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JACS CME-1 featured articles, volume 194, April 2002
CONTINUING MEDICAL EDUCATION PROGRAM JACS CME-1 FEATURED ARTICLES, VOLUME 194, APRIL 2002
HER2/neu in the management of invasive breast cancer Meric F, Hung M-C, Hortobagyi GN, Hunt KK J Am Coll Surg 2002;194:488–501 Optimizing the use of blood cultures in the febrile postoperative patient Badillo AT, Sarani B, Evans SRT J Am Coll Surg 2002;194:477–487 JACS CME Online provides four articles from each issue for two credits per month. The articles this month on JACS CME Online are:
Objectives: After reading the featured articles published in this issue of the Journal of the American College of Surgeons (JACS) participants in the JACS CME program should be able to demonstrate increased understanding of the material specific to the article featured and be able to apply relevant information to clinical practice. Objectives are stated at the beginning of each featured article; the questions follow with 5 response choices, and a critique discussing the objective. The American College of Surgeons is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. The JACS CME program fulfills the ACCME essentials. You can earn two CME credits using JACS CME Online, at http://jacscme.facs.org, or you can earn one CME credit if you submit this page by fax (see instructions in box below).
HER2/neu in the management of invasive breast cancer. Meric F, Hung M-C, Hortobagyi GN, Hunt KK Optimizing the use of blood cultures in the febrile postoperative patient. Badillo AT, Sarani B, Evans SRT Palliative care by the surgeon: How to do it. Dunn GP, Milch RA, Mosenthal AC, et al Surgical bypass for subclavian vein occlusion in hemodialysis patients. Chandler NM, Mistry BM, Garvin, PJ
Earn 1 CME Credit by FAX
Earn Two CME Credits Online
Based on 2 articles in this issue (see next page), complete information below and fax to 312/202-5027 (Fax only, no mail submissions)
Log on to JACS CME Web site:
Name: ACS Fellow ID# Your fax number:
http://jacscme.facs.org
ANSWERS: Article 1 Article 2 Question 1 Question 1 Question 2 Question 2
© 2002 by the American College of Surgeons Published by Elsevier Science Inc.
Questions: Wendy Cowles Husser, MA, MPA Executive Editor, JACS 633 N Saint Clair Street, Chicago, IL 60611 312-202-5306 (ph) 312-202-5027 (fax) [email protected]
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ISSN 1072-7515/02/$21.00 PII S1072-7515(01)01132-2
Vol. 194, No. 4, April 2002
HER2/neu in the management of invasive breast cancer Meric F, Hung M-C, Hortobagyi GN, Hunt KK J Am Coll Surg 2002;194:488–501 Learning Objectives: 1) To learn the impact of HER2/neu overexpression on breast cancer biology. 2) To learn the role of HER2/neu as a prognostic and predictive marker. 3) To learn the mechanism of action, indications, and limitations of therapies targeting HER2/neu.
Question 1 Which of the following is incorrect? a) HER2/neu overexpression is a poor prognostic factor in breast cancer. b) Only a subgroup of tumors with 2(⫹) HER2/neu overexpression by immunohistochemistry have HER2/neu gene amplification. c) Anthracyclines are contraindicated in HER2/neuoverexpressing tumors. d) Estrogen receptor and HER2/neu expression are usually inversely correlated. e) HER2/neu overexpression enhances invasion, metastasis, and angiogenesis. Critique: HER2/neu overexpression has been found to enhance cell invasion, metastasis, and angiogenesis. Both HER2/neu protein overexpression and gene amplification have been found to confer a poor prognosis, although gene amplification may be a stronger prognostic factor. Only 25% of patients with 2(⫹) HER2/neu on immunohistochemistry have gene amplification, so it is recommended that patients with 2(⫹) IHC undergo additional testing with FISH. Estrogen receptor and HER2/neu expression are usually inversely correlated; this may in part account for the relative tamoxifen resistance of HER2/neu-overexpressing tumors. HER2/neu overexpression is associated with a relative sensitivity to doxorubicin-containing anthracycline regimens. Question 2 Choose the best answer. a) HER2/neu mutations are found in 25–30% of breast cancers. b) Therapies targeting HER2/neu include antibody trastuzumab, and tyrosine kinase inhibitor STI571. c) Trastuzumab is first-line therapy in HER2/neu (⫹) patients with brain metastases. d) HER2/neu gene amplification is a predictor of response to trastuzumab.
Continuing Medical Education Program
555
e) The biggest limitation of trastuzumab is neurotoxicity. Critique: HER2/neu mutations in human cancers are rare, but HER2/neu overexpression is found in 25–30% of breast cancers. Several tyrosine kinase inhibitors such as ZD1839, OSI774, and CI 1-33 target HER2/neu and the EGFR family. None of the tyrosine kinase inhibitors are truly specific, but tyrosine kinase inhibitor STI-571 (Gleevec, Novartis Pharmaceuticals Corporation, East Hanover, NJ) mainly targets tyrosine kinases kit, abl, PDGFR, and arg, and is currently in clinical use for CML and gastrointestinal stromal tumors. Trastuzumab is a humanized monoclonal antibody against HER2/neu, which is first-line therapy in combination with paclitaxel for HER2/neu-overexpressing patients with metastatic disease. HER2/neu gene amplification is a predictor of response to trastuzumab. Trastuzumab poorly penetrates the cerebrospinal fluid, so it is not efficacious for metastases to the central nervous system. The most important toxicity of trastuzumab is cardiotoxicity; this effect is worse if administered with anthracyclines. Optimizing the use of blood cultures in the febrile postoperative patient Badillo AT, Sarani B, Evans SRT J Am Coll Surg 2002;194:477–487 Learning Objectives: To review the physiology of the fever response and the current use of blood cultures in the evaluation of the postoperative febrile patient, examine the literature that forms the rationale for this test, and define when blood cultures are indicated. Question 1 The positive predictive value of blood cultures in the workup of a general surgical patient with postoperative fever can be maximized by: a) obtaining cultures when patients have high fevers (eg, greater than 39° C). b) obtaining more than 3 culture sets per day for at least 2 consecutive days. c) obtaining cultures in febrile patients with elevated white blood cell counts. d) obtaining cultures in immunosuppressed patients. e) obtaining cultures in the early postoperative period (less than postoperative day 3). Critique: The positive predictive value of blood cultures is maximized by obtaining the test in a population that has the highest risk of becoming bacteremic. Although there are no large, well-designed, randomized
556
Continuing Medical Education Program
studies evaluating which surgical patients have the highest risk of becoming bacteremic, small studies of postoperative and ICU patients have shown that immunosuppressed patients, patients in the ICU, patients who have greater than 2 indwelling monitoring devices, patients beyond postoperative day 4, and patients with other major comorbidities may be at increased risk of becoming bacteremic. There is no evidence to suggest that the degree of fever or white blood cell count elevation is related to the development of bacteremia. Two blood culture sets are usually necessary and sufficient to rule out or establish a diagnosis of bacteremia. When an initial culture is positive due to a contaminant, the probability that subsequent cultures will be positive is very low in contrast to that of a true-positive result for which the probability of a subsequent positive culture is greater than 75%. Obtaining more than three culture sets in a 24-hr period is excessive and counterproductive for patients with a low to moderate probability of bacteremia, since the likelihood of generating false-positive results increases as the number of cultures in a series increases. Question 2 Blood cultures are useful in the evaluation of postoperative fever because: a) the mortality of bacteremia is greater than 25–60%. b) fever is a reliable marker of postoperative bacteremia. c) they are a cost-efficient method of isolating an infectious pathogen. d) randomized, blinded studies have confirmed that blood cultures significantly improve mortality or morbidity rates in febrile postoperative patients.
J Am Coll Surg
e) the results of the blood culture almost always cause a change in therapy. Critique: Blood cultures have a major role in the evaluation of febrile patients because the consequences of missing the diagnosis of bacteremia are severe. Although there are no studies on the mortality rates of bacteremic surgical patients in the hospital, such patients on the medical services have a mortality rate of 20–35%, and bacteremic patients in the ICU have a mortality rate as high as 60%. But the surgeon must remember that fever alone is also an especially poor marker of postoperative bacteremia. Reported rates of bacteremia range between 0 and 3% in febrile postoperative patients, and so the predictive value of blood cultures in this population is low. Because of this, there are no large, blinded, randomized studies evaluating the impact of blood cultures on the morbidity and mortality of surgical patients. Also, studies of hospitalized patients on medical and surgical services found that antibiotic treatment was modified based on blood culture results in 45–54% of positive cultures. The spectrum of antibiotic coverage was narrowed in only 16% of cases demonstrating a preference for broad-spectrum antibiotics despite species identification and antibiotic sensitivity results. Finally, the average cost of processing a blood culture set ranges from $70–$230, rendering the practice of routinely obtaining blood cultures a costly approach to the evaluation of postoperative fever. When blood cultures are utilized in this fashion, the estimated cost to identify a single bacteremic patient is almost $3,000. Such cost can be better justified if cultures are drawn in populations at risk for becoming bacteremic.
HER2/neu in the management of invasive breast cancer Meric F, Hung M-C, Hortobagyi GN, Hunt KK J Am Coll Surg 2002;194:488–501 Optimizing the use of blood cultures in the febrile postoperative patient Badillo AT, Sarani B, Evans SRT J Am Coll Surg 2002;194:477–487 JACS CME Online provides four articles from each issue for two credits per month. The articles this month on JACS CME Online are:
Objectives: After reading the featured articles published in this issue of the Journal of the American College of Surgeons (JACS) participants in the JACS CME program should be able to demonstrate increased understanding of the material specific to the article featured and be able to apply relevant information to clinical practice. Objectives are stated at the beginning of each featured article; the questions follow with 5 response choices, and a critique discussing the objective. The American College of Surgeons is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. The JACS CME program fulfills the ACCME essentials. You can earn two CME credits using JACS CME Online, at http://jacscme.facs.org, or you can earn one CME credit if you submit this page by fax (see instructions in box below).
HER2/neu in the management of invasive breast cancer. Meric F, Hung M-C, Hortobagyi GN, Hunt KK Optimizing the use of blood cultures in the febrile postoperative patient. Badillo AT, Sarani B, Evans SRT Palliative care by the surgeon: How to do it. Dunn GP, Milch RA, Mosenthal AC, et al Surgical bypass for subclavian vein occlusion in hemodialysis patients. Chandler NM, Mistry BM, Garvin, PJ
Earn 1 CME Credit by FAX
Earn Two CME Credits Online
Based on 2 articles in this issue (see next page), complete information below and fax to 312/202-5027 (Fax only, no mail submissions)
Log on to JACS CME Web site:
Name: ACS Fellow ID# Your fax number:
http://jacscme.facs.org
ANSWERS: Article 1 Article 2 Question 1 Question 1 Question 2 Question 2
© 2002 by the American College of Surgeons Published by Elsevier Science Inc.
Questions: Wendy Cowles Husser, MA, MPA Executive Editor, JACS 633 N Saint Clair Street, Chicago, IL 60611 312-202-5306 (ph) 312-202-5027 (fax) [email protected]
554
ISSN 1072-7515/02/$21.00 PII S1072-7515(01)01132-2
Vol. 194, No. 4, April 2002
HER2/neu in the management of invasive breast cancer Meric F, Hung M-C, Hortobagyi GN, Hunt KK J Am Coll Surg 2002;194:488–501 Learning Objectives: 1) To learn the impact of HER2/neu overexpression on breast cancer biology. 2) To learn the role of HER2/neu as a prognostic and predictive marker. 3) To learn the mechanism of action, indications, and limitations of therapies targeting HER2/neu.
Question 1 Which of the following is incorrect? a) HER2/neu overexpression is a poor prognostic factor in breast cancer. b) Only a subgroup of tumors with 2(⫹) HER2/neu overexpression by immunohistochemistry have HER2/neu gene amplification. c) Anthracyclines are contraindicated in HER2/neuoverexpressing tumors. d) Estrogen receptor and HER2/neu expression are usually inversely correlated. e) HER2/neu overexpression enhances invasion, metastasis, and angiogenesis. Critique: HER2/neu overexpression has been found to enhance cell invasion, metastasis, and angiogenesis. Both HER2/neu protein overexpression and gene amplification have been found to confer a poor prognosis, although gene amplification may be a stronger prognostic factor. Only 25% of patients with 2(⫹) HER2/neu on immunohistochemistry have gene amplification, so it is recommended that patients with 2(⫹) IHC undergo additional testing with FISH. Estrogen receptor and HER2/neu expression are usually inversely correlated; this may in part account for the relative tamoxifen resistance of HER2/neu-overexpressing tumors. HER2/neu overexpression is associated with a relative sensitivity to doxorubicin-containing anthracycline regimens. Question 2 Choose the best answer. a) HER2/neu mutations are found in 25–30% of breast cancers. b) Therapies targeting HER2/neu include antibody trastuzumab, and tyrosine kinase inhibitor STI571. c) Trastuzumab is first-line therapy in HER2/neu (⫹) patients with brain metastases. d) HER2/neu gene amplification is a predictor of response to trastuzumab.
Continuing Medical Education Program
555
e) The biggest limitation of trastuzumab is neurotoxicity. Critique: HER2/neu mutations in human cancers are rare, but HER2/neu overexpression is found in 25–30% of breast cancers. Several tyrosine kinase inhibitors such as ZD1839, OSI774, and CI 1-33 target HER2/neu and the EGFR family. None of the tyrosine kinase inhibitors are truly specific, but tyrosine kinase inhibitor STI-571 (Gleevec, Novartis Pharmaceuticals Corporation, East Hanover, NJ) mainly targets tyrosine kinases kit, abl, PDGFR, and arg, and is currently in clinical use for CML and gastrointestinal stromal tumors. Trastuzumab is a humanized monoclonal antibody against HER2/neu, which is first-line therapy in combination with paclitaxel for HER2/neu-overexpressing patients with metastatic disease. HER2/neu gene amplification is a predictor of response to trastuzumab. Trastuzumab poorly penetrates the cerebrospinal fluid, so it is not efficacious for metastases to the central nervous system. The most important toxicity of trastuzumab is cardiotoxicity; this effect is worse if administered with anthracyclines. Optimizing the use of blood cultures in the febrile postoperative patient Badillo AT, Sarani B, Evans SRT J Am Coll Surg 2002;194:477–487 Learning Objectives: To review the physiology of the fever response and the current use of blood cultures in the evaluation of the postoperative febrile patient, examine the literature that forms the rationale for this test, and define when blood cultures are indicated. Question 1 The positive predictive value of blood cultures in the workup of a general surgical patient with postoperative fever can be maximized by: a) obtaining cultures when patients have high fevers (eg, greater than 39° C). b) obtaining more than 3 culture sets per day for at least 2 consecutive days. c) obtaining cultures in febrile patients with elevated white blood cell counts. d) obtaining cultures in immunosuppressed patients. e) obtaining cultures in the early postoperative period (less than postoperative day 3). Critique: The positive predictive value of blood cultures is maximized by obtaining the test in a population that has the highest risk of becoming bacteremic. Although there are no large, well-designed, randomized
556
Continuing Medical Education Program
studies evaluating which surgical patients have the highest risk of becoming bacteremic, small studies of postoperative and ICU patients have shown that immunosuppressed patients, patients in the ICU, patients who have greater than 2 indwelling monitoring devices, patients beyond postoperative day 4, and patients with other major comorbidities may be at increased risk of becoming bacteremic. There is no evidence to suggest that the degree of fever or white blood cell count elevation is related to the development of bacteremia. Two blood culture sets are usually necessary and sufficient to rule out or establish a diagnosis of bacteremia. When an initial culture is positive due to a contaminant, the probability that subsequent cultures will be positive is very low in contrast to that of a true-positive result for which the probability of a subsequent positive culture is greater than 75%. Obtaining more than three culture sets in a 24-hr period is excessive and counterproductive for patients with a low to moderate probability of bacteremia, since the likelihood of generating false-positive results increases as the number of cultures in a series increases. Question 2 Blood cultures are useful in the evaluation of postoperative fever because: a) the mortality of bacteremia is greater than 25–60%. b) fever is a reliable marker of postoperative bacteremia. c) they are a cost-efficient method of isolating an infectious pathogen. d) randomized, blinded studies have confirmed that blood cultures significantly improve mortality or morbidity rates in febrile postoperative patients.
J Am Coll Surg
e) the results of the blood culture almost always cause a change in therapy. Critique: Blood cultures have a major role in the evaluation of febrile patients because the consequences of missing the diagnosis of bacteremia are severe. Although there are no studies on the mortality rates of bacteremic surgical patients in the hospital, such patients on the medical services have a mortality rate of 20–35%, and bacteremic patients in the ICU have a mortality rate as high as 60%. But the surgeon must remember that fever alone is also an especially poor marker of postoperative bacteremia. Reported rates of bacteremia range between 0 and 3% in febrile postoperative patients, and so the predictive value of blood cultures in this population is low. Because of this, there are no large, blinded, randomized studies evaluating the impact of blood cultures on the morbidity and mortality of surgical patients. Also, studies of hospitalized patients on medical and surgical services found that antibiotic treatment was modified based on blood culture results in 45–54% of positive cultures. The spectrum of antibiotic coverage was narrowed in only 16% of cases demonstrating a preference for broad-spectrum antibiotics despite species identification and antibiotic sensitivity results. Finally, the average cost of processing a blood culture set ranges from $70–$230, rendering the practice of routinely obtaining blood cultures a costly approach to the evaluation of postoperative fever. When blood cultures are utilized in this fashion, the estimated cost to identify a single bacteremic patient is almost $3,000. Such cost can be better justified if cultures are drawn in populations at risk for becoming bacteremic.