Breast Cancer

An automated breast ultrasound system is on track to become the first such device with an indication for use as an adjunct to mammography when screening asymptomatic women with dense breasts for breast cancer.

The Food and Drug Administration’s Radiological Devices Panel voted 13-0 that the benefits of U-Systems Inc.’s somo-v automated breast ultrasound system outweigh the risks for breast cancer screening.

During their meeting, the advisory group also voted unanimously that the noninvasive device is safe and effective, despite FDA concerns over whether the firm’s pivotal study data could be generalized to a broader population.

©2011 U-Systems, Inc. All Rights Reserved.

Approval is not guaranteed, but the agency usually follows the advice of its advisory panels.

U-Systems is seeking premarket approval to increase breast cancer detection in asymptomatic women with dense breasts who have not had a previous clinical breast intervention following a negative mammogram screening. Somo-v was 510(k) cleared in 2005 for diagnostic use as an adjunct to x-ray mammography.

A key question the FDA asked the panel was whether the proposed expanded indication – and the way it would be applied in practice – was appropriately reflected in the firm’s pivotal study design. The panel agreed that it was.

The proposed indication for use "is fine the way it’s written," said panel member Dr. Carl D’Orsi, professor of radiology and hematology/oncology at Emory University in Atlanta. "It should not be changed," Dr. D’Orsi said, reflecting the panel’s consensus.

Premarket approval would make somo-v the first ultrasound device available in the United States with a breast cancer screening indication, according to the company. The system is already the only ultrasound device approved for breast cancer screening in Canada and Europe.

Supporting the premarket approval application is a retrospective, multireader study that enrolled 200 subjects at 13 U.S. sites – culled from the firm’s larger SOMO-INSIGHT clinical trial – to evaluate whether digital mammography in combination with the somo-v automated breast ultrasound system (ABUS) is more sensitive in detecting breast cancer in women with dense breast tissue than x-ray mammography screening alone.

The primary end point of the study was to determine radiologist readers’ performance with and without ABUS using a statistical methodology called "receiver operator characteristic" curve analysis. The mean area under the curve (AUC) values were 0.604 for x-ray mammography alone and 0.747 for x-ray mammography plus ABUS.

"Results from our pivotal clinical retrospective reader study demonstrate that use of screening mammography with ABUS provides a substantial, statistically significant clinical improvement in a reader’s ability to detect mammographically negative breast cancers," said CEO Ronald Ho during the meeting.

"Our primary end point was met," added principal investigator Maryellen Giger, Ph.D., professor of radiology at the University of Chicago.

©2011 U-Systems, Inc. All Rights Reserved.

The difference of 0.143 in the AUC values "was statistically significant, given that the lower bound of an estimated 95% confidence interval for the difference in AUC is 0.074," the FDA agreed.

According to the company, mammography’s sensitivity for the detection of breast cancer is 85% in women overall, but the rate is reduced to 65% in women with dense breast tissue. "Dense breast tissue has been proven to conceal malignant lesions, limiting the effectiveness of mammography," Mr. Ho said. Dense breast tissue also increases a woman’s risk of breast cancer by up to four to six times, according to U-Systems.

"What differentiates our device is that we can detect lesions that are missed by mammography ... and we do it in a very fast work flow that’s reproducible and operator independent," the firm stated. The technology is designed to follow the same work flow as a traditional mammography procedure and provide an exam in 15 minutes.

Real-World Management Questioned

The FDA questioned whether the pivotal study’s results could be extrapolated to a real-world population of patients. One hundred sixty-four subjects were used in the study’s primary statistical analysis (133 normal cases chosen at random and 31 cancer cases), with 12 noncancer cases being evaluated by mammography alone.

Patients with prior clinical breast interventions, such as those who had a breast augmentation or breast cancer treatments including biopsy, radiation, lumpectomy, or mastectomy, were excluded from the study. U-Systems said it excluded these patients to eliminate potential bias and/or confounding effects.

But while the firm is seeking approval of somo-v as a screening tool for women with dense breasts "who have not had a previous clinical breast intervention," the FDA argued that in the real world, "patient management that includes an ABUS scan may be considered for patients who have had prior clinical breast intervention."

The panel discussed whether the exclusion of patients with a prior clinical breast intervention should be specified in the indication, and agreed that it should, given the pivotal study design. Additional studies would be needed to remove the restriction, the panel said.

©2011 U-Systems, Inc. All Rights Reserved.

Some panelists expressed concern over whether somo-v use on biopsy patients, for instance, might increase the device’s false-positive rate, given surgical scars’ similarity to malignancies on ultrasound.

Nevertheless, a majority did not seem overly concerned about potential off-label use on patients with prior interventions. "It seems to me that that’s not a big problem," said panel member Dr. Daniel Kopans, professor of radiology at Harvard Medical School, Boston. "If FDA approves the technology even with these limitations, those of us in breast imaging will use it as we see fit. ... I don’t think that [the indication] is a huge limitation."

Operator Training Concerns

The panel also discussed the sponsor’s proposed physician training program, concluding that it is adequate. However, after the panel voted on safety and effectiveness, some members debated whether potential use of the system by nonimaging specialists could adversely impact outcomes and whether controls were needed to restrict use to accredited radiologists.

According to the company, somo-v’s automation is intended to "reduce operator dependence," and the firm claims that "any medical staff member can be trained to operate the ABUS device consistently and reproducibly." But some panel members cautioned that the simplicity could lead to harm in clinical practice.

"Potentially, you could be in a situation where the mammogram is done by breast-imaging specialists, but the ultrasound is done by nonimaging specialists, which could significantly affect results," said panelist Dr. Robert Faulk, a diagnostic radiologist in private practice in Omaha, Neb.

Dr. Kopans agreed, citing the Mammography Quality Standards Act’s radiologist accreditation training and urging that "similar constraints" are needed for somo-v.

But in response, Janine Morris, the FDA’s acting radiologic devices division director, reminded the panelists that the FDA "doesn’t regulate [the] practice of medicine."

Somo-v relies on proprietary hardware and software, and incorporates a scan head that automatically acquires wide field-of-view breast images while the patient lies supine on a standard exam table.

The images are transferred to the system’s somo-VIEWer 3D workstation, which displays the images in a 3D reconstructed coronal view, as well as standard ultrasound formats, including transverse, radial, multislice, sagittal and antiradial views.

Elsevier Global Medical News and "The Gray Sheet" are owned by Elsevier.

An automated breast ultrasound system is on track to become the first such device with an indication for use as an adjunct to mammography when screening asymptomatic women with dense breasts for breast cancer.

The Food and Drug Administration’s Radiological Devices Panel voted 13-0 that the benefits of U-Systems Inc.’s somo-v automated breast ultrasound system outweigh the risks for breast cancer screening.

During their meeting, the advisory group also voted unanimously that the noninvasive device is safe and effective, despite FDA concerns over whether the firm’s pivotal study data could be generalized to a broader population.

©2011 U-Systems, Inc. All Rights Reserved.

Approval is not guaranteed, but the agency usually follows the advice of its advisory panels.

U-Systems is seeking premarket approval to increase breast cancer detection in asymptomatic women with dense breasts who have not had a previous clinical breast intervention following a negative mammogram screening. Somo-v was 510(k) cleared in 2005 for diagnostic use as an adjunct to x-ray mammography.

A key question the FDA asked the panel was whether the proposed expanded indication – and the way it would be applied in practice – was appropriately reflected in the firm’s pivotal study design. The panel agreed that it was.

The proposed indication for use "is fine the way it’s written," said panel member Dr. Carl D’Orsi, professor of radiology and hematology/oncology at Emory University in Atlanta. "It should not be changed," Dr. D’Orsi said, reflecting the panel’s consensus.

Premarket approval would make somo-v the first ultrasound device available in the United States with a breast cancer screening indication, according to the company. The system is already the only ultrasound device approved for breast cancer screening in Canada and Europe.

Supporting the premarket approval application is a retrospective, multireader study that enrolled 200 subjects at 13 U.S. sites – culled from the firm’s larger SOMO-INSIGHT clinical trial – to evaluate whether digital mammography in combination with the somo-v automated breast ultrasound system (ABUS) is more sensitive in detecting breast cancer in women with dense breast tissue than x-ray mammography screening alone.

The primary end point of the study was to determine radiologist readers’ performance with and without ABUS using a statistical methodology called "receiver operator characteristic" curve analysis. The mean area under the curve (AUC) values were 0.604 for x-ray mammography alone and 0.747 for x-ray mammography plus ABUS.

"Results from our pivotal clinical retrospective reader study demonstrate that use of screening mammography with ABUS provides a substantial, statistically significant clinical improvement in a reader’s ability to detect mammographically negative breast cancers," said CEO Ronald Ho during the meeting.

"Our primary end point was met," added principal investigator Maryellen Giger, Ph.D., professor of radiology at the University of Chicago.

©2011 U-Systems, Inc. All Rights Reserved.

The difference of 0.143 in the AUC values "was statistically significant, given that the lower bound of an estimated 95% confidence interval for the difference in AUC is 0.074," the FDA agreed.

According to the company, mammography’s sensitivity for the detection of breast cancer is 85% in women overall, but the rate is reduced to 65% in women with dense breast tissue. "Dense breast tissue has been proven to conceal malignant lesions, limiting the effectiveness of mammography," Mr. Ho said. Dense breast tissue also increases a woman’s risk of breast cancer by up to four to six times, according to U-Systems.

"What differentiates our device is that we can detect lesions that are missed by mammography ... and we do it in a very fast work flow that’s reproducible and operator independent," the firm stated. The technology is designed to follow the same work flow as a traditional mammography procedure and provide an exam in 15 minutes.

Real-World Management Questioned

The FDA questioned whether the pivotal study’s results could be extrapolated to a real-world population of patients. One hundred sixty-four subjects were used in the study’s primary statistical analysis (133 normal cases chosen at random and 31 cancer cases), with 12 noncancer cases being evaluated by mammography alone.

Patients with prior clinical breast interventions, such as those who had a breast augmentation or breast cancer treatments including biopsy, radiation, lumpectomy, or mastectomy, were excluded from the study. U-Systems said it excluded these patients to eliminate potential bias and/or confounding effects.

But while the firm is seeking approval of somo-v as a screening tool for women with dense breasts "who have not had a previous clinical breast intervention," the FDA argued that in the real world, "patient management that includes an ABUS scan may be considered for patients who have had prior clinical breast intervention."

The panel discussed whether the exclusion of patients with a prior clinical breast intervention should be specified in the indication, and agreed that it should, given the pivotal study design. Additional studies would be needed to remove the restriction, the panel said.

©2011 U-Systems, Inc. All Rights Reserved.

Some panelists expressed concern over whether somo-v use on biopsy patients, for instance, might increase the device’s false-positive rate, given surgical scars’ similarity to malignancies on ultrasound.

Nevertheless, a majority did not seem overly concerned about potential off-label use on patients with prior interventions. "It seems to me that that’s not a big problem," said panel member Dr. Daniel Kopans, professor of radiology at Harvard Medical School, Boston. "If FDA approves the technology even with these limitations, those of us in breast imaging will use it as we see fit. ... I don’t think that [the indication] is a huge limitation."

Operator Training Concerns

The panel also discussed the sponsor’s proposed physician training program, concluding that it is adequate. However, after the panel voted on safety and effectiveness, some members debated whether potential use of the system by nonimaging specialists could adversely impact outcomes and whether controls were needed to restrict use to accredited radiologists.

According to the company, somo-v’s automation is intended to "reduce operator dependence," and the firm claims that "any medical staff member can be trained to operate the ABUS device consistently and reproducibly." But some panel members cautioned that the simplicity could lead to harm in clinical practice.

"Potentially, you could be in a situation where the mammogram is done by breast-imaging specialists, but the ultrasound is done by nonimaging specialists, which could significantly affect results," said panelist Dr. Robert Faulk, a diagnostic radiologist in private practice in Omaha, Neb.

Dr. Kopans agreed, citing the Mammography Quality Standards Act’s radiologist accreditation training and urging that "similar constraints" are needed for somo-v.

But in response, Janine Morris, the FDA’s acting radiologic devices division director, reminded the panelists that the FDA "doesn’t regulate [the] practice of medicine."

Somo-v relies on proprietary hardware and software, and incorporates a scan head that automatically acquires wide field-of-view breast images while the patient lies supine on a standard exam table.

The images are transferred to the system’s somo-VIEWer 3D workstation, which displays the images in a 3D reconstructed coronal view, as well as standard ultrasound formats, including transverse, radial, multislice, sagittal and antiradial views.

Elsevier Global Medical News and "The Gray Sheet" are owned by Elsevier.

An automated breast ultrasound system is on track to become the first such device with an indication for use as an adjunct to mammography when screening asymptomatic women with dense breasts for breast cancer.

The Food and Drug Administration’s Radiological Devices Panel voted 13-0 that the benefits of U-Systems Inc.’s somo-v automated breast ultrasound system outweigh the risks for breast cancer screening.

During their meeting, the advisory group also voted unanimously that the noninvasive device is safe and effective, despite FDA concerns over whether the firm’s pivotal study data could be generalized to a broader population.

©2011 U-Systems, Inc. All Rights Reserved.

Approval is not guaranteed, but the agency usually follows the advice of its advisory panels.

U-Systems is seeking premarket approval to increase breast cancer detection in asymptomatic women with dense breasts who have not had a previous clinical breast intervention following a negative mammogram screening. Somo-v was 510(k) cleared in 2005 for diagnostic use as an adjunct to x-ray mammography.

A key question the FDA asked the panel was whether the proposed expanded indication – and the way it would be applied in practice – was appropriately reflected in the firm’s pivotal study design. The panel agreed that it was.

The proposed indication for use "is fine the way it’s written," said panel member Dr. Carl D’Orsi, professor of radiology and hematology/oncology at Emory University in Atlanta. "It should not be changed," Dr. D’Orsi said, reflecting the panel’s consensus.

Premarket approval would make somo-v the first ultrasound device available in the United States with a breast cancer screening indication, according to the company. The system is already the only ultrasound device approved for breast cancer screening in Canada and Europe.

Supporting the premarket approval application is a retrospective, multireader study that enrolled 200 subjects at 13 U.S. sites – culled from the firm’s larger SOMO-INSIGHT clinical trial – to evaluate whether digital mammography in combination with the somo-v automated breast ultrasound system (ABUS) is more sensitive in detecting breast cancer in women with dense breast tissue than x-ray mammography screening alone.

The primary end point of the study was to determine radiologist readers’ performance with and without ABUS using a statistical methodology called "receiver operator characteristic" curve analysis. The mean area under the curve (AUC) values were 0.604 for x-ray mammography alone and 0.747 for x-ray mammography plus ABUS.

"Results from our pivotal clinical retrospective reader study demonstrate that use of screening mammography with ABUS provides a substantial, statistically significant clinical improvement in a reader’s ability to detect mammographically negative breast cancers," said CEO Ronald Ho during the meeting.

"Our primary end point was met," added principal investigator Maryellen Giger, Ph.D., professor of radiology at the University of Chicago.

©2011 U-Systems, Inc. All Rights Reserved.

The difference of 0.143 in the AUC values "was statistically significant, given that the lower bound of an estimated 95% confidence interval for the difference in AUC is 0.074," the FDA agreed.

According to the company, mammography’s sensitivity for the detection of breast cancer is 85% in women overall, but the rate is reduced to 65% in women with dense breast tissue. "Dense breast tissue has been proven to conceal malignant lesions, limiting the effectiveness of mammography," Mr. Ho said. Dense breast tissue also increases a woman’s risk of breast cancer by up to four to six times, according to U-Systems.

"What differentiates our device is that we can detect lesions that are missed by mammography ... and we do it in a very fast work flow that’s reproducible and operator independent," the firm stated. The technology is designed to follow the same work flow as a traditional mammography procedure and provide an exam in 15 minutes.

Real-World Management Questioned

The FDA questioned whether the pivotal study’s results could be extrapolated to a real-world population of patients. One hundred sixty-four subjects were used in the study’s primary statistical analysis (133 normal cases chosen at random and 31 cancer cases), with 12 noncancer cases being evaluated by mammography alone.

Patients with prior clinical breast interventions, such as those who had a breast augmentation or breast cancer treatments including biopsy, radiation, lumpectomy, or mastectomy, were excluded from the study. U-Systems said it excluded these patients to eliminate potential bias and/or confounding effects.

But while the firm is seeking approval of somo-v as a screening tool for women with dense breasts "who have not had a previous clinical breast intervention," the FDA argued that in the real world, "patient management that includes an ABUS scan may be considered for patients who have had prior clinical breast intervention."

The panel discussed whether the exclusion of patients with a prior clinical breast intervention should be specified in the indication, and agreed that it should, given the pivotal study design. Additional studies would be needed to remove the restriction, the panel said.

©2011 U-Systems, Inc. All Rights Reserved.

Some panelists expressed concern over whether somo-v use on biopsy patients, for instance, might increase the device’s false-positive rate, given surgical scars’ similarity to malignancies on ultrasound.

Nevertheless, a majority did not seem overly concerned about potential off-label use on patients with prior interventions. "It seems to me that that’s not a big problem," said panel member Dr. Daniel Kopans, professor of radiology at Harvard Medical School, Boston. "If FDA approves the technology even with these limitations, those of us in breast imaging will use it as we see fit. ... I don’t think that [the indication] is a huge limitation."

Operator Training Concerns

The panel also discussed the sponsor’s proposed physician training program, concluding that it is adequate. However, after the panel voted on safety and effectiveness, some members debated whether potential use of the system by nonimaging specialists could adversely impact outcomes and whether controls were needed to restrict use to accredited radiologists.

According to the company, somo-v’s automation is intended to "reduce operator dependence," and the firm claims that "any medical staff member can be trained to operate the ABUS device consistently and reproducibly." But some panel members cautioned that the simplicity could lead to harm in clinical practice.

"Potentially, you could be in a situation where the mammogram is done by breast-imaging specialists, but the ultrasound is done by nonimaging specialists, which could significantly affect results," said panelist Dr. Robert Faulk, a diagnostic radiologist in private practice in Omaha, Neb.

Dr. Kopans agreed, citing the Mammography Quality Standards Act’s radiologist accreditation training and urging that "similar constraints" are needed for somo-v.

But in response, Janine Morris, the FDA’s acting radiologic devices division director, reminded the panelists that the FDA "doesn’t regulate [the] practice of medicine."

Somo-v relies on proprietary hardware and software, and incorporates a scan head that automatically acquires wide field-of-view breast images while the patient lies supine on a standard exam table.

The images are transferred to the system’s somo-VIEWer 3D workstation, which displays the images in a 3D reconstructed coronal view, as well as standard ultrasound formats, including transverse, radial, multislice, sagittal and antiradial views.

Elsevier Global Medical News and "The Gray Sheet" are owned by Elsevier.

MIAMI – Oncologists endorse the idea of connecting cancer patients to psychosocial care at the conclusion of active treatment. But practice doesn’t align with beliefs, perhaps because they are unfamiliar with where to refer their patients for care.

Among 57 oncologists who responded to a survey in the southeastern United States, 35, or 61%, considered psychosocial care to be beneficial. A majority thought it was "important" following cancer treatment, reported Laurie Freeman-Gibb at the annual conference of the American Psychosocial Oncology Society (APOS).

But the oncologists said they spent just 4.2 minutes, on average, discussing psychosocial care during consultations, according to Ms. Freeman-Gibb, a lecturer in the department of nursing at the University of Windsor in Ontario, and her colleague Dr. Andrew Hatchett, Ph.D., of the University of Louisiana at Lafayette’s department of kinesiology.

And since only about 1 in 6 oncologists responded to the survey – it was sent to 350 practitioners – the findings may present an overly optimistic picture of what happens in real-life practice when a patient leaves active treatment and returns to the community for care.

"I think it’s sometimes a time constraint," said Ms. Freeman-Gibb. "If you only have 20 minutes to see this person and you open the floodgates to what’s really going on, you might never get out the door ... especially if you don’t know whom to tell the patient to call."

Dr. Hatchett said the impetus for the study was a series of conversations he had with survivors, in which they seemed to indicate a "disconnect" in support after their active treatment ended. "It seemed as though after treatment the survivor was left to their own devices to acquire any additional help," he said.

Many oncologists told the researchers that they would like to refer survivors for follow-up psychosocial care, but they don’t know what’s available, the investigators said.

No comprehensive registry exists that would outline the locations and qualifications of therapists, exercise and rehabilitation specialists, and support agencies that specialize in the psychosocial needs of cancer survivors. In Ireland, a national registry does just that, detailing not only the services available but also their cost, said Ms. Freeman-Gibb.

The organization that sponsored the meeting, APOS, offers a free helpline intended to connect cancer patients and survivors with community counseling services and other sources of support. However, the oncologists in the survey were unaware of that resource, the investigators noted.

Development of a "network of resources" remains a goal of the researchers, who plan to conduct an expanded online survey of a larger pool of oncologists to build on the findings of their pilot questionnaire.

Having a better sense of available resources might make oncologists more comfortable bringing up survivors’ psychosocial adjustment, added Ms. Freeman-Gibb: "Their attitude is great. They say they would love to refer patients. But they don’t."

No outside funding was used to conduct the study.

MIAMI – Oncologists endorse the idea of connecting cancer patients to psychosocial care at the conclusion of active treatment. But practice doesn’t align with beliefs, perhaps because they are unfamiliar with where to refer their patients for care.

Among 57 oncologists who responded to a survey in the southeastern United States, 35, or 61%, considered psychosocial care to be beneficial. A majority thought it was "important" following cancer treatment, reported Laurie Freeman-Gibb at the annual conference of the American Psychosocial Oncology Society (APOS).

But the oncologists said they spent just 4.2 minutes, on average, discussing psychosocial care during consultations, according to Ms. Freeman-Gibb, a lecturer in the department of nursing at the University of Windsor in Ontario, and her colleague Dr. Andrew Hatchett, Ph.D., of the University of Louisiana at Lafayette’s department of kinesiology.

And since only about 1 in 6 oncologists responded to the survey – it was sent to 350 practitioners – the findings may present an overly optimistic picture of what happens in real-life practice when a patient leaves active treatment and returns to the community for care.

"I think it’s sometimes a time constraint," said Ms. Freeman-Gibb. "If you only have 20 minutes to see this person and you open the floodgates to what’s really going on, you might never get out the door ... especially if you don’t know whom to tell the patient to call."

Dr. Hatchett said the impetus for the study was a series of conversations he had with survivors, in which they seemed to indicate a "disconnect" in support after their active treatment ended. "It seemed as though after treatment the survivor was left to their own devices to acquire any additional help," he said.

Many oncologists told the researchers that they would like to refer survivors for follow-up psychosocial care, but they don’t know what’s available, the investigators said.

No comprehensive registry exists that would outline the locations and qualifications of therapists, exercise and rehabilitation specialists, and support agencies that specialize in the psychosocial needs of cancer survivors. In Ireland, a national registry does just that, detailing not only the services available but also their cost, said Ms. Freeman-Gibb.

The organization that sponsored the meeting, APOS, offers a free helpline intended to connect cancer patients and survivors with community counseling services and other sources of support. However, the oncologists in the survey were unaware of that resource, the investigators noted.

Development of a "network of resources" remains a goal of the researchers, who plan to conduct an expanded online survey of a larger pool of oncologists to build on the findings of their pilot questionnaire.

Having a better sense of available resources might make oncologists more comfortable bringing up survivors’ psychosocial adjustment, added Ms. Freeman-Gibb: "Their attitude is great. They say they would love to refer patients. But they don’t."

No outside funding was used to conduct the study.

MIAMI – Oncologists endorse the idea of connecting cancer patients to psychosocial care at the conclusion of active treatment. But practice doesn’t align with beliefs, perhaps because they are unfamiliar with where to refer their patients for care.

Among 57 oncologists who responded to a survey in the southeastern United States, 35, or 61%, considered psychosocial care to be beneficial. A majority thought it was "important" following cancer treatment, reported Laurie Freeman-Gibb at the annual conference of the American Psychosocial Oncology Society (APOS).

But the oncologists said they spent just 4.2 minutes, on average, discussing psychosocial care during consultations, according to Ms. Freeman-Gibb, a lecturer in the department of nursing at the University of Windsor in Ontario, and her colleague Dr. Andrew Hatchett, Ph.D., of the University of Louisiana at Lafayette’s department of kinesiology.

And since only about 1 in 6 oncologists responded to the survey – it was sent to 350 practitioners – the findings may present an overly optimistic picture of what happens in real-life practice when a patient leaves active treatment and returns to the community for care.

"I think it’s sometimes a time constraint," said Ms. Freeman-Gibb. "If you only have 20 minutes to see this person and you open the floodgates to what’s really going on, you might never get out the door ... especially if you don’t know whom to tell the patient to call."

Dr. Hatchett said the impetus for the study was a series of conversations he had with survivors, in which they seemed to indicate a "disconnect" in support after their active treatment ended. "It seemed as though after treatment the survivor was left to their own devices to acquire any additional help," he said.

Many oncologists told the researchers that they would like to refer survivors for follow-up psychosocial care, but they don’t know what’s available, the investigators said.

No comprehensive registry exists that would outline the locations and qualifications of therapists, exercise and rehabilitation specialists, and support agencies that specialize in the psychosocial needs of cancer survivors. In Ireland, a national registry does just that, detailing not only the services available but also their cost, said Ms. Freeman-Gibb.

The organization that sponsored the meeting, APOS, offers a free helpline intended to connect cancer patients and survivors with community counseling services and other sources of support. However, the oncologists in the survey were unaware of that resource, the investigators noted.

Development of a "network of resources" remains a goal of the researchers, who plan to conduct an expanded online survey of a larger pool of oncologists to build on the findings of their pilot questionnaire.

Having a better sense of available resources might make oncologists more comfortable bringing up survivors’ psychosocial adjustment, added Ms. Freeman-Gibb: "Their attitude is great. They say they would love to refer patients. But they don’t."

No outside funding was used to conduct the study.

CHICAGO – Maintenance immunotherapy with low-dose interleukin-2 and 13-cis-retinoic acid demonstrated an "unexpected" survival benefit in a phase II trial among 500 patients who had derived clinical benefit from chemotherapy for a variety of stage IV cancers, investigators from Italy reported.

The 15-year disease-free survival and overall survival rates reached 32.6% and 36.8%, respectively, in the open, nonrandomized trial, and a breakdown by tumor type showed better outcomes than seen in historic controls, Dr. Francesco Recchia reported at the annual meeting of the American Association for Cancer Research.

©AACR/Phil McCarten

Comparing their data with outcomes for the most commonly treated metastatic cancers in the Surveillance, Epidemiology, and End Results (SEER) database in the United States, the investigators found their 5-year overall survival rates were 42.7% vs. 23.3% for breast cancer, 26.4% vs. 3.6% for lung cancer, 43.6% vs. 11.7% for colorectal cancer, and 23% vs. 11% for renal cancer.

"The good and unexpected results of this immunotherapy regimen were seen in all types of cancer: ovarian cancer and recurrent ovarian cancer, non–small cell lung cancer, cardiac metastases of sarcoma, colorectal cancer, gastric cancer, renal cell carcinoma, melanoma, head and neck cancer, breast cancer, and pancreatic cancer," said Dr. Recchia, director of oncology at the Civilian Hospital in Avezzano (Italy).

"The best merit of our research is the low cost of this therapy," he added.

The impetus for the phase II trial was an observation, in 1995, that a patient, who could not tolerate standard high-dose (18 x 10⁶ IU/m²) IL-2 therapy for metastatic melanoma, experienced a long-lasting response to low-dose subcutaneous IL-2. Dr. Recchia and his colleagues conducted a series of phase I and II randomized studies of low-dose IL-2 with and without retinoic acid, ultimately determining that the combination of the two agents was most effective in increasing natural killer (NK) cell populations and decreasing vascular endothelial growth factor (VEGF) expression.

In the current study, after a median follow-up of 60 months, Dr. Recchia and his colleagues observed a statistically significant increase in the number of NK cells – mediators of lytic activity against cancer cell lines – from a baseline mean of 309/mm³ to a mean of 579/mm³. They also found a statistically significant decrease in VEGF expression, from a baseline mean of 520 pg/mm³ to a mean of 150 pg/mm³ in the study participants.

"Both of these mechanisms are associated with slowing cancer growth," he said in an interview.

All of the patients enrolled in the study were in chemotherapy-induced remission, with good performance status, from stage IV cancer, and all (median age 61 years) were treated for 1 year with self-administered subcutaneous IL-2 (1.8 x 10⁶ IU) and oral 13-cis-retinoic acid (0.5 mg/kg) 5 days per week for two consecutive 3-week cycles, with a 1-week rest. This was followed by continued intermittently scheduled therapy for 5 years or until disease progression, with assessment of NK cells, serum VEGF, tumor response, and toxicity every 4 months, Dr. Recchia said.

The study’s primary end point was NK cell and VEGF response, he added, noting that disease-free survival, overall survival, and toxicity in various tumor types were secondary end points.

The treatment was not associated with any World Health Organization grade 3 or 4 toxicities, Dr. Recchia reported. Grade 2 cutaneous toxicity (20%), fever (13%), mild hypothyroidism (5%), and triglyceride elevation (15%) were observed, he said; one patient discontinued treatment because of grade 2 urticaria.

Prior to using the maintenance regimen in clinical practice, the findings of the current study have to be validated in a blinded, controlled, randomized trial, said Dr. Recchia, noting that a phase III study is underway in patients with advanced breast cancer.

Dr. Recchia reported having no relevant financial conflicts of interest.

CHICAGO – Maintenance immunotherapy with low-dose interleukin-2 and 13-cis-retinoic acid demonstrated an "unexpected" survival benefit in a phase II trial among 500 patients who had derived clinical benefit from chemotherapy for a variety of stage IV cancers, investigators from Italy reported.

The 15-year disease-free survival and overall survival rates reached 32.6% and 36.8%, respectively, in the open, nonrandomized trial, and a breakdown by tumor type showed better outcomes than seen in historic controls, Dr. Francesco Recchia reported at the annual meeting of the American Association for Cancer Research.

©AACR/Phil McCarten

Comparing their data with outcomes for the most commonly treated metastatic cancers in the Surveillance, Epidemiology, and End Results (SEER) database in the United States, the investigators found their 5-year overall survival rates were 42.7% vs. 23.3% for breast cancer, 26.4% vs. 3.6% for lung cancer, 43.6% vs. 11.7% for colorectal cancer, and 23% vs. 11% for renal cancer.

"The good and unexpected results of this immunotherapy regimen were seen in all types of cancer: ovarian cancer and recurrent ovarian cancer, non–small cell lung cancer, cardiac metastases of sarcoma, colorectal cancer, gastric cancer, renal cell carcinoma, melanoma, head and neck cancer, breast cancer, and pancreatic cancer," said Dr. Recchia, director of oncology at the Civilian Hospital in Avezzano (Italy).

"The best merit of our research is the low cost of this therapy," he added.

The impetus for the phase II trial was an observation, in 1995, that a patient, who could not tolerate standard high-dose (18 x 10⁶ IU/m²) IL-2 therapy for metastatic melanoma, experienced a long-lasting response to low-dose subcutaneous IL-2. Dr. Recchia and his colleagues conducted a series of phase I and II randomized studies of low-dose IL-2 with and without retinoic acid, ultimately determining that the combination of the two agents was most effective in increasing natural killer (NK) cell populations and decreasing vascular endothelial growth factor (VEGF) expression.

In the current study, after a median follow-up of 60 months, Dr. Recchia and his colleagues observed a statistically significant increase in the number of NK cells – mediators of lytic activity against cancer cell lines – from a baseline mean of 309/mm³ to a mean of 579/mm³. They also found a statistically significant decrease in VEGF expression, from a baseline mean of 520 pg/mm³ to a mean of 150 pg/mm³ in the study participants.

"Both of these mechanisms are associated with slowing cancer growth," he said in an interview.

All of the patients enrolled in the study were in chemotherapy-induced remission, with good performance status, from stage IV cancer, and all (median age 61 years) were treated for 1 year with self-administered subcutaneous IL-2 (1.8 x 10⁶ IU) and oral 13-cis-retinoic acid (0.5 mg/kg) 5 days per week for two consecutive 3-week cycles, with a 1-week rest. This was followed by continued intermittently scheduled therapy for 5 years or until disease progression, with assessment of NK cells, serum VEGF, tumor response, and toxicity every 4 months, Dr. Recchia said.

The study’s primary end point was NK cell and VEGF response, he added, noting that disease-free survival, overall survival, and toxicity in various tumor types were secondary end points.

The treatment was not associated with any World Health Organization grade 3 or 4 toxicities, Dr. Recchia reported. Grade 2 cutaneous toxicity (20%), fever (13%), mild hypothyroidism (5%), and triglyceride elevation (15%) were observed, he said; one patient discontinued treatment because of grade 2 urticaria.

Prior to using the maintenance regimen in clinical practice, the findings of the current study have to be validated in a blinded, controlled, randomized trial, said Dr. Recchia, noting that a phase III study is underway in patients with advanced breast cancer.

Dr. Recchia reported having no relevant financial conflicts of interest.

CHICAGO – Maintenance immunotherapy with low-dose interleukin-2 and 13-cis-retinoic acid demonstrated an "unexpected" survival benefit in a phase II trial among 500 patients who had derived clinical benefit from chemotherapy for a variety of stage IV cancers, investigators from Italy reported.

The 15-year disease-free survival and overall survival rates reached 32.6% and 36.8%, respectively, in the open, nonrandomized trial, and a breakdown by tumor type showed better outcomes than seen in historic controls, Dr. Francesco Recchia reported at the annual meeting of the American Association for Cancer Research.

©AACR/Phil McCarten

Comparing their data with outcomes for the most commonly treated metastatic cancers in the Surveillance, Epidemiology, and End Results (SEER) database in the United States, the investigators found their 5-year overall survival rates were 42.7% vs. 23.3% for breast cancer, 26.4% vs. 3.6% for lung cancer, 43.6% vs. 11.7% for colorectal cancer, and 23% vs. 11% for renal cancer.

"The good and unexpected results of this immunotherapy regimen were seen in all types of cancer: ovarian cancer and recurrent ovarian cancer, non–small cell lung cancer, cardiac metastases of sarcoma, colorectal cancer, gastric cancer, renal cell carcinoma, melanoma, head and neck cancer, breast cancer, and pancreatic cancer," said Dr. Recchia, director of oncology at the Civilian Hospital in Avezzano (Italy).

"The best merit of our research is the low cost of this therapy," he added.

The impetus for the phase II trial was an observation, in 1995, that a patient, who could not tolerate standard high-dose (18 x 10⁶ IU/m²) IL-2 therapy for metastatic melanoma, experienced a long-lasting response to low-dose subcutaneous IL-2. Dr. Recchia and his colleagues conducted a series of phase I and II randomized studies of low-dose IL-2 with and without retinoic acid, ultimately determining that the combination of the two agents was most effective in increasing natural killer (NK) cell populations and decreasing vascular endothelial growth factor (VEGF) expression.

In the current study, after a median follow-up of 60 months, Dr. Recchia and his colleagues observed a statistically significant increase in the number of NK cells – mediators of lytic activity against cancer cell lines – from a baseline mean of 309/mm³ to a mean of 579/mm³. They also found a statistically significant decrease in VEGF expression, from a baseline mean of 520 pg/mm³ to a mean of 150 pg/mm³ in the study participants.

"Both of these mechanisms are associated with slowing cancer growth," he said in an interview.

All of the patients enrolled in the study were in chemotherapy-induced remission, with good performance status, from stage IV cancer, and all (median age 61 years) were treated for 1 year with self-administered subcutaneous IL-2 (1.8 x 10⁶ IU) and oral 13-cis-retinoic acid (0.5 mg/kg) 5 days per week for two consecutive 3-week cycles, with a 1-week rest. This was followed by continued intermittently scheduled therapy for 5 years or until disease progression, with assessment of NK cells, serum VEGF, tumor response, and toxicity every 4 months, Dr. Recchia said.

The study’s primary end point was NK cell and VEGF response, he added, noting that disease-free survival, overall survival, and toxicity in various tumor types were secondary end points.

The treatment was not associated with any World Health Organization grade 3 or 4 toxicities, Dr. Recchia reported. Grade 2 cutaneous toxicity (20%), fever (13%), mild hypothyroidism (5%), and triglyceride elevation (15%) were observed, he said; one patient discontinued treatment because of grade 2 urticaria.

Prior to using the maintenance regimen in clinical practice, the findings of the current study have to be validated in a blinded, controlled, randomized trial, said Dr. Recchia, noting that a phase III study is underway in patients with advanced breast cancer.

Dr. Recchia reported having no relevant financial conflicts of interest.

The cost-effectiveness agency for England and Wales says that it will not recommend bevacizumab in combination with capecitabine to treat advanced metastatic breast cancer.

In new draft guidance issued April 18, the National Institute for Health and Clinical Excellence (NICE) cited insufficient evidence in support of the drug combination, one of two bevacizumab regimens licensed in the European Union for the first-line treatment of advanced metastatic breast cancer.

Roche’s bevacizumab (Avastin) is a humanized monoclonal antibody that blocks vascular endothelial growth factor, reducing blood flow to tumors. The U.S. Food and Drug Administration revoked bevacizumab’s breast cancer indications altogether in November 2011, citing an unfavorable risk-benefit ratio.

The European Medicines Agency did not follow suit, however. Bevacizumab is licensed in Europe in combination with paclitaxel and also with capecitabine, which is used when paclitaxel is judged inappropriate, for advanced metastatic breast cancer.

In February 2011, NICE rejected bevacizumab and paclitaxel for the same indication.

In announcing its decision on bevacizumab and capecitabine, NICE cited uncertainties about overall survival benefit in results from RIBBON-1, a randomized controlled trial of bevacizumab in 1,237 women with advanced breast cancer. In the capecitabine arm of the trial, 615 patients were randomized to capecitabine plus bevacizumab or capecitabine plus placebo.

Although the results showed that capecitabine and bevacizumab prolonged progression-free survival by 2.9 months compared with capecitabine monotherapy, it remained unclear whether that benefit translated into an improvement in overall survival, NICE said, because so many patients on monotherapy crossed over to bevacizumab in the trial’s open-label postprogression phase.

NICE cited in its negative guidance the fact that no quality of life data had been collected in the trial, and that serious adverse reactions were higher with bevacizumab plus capecitabine (36.6%) than with capecitabine plus placebo (22.9%). "In addition, the number of patients with hypertension, proteinuria, sensory neuropathy, and venous thromboembolic events was higher with bevacizumab plus capecitabine compared with capecitabine plus placebo," NICE said in an April 18 press statement about its decision. "The Committee concluded that bevacizumab plus capecitabine had a less favorable toxicity profile than capecitabine plus placebo."

Finally, as in all NICE decisions, there was the question of cost. The manufacturer’s best-case incremental cost-effectiveness ratio (ICER) for bevacizumab plus capecitabine was £82,000 (U.S.$131,400) per quality-adjusted life year gained, and this only for a subgroup of patients. The ICER placed bevacizumab firmly out of NICE’s cost-effectiveness range.

Bevacizumab, which is administered by intravenous infusion, is dosed at 15 mg/kg every 3 weeks, amounting, NICE said, to an average monthly cost of around £3,689 (U.S.$5,913) per patient.

The cost-effectiveness agency for England and Wales says that it will not recommend bevacizumab in combination with capecitabine to treat advanced metastatic breast cancer.

In new draft guidance issued April 18, the National Institute for Health and Clinical Excellence (NICE) cited insufficient evidence in support of the drug combination, one of two bevacizumab regimens licensed in the European Union for the first-line treatment of advanced metastatic breast cancer.

Roche’s bevacizumab (Avastin) is a humanized monoclonal antibody that blocks vascular endothelial growth factor, reducing blood flow to tumors. The U.S. Food and Drug Administration revoked bevacizumab’s breast cancer indications altogether in November 2011, citing an unfavorable risk-benefit ratio.

The European Medicines Agency did not follow suit, however. Bevacizumab is licensed in Europe in combination with paclitaxel and also with capecitabine, which is used when paclitaxel is judged inappropriate, for advanced metastatic breast cancer.

In February 2011, NICE rejected bevacizumab and paclitaxel for the same indication.

In announcing its decision on bevacizumab and capecitabine, NICE cited uncertainties about overall survival benefit in results from RIBBON-1, a randomized controlled trial of bevacizumab in 1,237 women with advanced breast cancer. In the capecitabine arm of the trial, 615 patients were randomized to capecitabine plus bevacizumab or capecitabine plus placebo.

Although the results showed that capecitabine and bevacizumab prolonged progression-free survival by 2.9 months compared with capecitabine monotherapy, it remained unclear whether that benefit translated into an improvement in overall survival, NICE said, because so many patients on monotherapy crossed over to bevacizumab in the trial’s open-label postprogression phase.

NICE cited in its negative guidance the fact that no quality of life data had been collected in the trial, and that serious adverse reactions were higher with bevacizumab plus capecitabine (36.6%) than with capecitabine plus placebo (22.9%). "In addition, the number of patients with hypertension, proteinuria, sensory neuropathy, and venous thromboembolic events was higher with bevacizumab plus capecitabine compared with capecitabine plus placebo," NICE said in an April 18 press statement about its decision. "The Committee concluded that bevacizumab plus capecitabine had a less favorable toxicity profile than capecitabine plus placebo."

Finally, as in all NICE decisions, there was the question of cost. The manufacturer’s best-case incremental cost-effectiveness ratio (ICER) for bevacizumab plus capecitabine was £82,000 (U.S.$131,400) per quality-adjusted life year gained, and this only for a subgroup of patients. The ICER placed bevacizumab firmly out of NICE’s cost-effectiveness range.

Bevacizumab, which is administered by intravenous infusion, is dosed at 15 mg/kg every 3 weeks, amounting, NICE said, to an average monthly cost of around £3,689 (U.S.$5,913) per patient.

The cost-effectiveness agency for England and Wales says that it will not recommend bevacizumab in combination with capecitabine to treat advanced metastatic breast cancer.

In new draft guidance issued April 18, the National Institute for Health and Clinical Excellence (NICE) cited insufficient evidence in support of the drug combination, one of two bevacizumab regimens licensed in the European Union for the first-line treatment of advanced metastatic breast cancer.

Roche’s bevacizumab (Avastin) is a humanized monoclonal antibody that blocks vascular endothelial growth factor, reducing blood flow to tumors. The U.S. Food and Drug Administration revoked bevacizumab’s breast cancer indications altogether in November 2011, citing an unfavorable risk-benefit ratio.

The European Medicines Agency did not follow suit, however. Bevacizumab is licensed in Europe in combination with paclitaxel and also with capecitabine, which is used when paclitaxel is judged inappropriate, for advanced metastatic breast cancer.

In February 2011, NICE rejected bevacizumab and paclitaxel for the same indication.

In announcing its decision on bevacizumab and capecitabine, NICE cited uncertainties about overall survival benefit in results from RIBBON-1, a randomized controlled trial of bevacizumab in 1,237 women with advanced breast cancer. In the capecitabine arm of the trial, 615 patients were randomized to capecitabine plus bevacizumab or capecitabine plus placebo.

Although the results showed that capecitabine and bevacizumab prolonged progression-free survival by 2.9 months compared with capecitabine monotherapy, it remained unclear whether that benefit translated into an improvement in overall survival, NICE said, because so many patients on monotherapy crossed over to bevacizumab in the trial’s open-label postprogression phase.

NICE cited in its negative guidance the fact that no quality of life data had been collected in the trial, and that serious adverse reactions were higher with bevacizumab plus capecitabine (36.6%) than with capecitabine plus placebo (22.9%). "In addition, the number of patients with hypertension, proteinuria, sensory neuropathy, and venous thromboembolic events was higher with bevacizumab plus capecitabine compared with capecitabine plus placebo," NICE said in an April 18 press statement about its decision. "The Committee concluded that bevacizumab plus capecitabine had a less favorable toxicity profile than capecitabine plus placebo."

Finally, as in all NICE decisions, there was the question of cost. The manufacturer’s best-case incremental cost-effectiveness ratio (ICER) for bevacizumab plus capecitabine was £82,000 (U.S.$131,400) per quality-adjusted life year gained, and this only for a subgroup of patients. The ICER placed bevacizumab firmly out of NICE’s cost-effectiveness range.

Bevacizumab, which is administered by intravenous infusion, is dosed at 15 mg/kg every 3 weeks, amounting, NICE said, to an average monthly cost of around £3,689 (U.S.$5,913) per patient.

The risk of cardiotoxicity is five times higher in breast cancer patients given trastuzumab than in those receiving a standard chemotherapy regimen alone, according to a new systematic review from the Cochrane Collaboration.

The review found that regimens containing trastuzumab (Herceptin) significantly increased congestive heart failure and left ventricular ejection fraction (LVEF) decline, with relative risks of 5.11 and 1.83, respectively, in women with HER2-positive early and locally advanced breast cancer (Cochrane Database Syst. Rev. 2012;4 [doi: 10.1002/14651858.CD006243.pub2]).

However, trastuzumab regimens also significantly increased overall and disease-free survival, with hazard ratios of 0.66 and 0.60, respectively, noted Dr. Lorenzo Moja of the University of Milan and his coauthors. All these results were highly significant, with P values ranging from less than .0008 for risk of LVEF decline to less than .00001 for the others.

In a plain-language summary comparing trastuzumab-containing regimens with standard therapy alone in 1,000 women, the investigators wrote that 33 more women would have their lives prolonged with trastuzumab (933 women vs. 900 women with standard therapy alone). However, about 26 in 1,000 women taking trastuzumab would have serious heart toxicity, which is 21 more than the group treated with standard therapy alone.

Trastuzumab’s cardiotoxic effects have been well known, but the magnitude of the effect reported in the systematic review may be larger than what people have thought, commented Dr. Daniel J. Lenihan, director of clinical research in the cardiovascular medicine division at Vanderbilt University, Nashville, Tenn., in an interview.

And that risk may be even greater in the world outside of clinical studies, said Dr. Melinda Telli of Stanford (Calif.) University. The patients in the studies included in the systematic review were younger, and none had baseline cardiac disease, observed Dr. Telli, also in an interview.

Another issue: In practice, oncologists are offering trastuzumab to women at lower risk for cancer recurrence than those in the trials. Thus, she said, "it’s more likely the risks are underestimated in this Cochrane review."

Although the data in the systematic review were previously published, having them encapsulated – along with a number of scenarios outlining potential risks and benefits in women with different cancer recurrence and cardiac risk factors – is a significant addition to the literature, said Dr. Telli.

Cochrane reviews are known for being thorough and balanced. This review began by looking at about 3,900 studies; after applying exclusion criteria, the list was winnowed down to 35 publications that covered 8 randomized controlled clinical trials enrolling 11,991 women. A little more than 7,000 women were assigned to a trastuzumab-containing arm, and 4,971 women to a regimen without trastuzumab. The median age in the trials was 49 years. Pre- and postmenopausal women were included, but those with metastatic disease or preexisting heart conditions were excluded.

The review concluded that high-risk women with few cardiac risk factors would benefit from trastuzumab, while those at lower risk "must be carefully evaluated," adding, "The oncologist should share the decision with the patient concerning whether and how to start the treatment."

Dr. Lenihan said he was concerned that the potential cardiotoxicity might cause oncologists to steer away from trastuzumab. He is a proponent of a multidisciplinary team that involves a cardiologist at the outset of therapy.

If cardiac effects develop, "the key is not to ignore it, but to pay attention," said Dr. Lenihan, who is also president of the International CardiOncology Society USA/Canada.

Early identification enables rapid treatment, which can stabilize or correct the heart issues, he said. That allows patients to return to their cancer therapy.

Dr. Lenihan and his colleagues at Vanderbilt University are currently conducting a study testing various cardiac biomarkers to detect toxicity during chemotherapy.

It is still unknown, however, whether the cardiotoxicity that develops during therapy is ultimately reversible, or becomes a lifelong issue. While the ejection fraction may recover after withdrawal of trastuzumab, at least one study – the Herceptin Adjuvant (HERA) trial – has shown that some women had long-term loss of heart muscle cells, said Dr. Telli.

"So we know that the heart is taking a hit," she said, adding that the trastuzumab damage is not "some sort of reversible thing."

The key, she said, is for oncologists to weigh the risks and benefits individually in each patient.

A targeted therapy, trastuzumab is approved for treatment of HER2-positive breast cancer and of metastatic HER2-positive adenocarcinoma of the stomach or gastroesophageal junction. About 20% of tumors in women with early breast cancer are HER2-positive.

Dr. Telli reported no conflicts of interest. Dr. Lenihan reported receiving consulting fees from Roche and AstraZeneca and research support from Acorda.

The risk of cardiotoxicity is five times higher in breast cancer patients given trastuzumab than in those receiving a standard chemotherapy regimen alone, according to a new systematic review from the Cochrane Collaboration.

The review found that regimens containing trastuzumab (Herceptin) significantly increased congestive heart failure and left ventricular ejection fraction (LVEF) decline, with relative risks of 5.11 and 1.83, respectively, in women with HER2-positive early and locally advanced breast cancer (Cochrane Database Syst. Rev. 2012;4 [doi: 10.1002/14651858.CD006243.pub2]).

However, trastuzumab regimens also significantly increased overall and disease-free survival, with hazard ratios of 0.66 and 0.60, respectively, noted Dr. Lorenzo Moja of the University of Milan and his coauthors. All these results were highly significant, with P values ranging from less than .0008 for risk of LVEF decline to less than .00001 for the others.

In a plain-language summary comparing trastuzumab-containing regimens with standard therapy alone in 1,000 women, the investigators wrote that 33 more women would have their lives prolonged with trastuzumab (933 women vs. 900 women with standard therapy alone). However, about 26 in 1,000 women taking trastuzumab would have serious heart toxicity, which is 21 more than the group treated with standard therapy alone.

Trastuzumab’s cardiotoxic effects have been well known, but the magnitude of the effect reported in the systematic review may be larger than what people have thought, commented Dr. Daniel J. Lenihan, director of clinical research in the cardiovascular medicine division at Vanderbilt University, Nashville, Tenn., in an interview.

And that risk may be even greater in the world outside of clinical studies, said Dr. Melinda Telli of Stanford (Calif.) University. The patients in the studies included in the systematic review were younger, and none had baseline cardiac disease, observed Dr. Telli, also in an interview.

Another issue: In practice, oncologists are offering trastuzumab to women at lower risk for cancer recurrence than those in the trials. Thus, she said, "it’s more likely the risks are underestimated in this Cochrane review."

Although the data in the systematic review were previously published, having them encapsulated – along with a number of scenarios outlining potential risks and benefits in women with different cancer recurrence and cardiac risk factors – is a significant addition to the literature, said Dr. Telli.

Cochrane reviews are known for being thorough and balanced. This review began by looking at about 3,900 studies; after applying exclusion criteria, the list was winnowed down to 35 publications that covered 8 randomized controlled clinical trials enrolling 11,991 women. A little more than 7,000 women were assigned to a trastuzumab-containing arm, and 4,971 women to a regimen without trastuzumab. The median age in the trials was 49 years. Pre- and postmenopausal women were included, but those with metastatic disease or preexisting heart conditions were excluded.

The review concluded that high-risk women with few cardiac risk factors would benefit from trastuzumab, while those at lower risk "must be carefully evaluated," adding, "The oncologist should share the decision with the patient concerning whether and how to start the treatment."

Dr. Lenihan said he was concerned that the potential cardiotoxicity might cause oncologists to steer away from trastuzumab. He is a proponent of a multidisciplinary team that involves a cardiologist at the outset of therapy.

If cardiac effects develop, "the key is not to ignore it, but to pay attention," said Dr. Lenihan, who is also president of the International CardiOncology Society USA/Canada.

Early identification enables rapid treatment, which can stabilize or correct the heart issues, he said. That allows patients to return to their cancer therapy.

Dr. Lenihan and his colleagues at Vanderbilt University are currently conducting a study testing various cardiac biomarkers to detect toxicity during chemotherapy.

It is still unknown, however, whether the cardiotoxicity that develops during therapy is ultimately reversible, or becomes a lifelong issue. While the ejection fraction may recover after withdrawal of trastuzumab, at least one study – the Herceptin Adjuvant (HERA) trial – has shown that some women had long-term loss of heart muscle cells, said Dr. Telli.

"So we know that the heart is taking a hit," she said, adding that the trastuzumab damage is not "some sort of reversible thing."

The key, she said, is for oncologists to weigh the risks and benefits individually in each patient.

A targeted therapy, trastuzumab is approved for treatment of HER2-positive breast cancer and of metastatic HER2-positive adenocarcinoma of the stomach or gastroesophageal junction. About 20% of tumors in women with early breast cancer are HER2-positive.

Dr. Telli reported no conflicts of interest. Dr. Lenihan reported receiving consulting fees from Roche and AstraZeneca and research support from Acorda.

The risk of cardiotoxicity is five times higher in breast cancer patients given trastuzumab than in those receiving a standard chemotherapy regimen alone, according to a new systematic review from the Cochrane Collaboration.

The review found that regimens containing trastuzumab (Herceptin) significantly increased congestive heart failure and left ventricular ejection fraction (LVEF) decline, with relative risks of 5.11 and 1.83, respectively, in women with HER2-positive early and locally advanced breast cancer (Cochrane Database Syst. Rev. 2012;4 [doi: 10.1002/14651858.CD006243.pub2]).

However, trastuzumab regimens also significantly increased overall and disease-free survival, with hazard ratios of 0.66 and 0.60, respectively, noted Dr. Lorenzo Moja of the University of Milan and his coauthors. All these results were highly significant, with P values ranging from less than .0008 for risk of LVEF decline to less than .00001 for the others.

In a plain-language summary comparing trastuzumab-containing regimens with standard therapy alone in 1,000 women, the investigators wrote that 33 more women would have their lives prolonged with trastuzumab (933 women vs. 900 women with standard therapy alone). However, about 26 in 1,000 women taking trastuzumab would have serious heart toxicity, which is 21 more than the group treated with standard therapy alone.

Trastuzumab’s cardiotoxic effects have been well known, but the magnitude of the effect reported in the systematic review may be larger than what people have thought, commented Dr. Daniel J. Lenihan, director of clinical research in the cardiovascular medicine division at Vanderbilt University, Nashville, Tenn., in an interview.

And that risk may be even greater in the world outside of clinical studies, said Dr. Melinda Telli of Stanford (Calif.) University. The patients in the studies included in the systematic review were younger, and none had baseline cardiac disease, observed Dr. Telli, also in an interview.

Another issue: In practice, oncologists are offering trastuzumab to women at lower risk for cancer recurrence than those in the trials. Thus, she said, "it’s more likely the risks are underestimated in this Cochrane review."

Although the data in the systematic review were previously published, having them encapsulated – along with a number of scenarios outlining potential risks and benefits in women with different cancer recurrence and cardiac risk factors – is a significant addition to the literature, said Dr. Telli.

Cochrane reviews are known for being thorough and balanced. This review began by looking at about 3,900 studies; after applying exclusion criteria, the list was winnowed down to 35 publications that covered 8 randomized controlled clinical trials enrolling 11,991 women. A little more than 7,000 women were assigned to a trastuzumab-containing arm, and 4,971 women to a regimen without trastuzumab. The median age in the trials was 49 years. Pre- and postmenopausal women were included, but those with metastatic disease or preexisting heart conditions were excluded.

The review concluded that high-risk women with few cardiac risk factors would benefit from trastuzumab, while those at lower risk "must be carefully evaluated," adding, "The oncologist should share the decision with the patient concerning whether and how to start the treatment."

Dr. Lenihan said he was concerned that the potential cardiotoxicity might cause oncologists to steer away from trastuzumab. He is a proponent of a multidisciplinary team that involves a cardiologist at the outset of therapy.

If cardiac effects develop, "the key is not to ignore it, but to pay attention," said Dr. Lenihan, who is also president of the International CardiOncology Society USA/Canada.

Early identification enables rapid treatment, which can stabilize or correct the heart issues, he said. That allows patients to return to their cancer therapy.

Dr. Lenihan and his colleagues at Vanderbilt University are currently conducting a study testing various cardiac biomarkers to detect toxicity during chemotherapy.

It is still unknown, however, whether the cardiotoxicity that develops during therapy is ultimately reversible, or becomes a lifelong issue. While the ejection fraction may recover after withdrawal of trastuzumab, at least one study – the Herceptin Adjuvant (HERA) trial – has shown that some women had long-term loss of heart muscle cells, said Dr. Telli.

"So we know that the heart is taking a hit," she said, adding that the trastuzumab damage is not "some sort of reversible thing."

The key, she said, is for oncologists to weigh the risks and benefits individually in each patient.

A targeted therapy, trastuzumab is approved for treatment of HER2-positive breast cancer and of metastatic HER2-positive adenocarcinoma of the stomach or gastroesophageal junction. About 20% of tumors in women with early breast cancer are HER2-positive.

Dr. Telli reported no conflicts of interest. Dr. Lenihan reported receiving consulting fees from Roche and AstraZeneca and research support from Acorda.

Ultrasound, a technology that was once mainly in the purview of radiologists, is becoming an integral part of the surgeon’s toolbox.

Across specialties, an increasing number of surgeons are incorporating ultrasound into their practices, whether in the office or in the operating room, especially as procedures become less invasive.

The once-cumbersome machines have gotten smaller over the past three decades, the technology has improved dramatically, and – compared with some other types of imaging – ultrasound is more cost-effective and affordable, experts say.

"It’s a technology that I think is going to expand in use," said Dr. Jay K. Harness, an early adopter of ultrasound in breast surgery and coauthor of the textbook "Ultrasound in Surgical Practice." "I started using it in the 1990s, and it’s like we’ve gone from analog TV to digital."

Dr. Heidi Frankel, chair of American College of Surgeons’ (ACS) National Ultrasound Faculty, compared the developments in use of ultrasound in surgery to laparoscopy.

"Ultimately, the patients and the market pushed the need for it," said Dr. Frankel, professor of surgery at University of Maryland Shock Trauma Center, Baltimore. "Surgeons who didn’t do it had to learn to do it, and it became part of surgical training. I suspect the same thing is going to happen with ultrasound."

And while training and certification requirements vary widely, the surgeons currently using ultrasound predict that guidelines may ultimately become somewhat standardized within and across specialties.

Breast Surgery

Dr. Harness, who is also a member of the ACS National Ultrasound Faculty and the past-president of the American Society of Breast Surgeons (ASBS), was among the first to incorporate ultrasound into his practice. Today, he said, "for the contemporary breast surgeon, [ultrasound] is a fundamental tool ... Ultrasound is our stethoscope."

In breast surgery, ultrasound is an adjunctive tool for the physical exam, said Dr. Harness. It is used for diagnostic biopsy, and it can speed up the diagnostic process. Ultrasound also is used in the operating room, notably for procedures such as lumpectomies. And finally, ultrasound can help guide the placement of partial breast brachyradiation therapy devices.

Breast surgeons can obtain ultrasound certification through ASBS, although becoming certified is not a requirement. "A major goal of the Society’s breast ultrasound certification program is to improve the quality of care for patients with breast disease by encouraging education and training to advance expertise and clinical competency for surgeons who use ultrasound and ultrasound-guided procedures in their practices," according to the ASBS website.

Dr. Harness said that ultrasound combined with other imaging techniques such as MRI provides the most complete imaging possible, given that there’s no single technology that captures everything.

Abdominal Surgery

In the 1980s, not many surgeons used ultrasound in their day-to-day practice and there were few publications on the topic, said Dr. Junji Machi. At that time, x-rays were commonly used to check areas such as the bile duct for stones. "But, it was cumbersome and took 15-30 minutes. So we used ultrasound instead. It was quicker, and the results were accurate," said Dr. Machi, professor of surgery at University of Hawaii, and director of the Abdominal Ultrasound Module at the ACS.

Dr. Machi has published a number of studies on cases and findings, and he uses ultrasound, especially during liver, biliary, and pancreatic surgery.

"For liver surgery, intraoperative ultrasound is a must," he said. "Without it, we consider the procedure suboptimal, because we may miss lesions and cannot perform the best operations."

Among the indications for ultrasound use in abdominal surgery were laparoscopic procedures, which were introduced in the 1990s, he said. "You can see, but not touch, the tissue," said Dr. Machi. "So we needed something to evaluate under the surface. ... With ultrasound, we can see without much dissection."

Surgeons could be discouraged from using ultrasound because the learning curve is steep (usually several months’ experience is needed) and because the equipment is relatively expensive. Yet, "once you learn it, it’s much more cost effective," he said, adding that this imaging technique does not expose the patient and operative team to radiation.

There’s no specialty limitation in the use of ultrasound, and abdominal surgeons can perform it once they master ultrasound. The ACS ultrasound course is an excellent way to learn, said Dr. Machi. Surgeons receive a certificate upon completion of a course.

Indeed, "the training issues are really paramount," said Dr. Ellen Hagopian, who did her liver training in France, and studied with radiologists and surgeons. Ultrasound is used much more frequently in Europe than in the United States, she said. "I sit on the education and training committee of Americas Hepato-Pancreato-Biliary Association [AHPBA], and I think ultrasound training throughout the fellowship programs needs to be more consistent."

Dr. Hagopian, who sits on ACS’s National Ultrasound Faculty board, coordinated and taught the first advanced ultrasound course in hepato-pancreato-biliary surgery at the AHPBA Annual Meeting in March. The course will be given again this year at the ACS Clinical Congress in San Francisco. Surgeons receive a certification of completion.

"Feedback and interest at AHPBA was excellent," said Dr. Hagopian. "There were many more surgeons who wanted to take the course than we could accommodate." She anticipates that similar interest will be shown during the ACS Clinical Congress.

Head and Neck Surgery

"Basically, the best way to evaluate the thyroid gland is ultrasound," said Dr. Robert Sofferman, an otolaryngologist who does thyroid and parathyroid surgery as part of his practice. "It’s cheaper and incredibly accurate."

Dr. Sofferman, professor emeritus of surgery at the University of Vermont in Burlington, said that some 15 years ago, ultrasound machines were too big and didn’t have good resolution. But over time, the equipment has become smaller, better, portable, and less expensive, he said. He predicts that the machines will eventually shrink to the size of an iPad.

"We operate in the neck on a daily basis," said Dr. Sofferman. "Ultrasound is very helpful for us. I couldn’t do my work without it."

Having the imaging available in the office is also convenient for the patients. "We arrange everything before the patient comes in. We do the physical exam. We do the ultrasound exam. We do ultrasound-guided biopsy, so the patient is done in one visit."

He said ultrasound can be used to evaluate the size and characteristics of a tumor before deciding whether to operate or to monitor the tumor’s response to treatment. "It’s a technology that has some advantages. It’s an extension of our physical examination."

It also comes with a few drawbacks. Aside from the price, which can be upwards of $30,000, ultrasound can slow down the day, and it does have a moderate learning curve, according to Dr. Sofferman.

Neither the ACS nor American Association of Otolaryngology-Head and Neck Surgery (AAO-HNS) require certification for the use of ultrasound. However, the ACS offers training in thyroid/parathyroid ultrasound to all surgeons who do neck surgery, either during the annual Clinical Congress or in other courses. Participants who complete training receive certification from the ACS.

Vascular Surgery

Ultrasound is a major component of vascular surgery training and practice, and many vascular surgeons have obtained the Registered Vascular Technologist (RVT) credential from the American Registry for Diagnostic Medical Sonography (ARDMS.)

While the RVT credential has been available since the 1980s, the ARDMS introduced the Registered Physician in Vascular Interpretation (RPVI) credential in 2006 to provide a certification process that focuses more on interpretation of vascular ultrasound tests than on performing the examinations. The RPVI credential is open to all qualified physicians and is not restricted to vascular surgeons.

"The advantage of the RPVI is that it is a national, standardized credential that is available to all physicians with an interest in vascular testing," said Dr. Gene Zierler, a member of the National Ultrasound Faculty and professor of surgery at the University of Washington, Seattle. "So that means it can document expertise in vascular ultrasound across multiple specialties and training programs."

Starting in 2014, the RPVI will be a requirement for vascular surgery board certification, a decision supported by the Society for Vascular Surgery.

Trauma Surgery

Ultrasound is the quickest and most reliable diagnostic tool under emergency conditions, according to Dr. Frankel.

"We work with very time-sensitive injuries. Ultrasound in my specialty is absolutely necessary. We image trauma patients this way. We can’t wait for a radiologist to come in," she said.

Dr. Frankel, who began using ultrasound in 1994, echoed her colleagues who said that technology has improved over time. Her hospital has begun using ultrasound in the intensive care unit, and "our residents are starting to use it early on. And medical students are picking it up," she said.

Whether surgeons are permitted to use ultrasound in the hospital varies by system or institution. Hospitals may require board-certified surgeons to perform a certain number of ultrasound procedures before granting them certification or to show certain certification or credentialing in ultrasound, experts said.

"There’s no science [to show] how many of these procedures I should have done to get credentialed by the hospital to use ultrasound," Dr. Frankel said.

She and other surgeons predicted that the individual surgical societies will ultimately specify the training, certification, or accreditation requirements for performing ultrasound. In the meantime, ultrasound seems to be finding its place in surgery, and surgeons who have been using it say they wouldn’t practice without it.

"It adds to the joy of practicing medicine," said Dr. Sofferman. "It makes it enjoyable for us to be able to see everything. That’s a definite advantage. I couldn’t be as efficient and as accurate without it."

None of the surgeons reported any relevant disclosures.

Ultrasound, a technology that was once mainly in the purview of radiologists, is becoming an integral part of the surgeon’s toolbox.

Across specialties, an increasing number of surgeons are incorporating ultrasound into their practices, whether in the office or in the operating room, especially as procedures become less invasive.

The once-cumbersome machines have gotten smaller over the past three decades, the technology has improved dramatically, and – compared with some other types of imaging – ultrasound is more cost-effective and affordable, experts say.

"It’s a technology that I think is going to expand in use," said Dr. Jay K. Harness, an early adopter of ultrasound in breast surgery and coauthor of the textbook "Ultrasound in Surgical Practice." "I started using it in the 1990s, and it’s like we’ve gone from analog TV to digital."

Dr. Heidi Frankel, chair of American College of Surgeons’ (ACS) National Ultrasound Faculty, compared the developments in use of ultrasound in surgery to laparoscopy.

"Ultimately, the patients and the market pushed the need for it," said Dr. Frankel, professor of surgery at University of Maryland Shock Trauma Center, Baltimore. "Surgeons who didn’t do it had to learn to do it, and it became part of surgical training. I suspect the same thing is going to happen with ultrasound."

And while training and certification requirements vary widely, the surgeons currently using ultrasound predict that guidelines may ultimately become somewhat standardized within and across specialties.

Breast Surgery

Dr. Harness, who is also a member of the ACS National Ultrasound Faculty and the past-president of the American Society of Breast Surgeons (ASBS), was among the first to incorporate ultrasound into his practice. Today, he said, "for the contemporary breast surgeon, [ultrasound] is a fundamental tool ... Ultrasound is our stethoscope."

In breast surgery, ultrasound is an adjunctive tool for the physical exam, said Dr. Harness. It is used for diagnostic biopsy, and it can speed up the diagnostic process. Ultrasound also is used in the operating room, notably for procedures such as lumpectomies. And finally, ultrasound can help guide the placement of partial breast brachyradiation therapy devices.

Breast surgeons can obtain ultrasound certification through ASBS, although becoming certified is not a requirement. "A major goal of the Society’s breast ultrasound certification program is to improve the quality of care for patients with breast disease by encouraging education and training to advance expertise and clinical competency for surgeons who use ultrasound and ultrasound-guided procedures in their practices," according to the ASBS website.

Dr. Harness said that ultrasound combined with other imaging techniques such as MRI provides the most complete imaging possible, given that there’s no single technology that captures everything.

Abdominal Surgery

In the 1980s, not many surgeons used ultrasound in their day-to-day practice and there were few publications on the topic, said Dr. Junji Machi. At that time, x-rays were commonly used to check areas such as the bile duct for stones. "But, it was cumbersome and took 15-30 minutes. So we used ultrasound instead. It was quicker, and the results were accurate," said Dr. Machi, professor of surgery at University of Hawaii, and director of the Abdominal Ultrasound Module at the ACS.

Dr. Machi has published a number of studies on cases and findings, and he uses ultrasound, especially during liver, biliary, and pancreatic surgery.

"For liver surgery, intraoperative ultrasound is a must," he said. "Without it, we consider the procedure suboptimal, because we may miss lesions and cannot perform the best operations."

Among the indications for ultrasound use in abdominal surgery were laparoscopic procedures, which were introduced in the 1990s, he said. "You can see, but not touch, the tissue," said Dr. Machi. "So we needed something to evaluate under the surface. ... With ultrasound, we can see without much dissection."

Surgeons could be discouraged from using ultrasound because the learning curve is steep (usually several months’ experience is needed) and because the equipment is relatively expensive. Yet, "once you learn it, it’s much more cost effective," he said, adding that this imaging technique does not expose the patient and operative team to radiation.

There’s no specialty limitation in the use of ultrasound, and abdominal surgeons can perform it once they master ultrasound. The ACS ultrasound course is an excellent way to learn, said Dr. Machi. Surgeons receive a certificate upon completion of a course.

Indeed, "the training issues are really paramount," said Dr. Ellen Hagopian, who did her liver training in France, and studied with radiologists and surgeons. Ultrasound is used much more frequently in Europe than in the United States, she said. "I sit on the education and training committee of Americas Hepato-Pancreato-Biliary Association [AHPBA], and I think ultrasound training throughout the fellowship programs needs to be more consistent."

Dr. Hagopian, who sits on ACS’s National Ultrasound Faculty board, coordinated and taught the first advanced ultrasound course in hepato-pancreato-biliary surgery at the AHPBA Annual Meeting in March. The course will be given again this year at the ACS Clinical Congress in San Francisco. Surgeons receive a certification of completion.

"Feedback and interest at AHPBA was excellent," said Dr. Hagopian. "There were many more surgeons who wanted to take the course than we could accommodate." She anticipates that similar interest will be shown during the ACS Clinical Congress.

Head and Neck Surgery

"Basically, the best way to evaluate the thyroid gland is ultrasound," said Dr. Robert Sofferman, an otolaryngologist who does thyroid and parathyroid surgery as part of his practice. "It’s cheaper and incredibly accurate."

Dr. Sofferman, professor emeritus of surgery at the University of Vermont in Burlington, said that some 15 years ago, ultrasound machines were too big and didn’t have good resolution. But over time, the equipment has become smaller, better, portable, and less expensive, he said. He predicts that the machines will eventually shrink to the size of an iPad.

"We operate in the neck on a daily basis," said Dr. Sofferman. "Ultrasound is very helpful for us. I couldn’t do my work without it."

Having the imaging available in the office is also convenient for the patients. "We arrange everything before the patient comes in. We do the physical exam. We do the ultrasound exam. We do ultrasound-guided biopsy, so the patient is done in one visit."

He said ultrasound can be used to evaluate the size and characteristics of a tumor before deciding whether to operate or to monitor the tumor’s response to treatment. "It’s a technology that has some advantages. It’s an extension of our physical examination."

It also comes with a few drawbacks. Aside from the price, which can be upwards of $30,000, ultrasound can slow down the day, and it does have a moderate learning curve, according to Dr. Sofferman.

Neither the ACS nor American Association of Otolaryngology-Head and Neck Surgery (AAO-HNS) require certification for the use of ultrasound. However, the ACS offers training in thyroid/parathyroid ultrasound to all surgeons who do neck surgery, either during the annual Clinical Congress or in other courses. Participants who complete training receive certification from the ACS.

Vascular Surgery

Ultrasound is a major component of vascular surgery training and practice, and many vascular surgeons have obtained the Registered Vascular Technologist (RVT) credential from the American Registry for Diagnostic Medical Sonography (ARDMS.)

While the RVT credential has been available since the 1980s, the ARDMS introduced the Registered Physician in Vascular Interpretation (RPVI) credential in 2006 to provide a certification process that focuses more on interpretation of vascular ultrasound tests than on performing the examinations. The RPVI credential is open to all qualified physicians and is not restricted to vascular surgeons.

"The advantage of the RPVI is that it is a national, standardized credential that is available to all physicians with an interest in vascular testing," said Dr. Gene Zierler, a member of the National Ultrasound Faculty and professor of surgery at the University of Washington, Seattle. "So that means it can document expertise in vascular ultrasound across multiple specialties and training programs."

Starting in 2014, the RPVI will be a requirement for vascular surgery board certification, a decision supported by the Society for Vascular Surgery.

Trauma Surgery

Ultrasound is the quickest and most reliable diagnostic tool under emergency conditions, according to Dr. Frankel.

"We work with very time-sensitive injuries. Ultrasound in my specialty is absolutely necessary. We image trauma patients this way. We can’t wait for a radiologist to come in," she said.

Dr. Frankel, who began using ultrasound in 1994, echoed her colleagues who said that technology has improved over time. Her hospital has begun using ultrasound in the intensive care unit, and "our residents are starting to use it early on. And medical students are picking it up," she said.

Whether surgeons are permitted to use ultrasound in the hospital varies by system or institution. Hospitals may require board-certified surgeons to perform a certain number of ultrasound procedures before granting them certification or to show certain certification or credentialing in ultrasound, experts said.

"There’s no science [to show] how many of these procedures I should have done to get credentialed by the hospital to use ultrasound," Dr. Frankel said.

She and other surgeons predicted that the individual surgical societies will ultimately specify the training, certification, or accreditation requirements for performing ultrasound. In the meantime, ultrasound seems to be finding its place in surgery, and surgeons who have been using it say they wouldn’t practice without it.

"It adds to the joy of practicing medicine," said Dr. Sofferman. "It makes it enjoyable for us to be able to see everything. That’s a definite advantage. I couldn’t be as efficient and as accurate without it."

None of the surgeons reported any relevant disclosures.

Ultrasound, a technology that was once mainly in the purview of radiologists, is becoming an integral part of the surgeon’s toolbox.

Across specialties, an increasing number of surgeons are incorporating ultrasound into their practices, whether in the office or in the operating room, especially as procedures become less invasive.

The once-cumbersome machines have gotten smaller over the past three decades, the technology has improved dramatically, and – compared with some other types of imaging – ultrasound is more cost-effective and affordable, experts say.

"It’s a technology that I think is going to expand in use," said Dr. Jay K. Harness, an early adopter of ultrasound in breast surgery and coauthor of the textbook "Ultrasound in Surgical Practice." "I started using it in the 1990s, and it’s like we’ve gone from analog TV to digital."

Dr. Heidi Frankel, chair of American College of Surgeons’ (ACS) National Ultrasound Faculty, compared the developments in use of ultrasound in surgery to laparoscopy.

"Ultimately, the patients and the market pushed the need for it," said Dr. Frankel, professor of surgery at University of Maryland Shock Trauma Center, Baltimore. "Surgeons who didn’t do it had to learn to do it, and it became part of surgical training. I suspect the same thing is going to happen with ultrasound."

And while training and certification requirements vary widely, the surgeons currently using ultrasound predict that guidelines may ultimately become somewhat standardized within and across specialties.

Breast Surgery

Dr. Harness, who is also a member of the ACS National Ultrasound Faculty and the past-president of the American Society of Breast Surgeons (ASBS), was among the first to incorporate ultrasound into his practice. Today, he said, "for the contemporary breast surgeon, [ultrasound] is a fundamental tool ... Ultrasound is our stethoscope."

In breast surgery, ultrasound is an adjunctive tool for the physical exam, said Dr. Harness. It is used for diagnostic biopsy, and it can speed up the diagnostic process. Ultrasound also is used in the operating room, notably for procedures such as lumpectomies. And finally, ultrasound can help guide the placement of partial breast brachyradiation therapy devices.

Breast surgeons can obtain ultrasound certification through ASBS, although becoming certified is not a requirement. "A major goal of the Society’s breast ultrasound certification program is to improve the quality of care for patients with breast disease by encouraging education and training to advance expertise and clinical competency for surgeons who use ultrasound and ultrasound-guided procedures in their practices," according to the ASBS website.

Dr. Harness said that ultrasound combined with other imaging techniques such as MRI provides the most complete imaging possible, given that there’s no single technology that captures everything.

Abdominal Surgery

In the 1980s, not many surgeons used ultrasound in their day-to-day practice and there were few publications on the topic, said Dr. Junji Machi. At that time, x-rays were commonly used to check areas such as the bile duct for stones. "But, it was cumbersome and took 15-30 minutes. So we used ultrasound instead. It was quicker, and the results were accurate," said Dr. Machi, professor of surgery at University of Hawaii, and director of the Abdominal Ultrasound Module at the ACS.

Dr. Machi has published a number of studies on cases and findings, and he uses ultrasound, especially during liver, biliary, and pancreatic surgery.

"For liver surgery, intraoperative ultrasound is a must," he said. "Without it, we consider the procedure suboptimal, because we may miss lesions and cannot perform the best operations."

Among the indications for ultrasound use in abdominal surgery were laparoscopic procedures, which were introduced in the 1990s, he said. "You can see, but not touch, the tissue," said Dr. Machi. "So we needed something to evaluate under the surface. ... With ultrasound, we can see without much dissection."

Surgeons could be discouraged from using ultrasound because the learning curve is steep (usually several months’ experience is needed) and because the equipment is relatively expensive. Yet, "once you learn it, it’s much more cost effective," he said, adding that this imaging technique does not expose the patient and operative team to radiation.

There’s no specialty limitation in the use of ultrasound, and abdominal surgeons can perform it once they master ultrasound. The ACS ultrasound course is an excellent way to learn, said Dr. Machi. Surgeons receive a certificate upon completion of a course.

Indeed, "the training issues are really paramount," said Dr. Ellen Hagopian, who did her liver training in France, and studied with radiologists and surgeons. Ultrasound is used much more frequently in Europe than in the United States, she said. "I sit on the education and training committee of Americas Hepato-Pancreato-Biliary Association [AHPBA], and I think ultrasound training throughout the fellowship programs needs to be more consistent."

Dr. Hagopian, who sits on ACS’s National Ultrasound Faculty board, coordinated and taught the first advanced ultrasound course in hepato-pancreato-biliary surgery at the AHPBA Annual Meeting in March. The course will be given again this year at the ACS Clinical Congress in San Francisco. Surgeons receive a certification of completion.

"Feedback and interest at AHPBA was excellent," said Dr. Hagopian. "There were many more surgeons who wanted to take the course than we could accommodate." She anticipates that similar interest will be shown during the ACS Clinical Congress.

Head and Neck Surgery

"Basically, the best way to evaluate the thyroid gland is ultrasound," said Dr. Robert Sofferman, an otolaryngologist who does thyroid and parathyroid surgery as part of his practice. "It’s cheaper and incredibly accurate."

Dr. Sofferman, professor emeritus of surgery at the University of Vermont in Burlington, said that some 15 years ago, ultrasound machines were too big and didn’t have good resolution. But over time, the equipment has become smaller, better, portable, and less expensive, he said. He predicts that the machines will eventually shrink to the size of an iPad.

"We operate in the neck on a daily basis," said Dr. Sofferman. "Ultrasound is very helpful for us. I couldn’t do my work without it."

Having the imaging available in the office is also convenient for the patients. "We arrange everything before the patient comes in. We do the physical exam. We do the ultrasound exam. We do ultrasound-guided biopsy, so the patient is done in one visit."

He said ultrasound can be used to evaluate the size and characteristics of a tumor before deciding whether to operate or to monitor the tumor’s response to treatment. "It’s a technology that has some advantages. It’s an extension of our physical examination."

It also comes with a few drawbacks. Aside from the price, which can be upwards of $30,000, ultrasound can slow down the day, and it does have a moderate learning curve, according to Dr. Sofferman.

Neither the ACS nor American Association of Otolaryngology-Head and Neck Surgery (AAO-HNS) require certification for the use of ultrasound. However, the ACS offers training in thyroid/parathyroid ultrasound to all surgeons who do neck surgery, either during the annual Clinical Congress or in other courses. Participants who complete training receive certification from the ACS.

Vascular Surgery

Ultrasound is a major component of vascular surgery training and practice, and many vascular surgeons have obtained the Registered Vascular Technologist (RVT) credential from the American Registry for Diagnostic Medical Sonography (ARDMS.)

While the RVT credential has been available since the 1980s, the ARDMS introduced the Registered Physician in Vascular Interpretation (RPVI) credential in 2006 to provide a certification process that focuses more on interpretation of vascular ultrasound tests than on performing the examinations. The RPVI credential is open to all qualified physicians and is not restricted to vascular surgeons.

"The advantage of the RPVI is that it is a national, standardized credential that is available to all physicians with an interest in vascular testing," said Dr. Gene Zierler, a member of the National Ultrasound Faculty and professor of surgery at the University of Washington, Seattle. "So that means it can document expertise in vascular ultrasound across multiple specialties and training programs."

Starting in 2014, the RPVI will be a requirement for vascular surgery board certification, a decision supported by the Society for Vascular Surgery.

Trauma Surgery

Ultrasound is the quickest and most reliable diagnostic tool under emergency conditions, according to Dr. Frankel.

"We work with very time-sensitive injuries. Ultrasound in my specialty is absolutely necessary. We image trauma patients this way. We can’t wait for a radiologist to come in," she said.

Dr. Frankel, who began using ultrasound in 1994, echoed her colleagues who said that technology has improved over time. Her hospital has begun using ultrasound in the intensive care unit, and "our residents are starting to use it early on. And medical students are picking it up," she said.

Whether surgeons are permitted to use ultrasound in the hospital varies by system or institution. Hospitals may require board-certified surgeons to perform a certain number of ultrasound procedures before granting them certification or to show certain certification or credentialing in ultrasound, experts said.

"There’s no science [to show] how many of these procedures I should have done to get credentialed by the hospital to use ultrasound," Dr. Frankel said.

She and other surgeons predicted that the individual surgical societies will ultimately specify the training, certification, or accreditation requirements for performing ultrasound. In the meantime, ultrasound seems to be finding its place in surgery, and surgeons who have been using it say they wouldn’t practice without it.

"It adds to the joy of practicing medicine," said Dr. Sofferman. "It makes it enjoyable for us to be able to see everything. That’s a definite advantage. I couldn’t be as efficient and as accurate without it."

None of the surgeons reported any relevant disclosures.

Axillary lymph node dissection can be skipped in some early-stage breast cancer patients with minimal sentinel node involvement, as well as in those with negative findings on sentinel node biopsy, according to revised clinical practice guidelines issued by the National Comprehensive Cancer Network.

The recommendation that no further axial surgery be considered for certain patients with only one or two involved sentinel lymph nodes reflects an upgrade of the National Comprehensive Cancer Network (NCCN) guideline on sentinel node biopsy to a category 1 recommendation.

The change is based on the findings of recent prospective studies. In particular, the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, found no survival difference between early-stage breast cancer patients who underwent axillary lymph node dissection [ALND] and those who did not after one or two sentinel nodes were determined to be positive on biopsy (JAMA 2011;305:569-75).

The revised recommendation extends only to those patients with early-stage disease (tumor grades 1 or 2) who undergo breast-conserving surgery and whole-breast radiation and who have not received neoadjuvant chemotherapy, according to the guidelines. A primary objective is to reduce the risk of lymphedema associated with axillary lymph node dissection.

"In the absence of definitive data demonstrating superior survival from the performance of axillary lymph node dissection, patients who have particularly favorable tumors, patients for whom the selection of adjuvant systemic therapy is unlikely to be affected, for the elderly or those with serious comorbid conditions, the performance of axillary lymph node dissection may be considered optional," the guidelines advise.

The update was presented at the NCCN annual meeting in Hollywood, Fla. The Breast Cancer Panel lists potential conflict of interest disclosures on the NCCN website.

Axillary lymph node dissection can be skipped in some early-stage breast cancer patients with minimal sentinel node involvement, as well as in those with negative findings on sentinel node biopsy, according to revised clinical practice guidelines issued by the National Comprehensive Cancer Network.

The recommendation that no further axial surgery be considered for certain patients with only one or two involved sentinel lymph nodes reflects an upgrade of the National Comprehensive Cancer Network (NCCN) guideline on sentinel node biopsy to a category 1 recommendation.

The change is based on the findings of recent prospective studies. In particular, the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, found no survival difference between early-stage breast cancer patients who underwent axillary lymph node dissection [ALND] and those who did not after one or two sentinel nodes were determined to be positive on biopsy (JAMA 2011;305:569-75).

The revised recommendation extends only to those patients with early-stage disease (tumor grades 1 or 2) who undergo breast-conserving surgery and whole-breast radiation and who have not received neoadjuvant chemotherapy, according to the guidelines. A primary objective is to reduce the risk of lymphedema associated with axillary lymph node dissection.

"In the absence of definitive data demonstrating superior survival from the performance of axillary lymph node dissection, patients who have particularly favorable tumors, patients for whom the selection of adjuvant systemic therapy is unlikely to be affected, for the elderly or those with serious comorbid conditions, the performance of axillary lymph node dissection may be considered optional," the guidelines advise.

The update was presented at the NCCN annual meeting in Hollywood, Fla. The Breast Cancer Panel lists potential conflict of interest disclosures on the NCCN website.

Axillary lymph node dissection can be skipped in some early-stage breast cancer patients with minimal sentinel node involvement, as well as in those with negative findings on sentinel node biopsy, according to revised clinical practice guidelines issued by the National Comprehensive Cancer Network.

The recommendation that no further axial surgery be considered for certain patients with only one or two involved sentinel lymph nodes reflects an upgrade of the National Comprehensive Cancer Network (NCCN) guideline on sentinel node biopsy to a category 1 recommendation.

The change is based on the findings of recent prospective studies. In particular, the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, found no survival difference between early-stage breast cancer patients who underwent axillary lymph node dissection [ALND] and those who did not after one or two sentinel nodes were determined to be positive on biopsy (JAMA 2011;305:569-75).

The revised recommendation extends only to those patients with early-stage disease (tumor grades 1 or 2) who undergo breast-conserving surgery and whole-breast radiation and who have not received neoadjuvant chemotherapy, according to the guidelines. A primary objective is to reduce the risk of lymphedema associated with axillary lymph node dissection.

"In the absence of definitive data demonstrating superior survival from the performance of axillary lymph node dissection, patients who have particularly favorable tumors, patients for whom the selection of adjuvant systemic therapy is unlikely to be affected, for the elderly or those with serious comorbid conditions, the performance of axillary lymph node dissection may be considered optional," the guidelines advise.

The update was presented at the NCCN annual meeting in Hollywood, Fla. The Breast Cancer Panel lists potential conflict of interest disclosures on the NCCN website.

CHICAGO – Older breast cancer patients with the luminal A tumor subtype may be able to forgo whole breast radiation therapy if they are taking tamoxifen or other breast cancer hormone therapy.

Preliminary results from a randomized clinical trial of tamoxifen with and without radiation therapy showed that radiation therapy had minimal impact on the risk of developing ipsilateral breast tumor recurrence in patients aged 50 years and older with T1 and T2 node-negative breast cancer identified with luminal A disease based on 6-marker immunohistochemistry testing.

Diana Mahoney/IMNG Medical Media

In contrast, radiation therapy appeared to decrease the risk of breast cancer relapse in patients with luminal B, human epidermal growth factor receptor 2 (HER2)–enriched, and basal tumor subtypes, according to radiation oncologist Dr. Fei-Fei Liu of Princess Margaret Hospital, the Ontario Cancer Institute, and the University of Toronto, all in Toronto. She discussed the findings in a press conference April 1 at the annual meeting of the American Association for Cancer Research.

Luminal A tumors – estrogen receptor (ER) or progesterone receptor (PR) positive, HER2-negative, and low Ki-67 (a nuclear marker for cell proliferation) – are associated with a relatively good prognosis compared with the other subtypes, she noted.

To determine the predictive value of tumor subtype for ipsilateral recurrence in this population, Dr. Liu and her colleagues performed molecular subtyping for ER, PR, Ki-67, HER2, EGFR, and cytokeratine 5/6 on 304 available tumor specimens from 769 women in a clinical trial. All had been randomized to treatment with tamoxifen and whole breast radiation or tamoxifen alone between December 1992 and June 2000.

Based on the subtyping results, the patients were classified as luminal A, luminal B, luminal HER2, HER2-enriched, basal-like, or triple-negative phenotype–non-basal and followed for a median of 10 years, she said.

In the overall group of 769 women, the recurrence rate at a median of 10 years was 13.8% in the tamoxifen-only group and 5.0% in the combination group, Dr. Liu reported, noting that, in a multivariate analysis, "patient age, tumor size, estrogen-receptor positive status, and combination tamoxifen/whole breast radiation therapy were all significant factors."

Of the 304 tissue microarrays, 145 came from patients treated with tamoxifen only and 159 from patients treated with tamoxifen plus radiotherapy. In this population, the best outcomes were observed in 133 patients with luminal A tumors; their rate of ipsilateral recurrence was statistically similar at 8% among those in the tamoxifen-only group and 4.6% in the tamoxifen plus radiation group, Dr. Liu reported.

The 103 women older than 60 years with luminal A tumors fared particularly well, with rates of 4.3% with tamoxifen alone and 6.0% with tamoxifen and radiotherapy. The respective rates for the 114 women with grade I-II luminal A tumors also were similar at 4.9% and 5.5%, she said.

In contrast, the ipsilateral recurrence rates for the tamoxifen only and tamoxifen plus radiation groups were, respectively, 16.1% and 3.9% in 82 patients with luminal B tumors (differentiated from luminal A tumors by Ki-67 expression greater than 14%), said Dr. Liu.

Further, although the number of HER2 (11), HER2-enriched (11), and basal-like tumors (16) were small, "we saw higher relapse rates in patients who did not undergo radiation therapy," she said.

Luminal A lymph-node negative breast cancer represents approximately 25% of all cases of newly diagnosed breast cancer in North America, according to Dr. Liu. In addition to sparing a large number of women unnecessary radiation exposures, unwanted side effects, and inconvenience, bypassing radiation therapy in early cases would save millions of health care dollars each year.

"We estimated a savings of $20 million annually in Ontario if radiation therapy were avoided in early luminal A [breast cancer]," she said. "Extrapolating the figures to the [United States] resulted in a savings of about $400 million per year."

Dr. Liu stressed that the data presented at the meeting are preliminary but noted that, if the findings are validated through the analysis of a larger number of tumor samples, "we would recommend adding Ki-67 to the current standard immunohistochemistry panel, and discussing the possibility of avoiding radiation with lymph node–negative patients in whom the luminal A subtype is identified, if they are taking tamoxifen or an equivalent medication, especially patients who are 60 years old or older."

Dr. Liu disclosed no conflicts of interest.

CHICAGO – Older breast cancer patients with the luminal A tumor subtype may be able to forgo whole breast radiation therapy if they are taking tamoxifen or other breast cancer hormone therapy.

Preliminary results from a randomized clinical trial of tamoxifen with and without radiation therapy showed that radiation therapy had minimal impact on the risk of developing ipsilateral breast tumor recurrence in patients aged 50 years and older with T1 and T2 node-negative breast cancer identified with luminal A disease based on 6-marker immunohistochemistry testing.

Diana Mahoney/IMNG Medical Media

In contrast, radiation therapy appeared to decrease the risk of breast cancer relapse in patients with luminal B, human epidermal growth factor receptor 2 (HER2)–enriched, and basal tumor subtypes, according to radiation oncologist Dr. Fei-Fei Liu of Princess Margaret Hospital, the Ontario Cancer Institute, and the University of Toronto, all in Toronto. She discussed the findings in a press conference April 1 at the annual meeting of the American Association for Cancer Research.

Luminal A tumors – estrogen receptor (ER) or progesterone receptor (PR) positive, HER2-negative, and low Ki-67 (a nuclear marker for cell proliferation) – are associated with a relatively good prognosis compared with the other subtypes, she noted.

To determine the predictive value of tumor subtype for ipsilateral recurrence in this population, Dr. Liu and her colleagues performed molecular subtyping for ER, PR, Ki-67, HER2, EGFR, and cytokeratine 5/6 on 304 available tumor specimens from 769 women in a clinical trial. All had been randomized to treatment with tamoxifen and whole breast radiation or tamoxifen alone between December 1992 and June 2000.

Based on the subtyping results, the patients were classified as luminal A, luminal B, luminal HER2, HER2-enriched, basal-like, or triple-negative phenotype–non-basal and followed for a median of 10 years, she said.

In the overall group of 769 women, the recurrence rate at a median of 10 years was 13.8% in the tamoxifen-only group and 5.0% in the combination group, Dr. Liu reported, noting that, in a multivariate analysis, "patient age, tumor size, estrogen-receptor positive status, and combination tamoxifen/whole breast radiation therapy were all significant factors."

Of the 304 tissue microarrays, 145 came from patients treated with tamoxifen only and 159 from patients treated with tamoxifen plus radiotherapy. In this population, the best outcomes were observed in 133 patients with luminal A tumors; their rate of ipsilateral recurrence was statistically similar at 8% among those in the tamoxifen-only group and 4.6% in the tamoxifen plus radiation group, Dr. Liu reported.

The 103 women older than 60 years with luminal A tumors fared particularly well, with rates of 4.3% with tamoxifen alone and 6.0% with tamoxifen and radiotherapy. The respective rates for the 114 women with grade I-II luminal A tumors also were similar at 4.9% and 5.5%, she said.

In contrast, the ipsilateral recurrence rates for the tamoxifen only and tamoxifen plus radiation groups were, respectively, 16.1% and 3.9% in 82 patients with luminal B tumors (differentiated from luminal A tumors by Ki-67 expression greater than 14%), said Dr. Liu.

Further, although the number of HER2 (11), HER2-enriched (11), and basal-like tumors (16) were small, "we saw higher relapse rates in patients who did not undergo radiation therapy," she said.

Luminal A lymph-node negative breast cancer represents approximately 25% of all cases of newly diagnosed breast cancer in North America, according to Dr. Liu. In addition to sparing a large number of women unnecessary radiation exposures, unwanted side effects, and inconvenience, bypassing radiation therapy in early cases would save millions of health care dollars each year.

"We estimated a savings of $20 million annually in Ontario if radiation therapy were avoided in early luminal A [breast cancer]," she said. "Extrapolating the figures to the [United States] resulted in a savings of about $400 million per year."

Dr. Liu stressed that the data presented at the meeting are preliminary but noted that, if the findings are validated through the analysis of a larger number of tumor samples, "we would recommend adding Ki-67 to the current standard immunohistochemistry panel, and discussing the possibility of avoiding radiation with lymph node–negative patients in whom the luminal A subtype is identified, if they are taking tamoxifen or an equivalent medication, especially patients who are 60 years old or older."

Dr. Liu disclosed no conflicts of interest.

CHICAGO – Older breast cancer patients with the luminal A tumor subtype may be able to forgo whole breast radiation therapy if they are taking tamoxifen or other breast cancer hormone therapy.

Preliminary results from a randomized clinical trial of tamoxifen with and without radiation therapy showed that radiation therapy had minimal impact on the risk of developing ipsilateral breast tumor recurrence in patients aged 50 years and older with T1 and T2 node-negative breast cancer identified with luminal A disease based on 6-marker immunohistochemistry testing.

Diana Mahoney/IMNG Medical Media

In contrast, radiation therapy appeared to decrease the risk of breast cancer relapse in patients with luminal B, human epidermal growth factor receptor 2 (HER2)–enriched, and basal tumor subtypes, according to radiation oncologist Dr. Fei-Fei Liu of Princess Margaret Hospital, the Ontario Cancer Institute, and the University of Toronto, all in Toronto. She discussed the findings in a press conference April 1 at the annual meeting of the American Association for Cancer Research.

Luminal A tumors – estrogen receptor (ER) or progesterone receptor (PR) positive, HER2-negative, and low Ki-67 (a nuclear marker for cell proliferation) – are associated with a relatively good prognosis compared with the other subtypes, she noted.

To determine the predictive value of tumor subtype for ipsilateral recurrence in this population, Dr. Liu and her colleagues performed molecular subtyping for ER, PR, Ki-67, HER2, EGFR, and cytokeratine 5/6 on 304 available tumor specimens from 769 women in a clinical trial. All had been randomized to treatment with tamoxifen and whole breast radiation or tamoxifen alone between December 1992 and June 2000.

Based on the subtyping results, the patients were classified as luminal A, luminal B, luminal HER2, HER2-enriched, basal-like, or triple-negative phenotype–non-basal and followed for a median of 10 years, she said.

In the overall group of 769 women, the recurrence rate at a median of 10 years was 13.8% in the tamoxifen-only group and 5.0% in the combination group, Dr. Liu reported, noting that, in a multivariate analysis, "patient age, tumor size, estrogen-receptor positive status, and combination tamoxifen/whole breast radiation therapy were all significant factors."

Of the 304 tissue microarrays, 145 came from patients treated with tamoxifen only and 159 from patients treated with tamoxifen plus radiotherapy. In this population, the best outcomes were observed in 133 patients with luminal A tumors; their rate of ipsilateral recurrence was statistically similar at 8% among those in the tamoxifen-only group and 4.6% in the tamoxifen plus radiation group, Dr. Liu reported.

The 103 women older than 60 years with luminal A tumors fared particularly well, with rates of 4.3% with tamoxifen alone and 6.0% with tamoxifen and radiotherapy. The respective rates for the 114 women with grade I-II luminal A tumors also were similar at 4.9% and 5.5%, she said.

In contrast, the ipsilateral recurrence rates for the tamoxifen only and tamoxifen plus radiation groups were, respectively, 16.1% and 3.9% in 82 patients with luminal B tumors (differentiated from luminal A tumors by Ki-67 expression greater than 14%), said Dr. Liu.

Further, although the number of HER2 (11), HER2-enriched (11), and basal-like tumors (16) were small, "we saw higher relapse rates in patients who did not undergo radiation therapy," she said.

Luminal A lymph-node negative breast cancer represents approximately 25% of all cases of newly diagnosed breast cancer in North America, according to Dr. Liu. In addition to sparing a large number of women unnecessary radiation exposures, unwanted side effects, and inconvenience, bypassing radiation therapy in early cases would save millions of health care dollars each year.

"We estimated a savings of $20 million annually in Ontario if radiation therapy were avoided in early luminal A [breast cancer]," she said. "Extrapolating the figures to the [United States] resulted in a savings of about $400 million per year."

Dr. Liu stressed that the data presented at the meeting are preliminary but noted that, if the findings are validated through the analysis of a larger number of tumor samples, "we would recommend adding Ki-67 to the current standard immunohistochemistry panel, and discussing the possibility of avoiding radiation with lymph node–negative patients in whom the luminal A subtype is identified, if they are taking tamoxifen or an equivalent medication, especially patients who are 60 years old or older."

Dr. Liu disclosed no conflicts of interest.