A disease that affects 10%-15% of women of reproductive age, endometriosis is quite prevalent. In 1990, investigators in Belgium first described deep endometriosis to highlight the diagnostic and therapeutic aspects of the disease (Fertil. Steril. 1990;53:978–83). In contrast to superficial disease, deep endometriosis constitutes the most severe form of endometriosis and includes nodules affecting the pouch of Douglas, retrocervical area, bladder, ureter, or the intestinal wall. Less frequently, the rectovaginal septum is involved (Arq. Gastroenterol. 2003;40:192–7). The treatment of bowel endometriosis is challenging, as it is a benign disease that may infiltrate the bowel, requiring a surgical treatment with increased risks.

Preoperative Diagnosis Using Imaging

The definitive diagnosis of deep endometriosis with bowel involvement is reached principally at the time of surgery. However, some clinical characteristics identified by history and physical examination, laboratory tests, and diagnostic imaging may raise suspicion for this form of endometriosis. A surgical approach is still recommended for confirmation and treatment.

Transvaginal ultrasonography (TVUS) still appears to be the superior imaging technique, providing the best cost-benefit ratio for cases of ovarian or deep endometriosis. The presence of a hypoechoic lesion located in the posterior pelvic compartment (see

When performed after complete bowel preparation and during the perimenstrual phase, TVUS carried out by a trained professional provides useful information for therapeutic management.

MRI can be performed to identify deep lesions. (See

Excretory urography or uro-MRI also is useful for evaluating whether the ureters are involved. When urinary tract involvement is suspected, one of these types of imaging should be performed to fully document the state of the urinary tract before surgery.

If we have doubts about the bowel involvement even after TVUS with bowel preparation, we recommend rectal echoendoscopy. (See

Rectal echoendoscopy also permits identification of the distance between the lesion and the rectal lumen, as well as identification of extrinsic compression and lesions of the rectal submucosa. This information can be critical in the preoperative planning of the type of surgery required and the need to have the help of a colorectal surgeon. The chart on page 19 shows the algorithm for preoperative work-up depending on clinical and TVUS findings.

Treatment: Clinical or Surgical?

Medical treatment of deep endometriosis, as opposed to surgical treatment, remains controversial. Dr. Luigi Fedele and his associates in Italy reported a substantial improvement in pain during 6 months of treatment with GnRH analogs (Am. J. Obstet. Gynecol. 2000;183:1462–7). Similar improvements in pain were also observed by our group with both an intrauterine device medicated with levonorgestrel and with a GnRH analog (Hum. Reprod. 2005;20:1993–8). In Dr. Fedele's study, however, an early relapse occurred following discontinuation of treatment. In addition, the endometriotic lesions underwent a discrete but significant reduction in size as detected by TVUS during treatment, but returned to their original size 6 months after suspension of GnRH treatment.

In cases of intractable pain (measured by scores greater than 7 in the visual analog scale) and/or two previously failed IVF cycles, surgical treatment is required. Access for surgical treatment may be by laparotomy or laparoscopy, depending on the surgeon's experience; however, laparoscopy can provide a better visualization of the lesions, allowing a more precise excision.

Surgical Preparation and Technique

Whenever there is clinical suspicion of deep endometriosis, adequate presurgical bowel preparation is indicated. We recommend the use of 3–4 liters of an oral solution of polyethylene glycol (PEG) the day before surgery, followed by one or two Fleet enemas or a mannitol preparation.

Administration of antibiotics should be carried out during anesthetic induction, preferably using a second-generation cephalosporin (2 g intravenously).

When the preoperative rectal ultrasound permits identification of the depth of the lesion, this information can be used to define the type of surgery that will be performed. In the case of unifocal lesions less than 3 cm in size (major diameter) and affecting the serous and external muscular layers of the rectum or sigmoid, resection of the nodule alone may be indicated. This procedure may be done manually or with the help of a circular stapler. (

Our technique approached laparoscopically is as follows:

▸ The lesion on the rectosigmoid is delineated, and adhesions are lysed from contiguous organs such as adnexae, the uterus, or other loops of bowel. We prefer to use scissors or a hook.

▸ To resect the lesion manually (without the use of a disposable stapler), the endometriotic nodule is excised, taking care not to leave any residual disease behind. The defect is then repaired in a double-layer fashion. On the mucosal layer, 3–0 absorbable suture is used in a running and transverse manner to avoid bowel constriction. On the seromuscular layer, 3–0 permanent suture is used in a running manner to imbricate over the first layer.

▸ If a circular stapler is used, the following steps are followed: A stitch is placed in the lesion in order to invaginate it into the stapler. (See

▸ The anastomosis is tested by gently injecting air and/or methylene blue through the rectum (with an Asepto, or large bulb syringe) while the surgeon occludes the proximal sigmoid with an atraumatic instrument. Absence of air bubbles and/or methylene blue while the anastomotic site is submerged in sterile water in the pelvis confirms a tight anastomosis.

If, on the other hand, the lesion is deeper, affecting the deep muscle or the submucosal or mucosal layers, then segmental resection of the bowel is recommended. Complete surgical resection of endometrial foci has been shown to result in improved quality of life and decreased rates of recurrence (Fertil. Steril. 2004;82:878–84).

Segmental resection of the rectosigmoid can be performed laparoscopically (J. Minim. Invasive Gynecol. 2008;15:280–5). Our technique involves the following steps:

▸ Both ureters are identified (see

▸ The mesosigmoid is divided with an ultrasonic device.

▸ A linear stapler is utilized on the rectosigmoid distal to the lesion.

▸ After excision of all endometriotic implants, the right-lower trocar site is extended to 4 cm in order to remove the surgical specimen(s) and to prepare the proximal stump. (See

▸ An incision is made on the proximal stump in order to insert the anvil of the circular stapler.

▸ A purse-string suture holding the anvil in place is performed prior to replacement of the sigmoid into the abdominal cavity.

▸ The 4-cm fascial incision is closed in order to finish the procedure laparoscopically.

▸ The circular stapler is inserted through the anus in order to complete the end-to-end reanastomosis. The anastomosis is tested by gently injecting air and/or methylene blue through the rectum (with an Asepto, or large bulb syringe) while the surgeon occludes the proximal sigmoid with an atraumatic instrument. Absence of air bubbles and/or methylene blue while the anastomotic site is submerged in sterile water in the pelvis confirms a tight anastomosis.

▸ A large drain is left adjacent to the anastomosis prior to closure of trocar sites. The drain is generally removed 4 days postoperatively.

Deep endometriosis is associated with more severe pain and significantly greater rates of infertility, compared with superficial endometriosis. Because of the high risks of surgical intervention, preoperative diagnosis using imaging modalities can be helpful in planning surgical strategy. Improved outcomes are achieved with complete surgical resection, which can be performed through minimally invasive techniques.

Download a mobile quick response (QR) code reader from your smartphone's app store to view a video by Dr. Abrão, or visit

www.aagl.org/obgynnews

Vitals

Rectal Endometriosis

www.isge.org

www.aagl.org

Deep endometriosis compromising the rectum continues to be a diagnostic and therapeutic challenge. The resultant pelvic pain, dyspareunia, dysmenorrhea, and infertility risk are well documented in literature. Despite the fact that there are numerous studies to evaluate deep endometriosis, including colonoscopy, MRI, vaginal and rectal ultrasound, and barium enema, there continues to be no standard road map for evaluation. In addition, there continues to be debate in the literature when patients should undergo shaving of the endometrioma, discoid resection of the endometrioma, or complete bowel resection.

Since the inception of the Master Class in Gynecologic Surgery, as Editor, I have used only experts who practice within the confines of the United States. However, given the internationally recognized expertise in both the diagnosis and treatment of deep and extensive endometriosis, I believed it was imperative to invite Dr. Mauricio S. Abrão to discuss the diagnosis and treatment of deep endometriosis compromising the rectum.

Dr. Abrão was born in São Paulo, Brazil in 1962, where he went on to complete medical school, and in 1988, his residency in obstetrics and gynecology. In 1989, Dr. Abrão founded the endometriosis division within the department of the teaching hospital of the University of São Paulo School of Medicine, where he currently is Docent Professor.

Since 2007, Dr. Abrão has been president of the Brazilian Society of Endometriosis and Minimally Invasive Endoscopy, and has been a board member of the World Endometriosis Society since 1998. He currently is on the board of trustees of the AAGL and is the chairman of the society's special interest group on endometriosis. Dr. Abrão is leading the AAGL initiative on producing a new classification on endometriosis. A prolific author, Dr. Abrão has nearly 100 papers published in peer-reviewed journals, the majority dealing with endometriosis.

It is with great admiration and respect that I introduce my friend, Dr. Abrão, to this edition of the Master Class in gynecologic surgery.

A disease that affects 10%-15% of women of reproductive age, endometriosis is quite prevalent. In 1990, investigators in Belgium first described deep endometriosis to highlight the diagnostic and therapeutic aspects of the disease (Fertil. Steril. 1990;53:978–83). In contrast to superficial disease, deep endometriosis constitutes the most severe form of endometriosis and includes nodules affecting the pouch of Douglas, retrocervical area, bladder, ureter, or the intestinal wall. Less frequently, the rectovaginal septum is involved (Arq. Gastroenterol. 2003;40:192–7). The treatment of bowel endometriosis is challenging, as it is a benign disease that may infiltrate the bowel, requiring a surgical treatment with increased risks.

Preoperative Diagnosis Using Imaging

The definitive diagnosis of deep endometriosis with bowel involvement is reached principally at the time of surgery. However, some clinical characteristics identified by history and physical examination, laboratory tests, and diagnostic imaging may raise suspicion for this form of endometriosis. A surgical approach is still recommended for confirmation and treatment.

Transvaginal ultrasonography (TVUS) still appears to be the superior imaging technique, providing the best cost-benefit ratio for cases of ovarian or deep endometriosis. The presence of a hypoechoic lesion located in the posterior pelvic compartment (see

When performed after complete bowel preparation and during the perimenstrual phase, TVUS carried out by a trained professional provides useful information for therapeutic management.

MRI can be performed to identify deep lesions. (See

Excretory urography or uro-MRI also is useful for evaluating whether the ureters are involved. When urinary tract involvement is suspected, one of these types of imaging should be performed to fully document the state of the urinary tract before surgery.

If we have doubts about the bowel involvement even after TVUS with bowel preparation, we recommend rectal echoendoscopy. (See

Rectal echoendoscopy also permits identification of the distance between the lesion and the rectal lumen, as well as identification of extrinsic compression and lesions of the rectal submucosa. This information can be critical in the preoperative planning of the type of surgery required and the need to have the help of a colorectal surgeon. The chart on page 19 shows the algorithm for preoperative work-up depending on clinical and TVUS findings.

Treatment: Clinical or Surgical?

Medical treatment of deep endometriosis, as opposed to surgical treatment, remains controversial. Dr. Luigi Fedele and his associates in Italy reported a substantial improvement in pain during 6 months of treatment with GnRH analogs (Am. J. Obstet. Gynecol. 2000;183:1462–7). Similar improvements in pain were also observed by our group with both an intrauterine device medicated with levonorgestrel and with a GnRH analog (Hum. Reprod. 2005;20:1993–8). In Dr. Fedele's study, however, an early relapse occurred following discontinuation of treatment. In addition, the endometriotic lesions underwent a discrete but significant reduction in size as detected by TVUS during treatment, but returned to their original size 6 months after suspension of GnRH treatment.

In cases of intractable pain (measured by scores greater than 7 in the visual analog scale) and/or two previously failed IVF cycles, surgical treatment is required. Access for surgical treatment may be by laparotomy or laparoscopy, depending on the surgeon's experience; however, laparoscopy can provide a better visualization of the lesions, allowing a more precise excision.

Surgical Preparation and Technique

Whenever there is clinical suspicion of deep endometriosis, adequate presurgical bowel preparation is indicated. We recommend the use of 3–4 liters of an oral solution of polyethylene glycol (PEG) the day before surgery, followed by one or two Fleet enemas or a mannitol preparation.

Administration of antibiotics should be carried out during anesthetic induction, preferably using a second-generation cephalosporin (2 g intravenously).

When the preoperative rectal ultrasound permits identification of the depth of the lesion, this information can be used to define the type of surgery that will be performed. In the case of unifocal lesions less than 3 cm in size (major diameter) and affecting the serous and external muscular layers of the rectum or sigmoid, resection of the nodule alone may be indicated. This procedure may be done manually or with the help of a circular stapler. (

Our technique approached laparoscopically is as follows:

▸ The lesion on the rectosigmoid is delineated, and adhesions are lysed from contiguous organs such as adnexae, the uterus, or other loops of bowel. We prefer to use scissors or a hook.

▸ To resect the lesion manually (without the use of a disposable stapler), the endometriotic nodule is excised, taking care not to leave any residual disease behind. The defect is then repaired in a double-layer fashion. On the mucosal layer, 3–0 absorbable suture is used in a running and transverse manner to avoid bowel constriction. On the seromuscular layer, 3–0 permanent suture is used in a running manner to imbricate over the first layer.

▸ If a circular stapler is used, the following steps are followed: A stitch is placed in the lesion in order to invaginate it into the stapler. (See

▸ The anastomosis is tested by gently injecting air and/or methylene blue through the rectum (with an Asepto, or large bulb syringe) while the surgeon occludes the proximal sigmoid with an atraumatic instrument. Absence of air bubbles and/or methylene blue while the anastomotic site is submerged in sterile water in the pelvis confirms a tight anastomosis.

If, on the other hand, the lesion is deeper, affecting the deep muscle or the submucosal or mucosal layers, then segmental resection of the bowel is recommended. Complete surgical resection of endometrial foci has been shown to result in improved quality of life and decreased rates of recurrence (Fertil. Steril. 2004;82:878–84).

Segmental resection of the rectosigmoid can be performed laparoscopically (J. Minim. Invasive Gynecol. 2008;15:280–5). Our technique involves the following steps:

▸ Both ureters are identified (see

▸ The mesosigmoid is divided with an ultrasonic device.

▸ A linear stapler is utilized on the rectosigmoid distal to the lesion.

▸ After excision of all endometriotic implants, the right-lower trocar site is extended to 4 cm in order to remove the surgical specimen(s) and to prepare the proximal stump. (See

▸ An incision is made on the proximal stump in order to insert the anvil of the circular stapler.

▸ A purse-string suture holding the anvil in place is performed prior to replacement of the sigmoid into the abdominal cavity.

▸ The 4-cm fascial incision is closed in order to finish the procedure laparoscopically.

▸ The circular stapler is inserted through the anus in order to complete the end-to-end reanastomosis. The anastomosis is tested by gently injecting air and/or methylene blue through the rectum (with an Asepto, or large bulb syringe) while the surgeon occludes the proximal sigmoid with an atraumatic instrument. Absence of air bubbles and/or methylene blue while the anastomotic site is submerged in sterile water in the pelvis confirms a tight anastomosis.

▸ A large drain is left adjacent to the anastomosis prior to closure of trocar sites. The drain is generally removed 4 days postoperatively.

Deep endometriosis is associated with more severe pain and significantly greater rates of infertility, compared with superficial endometriosis. Because of the high risks of surgical intervention, preoperative diagnosis using imaging modalities can be helpful in planning surgical strategy. Improved outcomes are achieved with complete surgical resection, which can be performed through minimally invasive techniques.

Download a mobile quick response (QR) code reader from your smartphone's app store to view a video by Dr. Abrão, or visit

www.aagl.org/obgynnews

Vitals

Rectal Endometriosis

www.isge.org

www.aagl.org

Deep endometriosis compromising the rectum continues to be a diagnostic and therapeutic challenge. The resultant pelvic pain, dyspareunia, dysmenorrhea, and infertility risk are well documented in literature. Despite the fact that there are numerous studies to evaluate deep endometriosis, including colonoscopy, MRI, vaginal and rectal ultrasound, and barium enema, there continues to be no standard road map for evaluation. In addition, there continues to be debate in the literature when patients should undergo shaving of the endometrioma, discoid resection of the endometrioma, or complete bowel resection.

Since the inception of the Master Class in Gynecologic Surgery, as Editor, I have used only experts who practice within the confines of the United States. However, given the internationally recognized expertise in both the diagnosis and treatment of deep and extensive endometriosis, I believed it was imperative to invite Dr. Mauricio S. Abrão to discuss the diagnosis and treatment of deep endometriosis compromising the rectum.

Dr. Abrão was born in São Paulo, Brazil in 1962, where he went on to complete medical school, and in 1988, his residency in obstetrics and gynecology. In 1989, Dr. Abrão founded the endometriosis division within the department of the teaching hospital of the University of São Paulo School of Medicine, where he currently is Docent Professor.

Since 2007, Dr. Abrão has been president of the Brazilian Society of Endometriosis and Minimally Invasive Endoscopy, and has been a board member of the World Endometriosis Society since 1998. He currently is on the board of trustees of the AAGL and is the chairman of the society's special interest group on endometriosis. Dr. Abrão is leading the AAGL initiative on producing a new classification on endometriosis. A prolific author, Dr. Abrão has nearly 100 papers published in peer-reviewed journals, the majority dealing with endometriosis.

It is with great admiration and respect that I introduce my friend, Dr. Abrão, to this edition of the Master Class in gynecologic surgery.

A disease that affects 10%-15% of women of reproductive age, endometriosis is quite prevalent. In 1990, investigators in Belgium first described deep endometriosis to highlight the diagnostic and therapeutic aspects of the disease (Fertil. Steril. 1990;53:978–83). In contrast to superficial disease, deep endometriosis constitutes the most severe form of endometriosis and includes nodules affecting the pouch of Douglas, retrocervical area, bladder, ureter, or the intestinal wall. Less frequently, the rectovaginal septum is involved (Arq. Gastroenterol. 2003;40:192–7). The treatment of bowel endometriosis is challenging, as it is a benign disease that may infiltrate the bowel, requiring a surgical treatment with increased risks.

Preoperative Diagnosis Using Imaging

The definitive diagnosis of deep endometriosis with bowel involvement is reached principally at the time of surgery. However, some clinical characteristics identified by history and physical examination, laboratory tests, and diagnostic imaging may raise suspicion for this form of endometriosis. A surgical approach is still recommended for confirmation and treatment.

Transvaginal ultrasonography (TVUS) still appears to be the superior imaging technique, providing the best cost-benefit ratio for cases of ovarian or deep endometriosis. The presence of a hypoechoic lesion located in the posterior pelvic compartment (see

When performed after complete bowel preparation and during the perimenstrual phase, TVUS carried out by a trained professional provides useful information for therapeutic management.

MRI can be performed to identify deep lesions. (See

Excretory urography or uro-MRI also is useful for evaluating whether the ureters are involved. When urinary tract involvement is suspected, one of these types of imaging should be performed to fully document the state of the urinary tract before surgery.

If we have doubts about the bowel involvement even after TVUS with bowel preparation, we recommend rectal echoendoscopy. (See

Rectal echoendoscopy also permits identification of the distance between the lesion and the rectal lumen, as well as identification of extrinsic compression and lesions of the rectal submucosa. This information can be critical in the preoperative planning of the type of surgery required and the need to have the help of a colorectal surgeon. The chart on page 19 shows the algorithm for preoperative work-up depending on clinical and TVUS findings.

Treatment: Clinical or Surgical?

Medical treatment of deep endometriosis, as opposed to surgical treatment, remains controversial. Dr. Luigi Fedele and his associates in Italy reported a substantial improvement in pain during 6 months of treatment with GnRH analogs (Am. J. Obstet. Gynecol. 2000;183:1462–7). Similar improvements in pain were also observed by our group with both an intrauterine device medicated with levonorgestrel and with a GnRH analog (Hum. Reprod. 2005;20:1993–8). In Dr. Fedele's study, however, an early relapse occurred following discontinuation of treatment. In addition, the endometriotic lesions underwent a discrete but significant reduction in size as detected by TVUS during treatment, but returned to their original size 6 months after suspension of GnRH treatment.

In cases of intractable pain (measured by scores greater than 7 in the visual analog scale) and/or two previously failed IVF cycles, surgical treatment is required. Access for surgical treatment may be by laparotomy or laparoscopy, depending on the surgeon's experience; however, laparoscopy can provide a better visualization of the lesions, allowing a more precise excision.

Surgical Preparation and Technique

Whenever there is clinical suspicion of deep endometriosis, adequate presurgical bowel preparation is indicated. We recommend the use of 3–4 liters of an oral solution of polyethylene glycol (PEG) the day before surgery, followed by one or two Fleet enemas or a mannitol preparation.

Administration of antibiotics should be carried out during anesthetic induction, preferably using a second-generation cephalosporin (2 g intravenously).

When the preoperative rectal ultrasound permits identification of the depth of the lesion, this information can be used to define the type of surgery that will be performed. In the case of unifocal lesions less than 3 cm in size (major diameter) and affecting the serous and external muscular layers of the rectum or sigmoid, resection of the nodule alone may be indicated. This procedure may be done manually or with the help of a circular stapler. (

Our technique approached laparoscopically is as follows:

▸ The lesion on the rectosigmoid is delineated, and adhesions are lysed from contiguous organs such as adnexae, the uterus, or other loops of bowel. We prefer to use scissors or a hook.

▸ To resect the lesion manually (without the use of a disposable stapler), the endometriotic nodule is excised, taking care not to leave any residual disease behind. The defect is then repaired in a double-layer fashion. On the mucosal layer, 3–0 absorbable suture is used in a running and transverse manner to avoid bowel constriction. On the seromuscular layer, 3–0 permanent suture is used in a running manner to imbricate over the first layer.

▸ If a circular stapler is used, the following steps are followed: A stitch is placed in the lesion in order to invaginate it into the stapler. (See

▸ The anastomosis is tested by gently injecting air and/or methylene blue through the rectum (with an Asepto, or large bulb syringe) while the surgeon occludes the proximal sigmoid with an atraumatic instrument. Absence of air bubbles and/or methylene blue while the anastomotic site is submerged in sterile water in the pelvis confirms a tight anastomosis.

If, on the other hand, the lesion is deeper, affecting the deep muscle or the submucosal or mucosal layers, then segmental resection of the bowel is recommended. Complete surgical resection of endometrial foci has been shown to result in improved quality of life and decreased rates of recurrence (Fertil. Steril. 2004;82:878–84).

Segmental resection of the rectosigmoid can be performed laparoscopically (J. Minim. Invasive Gynecol. 2008;15:280–5). Our technique involves the following steps:

▸ Both ureters are identified (see

▸ The mesosigmoid is divided with an ultrasonic device.

▸ A linear stapler is utilized on the rectosigmoid distal to the lesion.

▸ After excision of all endometriotic implants, the right-lower trocar site is extended to 4 cm in order to remove the surgical specimen(s) and to prepare the proximal stump. (See

▸ An incision is made on the proximal stump in order to insert the anvil of the circular stapler.

▸ A purse-string suture holding the anvil in place is performed prior to replacement of the sigmoid into the abdominal cavity.

▸ The 4-cm fascial incision is closed in order to finish the procedure laparoscopically.

▸ The circular stapler is inserted through the anus in order to complete the end-to-end reanastomosis. The anastomosis is tested by gently injecting air and/or methylene blue through the rectum (with an Asepto, or large bulb syringe) while the surgeon occludes the proximal sigmoid with an atraumatic instrument. Absence of air bubbles and/or methylene blue while the anastomotic site is submerged in sterile water in the pelvis confirms a tight anastomosis.

▸ A large drain is left adjacent to the anastomosis prior to closure of trocar sites. The drain is generally removed 4 days postoperatively.

Deep endometriosis is associated with more severe pain and significantly greater rates of infertility, compared with superficial endometriosis. Because of the high risks of surgical intervention, preoperative diagnosis using imaging modalities can be helpful in planning surgical strategy. Improved outcomes are achieved with complete surgical resection, which can be performed through minimally invasive techniques.

Download a mobile quick response (QR) code reader from your smartphone's app store to view a video by Dr. Abrão, or visit

www.aagl.org/obgynnews

Vitals

Rectal Endometriosis

www.isge.org

www.aagl.org

Deep endometriosis compromising the rectum continues to be a diagnostic and therapeutic challenge. The resultant pelvic pain, dyspareunia, dysmenorrhea, and infertility risk are well documented in literature. Despite the fact that there are numerous studies to evaluate deep endometriosis, including colonoscopy, MRI, vaginal and rectal ultrasound, and barium enema, there continues to be no standard road map for evaluation. In addition, there continues to be debate in the literature when patients should undergo shaving of the endometrioma, discoid resection of the endometrioma, or complete bowel resection.

Since the inception of the Master Class in Gynecologic Surgery, as Editor, I have used only experts who practice within the confines of the United States. However, given the internationally recognized expertise in both the diagnosis and treatment of deep and extensive endometriosis, I believed it was imperative to invite Dr. Mauricio S. Abrão to discuss the diagnosis and treatment of deep endometriosis compromising the rectum.

Dr. Abrão was born in São Paulo, Brazil in 1962, where he went on to complete medical school, and in 1988, his residency in obstetrics and gynecology. In 1989, Dr. Abrão founded the endometriosis division within the department of the teaching hospital of the University of São Paulo School of Medicine, where he currently is Docent Professor.

Since 2007, Dr. Abrão has been president of the Brazilian Society of Endometriosis and Minimally Invasive Endoscopy, and has been a board member of the World Endometriosis Society since 1998. He currently is on the board of trustees of the AAGL and is the chairman of the society's special interest group on endometriosis. Dr. Abrão is leading the AAGL initiative on producing a new classification on endometriosis. A prolific author, Dr. Abrão has nearly 100 papers published in peer-reviewed journals, the majority dealing with endometriosis.

It is with great admiration and respect that I introduce my friend, Dr. Abrão, to this edition of the Master Class in gynecologic surgery.

They came for a second opinion. They were both in their 50s; she a lawyer, the husband a stockbroker. He had insulin dependent diabetes for 20 years but was otherwise well. She was concerned that her husband would die suddenly just as his father had at age 70. He was without symptoms but had a nuclear exercise stress test at the behest of his local medical doctor because of his diabetes.

The test was said to be abnormal, but three subsequent in-house readers found the results normal. He was advised to have an angiogram by another cardiologist. “What should we do?”

I told her that an angiogram or a stent would not prevent him from dying suddenly. I outlined all the pros and cons and advised against it. The wife was very anxious and wanted an angiogram so that her husband wouldn't die suddenly. They both left my office, never to be seen again.

A recent report by Dr. William B. Borden and colleagues (JAMA 2011;305:1882-9) examined the change in clinical practice in regard to percutaneous coronary intervention before and after the report of the COURAGE trial 4 years ago (N. Engl. J. Med. 2007;356:1503-16), which indicated that there was no mortality or morbidity benefit in patients with stable angina who received PCI when compared to optimal medical therapy.

Dr. Borden and colleagues presumed that the results of the COURAGE trial would transform clinical practice, and that most of the 293,795 patients in their study who went on to PCI in the COURAGE-like population would receive optimal medical therapy before PCI.

In fact, optimal medical therapy (defined as therapy with aspirin, a beta-blocker, an ACE inhibitor, and a statin) was used in 43.4% of the patients before COURAGE and in 45.0% after the COURAGE report. In COURAGE, 32% had diabetes, 12% of the patients were asymptomatic, and 30% had class I angina.

In the most recent analysis by Dr. Borden, one-third of patients (more than 70,000) had no angina prior to PCI. One must wonder what the perceived patient benefit was that led to the performance of a PCI in those patients.

My patient's other cardiologist advised angiography for my patient partly because of a concern for the early identification of ischemic heart disease in diabetic patients. Indeed, this concern had led the American Diabetes Association to recommend that in addition to standard secondary prevention therapy for both diabetes and coronary artery disease, patients with two or more risk factors for coronary artery disease undergo early screening (Diabetes Care 1998;13:1551-9).

These recommendations, however, were not evidence based, but made on the recommendation of an expert panel. The DIAD (Detection of Ischemia in Asymptomatic Diabetics) trial has since provided further insight into the issue of screening asymptomatic diabetic patients (JAMA 2009;301:1547-55), an issue that remains controversial.

Although not a randomized trial, DIAD indicates that the event rate in asymptomatic diabetic patients in general is low, and that a positive myocardial perfusion stress test did not identify patients who were at an increase risk of ischemic events.

Of the 522 asymptomatic patients screened, 409 (78%) had normal results, 50 (10%) had a small perfusion defect, and 33 (6%) had moderate or large perfusion defects. Although there was no significantly increased risk of cardiac events in patients with small defects when they were compared with those who had no perfusion defect, there was a sixfold increase risk in patients with moderate to large defects on myocardial perfusion imaging. Only 4.4% of patients went on to angiography, a decision driven by the clinical judgment of the patient's physician.

Of course, in my example, the greatest pressure for angiography came from the patient's wife, who was convinced that on the basis of conventional wisdom, myocardial perfusion imaging–guided PCI would identify a critical lesion that, when treated with PCI, would prolong her husband's life. And as a matter of fact, in order to prove the absence of coronary artery disease based on the normal perfusion test, I agreed to arrange an angiogram should they need reassurance that the test was normal. What would have eventuated should we have found a lesion remains for your conjecture.

But it is clear that there is an overabundance of angiograms being performed in asymptomatic patients, which more than likely leads to the performance of unnecessary PCIs in asymptomatic patients. Angiography has become the “carpenter's hammer,” with the little regard for its benefit.

A more reasonable and effective approach to diabetes patients (as well as other asymptomatic patients) is the institution of adequate primary prevention, which has been shown to have both morbidity and mortality benefits.

They came for a second opinion. They were both in their 50s; she a lawyer, the husband a stockbroker. He had insulin dependent diabetes for 20 years but was otherwise well. She was concerned that her husband would die suddenly just as his father had at age 70. He was without symptoms but had a nuclear exercise stress test at the behest of his local medical doctor because of his diabetes.

The test was said to be abnormal, but three subsequent in-house readers found the results normal. He was advised to have an angiogram by another cardiologist. “What should we do?”

I told her that an angiogram or a stent would not prevent him from dying suddenly. I outlined all the pros and cons and advised against it. The wife was very anxious and wanted an angiogram so that her husband wouldn't die suddenly. They both left my office, never to be seen again.

A recent report by Dr. William B. Borden and colleagues (JAMA 2011;305:1882-9) examined the change in clinical practice in regard to percutaneous coronary intervention before and after the report of the COURAGE trial 4 years ago (N. Engl. J. Med. 2007;356:1503-16), which indicated that there was no mortality or morbidity benefit in patients with stable angina who received PCI when compared to optimal medical therapy.

Dr. Borden and colleagues presumed that the results of the COURAGE trial would transform clinical practice, and that most of the 293,795 patients in their study who went on to PCI in the COURAGE-like population would receive optimal medical therapy before PCI.

In fact, optimal medical therapy (defined as therapy with aspirin, a beta-blocker, an ACE inhibitor, and a statin) was used in 43.4% of the patients before COURAGE and in 45.0% after the COURAGE report. In COURAGE, 32% had diabetes, 12% of the patients were asymptomatic, and 30% had class I angina.

In the most recent analysis by Dr. Borden, one-third of patients (more than 70,000) had no angina prior to PCI. One must wonder what the perceived patient benefit was that led to the performance of a PCI in those patients.

My patient's other cardiologist advised angiography for my patient partly because of a concern for the early identification of ischemic heart disease in diabetic patients. Indeed, this concern had led the American Diabetes Association to recommend that in addition to standard secondary prevention therapy for both diabetes and coronary artery disease, patients with two or more risk factors for coronary artery disease undergo early screening (Diabetes Care 1998;13:1551-9).

These recommendations, however, were not evidence based, but made on the recommendation of an expert panel. The DIAD (Detection of Ischemia in Asymptomatic Diabetics) trial has since provided further insight into the issue of screening asymptomatic diabetic patients (JAMA 2009;301:1547-55), an issue that remains controversial.

Although not a randomized trial, DIAD indicates that the event rate in asymptomatic diabetic patients in general is low, and that a positive myocardial perfusion stress test did not identify patients who were at an increase risk of ischemic events.

Of the 522 asymptomatic patients screened, 409 (78%) had normal results, 50 (10%) had a small perfusion defect, and 33 (6%) had moderate or large perfusion defects. Although there was no significantly increased risk of cardiac events in patients with small defects when they were compared with those who had no perfusion defect, there was a sixfold increase risk in patients with moderate to large defects on myocardial perfusion imaging. Only 4.4% of patients went on to angiography, a decision driven by the clinical judgment of the patient's physician.

Of course, in my example, the greatest pressure for angiography came from the patient's wife, who was convinced that on the basis of conventional wisdom, myocardial perfusion imaging–guided PCI would identify a critical lesion that, when treated with PCI, would prolong her husband's life. And as a matter of fact, in order to prove the absence of coronary artery disease based on the normal perfusion test, I agreed to arrange an angiogram should they need reassurance that the test was normal. What would have eventuated should we have found a lesion remains for your conjecture.

But it is clear that there is an overabundance of angiograms being performed in asymptomatic patients, which more than likely leads to the performance of unnecessary PCIs in asymptomatic patients. Angiography has become the “carpenter's hammer,” with the little regard for its benefit.

A more reasonable and effective approach to diabetes patients (as well as other asymptomatic patients) is the institution of adequate primary prevention, which has been shown to have both morbidity and mortality benefits.

They came for a second opinion. They were both in their 50s; she a lawyer, the husband a stockbroker. He had insulin dependent diabetes for 20 years but was otherwise well. She was concerned that her husband would die suddenly just as his father had at age 70. He was without symptoms but had a nuclear exercise stress test at the behest of his local medical doctor because of his diabetes.

The test was said to be abnormal, but three subsequent in-house readers found the results normal. He was advised to have an angiogram by another cardiologist. “What should we do?”

I told her that an angiogram or a stent would not prevent him from dying suddenly. I outlined all the pros and cons and advised against it. The wife was very anxious and wanted an angiogram so that her husband wouldn't die suddenly. They both left my office, never to be seen again.

A recent report by Dr. William B. Borden and colleagues (JAMA 2011;305:1882-9) examined the change in clinical practice in regard to percutaneous coronary intervention before and after the report of the COURAGE trial 4 years ago (N. Engl. J. Med. 2007;356:1503-16), which indicated that there was no mortality or morbidity benefit in patients with stable angina who received PCI when compared to optimal medical therapy.

Dr. Borden and colleagues presumed that the results of the COURAGE trial would transform clinical practice, and that most of the 293,795 patients in their study who went on to PCI in the COURAGE-like population would receive optimal medical therapy before PCI.

In fact, optimal medical therapy (defined as therapy with aspirin, a beta-blocker, an ACE inhibitor, and a statin) was used in 43.4% of the patients before COURAGE and in 45.0% after the COURAGE report. In COURAGE, 32% had diabetes, 12% of the patients were asymptomatic, and 30% had class I angina.

In the most recent analysis by Dr. Borden, one-third of patients (more than 70,000) had no angina prior to PCI. One must wonder what the perceived patient benefit was that led to the performance of a PCI in those patients.

My patient's other cardiologist advised angiography for my patient partly because of a concern for the early identification of ischemic heart disease in diabetic patients. Indeed, this concern had led the American Diabetes Association to recommend that in addition to standard secondary prevention therapy for both diabetes and coronary artery disease, patients with two or more risk factors for coronary artery disease undergo early screening (Diabetes Care 1998;13:1551-9).

These recommendations, however, were not evidence based, but made on the recommendation of an expert panel. The DIAD (Detection of Ischemia in Asymptomatic Diabetics) trial has since provided further insight into the issue of screening asymptomatic diabetic patients (JAMA 2009;301:1547-55), an issue that remains controversial.

Although not a randomized trial, DIAD indicates that the event rate in asymptomatic diabetic patients in general is low, and that a positive myocardial perfusion stress test did not identify patients who were at an increase risk of ischemic events.

Of the 522 asymptomatic patients screened, 409 (78%) had normal results, 50 (10%) had a small perfusion defect, and 33 (6%) had moderate or large perfusion defects. Although there was no significantly increased risk of cardiac events in patients with small defects when they were compared with those who had no perfusion defect, there was a sixfold increase risk in patients with moderate to large defects on myocardial perfusion imaging. Only 4.4% of patients went on to angiography, a decision driven by the clinical judgment of the patient's physician.

Of course, in my example, the greatest pressure for angiography came from the patient's wife, who was convinced that on the basis of conventional wisdom, myocardial perfusion imaging–guided PCI would identify a critical lesion that, when treated with PCI, would prolong her husband's life. And as a matter of fact, in order to prove the absence of coronary artery disease based on the normal perfusion test, I agreed to arrange an angiogram should they need reassurance that the test was normal. What would have eventuated should we have found a lesion remains for your conjecture.

But it is clear that there is an overabundance of angiograms being performed in asymptomatic patients, which more than likely leads to the performance of unnecessary PCIs in asymptomatic patients. Angiography has become the “carpenter's hammer,” with the little regard for its benefit.

A more reasonable and effective approach to diabetes patients (as well as other asymptomatic patients) is the institution of adequate primary prevention, which has been shown to have both morbidity and mortality benefits.

It’s easy to know whether a critique of some article or other was written by a statistician or a methodologist—it states how badly the study was done and how incompetently the data were analyzed. Indeed, it is extremely easy to criticize any study, no matter how well it was conducted, because all applied research involves compromises of one sort or another. Well, be prepared for a surprise. In this column, we will be discussing a study that we believe was carried out well and analyzed correctly. That’s not to say that we agree with their conclusions (we don’t), but at least the study yields data that people can argue about without dismissing the paper as a whole.

Click on the PDF icon at the top of this introduction to read the full article.

It’s easy to know whether a critique of some article or other was written by a statistician or a methodologist—it states how badly the study was done and how incompetently the data were analyzed. Indeed, it is extremely easy to criticize any study, no matter how well it was conducted, because all applied research involves compromises of one sort or another. Well, be prepared for a surprise. In this column, we will be discussing a study that we believe was carried out well and analyzed correctly. That’s not to say that we agree with their conclusions (we don’t), but at least the study yields data that people can argue about without dismissing the paper as a whole.

Click on the PDF icon at the top of this introduction to read the full article.

It’s easy to know whether a critique of some article or other was written by a statistician or a methodologist—it states how badly the study was done and how incompetently the data were analyzed. Indeed, it is extremely easy to criticize any study, no matter how well it was conducted, because all applied research involves compromises of one sort or another. Well, be prepared for a surprise. In this column, we will be discussing a study that we believe was carried out well and analyzed correctly. That’s not to say that we agree with their conclusions (we don’t), but at least the study yields data that people can argue about without dismissing the paper as a whole.

Click on the PDF icon at the top of this introduction to read the full article.

Ying-Kei Hui, MD,1 Thomas Slattery, MD,2 Dale M. Frank, MD,3 Carol Dolinskas, MD,4 and David Henry, MD, FACP5
Departments of 1Internal Medicine, Pennsylvania Hospital; 2Radiology, Pennsylvania Hospital; 3Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania; 4Nuclear Medicine, Diagnostic Radiology, Pennsylvania Hospital; and 5Medicine, Pennsylvania Hospital, Philadelphia, PA

Multiple myeloma (MM) is a neoplastic proliferation of monoclonal plasma cells within the bone marrow, which overproduces immunoglobulin. This disorder accounts for approximately 1% of all reported neoplasms and 12%– 15% of all hematologic malignancies.1 It is the second most common hematologic malignancy diagnosed.2 The etiology is still not fully understood. MM typically affects older patients, ranging from 50–78 years (median, 61 years).3 Common clinical presentations include fatigue, anemia, renal failure, hypercalcemia, bone pain, and pathologic fractures.

Bone involvement in MM may vary at presentation. Most commonly, radiographic findings include multiple small, sharply defined, lytic, “punched-out” lesions without reactive bone formation, arising in the medullary cavity at sites of preserved hematopoiesis in adults (the axial skeleton). The pathophysiology of the bone findings is uncertain, though presumed to be resultant of either inhibition of osteoblastic activity and/ or activation of osteoclastic activity. Involvement of the cortex results in endosteal scalloping, with invasion of the periosteum and occasionally extraosseous extension. Lesions are most commonly seen in the vertebrae, ribs, skull, pelvic bones, and femur, in descending order of prevalence. Distal bone involvement is less common, though cases with predominant involvement in peripheral bones have been described. Uncommon radiographic presentations include diffuse skeletal osteopenia without focal lesions or sclerotic lesions. 4,5 To our knowledge, multiple bone infarcts as a complication of MM have not been reported in the medical literature.

Case presentation
A 47-year-old man with no significant medical history presented after the recent onset of painless hematuria, which spontaneously resolved after 2 days. He complained of left knee pain, which he noted after doing yard work.

Routine laboratory examination showed normocytic normochromic anemia, with a hemoglobin level of 11.5 g/dL and a mildly elevated alkaline phosphatase (ALP) level at 124 units/L. An MRI of the left knee showed increased red bone marrow within the distal femur and proximal tibia/fibula, initially thought to be compatible with anemia from an unexplained inflammatory process. Further urologic and gastroenterologic workup was negative.

Several months later, our patient was noted to have progressive fatigue, with a decrease in hemoglobin level to 10.6 g/dL and a mildly elevated erythrocyte sedimentation rate. Physical examination was otherwise unremarkable. A repeat MRI of both knees showed an extensive marrow infiltrative process, with multiple presumed secondary bone infarcts in the distal femora and proximal tibias, proximal fibulae, and patellae (Figure 1). A tandem skeletal survey showed mild diffuse osteopenia and several small, rounded, lytic foci in the skull (Figure 2), which were suspicious for MM. No focal radiographic lesions were seen (Figure 3).

Bone marrow biopsy from the left posterior iliac crest revealed hypocellular marrow (20%). An expansion of plasmacytoid cells with eccentrically placed, round nuclei, clumped chromatin, occasional nucleoli, and moderate amounts of eosinophilic cytoplasm accounted for 75% of the marrow cellularity. An aspirate smear demonstrated scattered mature plasma cells, accounting for roughly 15% of the total cellularity. Flow cytometry showed no overt evidence of marrow involvement by a lymphocytic clone. Bone biopsy was not performed in the areas of the knees seen to be abnormal on MRI examination.

Serum protein electrophoresis (SPEP) showed a band in the betagamma region. Immunofixation confirmed the presence of a monoclonal paraprotein, consisting predominantly of immunoglobulin A (IgA) heavy chain and kappa light chain. A bone marrow biopsy and aspirate showed replacement of most hematopoietic elements by sheets of mature plasma cells, accounting for 75% of the total marrow cellularity (Figure 4). Confirmatory immunostains were positive for CD138, CD117, and kappa light chain (Figure 5) and negative for CD79a and lambda light chain (Figure 6). A diagnosis of MM was made based on the finding of M protein in the urine, the presence of greater than 10% clonal plasma cells in bone marrow, and related clinical symptomatology (including anemia and hypercalcemia).

The patient was started on immunomodulating therapy with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. Autologous stem cell transplantation may be considered after appropriate treatment.

Discussion
We offer the case of a patient with MM who presented with bilateral knee infarcts. Synonyms of bone infarct include osteonecrosis, bone necrosis, avascular necrosis, aseptic necrosis, ischemic bone necrosis, and bone death.6 MRI is the most sensitive imaging modality for evaluation of the bone marrow. It can detect early osteonecrotic changes in bones well before they are visible on radiography7; this fact was exemplified in our case, in which the patient had only mild osteopenia on knee radiographs but extensive osteonecrotic changes on MRI examination.

Bone infarct more commonly involves the hips than the knees.7 Knee involvement can be differentiated into two main categories: primary and secondary. Primary, spontaneous, or idiopathic involvement tends to be unilateral and usually is seen in the elderly, although the recent literature suggests that many of these socalled spontaneous cases are actually secondary to subcortical microfractures, which are then complicated by osteonecrosis.5 Secondary causes tend to present at a younger age, with bilateral and multifocal involvement. Examples of secondary causes include steroid therapy, alcoholism, decompression syndrome, hemoglobinopathies (sickle cell disease), autoimmune disease (lupus and antiphospholipid disease), infections (human immunodeficiency virus), radiation, and trauma.8–15 Other causes, such as chemotherapy toxicity in pediatric leukemia16 and Gaucher disease, have been reported.7 Osteonecrosis of the jaw is a known treatment complication of bisphosphonate therapy in patients with MM17; however, there have been no previous reports describing the presentation of multifocal bone infarcts in both knees in patients with MM.

Although the pathogenesis of bone infarction is unclear, it is thought to be caused by the combined effects of systemic and local factors affecting the blood supply, vascular damage, increased intraosseous pressure, and mechanical stresses. These processes lead to compromise of the bone vasculature, resulting in the death of bone and marrow cells.9 In our case, MRI of both knees revealed an extensive marrow infiltrative process, which may have caused local vasculature damage and diminished blood supply resulting in bone infarctions.

Conclusion
Bone infarction of any joint is not a well-established complication of MM. Physicians should be aware of this potential presentation. Although there is no cure for MM, early recognition of MM can lead to more effective treatment, thus slowing disease progression and improving overall clinical outcomes.

Disclosures
The authors have no conflicts of interest to disclose.

References
1. Phekoo KJ, Schey SA, Richards MA, et al. A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK. Br J Haematol 2004;127:299–304.

 2. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol 2007;20:613–624.

 3. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009;84:34–38.

 4. Winterbottom AP, Shaw AS. Imaging patients with myeloma. Clin Radiol 2009;64:1–11.

 5. Resnick D. Diagnosis of Bone and Joint Disorders. Philadelphia, PA: WB Saunders; 2002:2188–2233.

 6. Stoller D, Tirman P, Bredella M, Branstetter R. Diagnostic Imaging: Orthopaedics. Philadelphia, PA: WB Saunders; 2003:82.

 7. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124.

 8. Patel DV, Breazeale NM, Behr CT, Warren RF, Wickiewicz TL, O’Brien SJ. Osteonecrosis of the knee: current clinical concepts. Knee Surg Sports Traumatol Arthrosc 1998;6:2–11.

 9. Chang CC, Greenspan A, Gershwin ME. Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 1993;23:47–69.

 10. Jones LC, Mont MA, Le TB, et al. Procoagulants and osteonecrosis. J Rheumatol 2003; 30:783–791.

 11. Saito N, Nadgir RN, Flower EN, Sakai O. Clinical and radiologic manifestations of sickle cell disease in the head and neck. Radiographics 2010;30:1021–1034.

 12. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17–25.

 13. Mendenhall WM. Mandibular: osteoradionecrosis. J Clin Oncol 2004;22:4867–4868.

 14. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for antiphospholipid antibodies? Ann Rheum Dis 2000;59:462–467.

15. Kelman GJ, Williams GW, Colwell CW Jr, Walker RH. Steroid-related osteonecrosis of the knee: two case reports and a literature review. Clin Orthop Relat Res 1990;257:171–176.

 16. Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia? A 2- to 7-year study. Clin Orthop Relat Res 2010;468:2454–2459.

 17. Cafro AM, Barbarano L, Nosari AM, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma 2008;8:111–116.

Ying-Kei Hui, MD,1 Thomas Slattery, MD,2 Dale M. Frank, MD,3 Carol Dolinskas, MD,4 and David Henry, MD, FACP5
Departments of 1Internal Medicine, Pennsylvania Hospital; 2Radiology, Pennsylvania Hospital; 3Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania; 4Nuclear Medicine, Diagnostic Radiology, Pennsylvania Hospital; and 5Medicine, Pennsylvania Hospital, Philadelphia, PA

Multiple myeloma (MM) is a neoplastic proliferation of monoclonal plasma cells within the bone marrow, which overproduces immunoglobulin. This disorder accounts for approximately 1% of all reported neoplasms and 12%– 15% of all hematologic malignancies.1 It is the second most common hematologic malignancy diagnosed.2 The etiology is still not fully understood. MM typically affects older patients, ranging from 50–78 years (median, 61 years).3 Common clinical presentations include fatigue, anemia, renal failure, hypercalcemia, bone pain, and pathologic fractures.

Bone involvement in MM may vary at presentation. Most commonly, radiographic findings include multiple small, sharply defined, lytic, “punched-out” lesions without reactive bone formation, arising in the medullary cavity at sites of preserved hematopoiesis in adults (the axial skeleton). The pathophysiology of the bone findings is uncertain, though presumed to be resultant of either inhibition of osteoblastic activity and/ or activation of osteoclastic activity. Involvement of the cortex results in endosteal scalloping, with invasion of the periosteum and occasionally extraosseous extension. Lesions are most commonly seen in the vertebrae, ribs, skull, pelvic bones, and femur, in descending order of prevalence. Distal bone involvement is less common, though cases with predominant involvement in peripheral bones have been described. Uncommon radiographic presentations include diffuse skeletal osteopenia without focal lesions or sclerotic lesions. 4,5 To our knowledge, multiple bone infarcts as a complication of MM have not been reported in the medical literature.

Case presentation
A 47-year-old man with no significant medical history presented after the recent onset of painless hematuria, which spontaneously resolved after 2 days. He complained of left knee pain, which he noted after doing yard work.

Routine laboratory examination showed normocytic normochromic anemia, with a hemoglobin level of 11.5 g/dL and a mildly elevated alkaline phosphatase (ALP) level at 124 units/L. An MRI of the left knee showed increased red bone marrow within the distal femur and proximal tibia/fibula, initially thought to be compatible with anemia from an unexplained inflammatory process. Further urologic and gastroenterologic workup was negative.

Several months later, our patient was noted to have progressive fatigue, with a decrease in hemoglobin level to 10.6 g/dL and a mildly elevated erythrocyte sedimentation rate. Physical examination was otherwise unremarkable. A repeat MRI of both knees showed an extensive marrow infiltrative process, with multiple presumed secondary bone infarcts in the distal femora and proximal tibias, proximal fibulae, and patellae (Figure 1). A tandem skeletal survey showed mild diffuse osteopenia and several small, rounded, lytic foci in the skull (Figure 2), which were suspicious for MM. No focal radiographic lesions were seen (Figure 3).

Bone marrow biopsy from the left posterior iliac crest revealed hypocellular marrow (20%). An expansion of plasmacytoid cells with eccentrically placed, round nuclei, clumped chromatin, occasional nucleoli, and moderate amounts of eosinophilic cytoplasm accounted for 75% of the marrow cellularity. An aspirate smear demonstrated scattered mature plasma cells, accounting for roughly 15% of the total cellularity. Flow cytometry showed no overt evidence of marrow involvement by a lymphocytic clone. Bone biopsy was not performed in the areas of the knees seen to be abnormal on MRI examination.

Serum protein electrophoresis (SPEP) showed a band in the betagamma region. Immunofixation confirmed the presence of a monoclonal paraprotein, consisting predominantly of immunoglobulin A (IgA) heavy chain and kappa light chain. A bone marrow biopsy and aspirate showed replacement of most hematopoietic elements by sheets of mature plasma cells, accounting for 75% of the total marrow cellularity (Figure 4). Confirmatory immunostains were positive for CD138, CD117, and kappa light chain (Figure 5) and negative for CD79a and lambda light chain (Figure 6). A diagnosis of MM was made based on the finding of M protein in the urine, the presence of greater than 10% clonal plasma cells in bone marrow, and related clinical symptomatology (including anemia and hypercalcemia).

The patient was started on immunomodulating therapy with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. Autologous stem cell transplantation may be considered after appropriate treatment.

Discussion
We offer the case of a patient with MM who presented with bilateral knee infarcts. Synonyms of bone infarct include osteonecrosis, bone necrosis, avascular necrosis, aseptic necrosis, ischemic bone necrosis, and bone death.6 MRI is the most sensitive imaging modality for evaluation of the bone marrow. It can detect early osteonecrotic changes in bones well before they are visible on radiography7; this fact was exemplified in our case, in which the patient had only mild osteopenia on knee radiographs but extensive osteonecrotic changes on MRI examination.

Bone infarct more commonly involves the hips than the knees.7 Knee involvement can be differentiated into two main categories: primary and secondary. Primary, spontaneous, or idiopathic involvement tends to be unilateral and usually is seen in the elderly, although the recent literature suggests that many of these socalled spontaneous cases are actually secondary to subcortical microfractures, which are then complicated by osteonecrosis.5 Secondary causes tend to present at a younger age, with bilateral and multifocal involvement. Examples of secondary causes include steroid therapy, alcoholism, decompression syndrome, hemoglobinopathies (sickle cell disease), autoimmune disease (lupus and antiphospholipid disease), infections (human immunodeficiency virus), radiation, and trauma.8–15 Other causes, such as chemotherapy toxicity in pediatric leukemia16 and Gaucher disease, have been reported.7 Osteonecrosis of the jaw is a known treatment complication of bisphosphonate therapy in patients with MM17; however, there have been no previous reports describing the presentation of multifocal bone infarcts in both knees in patients with MM.

Although the pathogenesis of bone infarction is unclear, it is thought to be caused by the combined effects of systemic and local factors affecting the blood supply, vascular damage, increased intraosseous pressure, and mechanical stresses. These processes lead to compromise of the bone vasculature, resulting in the death of bone and marrow cells.9 In our case, MRI of both knees revealed an extensive marrow infiltrative process, which may have caused local vasculature damage and diminished blood supply resulting in bone infarctions.

Conclusion
Bone infarction of any joint is not a well-established complication of MM. Physicians should be aware of this potential presentation. Although there is no cure for MM, early recognition of MM can lead to more effective treatment, thus slowing disease progression and improving overall clinical outcomes.

Disclosures
The authors have no conflicts of interest to disclose.

References
1. Phekoo KJ, Schey SA, Richards MA, et al. A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK. Br J Haematol 2004;127:299–304.

 2. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol 2007;20:613–624.

 3. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009;84:34–38.

 4. Winterbottom AP, Shaw AS. Imaging patients with myeloma. Clin Radiol 2009;64:1–11.

 5. Resnick D. Diagnosis of Bone and Joint Disorders. Philadelphia, PA: WB Saunders; 2002:2188–2233.

 6. Stoller D, Tirman P, Bredella M, Branstetter R. Diagnostic Imaging: Orthopaedics. Philadelphia, PA: WB Saunders; 2003:82.

 7. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124.

 8. Patel DV, Breazeale NM, Behr CT, Warren RF, Wickiewicz TL, O’Brien SJ. Osteonecrosis of the knee: current clinical concepts. Knee Surg Sports Traumatol Arthrosc 1998;6:2–11.

 9. Chang CC, Greenspan A, Gershwin ME. Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 1993;23:47–69.

 10. Jones LC, Mont MA, Le TB, et al. Procoagulants and osteonecrosis. J Rheumatol 2003; 30:783–791.

 11. Saito N, Nadgir RN, Flower EN, Sakai O. Clinical and radiologic manifestations of sickle cell disease in the head and neck. Radiographics 2010;30:1021–1034.

 12. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17–25.

 13. Mendenhall WM. Mandibular: osteoradionecrosis. J Clin Oncol 2004;22:4867–4868.

 14. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for antiphospholipid antibodies? Ann Rheum Dis 2000;59:462–467.

15. Kelman GJ, Williams GW, Colwell CW Jr, Walker RH. Steroid-related osteonecrosis of the knee: two case reports and a literature review. Clin Orthop Relat Res 1990;257:171–176.

 16. Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia? A 2- to 7-year study. Clin Orthop Relat Res 2010;468:2454–2459.

 17. Cafro AM, Barbarano L, Nosari AM, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma 2008;8:111–116.

Ying-Kei Hui, MD,1 Thomas Slattery, MD,2 Dale M. Frank, MD,3 Carol Dolinskas, MD,4 and David Henry, MD, FACP5
Departments of 1Internal Medicine, Pennsylvania Hospital; 2Radiology, Pennsylvania Hospital; 3Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania; 4Nuclear Medicine, Diagnostic Radiology, Pennsylvania Hospital; and 5Medicine, Pennsylvania Hospital, Philadelphia, PA

Multiple myeloma (MM) is a neoplastic proliferation of monoclonal plasma cells within the bone marrow, which overproduces immunoglobulin. This disorder accounts for approximately 1% of all reported neoplasms and 12%– 15% of all hematologic malignancies.1 It is the second most common hematologic malignancy diagnosed.2 The etiology is still not fully understood. MM typically affects older patients, ranging from 50–78 years (median, 61 years).3 Common clinical presentations include fatigue, anemia, renal failure, hypercalcemia, bone pain, and pathologic fractures.

Bone involvement in MM may vary at presentation. Most commonly, radiographic findings include multiple small, sharply defined, lytic, “punched-out” lesions without reactive bone formation, arising in the medullary cavity at sites of preserved hematopoiesis in adults (the axial skeleton). The pathophysiology of the bone findings is uncertain, though presumed to be resultant of either inhibition of osteoblastic activity and/ or activation of osteoclastic activity. Involvement of the cortex results in endosteal scalloping, with invasion of the periosteum and occasionally extraosseous extension. Lesions are most commonly seen in the vertebrae, ribs, skull, pelvic bones, and femur, in descending order of prevalence. Distal bone involvement is less common, though cases with predominant involvement in peripheral bones have been described. Uncommon radiographic presentations include diffuse skeletal osteopenia without focal lesions or sclerotic lesions. 4,5 To our knowledge, multiple bone infarcts as a complication of MM have not been reported in the medical literature.

Case presentation
A 47-year-old man with no significant medical history presented after the recent onset of painless hematuria, which spontaneously resolved after 2 days. He complained of left knee pain, which he noted after doing yard work.

Routine laboratory examination showed normocytic normochromic anemia, with a hemoglobin level of 11.5 g/dL and a mildly elevated alkaline phosphatase (ALP) level at 124 units/L. An MRI of the left knee showed increased red bone marrow within the distal femur and proximal tibia/fibula, initially thought to be compatible with anemia from an unexplained inflammatory process. Further urologic and gastroenterologic workup was negative.

Several months later, our patient was noted to have progressive fatigue, with a decrease in hemoglobin level to 10.6 g/dL and a mildly elevated erythrocyte sedimentation rate. Physical examination was otherwise unremarkable. A repeat MRI of both knees showed an extensive marrow infiltrative process, with multiple presumed secondary bone infarcts in the distal femora and proximal tibias, proximal fibulae, and patellae (Figure 1). A tandem skeletal survey showed mild diffuse osteopenia and several small, rounded, lytic foci in the skull (Figure 2), which were suspicious for MM. No focal radiographic lesions were seen (Figure 3).

Bone marrow biopsy from the left posterior iliac crest revealed hypocellular marrow (20%). An expansion of plasmacytoid cells with eccentrically placed, round nuclei, clumped chromatin, occasional nucleoli, and moderate amounts of eosinophilic cytoplasm accounted for 75% of the marrow cellularity. An aspirate smear demonstrated scattered mature plasma cells, accounting for roughly 15% of the total cellularity. Flow cytometry showed no overt evidence of marrow involvement by a lymphocytic clone. Bone biopsy was not performed in the areas of the knees seen to be abnormal on MRI examination.

Serum protein electrophoresis (SPEP) showed a band in the betagamma region. Immunofixation confirmed the presence of a monoclonal paraprotein, consisting predominantly of immunoglobulin A (IgA) heavy chain and kappa light chain. A bone marrow biopsy and aspirate showed replacement of most hematopoietic elements by sheets of mature plasma cells, accounting for 75% of the total marrow cellularity (Figure 4). Confirmatory immunostains were positive for CD138, CD117, and kappa light chain (Figure 5) and negative for CD79a and lambda light chain (Figure 6). A diagnosis of MM was made based on the finding of M protein in the urine, the presence of greater than 10% clonal plasma cells in bone marrow, and related clinical symptomatology (including anemia and hypercalcemia).

The patient was started on immunomodulating therapy with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. Autologous stem cell transplantation may be considered after appropriate treatment.

Discussion
We offer the case of a patient with MM who presented with bilateral knee infarcts. Synonyms of bone infarct include osteonecrosis, bone necrosis, avascular necrosis, aseptic necrosis, ischemic bone necrosis, and bone death.6 MRI is the most sensitive imaging modality for evaluation of the bone marrow. It can detect early osteonecrotic changes in bones well before they are visible on radiography7; this fact was exemplified in our case, in which the patient had only mild osteopenia on knee radiographs but extensive osteonecrotic changes on MRI examination.

Bone infarct more commonly involves the hips than the knees.7 Knee involvement can be differentiated into two main categories: primary and secondary. Primary, spontaneous, or idiopathic involvement tends to be unilateral and usually is seen in the elderly, although the recent literature suggests that many of these socalled spontaneous cases are actually secondary to subcortical microfractures, which are then complicated by osteonecrosis.5 Secondary causes tend to present at a younger age, with bilateral and multifocal involvement. Examples of secondary causes include steroid therapy, alcoholism, decompression syndrome, hemoglobinopathies (sickle cell disease), autoimmune disease (lupus and antiphospholipid disease), infections (human immunodeficiency virus), radiation, and trauma.8–15 Other causes, such as chemotherapy toxicity in pediatric leukemia16 and Gaucher disease, have been reported.7 Osteonecrosis of the jaw is a known treatment complication of bisphosphonate therapy in patients with MM17; however, there have been no previous reports describing the presentation of multifocal bone infarcts in both knees in patients with MM.

Although the pathogenesis of bone infarction is unclear, it is thought to be caused by the combined effects of systemic and local factors affecting the blood supply, vascular damage, increased intraosseous pressure, and mechanical stresses. These processes lead to compromise of the bone vasculature, resulting in the death of bone and marrow cells.9 In our case, MRI of both knees revealed an extensive marrow infiltrative process, which may have caused local vasculature damage and diminished blood supply resulting in bone infarctions.

Conclusion
Bone infarction of any joint is not a well-established complication of MM. Physicians should be aware of this potential presentation. Although there is no cure for MM, early recognition of MM can lead to more effective treatment, thus slowing disease progression and improving overall clinical outcomes.

Disclosures
The authors have no conflicts of interest to disclose.

References
1. Phekoo KJ, Schey SA, Richards MA, et al. A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK. Br J Haematol 2004;127:299–304.

 2. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol 2007;20:613–624.

 3. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009;84:34–38.

 4. Winterbottom AP, Shaw AS. Imaging patients with myeloma. Clin Radiol 2009;64:1–11.

 5. Resnick D. Diagnosis of Bone and Joint Disorders. Philadelphia, PA: WB Saunders; 2002:2188–2233.

 6. Stoller D, Tirman P, Bredella M, Branstetter R. Diagnostic Imaging: Orthopaedics. Philadelphia, PA: WB Saunders; 2003:82.

 7. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124.

 8. Patel DV, Breazeale NM, Behr CT, Warren RF, Wickiewicz TL, O’Brien SJ. Osteonecrosis of the knee: current clinical concepts. Knee Surg Sports Traumatol Arthrosc 1998;6:2–11.

 9. Chang CC, Greenspan A, Gershwin ME. Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 1993;23:47–69.

 10. Jones LC, Mont MA, Le TB, et al. Procoagulants and osteonecrosis. J Rheumatol 2003; 30:783–791.

 11. Saito N, Nadgir RN, Flower EN, Sakai O. Clinical and radiologic manifestations of sickle cell disease in the head and neck. Radiographics 2010;30:1021–1034.

 12. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17–25.

 13. Mendenhall WM. Mandibular: osteoradionecrosis. J Clin Oncol 2004;22:4867–4868.

 14. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for antiphospholipid antibodies? Ann Rheum Dis 2000;59:462–467.

15. Kelman GJ, Williams GW, Colwell CW Jr, Walker RH. Steroid-related osteonecrosis of the knee: two case reports and a literature review. Clin Orthop Relat Res 1990;257:171–176.

 16. Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia? A 2- to 7-year study. Clin Orthop Relat Res 2010;468:2454–2459.

 17. Cafro AM, Barbarano L, Nosari AM, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma 2008;8:111–116.

Fainting in children most often is benign. Often from a history alone, you can determine critical information that will enable you to reassure the patient and family or to consider referral for a specialist evaluation.

The most important thing to determine is the course of events that preceded the syncopal event. That is, if the child just completed a sporting activity on a hot day, was in a hot shower, had a high fever, or was dehydrated before fainting, the level of anxiety about the event should be very low. The same applies if the syncope was triggered by a sudden fright or other strong emotional event.

If the child is old enough to provide a good description of the event, ask if they “knew” that something was about to happen before they fainted. Most patients with routine syncope report an “aura” that includes visual changes (tunnel vision or vision getting dark, for example) and dizziness. Also, witnesses will say that the child “woke up” quickly and without prolonged confusion after the event. Such a description helps to distinguish a simple syncopal event from a seizure or a life-threatening arrhythmia.

With most benign cases of syncope, the pediatrician should counsel the child and the parents about adequate hydration before participation in sports and to be mindful of getting enough salt in the diet.

A normal history and physical examination should reassure you. In most cases, these normal findings will mean that you can treat the child in your office without further referrals.

Don't forget to take the child's blood pressure. Low resting blood pressure, especially in rapidly growing teenagers, can predispose your patients to vasovagal syncope. Patients with low resting blood pressure often have a lower threshold for syncope, compared with children with normal pressure. Recommend addition of some salt to the patient's diet if he has low blood pressure – this can help to reduce the risk of future syncope.

Injury prevention is important, because children who experience syncope often fall unexpectedly. The best strategy to minimize this risk is to review the symptoms that herald the onset of syncope with each patient. Then instruct the child if she experiences any of the warning signs to get to the floor with her legs elevated as soon as possible. This also will reduce the severity and the length of the episode.

Patients and parents will naturally have questions after the child experiences syncope. Although noncardiac conditions such as hypothyroidism or epilepsy can cause a child to faint, fainting is usually a failure of the heart to pump enough blood to the brain. Syncope can result from low blood pressure (dehydration, vasodilation), poor pumping function of the heart, other structural heart issues, and/or from a change in the rhythm that leads to less-efficient pumping. Rhythm changes include both fast and slow heart rates.

In the absence of any structural or electrical abnormality of the heart, the most common reason for fainting is vasovagal syncope. There are two sets of nerves that connect the central nervous system to the heart. The sympathetic system sends the “speed up” signal to the heart and the vagus nerve sends the “slow-down” signal to the heart. Vasovagal syncope occurs when the body sends an erroneous signal to the heart to slow down, insufficient blood is pumped, blood pressure falls, and the child faints.

During a syncopal work-up, most important structural heart issues, which can cause fainting, will be obvious on a physical examination. In almost all cases, children with cardiac disease significant enough to cause syncope will have been diagnosed previously. The exam can feature significant cardiac murmurs, peripheral edema, chest pain, jugular venous distension, hepatomegaly, and absent or diminished pulses. Patients with significant congenital heart disease most often will present with shortness of breath on exertion. If you rule out these findings and the patient has a normal examination, you can be virtually certain that the event is not related to a structural heart problem.

If there is any doubt, an echocardiogram is the definitive test to rule out a subtle structural abnormality. Hypertrophic cardiomyopathies and coronary anomalies are among the conditions that may contribute to syncope and may only be detectable with specialized cardiac imaging.

The child with recurrent syncopal events or with an atypical history most often requires additional evaluation by a specialist, usually to reassure the family. When I see a patient for the first time, I take a thorough history and order an ECG to detect the most common electrical/arrhythmic reasons for syncope. A diagnosis of Wolff-Parkinson-White syndrome, heart block, and long QT syndrome can easily be identified from a routine ECG. Holter evaluations or 30-day home monitoring may be helpful in ruling out arrhythmias. Neurologic evaluation can be helpful to rule out seizure activity which may masquerade as syncope. Rarely, in teenagers and adults, atypical migraine headaches may present with alterations of consciousness. In these patients, there is often a strong family history of migraine. When these episodes recur, they are similar each time, as is stereotypical of other migraine aura.

Fainting in children most often is benign. Often from a history alone, you can determine critical information that will enable you to reassure the patient and family or to consider referral for a specialist evaluation.

The most important thing to determine is the course of events that preceded the syncopal event. That is, if the child just completed a sporting activity on a hot day, was in a hot shower, had a high fever, or was dehydrated before fainting, the level of anxiety about the event should be very low. The same applies if the syncope was triggered by a sudden fright or other strong emotional event.

If the child is old enough to provide a good description of the event, ask if they “knew” that something was about to happen before they fainted. Most patients with routine syncope report an “aura” that includes visual changes (tunnel vision or vision getting dark, for example) and dizziness. Also, witnesses will say that the child “woke up” quickly and without prolonged confusion after the event. Such a description helps to distinguish a simple syncopal event from a seizure or a life-threatening arrhythmia.

With most benign cases of syncope, the pediatrician should counsel the child and the parents about adequate hydration before participation in sports and to be mindful of getting enough salt in the diet.

A normal history and physical examination should reassure you. In most cases, these normal findings will mean that you can treat the child in your office without further referrals.

Don't forget to take the child's blood pressure. Low resting blood pressure, especially in rapidly growing teenagers, can predispose your patients to vasovagal syncope. Patients with low resting blood pressure often have a lower threshold for syncope, compared with children with normal pressure. Recommend addition of some salt to the patient's diet if he has low blood pressure – this can help to reduce the risk of future syncope.

Injury prevention is important, because children who experience syncope often fall unexpectedly. The best strategy to minimize this risk is to review the symptoms that herald the onset of syncope with each patient. Then instruct the child if she experiences any of the warning signs to get to the floor with her legs elevated as soon as possible. This also will reduce the severity and the length of the episode.

Patients and parents will naturally have questions after the child experiences syncope. Although noncardiac conditions such as hypothyroidism or epilepsy can cause a child to faint, fainting is usually a failure of the heart to pump enough blood to the brain. Syncope can result from low blood pressure (dehydration, vasodilation), poor pumping function of the heart, other structural heart issues, and/or from a change in the rhythm that leads to less-efficient pumping. Rhythm changes include both fast and slow heart rates.

In the absence of any structural or electrical abnormality of the heart, the most common reason for fainting is vasovagal syncope. There are two sets of nerves that connect the central nervous system to the heart. The sympathetic system sends the “speed up” signal to the heart and the vagus nerve sends the “slow-down” signal to the heart. Vasovagal syncope occurs when the body sends an erroneous signal to the heart to slow down, insufficient blood is pumped, blood pressure falls, and the child faints.

During a syncopal work-up, most important structural heart issues, which can cause fainting, will be obvious on a physical examination. In almost all cases, children with cardiac disease significant enough to cause syncope will have been diagnosed previously. The exam can feature significant cardiac murmurs, peripheral edema, chest pain, jugular venous distension, hepatomegaly, and absent or diminished pulses. Patients with significant congenital heart disease most often will present with shortness of breath on exertion. If you rule out these findings and the patient has a normal examination, you can be virtually certain that the event is not related to a structural heart problem.

If there is any doubt, an echocardiogram is the definitive test to rule out a subtle structural abnormality. Hypertrophic cardiomyopathies and coronary anomalies are among the conditions that may contribute to syncope and may only be detectable with specialized cardiac imaging.

The child with recurrent syncopal events or with an atypical history most often requires additional evaluation by a specialist, usually to reassure the family. When I see a patient for the first time, I take a thorough history and order an ECG to detect the most common electrical/arrhythmic reasons for syncope. A diagnosis of Wolff-Parkinson-White syndrome, heart block, and long QT syndrome can easily be identified from a routine ECG. Holter evaluations or 30-day home monitoring may be helpful in ruling out arrhythmias. Neurologic evaluation can be helpful to rule out seizure activity which may masquerade as syncope. Rarely, in teenagers and adults, atypical migraine headaches may present with alterations of consciousness. In these patients, there is often a strong family history of migraine. When these episodes recur, they are similar each time, as is stereotypical of other migraine aura.

Fainting in children most often is benign. Often from a history alone, you can determine critical information that will enable you to reassure the patient and family or to consider referral for a specialist evaluation.

The most important thing to determine is the course of events that preceded the syncopal event. That is, if the child just completed a sporting activity on a hot day, was in a hot shower, had a high fever, or was dehydrated before fainting, the level of anxiety about the event should be very low. The same applies if the syncope was triggered by a sudden fright or other strong emotional event.

If the child is old enough to provide a good description of the event, ask if they “knew” that something was about to happen before they fainted. Most patients with routine syncope report an “aura” that includes visual changes (tunnel vision or vision getting dark, for example) and dizziness. Also, witnesses will say that the child “woke up” quickly and without prolonged confusion after the event. Such a description helps to distinguish a simple syncopal event from a seizure or a life-threatening arrhythmia.

With most benign cases of syncope, the pediatrician should counsel the child and the parents about adequate hydration before participation in sports and to be mindful of getting enough salt in the diet.

A normal history and physical examination should reassure you. In most cases, these normal findings will mean that you can treat the child in your office without further referrals.

Don't forget to take the child's blood pressure. Low resting blood pressure, especially in rapidly growing teenagers, can predispose your patients to vasovagal syncope. Patients with low resting blood pressure often have a lower threshold for syncope, compared with children with normal pressure. Recommend addition of some salt to the patient's diet if he has low blood pressure – this can help to reduce the risk of future syncope.

Injury prevention is important, because children who experience syncope often fall unexpectedly. The best strategy to minimize this risk is to review the symptoms that herald the onset of syncope with each patient. Then instruct the child if she experiences any of the warning signs to get to the floor with her legs elevated as soon as possible. This also will reduce the severity and the length of the episode.

Patients and parents will naturally have questions after the child experiences syncope. Although noncardiac conditions such as hypothyroidism or epilepsy can cause a child to faint, fainting is usually a failure of the heart to pump enough blood to the brain. Syncope can result from low blood pressure (dehydration, vasodilation), poor pumping function of the heart, other structural heart issues, and/or from a change in the rhythm that leads to less-efficient pumping. Rhythm changes include both fast and slow heart rates.

In the absence of any structural or electrical abnormality of the heart, the most common reason for fainting is vasovagal syncope. There are two sets of nerves that connect the central nervous system to the heart. The sympathetic system sends the “speed up” signal to the heart and the vagus nerve sends the “slow-down” signal to the heart. Vasovagal syncope occurs when the body sends an erroneous signal to the heart to slow down, insufficient blood is pumped, blood pressure falls, and the child faints.

During a syncopal work-up, most important structural heart issues, which can cause fainting, will be obvious on a physical examination. In almost all cases, children with cardiac disease significant enough to cause syncope will have been diagnosed previously. The exam can feature significant cardiac murmurs, peripheral edema, chest pain, jugular venous distension, hepatomegaly, and absent or diminished pulses. Patients with significant congenital heart disease most often will present with shortness of breath on exertion. If you rule out these findings and the patient has a normal examination, you can be virtually certain that the event is not related to a structural heart problem.

If there is any doubt, an echocardiogram is the definitive test to rule out a subtle structural abnormality. Hypertrophic cardiomyopathies and coronary anomalies are among the conditions that may contribute to syncope and may only be detectable with specialized cardiac imaging.

The child with recurrent syncopal events or with an atypical history most often requires additional evaluation by a specialist, usually to reassure the family. When I see a patient for the first time, I take a thorough history and order an ECG to detect the most common electrical/arrhythmic reasons for syncope. A diagnosis of Wolff-Parkinson-White syndrome, heart block, and long QT syndrome can easily be identified from a routine ECG. Holter evaluations or 30-day home monitoring may be helpful in ruling out arrhythmias. Neurologic evaluation can be helpful to rule out seizure activity which may masquerade as syncope. Rarely, in teenagers and adults, atypical migraine headaches may present with alterations of consciousness. In these patients, there is often a strong family history of migraine. When these episodes recur, they are similar each time, as is stereotypical of other migraine aura.

While most academic hospitalist groups might be struggling with the practicalities of new resident work-hour rules, pediatric hospitalist Glenn Rosenbluth, MD, sees an opportunity if the rules spur a migration from traditional call models to shift-based work.

Dr. Rosenbluth and colleagues at University of California at San Francisco's (UCSF) Benioff Children's Hospital are working on research that shows a shift-based model that complies with Accreditation Council for Graduate Medical Education (ACGME) guidelines can cut costs and reduce length of stay (LOS). The ACGME work-hour rules limit first-year residents to 16-hour shifts.

At UCSF Benioff, the traditional call model (with 30-hour shifts) was replaced by shift work in 2008. Medical inpatient teams now feature four interns working four-week blocks. Three weeks are scheduled as day shifts, with one week of night shifts.

"It's not that I think scheduling is the magic bullet," Dr. Rosenbluth says. "But I think scheduling can be leveraged."

In an abstract published in the Journal of Hospital Medicine, Dr. Rosenbluth and colleagues compared LOS and total cost for admitted patients diagnosed with the hospital's 10 most common pediatric diagnoses during the year before and after the schedule change. When the review was limited to non-ICU patients, LOS was reduced by 18% (rate ratio, 0.82; 95% CI, 0.73-0.93), and total costs were cut 10% (0.90; 95% CI,0.81-0.99). Dr. Rosenbluth says the model also has increased the staff's ownership of night patients, as interns moving from night shift to day shift will often see the same children.

Dr. Rosenbluth hopes to further his research to draw even more evidence-based conclusions. "I think shorter shifts are the way to go and I think our model shows that," he says. "I haven't proven that, but I do believe that. And that’s what we’re looking to study."

While most academic hospitalist groups might be struggling with the practicalities of new resident work-hour rules, pediatric hospitalist Glenn Rosenbluth, MD, sees an opportunity if the rules spur a migration from traditional call models to shift-based work.

Dr. Rosenbluth and colleagues at University of California at San Francisco's (UCSF) Benioff Children's Hospital are working on research that shows a shift-based model that complies with Accreditation Council for Graduate Medical Education (ACGME) guidelines can cut costs and reduce length of stay (LOS). The ACGME work-hour rules limit first-year residents to 16-hour shifts.

At UCSF Benioff, the traditional call model (with 30-hour shifts) was replaced by shift work in 2008. Medical inpatient teams now feature four interns working four-week blocks. Three weeks are scheduled as day shifts, with one week of night shifts.

"It's not that I think scheduling is the magic bullet," Dr. Rosenbluth says. "But I think scheduling can be leveraged."

In an abstract published in the Journal of Hospital Medicine, Dr. Rosenbluth and colleagues compared LOS and total cost for admitted patients diagnosed with the hospital's 10 most common pediatric diagnoses during the year before and after the schedule change. When the review was limited to non-ICU patients, LOS was reduced by 18% (rate ratio, 0.82; 95% CI, 0.73-0.93), and total costs were cut 10% (0.90; 95% CI,0.81-0.99). Dr. Rosenbluth says the model also has increased the staff's ownership of night patients, as interns moving from night shift to day shift will often see the same children.

Dr. Rosenbluth hopes to further his research to draw even more evidence-based conclusions. "I think shorter shifts are the way to go and I think our model shows that," he says. "I haven't proven that, but I do believe that. And that’s what we’re looking to study."

While most academic hospitalist groups might be struggling with the practicalities of new resident work-hour rules, pediatric hospitalist Glenn Rosenbluth, MD, sees an opportunity if the rules spur a migration from traditional call models to shift-based work.

Dr. Rosenbluth and colleagues at University of California at San Francisco's (UCSF) Benioff Children's Hospital are working on research that shows a shift-based model that complies with Accreditation Council for Graduate Medical Education (ACGME) guidelines can cut costs and reduce length of stay (LOS). The ACGME work-hour rules limit first-year residents to 16-hour shifts.

At UCSF Benioff, the traditional call model (with 30-hour shifts) was replaced by shift work in 2008. Medical inpatient teams now feature four interns working four-week blocks. Three weeks are scheduled as day shifts, with one week of night shifts.

"It's not that I think scheduling is the magic bullet," Dr. Rosenbluth says. "But I think scheduling can be leveraged."

In an abstract published in the Journal of Hospital Medicine, Dr. Rosenbluth and colleagues compared LOS and total cost for admitted patients diagnosed with the hospital's 10 most common pediatric diagnoses during the year before and after the schedule change. When the review was limited to non-ICU patients, LOS was reduced by 18% (rate ratio, 0.82; 95% CI, 0.73-0.93), and total costs were cut 10% (0.90; 95% CI,0.81-0.99). Dr. Rosenbluth says the model also has increased the staff's ownership of night patients, as interns moving from night shift to day shift will often see the same children.

Dr. Rosenbluth hopes to further his research to draw even more evidence-based conclusions. "I think shorter shifts are the way to go and I think our model shows that," he says. "I haven't proven that, but I do believe that. And that’s what we’re looking to study."

Kate Goodrich, MD, medical officer for the Office of the Assistant Secretary for Planning and Evaluation (ASPE) in the U.S. Department of Health and Human Services (HHS), says she frequently is surprised at how much her work as an academic hospitalist is valued in her current role in planning health policy and overseeing government quality and comparative-effectiveness initiatives.

Dr. Goodrich was director of the Division of Hospital Medicine at George Washington University Medical Center in Washington, D.C., before an abiding interest in policy development led her to seek a Robert Wood Johnson Clinical Scholars fellowship to Yale University, which started in 2008. From there, she landed a government position in March 2010.

"I really loved hospital medicine, but I became more aware of the issues the country grapples with, such as poor access to primary care for large numbers of patients," she says. "I became interested in researching those questions even before I really knew what health services research was. I found myself drawn like a magnet to the policy stuff, especially during the 2008 election, with everything policy-related in the news. It finally dawned on me that if I love this so much, why not see if I can make it a career?"

During a summer internship at HHS in 2009, she enjoyed the mentorship of another hospitalist leader, Patrick Conway, MD, MSc, SFHM, who then held the job she now holds and currently is chief medical officer for the Centers for Medicare & Medicaid Services. Given all of the focus on health care reform, Dr. Goodrich says, this is the best of times to be working for the government, "especially for someone who strongly feels that health reform was needed."

She recommends ways other hospitalists can learn more about health policy and participate in its development:

• Start by becoming involved in local quality initiatives in the hospital and the community.

• Join SHM's Public Policy Committee.

• Follow health policy blogs, websites, and other resources offered by HHS, SHM, and private groups, such as the Commonwealth Fund.

• Look into the health policy fellowships or training opportunities offered by a number of national organizations, such as the Robert Wood Johnson Foundation.

Kate Goodrich, MD, medical officer for the Office of the Assistant Secretary for Planning and Evaluation (ASPE) in the U.S. Department of Health and Human Services (HHS), says she frequently is surprised at how much her work as an academic hospitalist is valued in her current role in planning health policy and overseeing government quality and comparative-effectiveness initiatives.

Dr. Goodrich was director of the Division of Hospital Medicine at George Washington University Medical Center in Washington, D.C., before an abiding interest in policy development led her to seek a Robert Wood Johnson Clinical Scholars fellowship to Yale University, which started in 2008. From there, she landed a government position in March 2010.

"I really loved hospital medicine, but I became more aware of the issues the country grapples with, such as poor access to primary care for large numbers of patients," she says. "I became interested in researching those questions even before I really knew what health services research was. I found myself drawn like a magnet to the policy stuff, especially during the 2008 election, with everything policy-related in the news. It finally dawned on me that if I love this so much, why not see if I can make it a career?"

During a summer internship at HHS in 2009, she enjoyed the mentorship of another hospitalist leader, Patrick Conway, MD, MSc, SFHM, who then held the job she now holds and currently is chief medical officer for the Centers for Medicare & Medicaid Services. Given all of the focus on health care reform, Dr. Goodrich says, this is the best of times to be working for the government, "especially for someone who strongly feels that health reform was needed."

She recommends ways other hospitalists can learn more about health policy and participate in its development:

• Start by becoming involved in local quality initiatives in the hospital and the community.

• Join SHM's Public Policy Committee.

• Follow health policy blogs, websites, and other resources offered by HHS, SHM, and private groups, such as the Commonwealth Fund.

• Look into the health policy fellowships or training opportunities offered by a number of national organizations, such as the Robert Wood Johnson Foundation.

Kate Goodrich, MD, medical officer for the Office of the Assistant Secretary for Planning and Evaluation (ASPE) in the U.S. Department of Health and Human Services (HHS), says she frequently is surprised at how much her work as an academic hospitalist is valued in her current role in planning health policy and overseeing government quality and comparative-effectiveness initiatives.

Dr. Goodrich was director of the Division of Hospital Medicine at George Washington University Medical Center in Washington, D.C., before an abiding interest in policy development led her to seek a Robert Wood Johnson Clinical Scholars fellowship to Yale University, which started in 2008. From there, she landed a government position in March 2010.

"I really loved hospital medicine, but I became more aware of the issues the country grapples with, such as poor access to primary care for large numbers of patients," she says. "I became interested in researching those questions even before I really knew what health services research was. I found myself drawn like a magnet to the policy stuff, especially during the 2008 election, with everything policy-related in the news. It finally dawned on me that if I love this so much, why not see if I can make it a career?"

During a summer internship at HHS in 2009, she enjoyed the mentorship of another hospitalist leader, Patrick Conway, MD, MSc, SFHM, who then held the job she now holds and currently is chief medical officer for the Centers for Medicare & Medicaid Services. Given all of the focus on health care reform, Dr. Goodrich says, this is the best of times to be working for the government, "especially for someone who strongly feels that health reform was needed."

She recommends ways other hospitalists can learn more about health policy and participate in its development:

• Start by becoming involved in local quality initiatives in the hospital and the community.

• Join SHM's Public Policy Committee.

• Follow health policy blogs, websites, and other resources offered by HHS, SHM, and private groups, such as the Commonwealth Fund.

• Look into the health policy fellowships or training opportunities offered by a number of national organizations, such as the Robert Wood Johnson Foundation.

AMSTERDAM  – Quantifying the amount of epidermal growth factor receptor in a patient’s advanced nonsmall cell lung cancer tumor appeared to identify the tumors that best responded to treatment with cetuximab in an analysis of 1,125 patients enrolled in a key multicenter treatment trial.

The analysis was a follow-up to the positive Cetuximab Plus Chemotherapy in Patients with Non–Small Cell Lung Cancer (FLEX) study, which showed a benefit from the addition of cetuximab (Erbitux) to platinum-based therapy (Lancet 2009;373:1525-31).

Division of the study population into 31% with a high level of epidermal growth factor receptor (EGFR) expression on the surface of tumor cells and 69% with lower expression identified a patient subgroup, the high expressors, that responded best to cetuximab with no increased toxicity, Dr. Robert Pirker reported at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

"The data clearly show that EGFR is a predictive biomarker because in high-EGFR cancers cetuximab changed survival, reduced the hazard ratio to 0.73 [compared with patients not getting cetuximab], but in patients with lower EGFR, cetuximab added nothing to survival," said Dr. Pirker, professor and program director for lung cancer at the Medical University of Vienna.

"We increase efficacy without increasing toxicity, improving the benefit-to-risk ratio. This is a major step forward toward personalized medicine, especially for patients with high EGFR, about a third of patients with advanced disease," he said.

Because the FLEX study’s prespecified goals included analysis of the link between EGFR density and cetuximab response, the new findings warrant immediate application to practice, according to Dr. Pirker. "I believe this is such a significant improvement in survival that we’ve never seen before that we should be able to provide it to our patients," he said.

Future work should examine the potential role of other drugs that affect EGFR activity (the tyrosine kinase inhibitors such as erlotinib and gefitinib) and also the potential role of cetuximab in high EGFR expressors with earlier-stage lung cancer, he added.

But while other lung cancer specialists saw this finding as an exciting new opportunity for directing EGFR-based treatment to the patients who stand to benefit most, they also called for caution in using EGFR quantification in routine practice.

"It needs prospective validation before it can be standard of care," commented Dr. Roy S. Herbst, chief of medical oncology at the Yale Cancer Center in New Haven, Conn. "It’s very intriguing and makes sense that the amount of receptor will make a difference for cetuximab, but it needs to be tested prospectively because they determined the cutoff retrospectively. It’s always dangerous to use a cutoff determined post hoc, because it becomes a self-fulfilling prophesy. It needs to be studied in a validation set. But it gives new hope for the potential use" of cetuximab and other drugs aimed at EGFR function, Dr. Herbst said in an interview.

"These findings from a post hoc analysis for the selected cutoff are extremely interesting and important, but it needs prospective validation," agreed Dr. Giorgio V. Scagliotti, professor of respiratory medicine at the University of Torino, Italy.

The EGFR scoring formula that Dr. Pirker and his associates developed used a commercially available immunohistochemistry staining kit, made by DAKO. Scoring involved rating the staining intensity of each stained cell in a tumor specimen on a scale of 0-3, where 0 is no staining and 3 is the highest level of staining, and then multiplying each score level by the percent of cells in the specimen with that score. This results in a potential score range of 0 (100% of cells have a score of 0) to 300 (100% of cells have a score of 3).

In their review of the FLEX data, the researchers found that 345 (31%) of patients had tumors with a score of at least 200, the cutoff they selected post hoc for a high level of EGFR expression, and the other 776 (69%) had a low score, less than 200.

With this method distinguishing tumors with high and low levels of EGFR expression, the 345 patients in the high category had a 0.73 hazard ratio for mortality when treated with cetuximab plus chemotherapy (cisplatin plus vinorelbine), compared with patients treated with chemotherapy only (P = .011). This appeared to improve on the reduced mortality seen with cetuximab treatment in the entire study of 1,125 patients, which produced a hazard ratio of 0.87 (P = .044). In the 776 patients with lower EGFR expression, the addition of cetuximab led to no change in survival compared with patients who received the control treatment regimen.

Cetuximab’s enhanced efficacy in high EGFR expressors occurred in both the 135 patients with an adenocarcinoma, and in the 144 patients with a squamous cell carcinoma. Among the high expressors, cetuximab also had significantly better performance measures by tumor response rate, with a twofold higher response rate with cetuximab compared with controls (P = .002), and by time-to-treatment-failure, with a statistically significant, average 22% drop in this time (P = .026) with cetuximab compared with controls.

But focusing on high expressors did not result in a significantly improved duration of progression-free survival. The analysis also showed no increased rate of safety issues in the high expressors who received cetuximab, including no increased rate of skin or subcutaneous disorders.

The FLEX study was funded by Merck, which markets cetuximab (Erbitux) outside the United States. Dr. Pirker disclosed relationships with seven companies, including Merck and Eli Lilly, which markets cetuximab in the United States. Dr. Herbst also cited ties to numerous companies, including ImClone, a Lilly subsidiary that developed cetuximab. Dr. Scagliotti had relationships with four companies, including Lilly.

AMSTERDAM  – Quantifying the amount of epidermal growth factor receptor in a patient’s advanced nonsmall cell lung cancer tumor appeared to identify the tumors that best responded to treatment with cetuximab in an analysis of 1,125 patients enrolled in a key multicenter treatment trial.

The analysis was a follow-up to the positive Cetuximab Plus Chemotherapy in Patients with Non–Small Cell Lung Cancer (FLEX) study, which showed a benefit from the addition of cetuximab (Erbitux) to platinum-based therapy (Lancet 2009;373:1525-31).

Division of the study population into 31% with a high level of epidermal growth factor receptor (EGFR) expression on the surface of tumor cells and 69% with lower expression identified a patient subgroup, the high expressors, that responded best to cetuximab with no increased toxicity, Dr. Robert Pirker reported at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

"The data clearly show that EGFR is a predictive biomarker because in high-EGFR cancers cetuximab changed survival, reduced the hazard ratio to 0.73 [compared with patients not getting cetuximab], but in patients with lower EGFR, cetuximab added nothing to survival," said Dr. Pirker, professor and program director for lung cancer at the Medical University of Vienna.

"We increase efficacy without increasing toxicity, improving the benefit-to-risk ratio. This is a major step forward toward personalized medicine, especially for patients with high EGFR, about a third of patients with advanced disease," he said.

Because the FLEX study’s prespecified goals included analysis of the link between EGFR density and cetuximab response, the new findings warrant immediate application to practice, according to Dr. Pirker. "I believe this is such a significant improvement in survival that we’ve never seen before that we should be able to provide it to our patients," he said.

Future work should examine the potential role of other drugs that affect EGFR activity (the tyrosine kinase inhibitors such as erlotinib and gefitinib) and also the potential role of cetuximab in high EGFR expressors with earlier-stage lung cancer, he added.

But while other lung cancer specialists saw this finding as an exciting new opportunity for directing EGFR-based treatment to the patients who stand to benefit most, they also called for caution in using EGFR quantification in routine practice.

"It needs prospective validation before it can be standard of care," commented Dr. Roy S. Herbst, chief of medical oncology at the Yale Cancer Center in New Haven, Conn. "It’s very intriguing and makes sense that the amount of receptor will make a difference for cetuximab, but it needs to be tested prospectively because they determined the cutoff retrospectively. It’s always dangerous to use a cutoff determined post hoc, because it becomes a self-fulfilling prophesy. It needs to be studied in a validation set. But it gives new hope for the potential use" of cetuximab and other drugs aimed at EGFR function, Dr. Herbst said in an interview.

"These findings from a post hoc analysis for the selected cutoff are extremely interesting and important, but it needs prospective validation," agreed Dr. Giorgio V. Scagliotti, professor of respiratory medicine at the University of Torino, Italy.

The EGFR scoring formula that Dr. Pirker and his associates developed used a commercially available immunohistochemistry staining kit, made by DAKO. Scoring involved rating the staining intensity of each stained cell in a tumor specimen on a scale of 0-3, where 0 is no staining and 3 is the highest level of staining, and then multiplying each score level by the percent of cells in the specimen with that score. This results in a potential score range of 0 (100% of cells have a score of 0) to 300 (100% of cells have a score of 3).

In their review of the FLEX data, the researchers found that 345 (31%) of patients had tumors with a score of at least 200, the cutoff they selected post hoc for a high level of EGFR expression, and the other 776 (69%) had a low score, less than 200.

With this method distinguishing tumors with high and low levels of EGFR expression, the 345 patients in the high category had a 0.73 hazard ratio for mortality when treated with cetuximab plus chemotherapy (cisplatin plus vinorelbine), compared with patients treated with chemotherapy only (P = .011). This appeared to improve on the reduced mortality seen with cetuximab treatment in the entire study of 1,125 patients, which produced a hazard ratio of 0.87 (P = .044). In the 776 patients with lower EGFR expression, the addition of cetuximab led to no change in survival compared with patients who received the control treatment regimen.

Cetuximab’s enhanced efficacy in high EGFR expressors occurred in both the 135 patients with an adenocarcinoma, and in the 144 patients with a squamous cell carcinoma. Among the high expressors, cetuximab also had significantly better performance measures by tumor response rate, with a twofold higher response rate with cetuximab compared with controls (P = .002), and by time-to-treatment-failure, with a statistically significant, average 22% drop in this time (P = .026) with cetuximab compared with controls.

But focusing on high expressors did not result in a significantly improved duration of progression-free survival. The analysis also showed no increased rate of safety issues in the high expressors who received cetuximab, including no increased rate of skin or subcutaneous disorders.

The FLEX study was funded by Merck, which markets cetuximab (Erbitux) outside the United States. Dr. Pirker disclosed relationships with seven companies, including Merck and Eli Lilly, which markets cetuximab in the United States. Dr. Herbst also cited ties to numerous companies, including ImClone, a Lilly subsidiary that developed cetuximab. Dr. Scagliotti had relationships with four companies, including Lilly.

AMSTERDAM  – Quantifying the amount of epidermal growth factor receptor in a patient’s advanced nonsmall cell lung cancer tumor appeared to identify the tumors that best responded to treatment with cetuximab in an analysis of 1,125 patients enrolled in a key multicenter treatment trial.

The analysis was a follow-up to the positive Cetuximab Plus Chemotherapy in Patients with Non–Small Cell Lung Cancer (FLEX) study, which showed a benefit from the addition of cetuximab (Erbitux) to platinum-based therapy (Lancet 2009;373:1525-31).

Division of the study population into 31% with a high level of epidermal growth factor receptor (EGFR) expression on the surface of tumor cells and 69% with lower expression identified a patient subgroup, the high expressors, that responded best to cetuximab with no increased toxicity, Dr. Robert Pirker reported at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

"The data clearly show that EGFR is a predictive biomarker because in high-EGFR cancers cetuximab changed survival, reduced the hazard ratio to 0.73 [compared with patients not getting cetuximab], but in patients with lower EGFR, cetuximab added nothing to survival," said Dr. Pirker, professor and program director for lung cancer at the Medical University of Vienna.

"We increase efficacy without increasing toxicity, improving the benefit-to-risk ratio. This is a major step forward toward personalized medicine, especially for patients with high EGFR, about a third of patients with advanced disease," he said.

Because the FLEX study’s prespecified goals included analysis of the link between EGFR density and cetuximab response, the new findings warrant immediate application to practice, according to Dr. Pirker. "I believe this is such a significant improvement in survival that we’ve never seen before that we should be able to provide it to our patients," he said.

Future work should examine the potential role of other drugs that affect EGFR activity (the tyrosine kinase inhibitors such as erlotinib and gefitinib) and also the potential role of cetuximab in high EGFR expressors with earlier-stage lung cancer, he added.

But while other lung cancer specialists saw this finding as an exciting new opportunity for directing EGFR-based treatment to the patients who stand to benefit most, they also called for caution in using EGFR quantification in routine practice.

"It needs prospective validation before it can be standard of care," commented Dr. Roy S. Herbst, chief of medical oncology at the Yale Cancer Center in New Haven, Conn. "It’s very intriguing and makes sense that the amount of receptor will make a difference for cetuximab, but it needs to be tested prospectively because they determined the cutoff retrospectively. It’s always dangerous to use a cutoff determined post hoc, because it becomes a self-fulfilling prophesy. It needs to be studied in a validation set. But it gives new hope for the potential use" of cetuximab and other drugs aimed at EGFR function, Dr. Herbst said in an interview.

"These findings from a post hoc analysis for the selected cutoff are extremely interesting and important, but it needs prospective validation," agreed Dr. Giorgio V. Scagliotti, professor of respiratory medicine at the University of Torino, Italy.

The EGFR scoring formula that Dr. Pirker and his associates developed used a commercially available immunohistochemistry staining kit, made by DAKO. Scoring involved rating the staining intensity of each stained cell in a tumor specimen on a scale of 0-3, where 0 is no staining and 3 is the highest level of staining, and then multiplying each score level by the percent of cells in the specimen with that score. This results in a potential score range of 0 (100% of cells have a score of 0) to 300 (100% of cells have a score of 3).

In their review of the FLEX data, the researchers found that 345 (31%) of patients had tumors with a score of at least 200, the cutoff they selected post hoc for a high level of EGFR expression, and the other 776 (69%) had a low score, less than 200.

With this method distinguishing tumors with high and low levels of EGFR expression, the 345 patients in the high category had a 0.73 hazard ratio for mortality when treated with cetuximab plus chemotherapy (cisplatin plus vinorelbine), compared with patients treated with chemotherapy only (P = .011). This appeared to improve on the reduced mortality seen with cetuximab treatment in the entire study of 1,125 patients, which produced a hazard ratio of 0.87 (P = .044). In the 776 patients with lower EGFR expression, the addition of cetuximab led to no change in survival compared with patients who received the control treatment regimen.

Cetuximab’s enhanced efficacy in high EGFR expressors occurred in both the 135 patients with an adenocarcinoma, and in the 144 patients with a squamous cell carcinoma. Among the high expressors, cetuximab also had significantly better performance measures by tumor response rate, with a twofold higher response rate with cetuximab compared with controls (P = .002), and by time-to-treatment-failure, with a statistically significant, average 22% drop in this time (P = .026) with cetuximab compared with controls.

But focusing on high expressors did not result in a significantly improved duration of progression-free survival. The analysis also showed no increased rate of safety issues in the high expressors who received cetuximab, including no increased rate of skin or subcutaneous disorders.

The FLEX study was funded by Merck, which markets cetuximab (Erbitux) outside the United States. Dr. Pirker disclosed relationships with seven companies, including Merck and Eli Lilly, which markets cetuximab in the United States. Dr. Herbst also cited ties to numerous companies, including ImClone, a Lilly subsidiary that developed cetuximab. Dr. Scagliotti had relationships with four companies, including Lilly.

The US Food and Drug Administration (FDA) has approved the antiplatelet agent ticagrelor for reducing thrombotic events in patients with acute coronary syndromes.

The FDA based its decision on results of the PLATO trial, which compared ticagrelor to clopidogrel.

Some 9.8% of patients treated with ticagrelor experienced cardiovascular death, myocardial infarction, or stroke at 12 months compared to 11.7% of patients treated with clopidogrel, which amounted to a relative risk reduction of 16% (P<0.001).

The product label includes a boxed warning that aspirin doses above 100 mg per day decrease the effectiveness of the medication and should be avoided.

For more information on the approval, visit FDA.gov.

The US Food and Drug Administration (FDA) has approved the antiplatelet agent ticagrelor for reducing thrombotic events in patients with acute coronary syndromes.

The FDA based its decision on results of the PLATO trial, which compared ticagrelor to clopidogrel.

Some 9.8% of patients treated with ticagrelor experienced cardiovascular death, myocardial infarction, or stroke at 12 months compared to 11.7% of patients treated with clopidogrel, which amounted to a relative risk reduction of 16% (P<0.001).

The product label includes a boxed warning that aspirin doses above 100 mg per day decrease the effectiveness of the medication and should be avoided.

For more information on the approval, visit FDA.gov.

The US Food and Drug Administration (FDA) has approved the antiplatelet agent ticagrelor for reducing thrombotic events in patients with acute coronary syndromes.

The FDA based its decision on results of the PLATO trial, which compared ticagrelor to clopidogrel.

Some 9.8% of patients treated with ticagrelor experienced cardiovascular death, myocardial infarction, or stroke at 12 months compared to 11.7% of patients treated with clopidogrel, which amounted to a relative risk reduction of 16% (P<0.001).

The product label includes a boxed warning that aspirin doses above 100 mg per day decrease the effectiveness of the medication and should be avoided.

For more information on the approval, visit FDA.gov.

Earlier this month, the FDA approved Xarelto (rivaroxaban) to cut the risk of blood clots, DVT, and pulmonary embolism after knee and hip replacement surgery. According to one hospitalist, the drug approval represents another way to prevent blood clots on an outpatient basis.

The drug is a pill that is taken once a day. Those having knee replacements should take the medication for 12 days, and those having hip replacements should take it for 35 days, according to FDA guidelines.

"I think that it has the potential of being a game-changer," says Robert Pendleton, MD, codirector of the hospitalist program and medical director of the University Healthcare Thrombosis Service at the University of Utah Medical Center in Salt Lake City. "It definitely could turn out to be a blockbuster drug."

In a statement, Paul Chang, MD, vice president of medical affairs in internal medicine at Janssen Pharmaceuticals Inc., said, "Shorter hospital stays following hip and knee replacement surgeries have made the prevention of venous blood clots an outpatient issue, and Xarelto provides a safe and effective oral treatment option that can be easily transitioned from use in hospital to home."

The approval is the latest challenge to warfarin. It comes on the heels of the approval of Pradaxa (dabigatran) for stroke prevention in nonvalvular atrial fibrillation patients. (Updated July 21). Xarelto, however, is the only new oral anticoagulant approved for its indication.

Dr. Pendleton says the advantage of Xarelto is that it only has to be taken once a day. He said the full potential lies in the "high likelihood of subsequent indications" for the drug.

Still, this is a new drug and care has to be taken, he says.

"If it's not used appropriately in the proper patient with proper attention to renal function and drug-drug interaction," he adds, "a very promising drug could have difficulty."

Earlier this month, the FDA approved Xarelto (rivaroxaban) to cut the risk of blood clots, DVT, and pulmonary embolism after knee and hip replacement surgery. According to one hospitalist, the drug approval represents another way to prevent blood clots on an outpatient basis.

The drug is a pill that is taken once a day. Those having knee replacements should take the medication for 12 days, and those having hip replacements should take it for 35 days, according to FDA guidelines.

"I think that it has the potential of being a game-changer," says Robert Pendleton, MD, codirector of the hospitalist program and medical director of the University Healthcare Thrombosis Service at the University of Utah Medical Center in Salt Lake City. "It definitely could turn out to be a blockbuster drug."

In a statement, Paul Chang, MD, vice president of medical affairs in internal medicine at Janssen Pharmaceuticals Inc., said, "Shorter hospital stays following hip and knee replacement surgeries have made the prevention of venous blood clots an outpatient issue, and Xarelto provides a safe and effective oral treatment option that can be easily transitioned from use in hospital to home."

The approval is the latest challenge to warfarin. It comes on the heels of the approval of Pradaxa (dabigatran) for stroke prevention in nonvalvular atrial fibrillation patients. (Updated July 21). Xarelto, however, is the only new oral anticoagulant approved for its indication.

Dr. Pendleton says the advantage of Xarelto is that it only has to be taken once a day. He said the full potential lies in the "high likelihood of subsequent indications" for the drug.

Still, this is a new drug and care has to be taken, he says.

"If it's not used appropriately in the proper patient with proper attention to renal function and drug-drug interaction," he adds, "a very promising drug could have difficulty."

Earlier this month, the FDA approved Xarelto (rivaroxaban) to cut the risk of blood clots, DVT, and pulmonary embolism after knee and hip replacement surgery. According to one hospitalist, the drug approval represents another way to prevent blood clots on an outpatient basis.

The drug is a pill that is taken once a day. Those having knee replacements should take the medication for 12 days, and those having hip replacements should take it for 35 days, according to FDA guidelines.

"I think that it has the potential of being a game-changer," says Robert Pendleton, MD, codirector of the hospitalist program and medical director of the University Healthcare Thrombosis Service at the University of Utah Medical Center in Salt Lake City. "It definitely could turn out to be a blockbuster drug."

In a statement, Paul Chang, MD, vice president of medical affairs in internal medicine at Janssen Pharmaceuticals Inc., said, "Shorter hospital stays following hip and knee replacement surgeries have made the prevention of venous blood clots an outpatient issue, and Xarelto provides a safe and effective oral treatment option that can be easily transitioned from use in hospital to home."

The approval is the latest challenge to warfarin. It comes on the heels of the approval of Pradaxa (dabigatran) for stroke prevention in nonvalvular atrial fibrillation patients. (Updated July 21). Xarelto, however, is the only new oral anticoagulant approved for its indication.

Dr. Pendleton says the advantage of Xarelto is that it only has to be taken once a day. He said the full potential lies in the "high likelihood of subsequent indications" for the drug.

Still, this is a new drug and care has to be taken, he says.

"If it's not used appropriately in the proper patient with proper attention to renal function and drug-drug interaction," he adds, "a very promising drug could have difficulty."