea, vomiting, bloating, and abdominal wall rigidity.

With incomplete infarction, there are nonspecific abdominal complaints.

Front 156

154. What are some clinical conditions that cause ischemic intestinal injury?

Back 156

1. Severe atherosclerosis of the aorta and mesenteric vasculature. Cholesterol emboli dislodged from large vessels occlude smaller vessels downstream.

2. Vasculitis affecting the mesenteric vasculature may cause ischemic injury. The commonly seen vasculatides that affect the intestine are polyarteritis nodosum, Hemoch-Schonlein disease, and Wegener granulomatosis.

3. Amyloidosis often present as chronic intestinal ischemia.

Front 157

155. What is an angiodysplasia?

Back 157

Angiodysplasia is a non-neoplastic intestinal lesion of vascualr dilation and malformation. These dilations of submucosal and mucosal blood vessels are seen most often in the cecum or right colon, usually only after the 6th decade of life.

Although they are rare, they account for 20% of significant lower intestinal bleeding; intestinal hemorrhage may be chronic and intermittent, or acute and massive.

Front 158

156. What is the pathogenesis of angiodysplasia?

Which part of the bowel has the greatest wall tension?

Back 158

Acquired ectasias are attributed to partial, intermittent occlusion of submucosal veins. These occur largely in the cecum.

B/c the cecum has the widest diameter of the colon, it develops the greatest wall tension, perhaps explaining the distribution of these lesions.

Front 159

157. What is the morphology of hemorrhoids?

Back 159

The varicosities may develop in the inferior hemorrhoidal plexus and thus are located below the anorectal line (external hemorrhoids). Alternatively, they may develop from dilation of the superior hemorrhoidal plexus and produce internal hemorrhoids. Commonly, both plexuses are affected.

Histologically, these lesions consist only of thin-walled, dilated, submucosal varices that protrude beneath the anal or rectal mucosa. In their exposed, traumatized position, they tend to become thrombosed, and in the course of time, recanalized. Superficial ulceration, fissure formation, and infarction w/strangulation may develop.

Front 160

158. Where is the most common site for diverticula?

In which population do they most commonly occur?

Back 160

Acquried diverticula may occur in the esophagus, stomach, and duodenum, but the most common site is the left side of the colon, w/the majority in the sigmoid colon.

Colonic diverticula are rare in persons under the age of 30, but in Western adult populations over 60 the prevalence approaches 50%. They generally occur multiply and are referred to as diverticulosis.

Front 161

159. What is the morphology of colonic diverticula?

Back 161

Most colonic diverticula are small, flask-like or spherical outpouchings, usually .5 - 1 cm in diamtere and located int eh sigmoid colon. They tend to occur alongside the taeniae coli and are elastic, compressible, and easily emptied of fecal contents.

Histologically, they have a thin wall composed of a flattened or atrophic mucosa, compressed submucosa, and attenuated or totally absent muscularis propria. Hypertrophy of the circular layer of the muscularis propria in the affected bowel segment is usually seen.

Front 162

160. Obstruction and/or perforation of diverticula leads to...?

Back 162

Inflammatory changes, producing peridiverticulitis and dissecting into the immediately adjacent pericolic fat. In time, the inflammation may lead to marked fibrotic thickening in and about the colonic wall, sometimes producing narrowing sufficient to resemble a colonic cancer.

Front 163

161. What two factors are important in the pathogenesis of colonic diverticula?

Back 163

1. Focal weakenss in the colonic wall
-The colon is unique in that the longitudinal muscle coat is not complete, providing points of weakness for herniations.

2. Increased intraluminal pressure
Exaggerated peristaltic contractions, with spasmodic sequestration of bowel segments are the likely cause of increased intraluminal pressure.

Front 164

162. What are the clinical features of colonic diverticula?

Back 164

Most individuals remain asymptomatic, but may be associated with cramping, abdominal discomfort, and constipation. Diverticulitis can result in pericolic abscesses, sinus tracts, and peritonitis.

Front 165

163. What are the four categories of intestinal obstruction?

What are the clinical manifestations of intestinal obstruction?

Back 165

1. Hernias
2. Intestinal adhesions
3. Intussusceptions
4. Volulus

The clinical manifestations are abdominal pain and distention, vomiting, constipation and failure to pass flatus.

Front 166

164. What are hernias, and where do they commonly occur?

Back 166

A weakness or defect in the wall of the peritoneal cavity may permit protrusion of a pouch-like, serosa-lined sac of peritoneum called a hernial sac. The usual sites of such weakness are anterior at the inguinal and femoral canals, umbilicus, and in surgical scars. Rarely, retroperitoneal hernias may occur, chiefly about the ligament of Trietz.

Front 167

165. Why are hernias a concern?

Back 167

Segments of viscera frequently protrude and become trapped in them. This is particularly true to inguinal hernias. The most frequent intruders are small bowel loops, but portions of omentum or large bowel also may become trapped. Pressure at the neck of the pouch may impair venous drainage of the trapped viscus. The resultant stasis and edema increase the bulk of the herniated loop, leading to permanent trapping or incarceration.

With time, compromise of arterial supply and venous drainage (strangulation) leads to infarction of the trapped segment.

Front 168

166. What are bowel adhesions and what causes them?

Back 168

Surgical procedures, infection, and even endometriosis often cause localized or more general peritoneal inflammation (peritonitis). As the peritonitis heals, adhesions may develop between bowel segments and/or the abdominal wall and operative site. These fibrous bridges can create closed loops thru which other viscera may slide and eventually become trapped (internal herniation). The sequence of events that follow is the same as herniation.

Front 169

167. What is intussusception?

Back 169

Intussusception occurs when one segment of the intestine, constricted by a wave of peristalsis, suddenly becomes telescoped into the immediately distal segment of bowel. Once trapped, the invaginated segment is propelled by peristalsis farther into the distal segment, pulling its mesentery along behind it.

Some cases are associated w/rotavirus infection, suggesting that localized intestinal inflammation may serve as a traction point for the intussusception. However, intussusception in adults signifies an intraluminal mass or tumor as the point of traction. Intestinal obstruction ensues, and trapping of mesenteric vessels leads to infarction.

Front 170

168. What is a volvulus?

Where does it usually occur?

Back 170

Complete twisting of a loop of bowel about its mesenteric base of attachment also produces intestinal obstruction and infarction.

This lesion occurs most often in large redundant loops of sigmoid, followed by the cecum, small bowel, stomach or (rarely) transverse colon.

Front 171

169. What type of CA makes up most of the colorectal CAs?

Back 171

Adenocarcinomas constitute the vast majority of colorectal cancers and represent 70% of all malignancies arising in the GI tract.

Curiously, the small intestine is an uncommon site for benign or malignant tumors despite its great length.

Front 172

170. What are adenomas of the small bowel, and where do they most commonly occur?

Back 172

Most adenomas occur in the region of the ampulla of Vater. The usually presentation is that of a 30-60 y.o patient with occult blood loss, rarely w/obstruction or intussusception.

Macroscopically, the ampulla of Vater is enlarged and exhibits a velvety surface. Microscopically, these adenomas resemble their counterparts in the colon. Frequently, there is extension of adenomatous tissue into the ampullary orifice, rendering surgical excision difficult. It is a premalignant lesion.

Front 173

171. What are adenocarcinomas of the small bowel?

Back 173

The large majority of small intestinal adenocarcinomas occur in the duodenum, usually in 40-70 y/o patients. These tumors grow in a napkin-ring encircling pattern or as polypoid exophytic masses. Tumors in the duodenum, especially those involving the ampulla of Vater, may cause obstructive jaundice early in their course.

The typical presentation is intestinal obstruction, w/symptoms of cramping pain, nausea, vomiting, and weight loss.

At the time of Dx, most have already penetrated the bowel wall, invaded the mesentery or other segments of the gut, spread to regional nodes, and sometimes metastasized to the liver.

Front 174

172. What is the definition of a polyp?

Back 174

A polyp is a tumorous mass that protrudes into the lumen of the gut. Presumably all polyps start as small, sessile lesions w/o a definable stalk. In many instances, traction on the mass may create a stalked, or pedunculated polyp.

Front 175

173. Are polyps neoplastic?

Back 175

Polyps may be formed as the result of abnormal mucosal maturation, inflammation, or architecture. These polyps are non-neoplastic and do not have malignant potential. An example is the hyperplastic polyp.

Those epithelial polyps that arise as the result of proliferation and dysplasia are termed adenomatous polyps, or adenomas. They are true neoplastic lesions and are precursors of carcinoma.

Front 176

174. What are non-neoplastic polyps?

Which one is most common?

Back 176

The majority of intestinal polyps occur on a sporadic basis, particularly in the colon, and increase in frequency w/age. Non-neoplastic polyps include the hyperplastic polyp, the hamartomatous polyp, the inflammatory polyp, and the lymphoid polyp.

Hyperplastic polyps are the most common (90%), and are found in more than half of all persons age 60+.

Front 177

175. What is the pathogenesis of hyperplastic polyps?

Back 177

It is believed that the hyperplastic polyp results from decreased epithelial cell turnover and accumulation of mature cells on the surface.

Front 178

176. What is the pathogenesis of harmatomatous, inflammatory, and lymphoid polyps?

Back 178

Harmatomatous polyps are malformations of the glands and the stroma. They can occur sporadically or in the setting of genetic syndromes.

Inflammatory polyps, AKA pseudopolyps, represent islands of inflamed regenerating mucosa surrounded by ulceration. These are primarily seen in patients w/severe, active IBD.

Lymphoid polyps are an essentially normal variant of the mucosal bumps containing intramucosal lymphoid tissue.

Front 179

177. What is the morphology of hyperplastic polyps?

Back 179

*No malignant potential! These are small (usually <5 mm in diameter) epithelial polyps that appear as nipple-like, hemispheric, smooth, moist protrusions of the mucosa, usually positioned in the tops of mucosal folds. They may occur singly but more often are multiple, and over half are found in the rectosigmoid colon.

Histologically, they are composed of well formed glands and crypts lined by non-neoplastic epithelial cells, most of which show differentiation into mature goblet or absorptive cells.

The delayed shedding of surface epithelial cells leads to infoldings of the crowded epithelial cells and fission of the crypts, creating a serrated epithelial profile and an irregular crypt architecture.

Front 180

178. What is the morphology of juvenile hamartomatous polyps?

Back 180

Juvenile polyps represent focal hamartomatous malformations of the mucosal epithelium and lamina propria. For the most part they are sporadic lesions, w/the majority occurring in children younger than 5.

Most occur in the rectum. They tend to be large (1-3cm) rounded, smooth or slightly lobulated lesions w/stalks up to 2 cm in length.

Front 181

179. What is the morphology of retention hamartomatous polyps?

What are the histological characteristics of hamartomatous polyps?

Back 181

Isolated hamartomatous polyps may be identified in the colon of adults; these incidental lesions are referred to as retention polyps. They also mostly occur in the rectum.

Retention polyps tend to be smaller (<1 cm in diameter).

Histologically, both retention and juvenile hamartomatous polyps have the lamina propria comprising the bulk, enclosing abundant cystically dilated glands. Inflammation is common, and the surface may be congested or ulcerated. In general they occur singly and being hamartomatous lesions have no malignant potential.

Front 182

180. What is juvenile polyposis syndrome?

What genetic mutations cause this syndrome?

Back 182

The rare autosomal dominant juvenile polyposis syndrome, in which there are multiple (50-100) juvenile polyps in the GI tract, does carry a risk of adenomas and hence adenocarcinoma.

Mutations in the SMAD4/DPC4 gene (which encodes a TGF-β signaling intermediate) account for some cases of juvenile polyposis syndrome.

Front 183

181. What are Peutz-Jeghers polyps?

Back 183

Peutz-Jeghers polyps are hamartomatous polyps that involve the mucosal epithelium, lamina propria, and muscularis mucosa. These lesions may also occur singly or multiply in the Peutz-Jeghers syndrome.

These polyps can be large and pedunculated with a firm lobulated contour.

Front 184

182. What is Peutz-Jeghers syndrome?

What is the underlying genetic basis for this syndrome?

Back 184

This rare autosomal dominant syndrome is characterized by multiple hamartomatous polyps scattered thru the entire GI tract and melanotic mucosal and cutaneous pigmentation around the lips, oral mucosa, face, genitalia, and palmar surfaces of the hands. Patients with this syndrome are at increased risk for intussusception, which is a common cause of mortality.

*Mutation of the gene (STK11 (LKB1) located on chromosome 19 is the genetic basis. This gene encodes a protein with serine/threonine kinase activity.

Front 185

183. What is the morphology of Peutz-Jeghers polyps?

Back 185

Again, they tend to be large and pedunculated w/a firm lobulated contour. HIstologically, an arborizing netowrk of connective tissue and well-developed smooth muscle extends into the polyp and surrounds normal abundant glands lined by normal intestinal epithelium rich in goblet cells.

While these polyps themselves do not have malignant potential, patients w/the syndrome have an increased risk of developing CA of the pancreas, breast, lung, ovary and uterus.

Front 186

184. What is Cowden syndrome?

What is the genetic basis underlying this syndrome?

Back 186

Cowden syndrome is an autosomal dominant genetic syndrome characterized by multiple hamartomas involving organs derived from all three germinal layers. The commonly involved sites are GI tract and mucocutaneous locations.

Intestinal hamartomatous polyps, facial trichilemmomas, acral keratoses, and oral papillomas are characteristic. While these hamartomas do not have malignant potential, the syndrome predisposes the patient to develop thyroid and breast cancers.

*Mutations in the PTEN gene

Front 187

185. What is Cronkhite-Canada syndrome?

Back 187

Cronkhite-Canada syndrome is a nonhereditary disorder characterized by the presence of GI hamartomatous polyposis and ectodermal abnormalities such as nail atrophy, skin pigmentation, and alopecia.

Front 188

186. What are adenomas of the bowel?

Back 188

Adenomas (adenomatous polyps) are intraepithelial neoplasms that range from small, often pedunculated lesions to large neoplasms that are usually sessile.

Prevalence of adenomas approaches 50% after age 60; they are frequently multiple.

*All adenomatous lesions arise as the result of epithelial proliferative dysplasia, which may range from low to high grade dysplasia (carcinoma in situ).

*These lesions are a precursor for invasive colorectal adenocarcinomas.

Front 189

187. What are the three subtypes of adenomatous polyps?

Which is the most common?

Back 189

1. *Tubular adenomas: tubular glands

2. Villous adenomas: villous projections

3. Tubulovillous adenoma: a mixture of the above

*Most common

Front 190

188. The malignant risk with an adenomatous polyp is correlated with what three interdependent features?

Back 190

1. Polyp size (cancer is rare in tubular adenomas smaller than 1 cm)

2. Architecture (the risk of CA is high (40%) in sessile villous adenomas more than 4 cm)

3. Severity of epithelial dysplasia (severe dysplasia, when present, is often found in villous areas)

Front 191

189. What is the morphology of tubular adenomas?

1/2

Back 191

Most tubular adenomas are found in the colon, bu they can occur in the stomach and small intestine, especially in the ampulla of Vater.

The smallest tubular adenomas are smooth contoured and sessile; large ones tend to be coarsely lobulated and have slender stalks.

Histologically, the stalk is composed of fibromuscular tissue and it is usually covered by normal, non-neoplastic mucosa. However, adenomatous epithelium may extend down the stalk and into adjacent regions of the mucosa, particularly in the stomach.

Front 192

190. What is the morphology of tubular adenomas?

2/2

Back 192

Whether small or large, adenomatous lesions are composed of neoplastic epithelium, which lines glands as a tall hyperchromatic somewhat disordered epithelium that may or may not show mucin vacuoles.

In the benign tubular adenoma, the branching glands are well separated by lamina propria and the degree of dysplasia is low grade.

However, high grade dysplasia may be present and may merge w/areas of overt malignant change confined to the mucosa (intramucosal CA).

Front 193

191. What is the morphology of villous adenomas?

Back 193

Villous adenomas are the larger and more ominous of the epithelial polyps. They tend to occur in older persons, most commonly in the rectum and rectosigmoid colon, but they may be located elsewhere.

They generally are sessile, up to 10 cm in diameter, velvety or cauliflower-like masses projecting 1-3 cm above the surrounding normal mucosa.

Their histology is that of frondlike villiform extensions of the mucosa covered by dysplastic, sometimes very disorderly columnar epithelium.

Front 194

192. What is the morphology of tubulovillous adenomas?

Back 194

Tubulovillous adenomas are typically intermediate between the tubular and villous lesions in terms of their frequency of having a stalk or being sessile. their size, and the general level of dysplasia found in such lesions.

The risk of harboring in situ or invasive CA generally correlates w/the proportion of the lesion that is villous.

Front 195

193. What are the clinical features of colorectal adenomas?

Back 195

Adenomas may be asymptomatic or may cause occult bleeding w/anemia. Small intestine adenomas can cause obstruction and intussusception. Rarely, large villous adenomas in colon hypersecrete copious amts of protein-and potassium-rich mucus, leading to either hypoproteinemia or hypokalemia.

tubular (and tubulovillous adenomas)

Front 196

194. What are five things that the clinical impact of malignant change depend upon?

Back 196

1. High-grade dysplasia (CA in situ) has not yet acquired the ability to metastasize and is still a clinically benign lesion.
2. Intramucosal CA w/lamina propria invasion is only regarded also as having little or no metastatic potential (b/c of no lymphatic channels in the colonic mucosa)
3. Endoscopic removal of a pedunculated adenoma is regarded as an adequate excision (more on next card).
4. Invasive adenocarcinoma arising in a sessile polyp cannot be adequately resected by polypectomy, and further surgery may be required.
5. The only adequate treatment for a pedunculated or sessile adenoma is complete resection.

Front 197

195. Endoscopic removal of a pedunculated adenoma is regarded as an adequate excision as long as what three histologic conditions are met?

Back 197

1. The adenocarcinoma is superficial and does not approach the margin of excision across the base of the stalk.
2. There is no vascular or lymphatic invasion.
3. The carcinoma is not poorly differentiated.

Front 198

196. What is familial adenomatous polyposis (FAP) syndrome?

What are the four types?

Back 198

FAP exhibits innumerable adenomatous polyps and has a frequency of progression to colon adenocarcinoma approaching 100%. It is caused by mutations of the APC gene.

Subtypes:
1. Classic FAP
2. Attenuated FAP
3. Gardner syndrome
4. Turcot syndrome

Front 199

197. What is the classic FAP syndrome?

Back 199

In the classic FAP syndrome, patients typically develop 500-2500 colonic adenomas that carpet the mucosal surface. A minimum of 100 polyps is necessary for Dx.

Histologically, the vast majority of polyps are tubular adenomas; occasional polyps may have villous features. Some patients already have cancer of the colon or rectum at the time of Dx.

Front 200

198. What is the attenuated FAP syndrome?

Back 200

In attenuated FAP, patients tend to develop fewer polyps (avg = 30) and most of the polyps are located in the proximal colon. The lifetime risk of CA is around 50%.

Front 201

199. What is Gardner syndrome?

Back 201

Patients with Gardner syndrome exhibit intestinal polyps identical to those in class FAP, combined w/multiple osteomas (particularly of the mandible, skull, and long bones), epidermal cysts, and fibromatosis.

Less frequent are abnormalities of dentition, such as unerupted and supernumerary teeth, and a higher freq of duodenal and thyroid CA.

Front 202

200. What is Turcot syndrome?

Back 202

Turcot syndrome is a rare clinical syndrome marked by the combo of adenomatous colonic polyposis and tumors of the CNS system.

2/3rds of patients with Turcot syndrome have APC gene mutations and develop brain medulloblastomas.

The remaining 1/3rd have mutations in one of the genes associated with HNPCC and develop brain glioblastomas.

Front 203

201. What is hereditary nonpolyposis colorectal cancer syndrome (HNPCC)?

Back 203

HNPCC is an autosomal dominant familial syndrome. It is characterized by an increased risk of colorectal CA and extraintestinal CA, particularly of the endometrium.

Adenomas can occur in low numbers and considerably earlier than in the general adult population. However, the colonic malignancies that develop often are multiple and are not usually associated with pre-existing adenomas.

*Hallmark of HNPCC is mutations in DNA repair genes, leading to microsatellite instability.

Front 204

202. What is the adenoma-carcinoma sequence?

Six parts...

Back 204

☑ Populations that have a high prevalence of adenomas also have a high prevalence of colorectal CA, and vice versa.
☑ The distribution of adenomas within the colorectum is more or less comparable to that of colorectal CA.
☑ The peak incidence of adenomatous polyps antedates by some years the peak for colorectal CA.
☑ When invasive CA is identified at an early stage, surrounding adenomatous tissue is often present.
☑ The risk of CA is directly related to the # of adenomas, and hence the virtual certainty of CA in FAP syndromes.
☑ Programs that assiduously follow patients for the development of adenomas and remove all that are suspicious reduce the incidence of colorectal CA.

Front 205

203. What are the two pathogenetically distinct pathways for the development of colon cancer?

Back 205

1. APC/β-catenin pathway

2. DNA mismatch repair genes

Front 206

204. What is the role of the APC gene?

Loss of APC causes?

Back 206

This dual function tumro suppressor gene encodes a protein that binds to microtubule bundles and promotes cell migration and adhesion. APC also acts as a gatekeeper protein, as it regulates levels of β-catenin, an important mediator of the Wnt/β-catenin signaling pathway.

Normal APC function promotes cell adhesion and regulates cell proliferation; *absence of APC function leads to decreased cell adhesion and increased cellular proliferation. Loss of this gene is believed to be the earliest event in the formation of adenomas.

Front 207

205. What is β-catenin, and what does it do?

Back 207

β-catenin is a member of the cadherin-based cell adhesive complex. When it is not bound to E-cadherin and participating in cell-to-cell adhesion, a cytoplasmic degradation complex (APC+Axin+GSK-3β+β-catenin) leads to β-catenin phosphorylation and degradation.

In the setting of APC mutations, β-catenin accumulates in the cytoplasm and is translocated to the nucleus to bind to a family of transcription factors called T-cell factor proteins (TCF). The TCF contributes a DNA binding domain and β-catenin contributes a transactivation domain. Genes activated by the β-catenin-TCF complex are thought to include those regulating cell proliferation and apoptosis, such as c-MYC and CYCLIN D1. ***Absence of APC function leads to decreased cell adhesion and increased cellular proliferation.

Front 208

206. What is the most frequently activated oncogene in adenomas and colon cancers?

Back 208

K-RAS oncogene.

K-RAS plays a role in intracellular signal transduction and is mutated in fewer than 10% of adenomas less than 1 cm in size, in about 50% of adenomas larger than 1 cm, and in approx 50% of carcinomas.

Front 209

207. Loss of SMAD4 leads to...?

Back 209

Loss of SMAD4 (tumor suppressor gene) increases GI tumorigenesis.

Front 210

208. Mutation in what other tumor suppressor gene is important in colon cancers?

Back 210

Losses of p53 have been found in 70-80% of colon cancers, yet comparable losses are infrequent in adenomas.

This suggests that mutations in p53 occur late in colon carcinogenesis.

Front 211

209. How is telomerase activity in colorectal cancers compared to its activity in adenomas?

Back 211

Telomerase activity is increased in most cancers; whereas most adenomas lack telomerase activity.

Front 212

210. What are the two most common human mismatch repair genes that become mutated?

What is the result?

Back 212

The majority of mutations (90%) involve MSH2 and MLH1.

Mutations in the mismatch repair genes cause alteration of microsatellites, leading to microsatellite instability. Loss of mismatch repair leads to the accumulation of mutations in other growth-regulating genes, culminating in the emergence of colorectal CA.

Front 213

211. What are four distinctive morphological features in fully developed tumors that are a result of mutated DNA mismatch repair genes?

Back 213

1. Proximal colonic location
2. Mucinous histology
3. Infiltration by lymphocytes
4. In general, these tumors have better prognosis than stage-matched tumors that arise by the APC pathway.

Front 214

212. What is the pathogenesis of colorectal CA?

Back 214

Hereditary polyp syndromes, HNPCC, and IBD significantly increase the risk of developing CA. However, most colonic CAs arise sporadically in polypoid adenomas. Diet likely contributes to risk in these sporadic cancers. These diets may promote increased mucosal exposure to bile acids and bacterial degradative byproducts.

Front 215

213. What are five features of such diets that promote colon cancer?

Back 215

1. Energy intake greater than requirement
2. Low vegetabel fiber intake
3. High content of refined carbs
4. High intake of red meat
5. Decreased intake of protective micronutrients (vitamins A, C, and E)

Front 216

214. Can aspirin or other NSAIDs exert a protective effect against colon cancer?

Back 216

Yes, aspirin reduces the risk of recurrent adenomas in patients w/previous coloretal CA or adenomas.

This is because of the inhibition of COX-2. This enzyme is overexpressed in neoplastic epithelium and seems to regulate angiogenesis and apoptosis.

Thus, COX-2 inhibitors are chemoprotective agents in patients with FAP syndrome.

Front 217

215. Where are most cancers in the colorectum found?

Which sides (right/left) tend to have greater microsatellite instability?

Back 217

Rectosigmoid (55%)
Cecum/ascending colon (22%)
Transverse colon (11%)
Descending colon (6%)
Other (6%)

The right-sided colon cancers tend to have greater microsatellite instability.

Front 218

216. What is the morphology of colon CAs in the proximal colon?

Back 218

Tumors in the proximal colon tend to grow as polypoid, exophytic masses that extend along one wall of the capacious cecum and ascending colon. Obstruction is uncommon.

Front 219

217. What is the morphology of colon CAs in the distal colon?

Back 219

When CA in the distal colon are discovered, they tend to be annular, encircling lesions that produce so-called napkin-ring constrictions of the bowel.

The margins of the napkin ring are classically heaped up, beaded and firm, and the midregion is ulcerated. The lumen is markedly narrowed, and the proximal bowel may be distended.

Front 220

218. What is the morphology of colon CAs?

Back 220

Both forms (distal/proximal) directly penetrate the bowel wall over time and may appear as subserosal and serosal white, firm masses, freq causing puckering of the serosive surface.

On microscopic exam, differentiation may range from tall, columnar cells resembling their counterparts in adenomatous lesions, which now invade the sumucosa and muscularis propria, to undifferentiated, frankly anaplastic masses.

Front 221

219. Invasive colon tumors incites what type of response?

Back 221

Invasive tumor incites a strong desmoplastic stromal response, leading to the characteristic firm, hard consistency of most colonic carcinomas.

Front 222

220. What are some specific features of colorectal CAs?

Back 222

1. In some cancer the cells take on a signet-ring appearance.
2. The small cell undifferentiated CA appears to arise from endocrine cells per se and elaborates a variety of bioactive secretory products.
3. Many tumors produce mucin which dissects thru the gut wall and aids in the extension of malignancy and worsens the prognosis.
4. Tumors associated with HNPCC tend to be poorly differentiated and rich in mucin.

Front 223

221. Cancers in the distal colon vs. anorectal canal...

Back 223

Some cancers, particular in the distal colon, have foci of squamous cell differentiation and are therefore referred to as adenosquamous CAs.

In contrast, CAs arising in the anorectal canal constitute a distinct subgroup of tumors, dominated by squamous cell CA.

Front 224

222. What are the clinical features in colorectal cancers?

What is the single most important prognostic indicator of colorectal CA?

Back 224

Colorectal CA is usually asymptomatic at first. Fatigue, iron deficiency, anemia, abdominal discomfort, progressive bowel obstruction, and liver enlargement (metastases) eventually occur.

The single most important prognostic indicator of colorectal CA is the extent of the tumor at the time of Dx; the so called stage.

Currently, only surgery can be curative.

Front 225

223. Iron deficiency anemia in an older male most always means what until proven otherwise...?

Back 225

It is a clinical maxim that iron-deficiency anemia in an older male means GI cancer until proven otherwise.

Front 226

224. What are carcinoid tumors?

Back 226

Carcinoid tumors are derived from resident endocrine cells, w/the GI tract and lung as the predominant sites of occurrence. Many elaborate bioactive produces (e.g. amines or peptides)

Although most arise in the gut, they can also occur in the pancreas, lungs, biliary tree, and liver.

Carcinoid tumors represent 50% of small intestine cancers; peak incidence is in the 6th decade.

Front 227

225. Which type of carcinoid tumors rarely metastasize?

Which type metastasize?

Back 227

Appendiceal and rectal carcinoids infrequently metastasize, even though they show extensive spread.

By contrast, 90% of ileal, gastric, and colonic carcinoids that have penetrated halfway thru the muscle wall have spread to lymph nodes and distant sites such as the liver at the time of Dx.

Front 228

226. Where is the most common site for carcinoid tumors in the gut?

Back 228

The appendix is the most common site, followed by the small intestine (primarily ileum), rectum, stomach, and colon.

In the appendix they appear as bulbous swellings of the tip, which frequently obliterate the lumen.

Front 229

227. What is the morphology of carcinoid tumors of the gut?

1/2

Back 229

A characteristic feature is a solid, yellow-tan appearance on transection.

Histologically, the neoplastic cells may form discrete islands, trabeculae, stands, glands, or undifferentiated sheets. Whatever their organization the tumor cells are monotonously similar, having a scant, pink granular cytoplasm and a round to oval stippled nucleus. In most tumors there is minimal variation in cell and nuclear size and mitoses are infrequent.

Front 230

228. What is the morphology of carcinoid tumors of the gut?

2/2

Back 230

Rarely, tumors arise resembling small cell carcinomas of the lung or contain abundant psammoma bodies similar to those seen in thyroid CA.

By electron microscopy, the cells in most tumors contain membrane-bound secretory granules w/osmophilic centers (dense-core granules) in the cytoplasm.

Most carcinoids contain chromogranin A, synaptophysin, and neuron-specific enolase.

Front 231

229. What are the clinical features of carcinoids?

Back 231

Carcinoid tumors are generally asymptomatic, although local symptoms can occur from obstruction or bleeding. Symptoms can also be caused by tumor secretory products:
●Gastrin causing Zollinger-Ellison syndrome with peptic ulceration
●Corticotropin causing Cushing syndrome
●Insulin causing hyperinsulinism
●Serotonin and other bioactive amines causing carcinoid syndrome

Front 232

230. What is carcinoid syndrome?

Back 232

Some neoplasms are associated w/a distinctive carcinoid syndrome; this occurs in about 1% of all patients w/carcinoids and in 20% of those w/widespread metastases.

Carcinoid syndrome is seen only with extraintestinal carcinoid or w/extensive hepatic metastases (allowing bioactive amines, specifically 5-HT, to reach the systemic circulation without being metabolized). Thus, hepatic metastases are usually not required for the production of a carcinoid syndrome.

Front 233

231. What are the symptoms of carcinoid syndrome?

Back 233

1. Vasomotor disturbances: flushing, cyanosis
2. Intestinal hypermotility: diarrhea, cramps, nausea, vomiting
3. Asthmatic bronchoconstriction: cough, wheezing, dyspnea
4. Hepatomegaly from hepatic metastases
5. Systemic fibrosis: pulmonary and tricuspid valve thickening and stenosis, endocardial fibrosis, retroperitoneal and pelvic fibrosis.

Front 234

232. How is carcinoid syndrome diagnosed?

Back 234

Dx via documenting excess urinary 5-hydroxyindoleacetic acid, a breakdown product of serotonin.

Front 235

233. What is a gastrointestinal lymphoma?

Back 235

The gut is the most common location for the 40% of lymphomas arising in extranodal sites.

By definition, primary GI lymphomas exhibit no evidence of liver, spleen, mediastinal lymph node, or bone marrow involvement at the time of Dx- regional lymph node involvement may be present.

Front 236

234. Primary GI lymphomas usually arise as sporadic neoplasms but also occur more frequently in which 6 patient populations?

Back 236

1. Chronic gastritis caused by H. pylori
2. Chronic sprue-like syndromes
3. Natives of the Mediterranean region
4. Congenital immunodeficiency states
5. Infection w/HIV
6. Following organ transplantation w/immunosuppression

Front 237

235. What are the different categories of GI lymphomas?

Back 237

Intestinal tract lymphomas can be classified into B-cell and T-cell lymphomas.

The B-cell lymphoma can be subdivided into MALT lymphoma, immunoproliferative small-intestinal disease (IPSID), and Burkitt lymphoma.

Front 238

236. What is MALT lymphoma?

Back 238

MALT lymphoma is a sporadic lymphoma, which arises from the B-cells of MALT (mucosa-associated lymphoid tissue). This type of lymphoma is the most common form in the Western hemisphere.

This type of lymphoma usually affects adults, has no gender predilection, and may arise anywhere in the gut.

Front 239

237. What are four biologic factors of MALT lymphomas?

Back 239

1. Many behave as focal tumors in their early stages and are amenable to surgical resection
2. Relapse may occur exclusively in the GI tract
3. Genotypic changes are different than those observed in nodal lymphomas: the t(11;18) translocation is relatively common in MALT lymphoma
4. The cells are usually CD5- and CD10-negative

Front 240

238. What is the pathogenesis of MALT lymphomas?

Back 240

The idea is that lymphomas of MALT origin arise in the setting of mucosal lymphoid activation and that these lymphomas are the malignant counterparts of hypermutated, postgerminal-center memory B cells.

H. pylori associated chronic gastritis has been proposed as a driving force, the result of antigen-driven somatic mutation of gastric lymphoid tissue.

Front 241

239. What is immunoproliferative small-intestinal disease (IPSID)?

Back 241

Immunoproliferative small-intestinal disease (IPSID) is also referred to as Mediterranean lymphoma. It is an unusual intestinal B-cell lymphoma arising in patients w/Mediterranean ancestry, having a background of chronic diffuse mucosal plasmacytosis. The plasma cells synthesize an abnormal IgA heavy chain, in which the variable portion has been deleted.

A high proportion of patients have malabsorption and weight loss preceding the development of the lymphoma. The Dx is made most commonly in children and young adults, and both sexes are affected equally.

Front 242

240. What is the intestinal T-cell lymphoma?

Back 242

The intestinal T-cell lymphoma is usually associated w/a long standing malabsorption syndrome (such as celiac disease) that may not constitute a true gluten-sensitive enteropathy. This lymphoma occurs in relatively young individuals (age 30-40) often following a 10- to 20-year history of symptomatic malabsorption.

Alternatively, a diffuse enteropathy w/malabsorption may accompany the development of a lymphoma. Intestinal T-cell lymphomas arise most often in the proximal small bowel and its prognosis is poor.

Front 243

241. What is the morphology of GI lymphomas?

1/2

Back 243

Since all gut lymphoid tissue is mucosal and submucosal, early lesions appear as plaque-liek expansions of the mucosa and submucosa. Diffusely infiltrating lesions may produce full-thickness mural thickening, with effacement of the overlying mucosal folds and focal ulceration. Others may be polypoid, protruding into the lumen, or form large, fungating, ulcerated masses.

Tumor infiltration into the muscularis propria splays the muscle fibers and destroys them. B/c of this feature, advanced lesions freq cause motility problems w/secondary obstruction.

Front 244

242. What is the morphology of GI lymphomas?

2/2

Back 244

In the earliest histological lesions, atypical lymphoid cells may be seen infiltrating the mucosa, w/effacement and loss of glands and massive expansion of lymphoid tissue. Extreme number of atypical lymphoid cells may populate the superficial or glandular epithelium (lymphoeptiehlial lesion).

**W/established lymphomas, the mucosa, submucosa, and the muscle wall are replaced by a monotonous infiltrate of malignant cells and immunoblasts in varying proportions. Lymphoid follicles are occasionally formed.

Front 245

243. What are the clinical features of GI lymphomas?

Back 245

Sporadic lymphomas are amenable to surgical resection and are chemoresponsive. Outcome depends on size, grade, and tumor invasiveness at resection.

Low grade lymphomas associated w/H. pylori infection may be treated by eradicating the H. pylori organism.

Front 246

244. What are mesenchymal tumors?

What is the most common type?

Back 246

Mesenchymal tumors may occur anywhere in the GI tract.

Lipomas are the most common GI mesenchymal tumor, generally found in the small intestine or colon submucosa.

Other types are GIST, Leimyoma, Leiomyosarcoma, and Kaposi sarcoma

Front 247

245. What is the morphology of lipomas?

Back 247

Lipomas are usually well demarcated, firm nodules (almost always less than 4 cm in diameter) arising w/in the submucosa or muscularis propria. The overlying mucosa is stretched and attenuated. Rarely, they grow to larger size and produce hemispheric elevation of the mucosa w/ulceration over the dome of the tumor.

Front 248

246. What is GIST?

Back 248

Gastrointestinal stromal tumors (GISTs) are now considered to be a distinctive tumor type characterized by c-KIT immunoreactivity.

The small intestine is the second most common location for this tumor (the stomach being the most common). Both benign and malignant versions of GIST may occur at any age and in either sex.

Front 249

246. What is the morphology of leiomyosarcomas?

Back 249

Malignant stomal tumors (primarily leiomyosarcomas) tend to produce large, bulky, intramural masses that eventually fungate and ulcerate into the lumen or project subserosally into the abdominal space.

Large size and a high mitotic rate are correlated w/an aggressive course.

Front 250

247. What are the clinical features of mesenchymal tumors?

Back 250

Most mesenchymal tumors are asymptomatic. Larger lesions may cause mucosal ulceration w/bleeding (especially in stomach), obstruction, or intussusception.

Benign lesions are easily resectable. Surgical removal is usually possible for the malignant lesions as well, since they tend to grow as cohesive masses.

Front 251

248. What are the three patterns of differentiation for tumors in the anal canal?

Back 251

1. Basaloid pattern
2. Squamous cell CA
3. Adenomcarcinoma

Front 252

249. What are the features of basaloid anal carcinomas?

Back 252

Anal canal carcinoma w/basaloid differentiation is a tumor populated by immature proliferative cells derived from the basal layer of a stratified squamous epithelium. These tumors may occur sporadically and be uniform in their histologic features.

Alternatively, basaloid differentiation may be a component of a tumor that exhibits more genuine squamous cell differentiation and or the mucin vacuole-containing features of adenocarcinoma.

Front 253

250. What are the features of pure squamous cell CAs of the anal canal?

Back 253

Pure squamous cell CAs of the anal canal are closely associated w/chronic HPV infection. Some rare cases are also related to immunosuppression, as encountered in renal transplantation and in AIDS patients.

As w/the genital tract, chronic HPV infection of the anal canal often causes precursor lesions such as condyloma acuminatum, squamous epithelium dysplasia, and carcinoma in situ.

Front 254

251. What are the features of pure adenocarcinomas of the anal canal?

Back 254

Pure adenocarcinoma of the anal canal is often the extension of rectal adenocarcinoma.

Rarely, other tumors may arise from the anal canal, notably Paget disease, small-cell carcinoma, and melanoma.

Front 255

252. What is acute appendicitis?

What is the pathogenesis of acute appendicitis?

Back 255

Acute appendicitis is the most common acute abdominal condition requiring surgery. The differential Dx includes virtually every acute process that can occur in the abdomen as well as some acute thorax conditions.

Obstruction of the appendiceal lumen by a fecalith, calculus, tumor, or worms (Oxyuriasis vermincularis or pinworm) causes increased intraluminal pressure, followed by ischemia (exacerbated by edema, continued secretion of mucinous fluid in the obstructed viscus and exudate), and bacterial invasion.

Front 256

253. What is the morphology of early acute appendicitis?

Back 256

At the earliest stages, only a scant neutrophilic exudate may be found throughout the mucosa, submucosa, and muscularis proria. Subserosal vessels are congested and often there is a modest perivascular neutrophilic infiltrate.

**The inflammatory reaction transforms the normal glistening serosa into a dull, granular, red membrane; this transformation signifies early acute appendicitis for the operating surgeon.

Front 257

254. What is the morphology of later stages of acute appendicitis?

Back 257

At a later stage, a prominent neutrophilic exudate generates a fibrinopurulent reaction over the serosa. As the inflammatory process worsens, there is abscess formation w/in the wall, along w/ulcerations and foci of suppurative necrosis in the mucosa. *This state constitutes acute suppurative appendicitis.

Front 258

255. Further appendiceal compromise leads to...?

Back 258

Further appendiceal compromise leads to large areas of hemorrhagic green ulceration of the mucosa and green-black gangrenous necrosis thru the wall, extending to the serosa, creating acute gangrenous appendicitis, which is quickly followed by rupture, and suppurative peritonitis.

Front 259

256. What is the histologic criteria for the Dx of acute appendicitis?

Why is this needed?

Back 259

Neutrophilic infiltration of the muscularis propria.

Usually, neutrophils and ulcerations are also present w/in the mucosa. Since drainage of an exudate into the appendix from GI tract infections may also induce a mucosal neutrophilic infiltrate, evidence of muscular wall inflammation is requisite for the Dx.

Front 260

257. What are the clinical features of acute appendicitis?

Back 260

Can occur at any age, but mainly affects adolescents and young adults.

Classically, there is periumbilical pain migrating to the right lower quadrant; nausea or vomtiing; abdominal tenderness; mild fever; and leukocytosis greater than 15,000 cell/μL.

Symptoms may be variably present in very young and elderly patients making Dx more difficult.

Front 261

258. What are other conditions that can mimic the symptoms of acute appendicitis?

Back 261

Other conditions that mimic appendicitis include enterocolitis, mesenteric lymphadenitis, systemic viral infection, acute salpingitis, ectopic pregnancy, mittelschmerz, and Meckel diverticulitis.

Front 262

259. What are the complications of appendicitis?

Back 262

Pyelophlebitis and thrombosis of portal venous drainage, liver abscess, and bacteremia are other important complications of appendicitis.

Front 263

260. Should a surgeon take out an appendix even if it's not inflamed?

Back 263

Highly competent surgeons make false-positive diagnoses of acute appendicitis and remove normal appendices about 20-25% of the time.

The discomfort and risks associated w/an exploratory laparotomy and discovery of "no disease" are far outweighed by the morbidity and mortality (2%) associated with appendiceal perforation.

Front 264

261. What is the most common appendiceal tumor?

Back 264

The carcinoid; it is usually discovered incidentally at the time of surgery or exam of a resected appendix; this neoplasm most freq occurs at the distal tip of the appendix, where it produces a solid bulbous swelling up to 2-3 cm in diameter.

Front 265

262. What is a goblet cell carcinoid (adnocarcinoid)?

Back 265

This is a unique type of appendiceal tumor. Histologically, the tumor shows a typical carcinoid pattern, but w/plump mucin vacuole-containing cells.

The biologic behavior of the tumor is between that of typical carcinoid and adenocarcinoma.

Front 266

263. What is a mucocele of the appendix?

What are the other types?

Back 266

Mucocele is the macroscopic description of a dilated appendix filled w/mucin.

The causes range from an innocuous obstructed appendix containing inpissated mucin, to a mucin secreted adenoma (mucinous cystadenomas) and adenocarcinoma (mucinous cystadenoma).

Front 267

264. What is the morphology of mucoceles?

Back 267

All mucinous lesions are associated w/appendiceal dilatation secondary to mucinous secretions. With the simple mucocele, globular enlargement of the appendix by inpissated mucus occurs, usually the result of obstruction by a fecalith or other lesion such as an inflammatory stricture. Eventually, the distention produces sufficient atrophy of the mucin secreting mucosal cells and the secretions stop.

This condition is usually asymptomatic; rarely a mucocele ruptures, spilling otherwise innocuous mucus into the peritoneal cavity.

Front 268

265. What is the most common mucinous neoplasm of the appendix?

What is the morphology?

Back 268

The mucinous cystadenoma, which replaces the appendiceal mucosa and is histologically identical to analogous tumors in the ovary.

The luminal dilation is associated w/appendiceal perforations in 20% of instances, producing localized collections of mucus attached to the serosa of the appendix or lying free within the peritoneal cavity. Histologic exam of the mucus reveals no malignant cells.

Front 269

266. What is the morphology of malignant mucinous cystadenomas?

Back 269

Malignant mucinous cystadenocarcinomas are one fifth as common as cystadenomas. Macroscopically they produce mucin-filled cystic dilatation fo the appendix indistinguishable from that seen w/benign cystadenomas. Penetration of the appendiceal wall by invasive cells and spread beyond the appendix in the form of localized or disseminated peritoneal implants, however, is freq present.

Front 270

267. What is a pseudomyxoma peritoneii?

What is the morphology of pseudomyxoma peritoneii?

Back 270

In its fully developed state, continued cellular proliferation and mucin secretion fills the abdomen with tenacious, semisolid mucin - pseudomyxoma peritoneii.

Anaplastic adenocarcinomatous cells can be found, distinguishing this process from mucinous spillage.

Front 271

268. What are the five common causes of peritonitis?

Back 271

1. Sterile peritonitis
2. Perforation or rupture of the biliary system
3. Acute hemorrhagic pancreatitis
4. Surgical procedures
5. Gynecologic conditions (endometriosis)

Front 272

269. What is sterile peritonitis?

Back 272

Peritonitis cause by bile leakage or leakage of pancreatic enzymes.

Front 273

270. What are the main causes of peritoneal infection?

Back 273

Bacterial infections can result from appendicitis, peptic ulcer, cholecystitis, diverticulitis, bowel strangulation, acute salpingitis, abdominal trauma, or peritoneal dialysis.

Virtually every bacterial organism has been implicated, most commonly E. coli.

Front 274

271. What is spontaneous bacterial peritonitis?

Back 274

Spontaneous bacterial peritonitis may develop in the absence of an obvious source of contamination. It can develop in the setting of ascites of other causes (e.g. nephrotic syndrome or cirrhosis).

The usual causal agents of the latter are E. coli and pneumococci.

Front 275

272. What is the morphology of peritoneal infection?

Back 275

Peritoneal membranes lose their glistening quality, and become dull and gray, followed by exudation (creamy appearance) and frank suppuration; localized abscesses can develop (subhepatic, subdiaphragmatic), although the inflammation tends to remain superficial.

Tuberculous peritonitis tends to produce a plastic exudate studded with minute, pale granulomas.

Front 276

273. What is the clinical course for peritoneal infection?

Back 276

These inflammatory processes can either heal spontaneously or with therapy.

In the course of healing, the following may occur:
1. The exudate may be totally resolved, leaving no residual fibrosis.
2. Residual, walled-off abscesses may persist, eventually to heal or serve as foci of new infection.
3. Organization of the exudate may occur, with the formation of fibrous adhesions, which may be delicate or quite dense.

Front 277

274. What is sclerosing retroperitonitis?

Back 277

Dense, fibromatous overgrowth of the retroperitoneal tissues may sometimes develop, designated sclerosing retroperitonitis (Ormond disease). In some instances the mesentery is also involved.

The fibrous overgrowth is nondistinctive and does not display anaplasia. There is usually an accompanying inflammatory infiltrate of lymphocytes, plasma cells, and neutrophils. The fibrosis may encroach on the ureter causing hydronephrosis, or it may encroach on bowel segments.

Although usually sporadic, it can occur with methysergide use or in fibrosing disorders.

Front 278

275. What are mesenteric cysts?

Where do they come from?

Back 278

Large cysts in the abdominal cavity can present as abdominal masses in the mesentery.

These cysts arise from sequestered lymphatic channels, pinched-off enteric diverticula of developing foregut or hindgut, developmental cysts of urogenital origin, pancreatic pseudocyts, or walled-off infections.

Occasionally, these cysts are malignant, arising from other primary sites.

Front 279

276. What are primary tumors of the peritoneum (mesotheliomas)?

Back 279

Primary tumors arising from the mesothelium of the peritoneum are extremely rare and are called mesotheliomas.

These exactly duplicate those found in the pleura and the pericardium, but the prognosis is poor.

Front 280

277. What are desmoplastic small round cell tumors?

Back 280

Desmoplastic small round cell tumors are rare tumors arising from the peritoneum. Molecular marker stidies suggest that this tumor is in the family of small round cell tumors such as Ewing sarcoma, rhabdoid myosarcoma, and primitive neuroectodermal tumor.

*The characteristic genetic marker for this tumor is the reciprocal chromosome translocation t(11;22) (p13;q12) resulting in EWS-WT1 fusion.

Front 281

278. What are secondary tumors of the peritoneum?

Back 281

Secondary tumors are in contrast quite common. In any form of advanced cancer, penetration to the serosal membrane or metastatic seeding (peritoneal carcinomatosis) may occur.

The most common tumors producing diffuse serosal implantation are ovarian and pancreatic.