Lab mouse

Preclinical research suggests that activating the STING pathway may be a feasible approach for treating acute myeloid leukemia (AML).

The STING protein has been shown to play a crucial role in the immune system’s ability to “sense” cancer by recognizing and responding to DNA from tumor cells.

In past studies, researchers injected compounds that activate the STING pathway directly into solid tumors in mice, and this produced potent anti-tumor immune responses.

In a new study, researchers injected substances that mimic tumor-cell DNA into the bloodstream and found they could stimulate STING to provoke a life-extending immune response in mice with AML.

“Delivery of these substances into the blood led to massive immune responses,” said study author Justin Kline, MD, of the University of Chicago in Illinois.

“I’ve worked extensively with animal models of this disease, and have never seen responses like this.”

This research, published in Cell Reports, is the first demonstration that activating the STING pathway could be effective in hematologic malignancies.

STING (short for STimulator of INterferon Genes) plays a role in detecting threats, such as viral infections or cancer. STING is activated when DNA turns up in the wrong place, inside the cell but outside the nucleus.

When it encounters such misplaced DNA, STING induces the production of interferon-beta and other chemical signals that recruit certain components of the immune system to manage the threat, such as leukemia-specific killer T cells.

In this study, the researchers found that mice with established AML were rarely able to launch an effective immune response against the disease.

But when the team exposed the mice to DMXAA (5,6-dimethylxanthenone-4-acetic acid), a molecule that activates STING, the immune system responded aggressively, culminating in the activation of highly potent, cancer-cell killing T cells.

This response prolonged survival and, in some cases, cured the mice of their leukemia. About 60% of DMXAA-treated mice survived long-term. They were even able to protect themselves when “re-challenged” with AML cells.

Because of significant differences between mice and humans, DMXAA does not activate the human STING pathway, but researchers have found that several cyclic dinucleotides—signaling molecules produced by bacteria—have a comparable effect in stimulating the STING pathway.

This leads to an immune response that begins with the production of type I interferons and proceeds to later, more powerful stages, ultimately including leukemia-specific T cells.

“Our results provide strong rationale for the clinical translation of STING agonists as immune therapy for leukemia and possibly other hematologic

malignancies,” said study author Emily Curran, MD, of the University of Chicago.

However, Dr Kline noted that this approach is “not without risk.” He said it can induce “a lot of inflammation, fever, even shock.” Such a stimulated immune system can be “too effective,” especially when the therapy is given through the blood stream, rather than injected into a solid tumor.

“I think drug makers will want to focus on intra-tumoral injection studies before they are ready to bet on systemic infusion,” Dr Kline said. “But this is an important first step.”

Lab mouse

Preclinical research suggests that activating the STING pathway may be a feasible approach for treating acute myeloid leukemia (AML).

The STING protein has been shown to play a crucial role in the immune system’s ability to “sense” cancer by recognizing and responding to DNA from tumor cells.

In past studies, researchers injected compounds that activate the STING pathway directly into solid tumors in mice, and this produced potent anti-tumor immune responses.

In a new study, researchers injected substances that mimic tumor-cell DNA into the bloodstream and found they could stimulate STING to provoke a life-extending immune response in mice with AML.

“Delivery of these substances into the blood led to massive immune responses,” said study author Justin Kline, MD, of the University of Chicago in Illinois.

“I’ve worked extensively with animal models of this disease, and have never seen responses like this.”

This research, published in Cell Reports, is the first demonstration that activating the STING pathway could be effective in hematologic malignancies.

STING (short for STimulator of INterferon Genes) plays a role in detecting threats, such as viral infections or cancer. STING is activated when DNA turns up in the wrong place, inside the cell but outside the nucleus.

When it encounters such misplaced DNA, STING induces the production of interferon-beta and other chemical signals that recruit certain components of the immune system to manage the threat, such as leukemia-specific killer T cells.

In this study, the researchers found that mice with established AML were rarely able to launch an effective immune response against the disease.

But when the team exposed the mice to DMXAA (5,6-dimethylxanthenone-4-acetic acid), a molecule that activates STING, the immune system responded aggressively, culminating in the activation of highly potent, cancer-cell killing T cells.

This response prolonged survival and, in some cases, cured the mice of their leukemia. About 60% of DMXAA-treated mice survived long-term. They were even able to protect themselves when “re-challenged” with AML cells.

Because of significant differences between mice and humans, DMXAA does not activate the human STING pathway, but researchers have found that several cyclic dinucleotides—signaling molecules produced by bacteria—have a comparable effect in stimulating the STING pathway.

This leads to an immune response that begins with the production of type I interferons and proceeds to later, more powerful stages, ultimately including leukemia-specific T cells.

“Our results provide strong rationale for the clinical translation of STING agonists as immune therapy for leukemia and possibly other hematologic

malignancies,” said study author Emily Curran, MD, of the University of Chicago.

However, Dr Kline noted that this approach is “not without risk.” He said it can induce “a lot of inflammation, fever, even shock.” Such a stimulated immune system can be “too effective,” especially when the therapy is given through the blood stream, rather than injected into a solid tumor.

“I think drug makers will want to focus on intra-tumoral injection studies before they are ready to bet on systemic infusion,” Dr Kline said. “But this is an important first step.”

Lab mouse

Preclinical research suggests that activating the STING pathway may be a feasible approach for treating acute myeloid leukemia (AML).

The STING protein has been shown to play a crucial role in the immune system’s ability to “sense” cancer by recognizing and responding to DNA from tumor cells.

In past studies, researchers injected compounds that activate the STING pathway directly into solid tumors in mice, and this produced potent anti-tumor immune responses.

In a new study, researchers injected substances that mimic tumor-cell DNA into the bloodstream and found they could stimulate STING to provoke a life-extending immune response in mice with AML.

“Delivery of these substances into the blood led to massive immune responses,” said study author Justin Kline, MD, of the University of Chicago in Illinois.

“I’ve worked extensively with animal models of this disease, and have never seen responses like this.”

This research, published in Cell Reports, is the first demonstration that activating the STING pathway could be effective in hematologic malignancies.

STING (short for STimulator of INterferon Genes) plays a role in detecting threats, such as viral infections or cancer. STING is activated when DNA turns up in the wrong place, inside the cell but outside the nucleus.

When it encounters such misplaced DNA, STING induces the production of interferon-beta and other chemical signals that recruit certain components of the immune system to manage the threat, such as leukemia-specific killer T cells.

In this study, the researchers found that mice with established AML were rarely able to launch an effective immune response against the disease.

But when the team exposed the mice to DMXAA (5,6-dimethylxanthenone-4-acetic acid), a molecule that activates STING, the immune system responded aggressively, culminating in the activation of highly potent, cancer-cell killing T cells.

This response prolonged survival and, in some cases, cured the mice of their leukemia. About 60% of DMXAA-treated mice survived long-term. They were even able to protect themselves when “re-challenged” with AML cells.

Because of significant differences between mice and humans, DMXAA does not activate the human STING pathway, but researchers have found that several cyclic dinucleotides—signaling molecules produced by bacteria—have a comparable effect in stimulating the STING pathway.

This leads to an immune response that begins with the production of type I interferons and proceeds to later, more powerful stages, ultimately including leukemia-specific T cells.

“Our results provide strong rationale for the clinical translation of STING agonists as immune therapy for leukemia and possibly other hematologic

malignancies,” said study author Emily Curran, MD, of the University of Chicago.

However, Dr Kline noted that this approach is “not without risk.” He said it can induce “a lot of inflammation, fever, even shock.” Such a stimulated immune system can be “too effective,” especially when the therapy is given through the blood stream, rather than injected into a solid tumor.

“I think drug makers will want to focus on intra-tumoral injection studies before they are ready to bet on systemic infusion,” Dr Kline said. “But this is an important first step.”

Ibrutinib given at doses lower than the standard dose of 420 mg/day was associated with comparable overall survival and progression-free survival as the standard dose in patients with chronic lymphocytic leukemia (CLL), based on the results of a multicenter, retrospective study submitted as a poster at the annual meeting of the American Society of Clinical Oncology.

The initial findings indicate patients who experience toxicity on the 420 mg/day dosage can still do well on a slightly lower dose of ibrutinib, reported Colleen Timlin, Pharm.D., of the Hospital of the University of Pennsylvania, Philadelphia, and her associates.

At a median follow-up of 13.5 months, the median progression-free survival was 37.4 months in the standard dose group and the median progression-free survival had not been reached in the reduced-dose group. The median overall survival had not been reached in either group. The hazard ratio in the reduced-dose group was 1.2 for progression-free survival and 0.6 for overall survival; neither difference was statistically significant. Best overall response rate was 85% in the standard-dose group and 84% in the reduced-dose group.

The study included 197 patients, 37 of whom were shifted to reduced doses of ibrutinib within 3 months of initiating therapy at the recommended 420 mg/day dosage. For reduced-dose patients, the median ibrutinib dose was 4.3 mg/kg per day. The most common reasons for reducing the ibrutinib dose were gastrointestinal toxicity, bleeding, rash, cardiotoxicity, and renal insufficiency, the researchers said.

Most of the patients treated with doses less than 420 mg/day still maintained a dose of greater than 2.5 mg/kg per day, which assured adequate Bruton’s tyrosine kinase occupancy. The 420 mg/day dosage noted in the labeling was established, based on achievement of greater than 90% Bruton’s tyrosine kinase occupancy. Fewer patients achieve greater than 90% occupancy at lower doses, but lower doses may not translate into inferior outcomes.

Weight-based dosing should be considered in future studies and pharmacoeconomic analyses. Comparative analyses of toxicity profiles stratified by ibrutinib dose are underway, according to Dr. Timlin and her colleagues.

Dr. Timlin had no relevant disclosures. Several of her colleagues had multiple financial disclosures.

[email protected]

On Twitter @maryjodales

Ibrutinib given at doses lower than the standard dose of 420 mg/day was associated with comparable overall survival and progression-free survival as the standard dose in patients with chronic lymphocytic leukemia (CLL), based on the results of a multicenter, retrospective study submitted as a poster at the annual meeting of the American Society of Clinical Oncology.

The initial findings indicate patients who experience toxicity on the 420 mg/day dosage can still do well on a slightly lower dose of ibrutinib, reported Colleen Timlin, Pharm.D., of the Hospital of the University of Pennsylvania, Philadelphia, and her associates.

At a median follow-up of 13.5 months, the median progression-free survival was 37.4 months in the standard dose group and the median progression-free survival had not been reached in the reduced-dose group. The median overall survival had not been reached in either group. The hazard ratio in the reduced-dose group was 1.2 for progression-free survival and 0.6 for overall survival; neither difference was statistically significant. Best overall response rate was 85% in the standard-dose group and 84% in the reduced-dose group.

The study included 197 patients, 37 of whom were shifted to reduced doses of ibrutinib within 3 months of initiating therapy at the recommended 420 mg/day dosage. For reduced-dose patients, the median ibrutinib dose was 4.3 mg/kg per day. The most common reasons for reducing the ibrutinib dose were gastrointestinal toxicity, bleeding, rash, cardiotoxicity, and renal insufficiency, the researchers said.

Most of the patients treated with doses less than 420 mg/day still maintained a dose of greater than 2.5 mg/kg per day, which assured adequate Bruton’s tyrosine kinase occupancy. The 420 mg/day dosage noted in the labeling was established, based on achievement of greater than 90% Bruton’s tyrosine kinase occupancy. Fewer patients achieve greater than 90% occupancy at lower doses, but lower doses may not translate into inferior outcomes.

Weight-based dosing should be considered in future studies and pharmacoeconomic analyses. Comparative analyses of toxicity profiles stratified by ibrutinib dose are underway, according to Dr. Timlin and her colleagues.

Dr. Timlin had no relevant disclosures. Several of her colleagues had multiple financial disclosures.

[email protected]

On Twitter @maryjodales

Ibrutinib given at doses lower than the standard dose of 420 mg/day was associated with comparable overall survival and progression-free survival as the standard dose in patients with chronic lymphocytic leukemia (CLL), based on the results of a multicenter, retrospective study submitted as a poster at the annual meeting of the American Society of Clinical Oncology.

The initial findings indicate patients who experience toxicity on the 420 mg/day dosage can still do well on a slightly lower dose of ibrutinib, reported Colleen Timlin, Pharm.D., of the Hospital of the University of Pennsylvania, Philadelphia, and her associates.

At a median follow-up of 13.5 months, the median progression-free survival was 37.4 months in the standard dose group and the median progression-free survival had not been reached in the reduced-dose group. The median overall survival had not been reached in either group. The hazard ratio in the reduced-dose group was 1.2 for progression-free survival and 0.6 for overall survival; neither difference was statistically significant. Best overall response rate was 85% in the standard-dose group and 84% in the reduced-dose group.

The study included 197 patients, 37 of whom were shifted to reduced doses of ibrutinib within 3 months of initiating therapy at the recommended 420 mg/day dosage. For reduced-dose patients, the median ibrutinib dose was 4.3 mg/kg per day. The most common reasons for reducing the ibrutinib dose were gastrointestinal toxicity, bleeding, rash, cardiotoxicity, and renal insufficiency, the researchers said.

Most of the patients treated with doses less than 420 mg/day still maintained a dose of greater than 2.5 mg/kg per day, which assured adequate Bruton’s tyrosine kinase occupancy. The 420 mg/day dosage noted in the labeling was established, based on achievement of greater than 90% Bruton’s tyrosine kinase occupancy. Fewer patients achieve greater than 90% occupancy at lower doses, but lower doses may not translate into inferior outcomes.

Weight-based dosing should be considered in future studies and pharmacoeconomic analyses. Comparative analyses of toxicity profiles stratified by ibrutinib dose are underway, according to Dr. Timlin and her colleagues.

Dr. Timlin had no relevant disclosures. Several of her colleagues had multiple financial disclosures.

[email protected]

On Twitter @maryjodales

Yes: MRI should be considered in the preoperative setting for specific clinical indications.

MRI, like any technology, has its strengths and weaknesses, with high sensitivity but low specificity. Importantly, MRI provides excellent soft tissue contrast with anatomic 3-D detail, and is not impeded by high breast density.

Admittedly, MRI only incrementally increases cancer detection rates in either the ipsilateral or contralateral breasts of all patients, and when used in the preoperative setting does not affect short-term surgical outcomes for all patients. Therefore, MRI should not be used for routine screening or routine preoperative screening.

That said, there are specific clinical situations where preoperative MRI may provide surgeons with valuable information. These include patients who have:

• Invasive lobular carcinoma.

• Neoadjuvant chemotherapy.

• Occult primaries in extremely dense breasts.

Invasive lobular carcinomas are more likely to be multi-centric, multi-focal, and/or bilateral than other breast cancer types, and they are more difficult to diagnose because they infiltrate into tissue, making it extremely difficult to determine the extent of disease. In this setting, MRI can more accurately determine tumor size than mammography. Mammography underestimates the tumor size significantly more frequently than does MRI. In addition, among women with this cancer subtype, MRI can significantly reduce the rate of excision (Breast Cancer Res Treat. 2010;119;415-22).

We know that women at risk for systemic recurrence will not be cured with surgery alone. Neoadjuvant therapies give us the opportunity to refine local therapy options, better understand the patient’s response to therapy and prognosis, and accelerate targeted drug development to improve outcomes. To accomplish all of these goals, we need a noninvasive way to assess tumors before, during, and after neoadjuvant treatment. MRI is unsurpassed for evaluating the extent of tumors, showing in larger tumors, for example, the complexity of tumor and stroma.

MRI is also a biomarker for response to therapy and has been shown to be an independent predictor of event-free survival. In addition, MRI is more accurate than either clinical exam, mammography, or ultrasound for determining residual tumor size following neoadjuvant chemotherapy (Radiology. 2012;263:663-72).

Lastly, for patients with an occult primary (by imaging) breast cancer or primary presentation of axillary node involvement, MRI has been found to have an approximately 90% sensitivity for identifying a primary tumor, and a 95% accuracy at locating the tumor in patients who undergo surgical excision. Mammography cannot distinguish a tumor mass that is dense relative to surrounding tissue. However, MRI can distinguish a tumor which is obscured by dense breast tissue because tumors are visualized on MRI by rapid contrast uptake and washout.

MRI is a catalyst for change, but you have to use it and all technology wisely: At the time of diagnosis for select patients, for screening only those patients with very breast dense tissue and very high risk for developing breast cancer, and, perhaps most importantly, for postcancer surveillance only in women at very high risk of recurrence where standard tools such as mammography are expected to have lower performance (for example, very dense breast tissue). Overuse of MRI will increase false positives, anxiety, and cost. However, used appropriately, MRI can be used to help usher in a change in practice through the evaluation of response to neoadjuvant therapy and novel therapeutic approaches to both invasive and in situ lesions.

With improvements in technology and techniques such as diffusion-weighted imaging, the value of MRI in the preoperative setting can only continue to grow. We can also expect greater performance for presurgical staging with more refined technologies for breast imaging, localization, and biopsy, but the costs have to come down. Breast-dedicated MRI technologies may address this need.

Laura Esserman, MD, is a professor of surgery and radiology at the University of California, San Francisco, and Director of the Carol Franc Buck Breast Care Center at the UCSF Mount Zion campus.

No: MRI leads to unnecessary surgeries and does not improve short-term surgical outcomes.

The key word in this debate is “routinely.” I agree that preoperative MRI may have a role in about 5% of all cases – namely in women with occult primaries and those who undergo neoadjuvant chemotherapy. But for the vast majority of patients, the 95%, I would argue that preoperative MRI has the potential to do more harm than good.

Thirty years of experience providing breast conserving therapies without MRI has taught us several important lessons:

• Selection of patients for breast-conserving therapy is not a big problem.

• The incidences of local recurrence and contralateral breast cancers have decreased over time, antedating the use of MRI.

• Surgical excision of all microscopic subclinical disease is not necessary to achieve good long-term outcomes.

In National Surgical Adjuvant Breast and Bowel Project studies from the 1990s, in the era before the use of aromatase inhibitors or HER-2 blockade, the 10-year incidence of ipsilateral breast tumor recurrence ranged from 3.5% to 6.5% in the breast cancer population at large.

In addition, the incidence of contralateral breast cancers has been declining at a rate of approximately 3% per year, thanks to the use of adjuvant systemic therapies.

We have known since the 1960s, thanks to our colleagues in pathology, that somewhere between 30% and 60% of breast cancers that appear to be localized have microscopic subclinical disease which is treated with breast irradiation. More recently, we have recognized that we can leave behind cancer in the axilla in anywhere from 13% to 27% of patients who are not receiving direct axillary radiation, and see failure rates of 1% or less.

In the context, then, of our current understanding of breast cancer biology, what outcomes could MRI be expected to improve, since the purpose of a test is to improve patient outcomes?

We know that MRI will not improve survival, because 30 years ago randomized trials showed us that survival was equal between breast conservation and mastectomy.

MRI has no apparent effect on reducing local recurrences either, as shown in an analysis of data on 3,180 patients published in 2014 (J Clin Oncol. 2014;32:292).

Regarding contralateral breast cancer, a 2007 study (N Engl J Med. 2007;356:1295-303) showed that among 969 women, MRI found unsuspected cancer in the contralateral breast within 1 year of diagnosis in 3.1%, a finding used to support the argument that all women with breast cancer should have an MRI. But a second study using Surveillance, Epidemiology and End Results (SEER) data on 339,790 women with 2.5 million person-years of follow-up found that the 10-year rate of contralateral cancers was 2%-3% of women with estrogen-receptor–positive tumors, and in 5%-6% of those with estrogen-receptor–negative tumors, strongly suggesting that MRI leads to detection and treatment of disease that would never become clinically evident.

Finally, I would point to evidence that MRI does not improve short-term surgical outcomes, as shown in a meta-analysis my colleagues and I conducted of two randomized controlled trials and seven cohort studies, involving a total of 3,112 patients (Ann Surg. 2013;257:249-55).

We found that after adjustment for age, having an MRI was associated with a three-fold greater chance of having a mastectomy, and MRI did not significantly reduce either the need for re-excision or unexpected conversion to mastectomy. We also performed a subanalysis of infiltrating lobular cancers, and found that there was no statistically significant benefit for MRI in these patients.

The overall rate of mastectomy was 25.5% among patients who had an MRI, vs. 18.2% for those who did not.

So to summarize: MRI finds two to three times more cancer than observed rates of local recurrence, leading to unnecessary mastectomies and does not improve short-term surgical outcomes, and there is no evidence indicating that MRI decreases local recurrence.

Monica Morrow, MD, FACS, is chief of the breast service in the department of surgery and holds the Anne Burnett Windfohr Chair of Clinical Oncology at Memorial Sloan Kettering Cancer Center in New York.

Yes: MRI should be considered in the preoperative setting for specific clinical indications.

MRI, like any technology, has its strengths and weaknesses, with high sensitivity but low specificity. Importantly, MRI provides excellent soft tissue contrast with anatomic 3-D detail, and is not impeded by high breast density.

Admittedly, MRI only incrementally increases cancer detection rates in either the ipsilateral or contralateral breasts of all patients, and when used in the preoperative setting does not affect short-term surgical outcomes for all patients. Therefore, MRI should not be used for routine screening or routine preoperative screening.

That said, there are specific clinical situations where preoperative MRI may provide surgeons with valuable information. These include patients who have:

• Invasive lobular carcinoma.

• Neoadjuvant chemotherapy.

• Occult primaries in extremely dense breasts.

Invasive lobular carcinomas are more likely to be multi-centric, multi-focal, and/or bilateral than other breast cancer types, and they are more difficult to diagnose because they infiltrate into tissue, making it extremely difficult to determine the extent of disease. In this setting, MRI can more accurately determine tumor size than mammography. Mammography underestimates the tumor size significantly more frequently than does MRI. In addition, among women with this cancer subtype, MRI can significantly reduce the rate of excision (Breast Cancer Res Treat. 2010;119;415-22).

We know that women at risk for systemic recurrence will not be cured with surgery alone. Neoadjuvant therapies give us the opportunity to refine local therapy options, better understand the patient’s response to therapy and prognosis, and accelerate targeted drug development to improve outcomes. To accomplish all of these goals, we need a noninvasive way to assess tumors before, during, and after neoadjuvant treatment. MRI is unsurpassed for evaluating the extent of tumors, showing in larger tumors, for example, the complexity of tumor and stroma.

MRI is also a biomarker for response to therapy and has been shown to be an independent predictor of event-free survival. In addition, MRI is more accurate than either clinical exam, mammography, or ultrasound for determining residual tumor size following neoadjuvant chemotherapy (Radiology. 2012;263:663-72).

Lastly, for patients with an occult primary (by imaging) breast cancer or primary presentation of axillary node involvement, MRI has been found to have an approximately 90% sensitivity for identifying a primary tumor, and a 95% accuracy at locating the tumor in patients who undergo surgical excision. Mammography cannot distinguish a tumor mass that is dense relative to surrounding tissue. However, MRI can distinguish a tumor which is obscured by dense breast tissue because tumors are visualized on MRI by rapid contrast uptake and washout.

MRI is a catalyst for change, but you have to use it and all technology wisely: At the time of diagnosis for select patients, for screening only those patients with very breast dense tissue and very high risk for developing breast cancer, and, perhaps most importantly, for postcancer surveillance only in women at very high risk of recurrence where standard tools such as mammography are expected to have lower performance (for example, very dense breast tissue). Overuse of MRI will increase false positives, anxiety, and cost. However, used appropriately, MRI can be used to help usher in a change in practice through the evaluation of response to neoadjuvant therapy and novel therapeutic approaches to both invasive and in situ lesions.

With improvements in technology and techniques such as diffusion-weighted imaging, the value of MRI in the preoperative setting can only continue to grow. We can also expect greater performance for presurgical staging with more refined technologies for breast imaging, localization, and biopsy, but the costs have to come down. Breast-dedicated MRI technologies may address this need.

Laura Esserman, MD, is a professor of surgery and radiology at the University of California, San Francisco, and Director of the Carol Franc Buck Breast Care Center at the UCSF Mount Zion campus.

No: MRI leads to unnecessary surgeries and does not improve short-term surgical outcomes.

The key word in this debate is “routinely.” I agree that preoperative MRI may have a role in about 5% of all cases – namely in women with occult primaries and those who undergo neoadjuvant chemotherapy. But for the vast majority of patients, the 95%, I would argue that preoperative MRI has the potential to do more harm than good.

Thirty years of experience providing breast conserving therapies without MRI has taught us several important lessons:

• Selection of patients for breast-conserving therapy is not a big problem.

• The incidences of local recurrence and contralateral breast cancers have decreased over time, antedating the use of MRI.

• Surgical excision of all microscopic subclinical disease is not necessary to achieve good long-term outcomes.

In National Surgical Adjuvant Breast and Bowel Project studies from the 1990s, in the era before the use of aromatase inhibitors or HER-2 blockade, the 10-year incidence of ipsilateral breast tumor recurrence ranged from 3.5% to 6.5% in the breast cancer population at large.

In addition, the incidence of contralateral breast cancers has been declining at a rate of approximately 3% per year, thanks to the use of adjuvant systemic therapies.

We have known since the 1960s, thanks to our colleagues in pathology, that somewhere between 30% and 60% of breast cancers that appear to be localized have microscopic subclinical disease which is treated with breast irradiation. More recently, we have recognized that we can leave behind cancer in the axilla in anywhere from 13% to 27% of patients who are not receiving direct axillary radiation, and see failure rates of 1% or less.

In the context, then, of our current understanding of breast cancer biology, what outcomes could MRI be expected to improve, since the purpose of a test is to improve patient outcomes?

We know that MRI will not improve survival, because 30 years ago randomized trials showed us that survival was equal between breast conservation and mastectomy.

MRI has no apparent effect on reducing local recurrences either, as shown in an analysis of data on 3,180 patients published in 2014 (J Clin Oncol. 2014;32:292).

Regarding contralateral breast cancer, a 2007 study (N Engl J Med. 2007;356:1295-303) showed that among 969 women, MRI found unsuspected cancer in the contralateral breast within 1 year of diagnosis in 3.1%, a finding used to support the argument that all women with breast cancer should have an MRI. But a second study using Surveillance, Epidemiology and End Results (SEER) data on 339,790 women with 2.5 million person-years of follow-up found that the 10-year rate of contralateral cancers was 2%-3% of women with estrogen-receptor–positive tumors, and in 5%-6% of those with estrogen-receptor–negative tumors, strongly suggesting that MRI leads to detection and treatment of disease that would never become clinically evident.

Finally, I would point to evidence that MRI does not improve short-term surgical outcomes, as shown in a meta-analysis my colleagues and I conducted of two randomized controlled trials and seven cohort studies, involving a total of 3,112 patients (Ann Surg. 2013;257:249-55).

We found that after adjustment for age, having an MRI was associated with a three-fold greater chance of having a mastectomy, and MRI did not significantly reduce either the need for re-excision or unexpected conversion to mastectomy. We also performed a subanalysis of infiltrating lobular cancers, and found that there was no statistically significant benefit for MRI in these patients.

The overall rate of mastectomy was 25.5% among patients who had an MRI, vs. 18.2% for those who did not.

So to summarize: MRI finds two to three times more cancer than observed rates of local recurrence, leading to unnecessary mastectomies and does not improve short-term surgical outcomes, and there is no evidence indicating that MRI decreases local recurrence.

Monica Morrow, MD, FACS, is chief of the breast service in the department of surgery and holds the Anne Burnett Windfohr Chair of Clinical Oncology at Memorial Sloan Kettering Cancer Center in New York.

Yes: MRI should be considered in the preoperative setting for specific clinical indications.

MRI, like any technology, has its strengths and weaknesses, with high sensitivity but low specificity. Importantly, MRI provides excellent soft tissue contrast with anatomic 3-D detail, and is not impeded by high breast density.

Admittedly, MRI only incrementally increases cancer detection rates in either the ipsilateral or contralateral breasts of all patients, and when used in the preoperative setting does not affect short-term surgical outcomes for all patients. Therefore, MRI should not be used for routine screening or routine preoperative screening.

That said, there are specific clinical situations where preoperative MRI may provide surgeons with valuable information. These include patients who have:

• Invasive lobular carcinoma.

• Neoadjuvant chemotherapy.

• Occult primaries in extremely dense breasts.

Invasive lobular carcinomas are more likely to be multi-centric, multi-focal, and/or bilateral than other breast cancer types, and they are more difficult to diagnose because they infiltrate into tissue, making it extremely difficult to determine the extent of disease. In this setting, MRI can more accurately determine tumor size than mammography. Mammography underestimates the tumor size significantly more frequently than does MRI. In addition, among women with this cancer subtype, MRI can significantly reduce the rate of excision (Breast Cancer Res Treat. 2010;119;415-22).

We know that women at risk for systemic recurrence will not be cured with surgery alone. Neoadjuvant therapies give us the opportunity to refine local therapy options, better understand the patient’s response to therapy and prognosis, and accelerate targeted drug development to improve outcomes. To accomplish all of these goals, we need a noninvasive way to assess tumors before, during, and after neoadjuvant treatment. MRI is unsurpassed for evaluating the extent of tumors, showing in larger tumors, for example, the complexity of tumor and stroma.

MRI is also a biomarker for response to therapy and has been shown to be an independent predictor of event-free survival. In addition, MRI is more accurate than either clinical exam, mammography, or ultrasound for determining residual tumor size following neoadjuvant chemotherapy (Radiology. 2012;263:663-72).

Lastly, for patients with an occult primary (by imaging) breast cancer or primary presentation of axillary node involvement, MRI has been found to have an approximately 90% sensitivity for identifying a primary tumor, and a 95% accuracy at locating the tumor in patients who undergo surgical excision. Mammography cannot distinguish a tumor mass that is dense relative to surrounding tissue. However, MRI can distinguish a tumor which is obscured by dense breast tissue because tumors are visualized on MRI by rapid contrast uptake and washout.

MRI is a catalyst for change, but you have to use it and all technology wisely: At the time of diagnosis for select patients, for screening only those patients with very breast dense tissue and very high risk for developing breast cancer, and, perhaps most importantly, for postcancer surveillance only in women at very high risk of recurrence where standard tools such as mammography are expected to have lower performance (for example, very dense breast tissue). Overuse of MRI will increase false positives, anxiety, and cost. However, used appropriately, MRI can be used to help usher in a change in practice through the evaluation of response to neoadjuvant therapy and novel therapeutic approaches to both invasive and in situ lesions.

With improvements in technology and techniques such as diffusion-weighted imaging, the value of MRI in the preoperative setting can only continue to grow. We can also expect greater performance for presurgical staging with more refined technologies for breast imaging, localization, and biopsy, but the costs have to come down. Breast-dedicated MRI technologies may address this need.

Laura Esserman, MD, is a professor of surgery and radiology at the University of California, San Francisco, and Director of the Carol Franc Buck Breast Care Center at the UCSF Mount Zion campus.

No: MRI leads to unnecessary surgeries and does not improve short-term surgical outcomes.

The key word in this debate is “routinely.” I agree that preoperative MRI may have a role in about 5% of all cases – namely in women with occult primaries and those who undergo neoadjuvant chemotherapy. But for the vast majority of patients, the 95%, I would argue that preoperative MRI has the potential to do more harm than good.

Thirty years of experience providing breast conserving therapies without MRI has taught us several important lessons:

• Selection of patients for breast-conserving therapy is not a big problem.

• The incidences of local recurrence and contralateral breast cancers have decreased over time, antedating the use of MRI.

• Surgical excision of all microscopic subclinical disease is not necessary to achieve good long-term outcomes.

In National Surgical Adjuvant Breast and Bowel Project studies from the 1990s, in the era before the use of aromatase inhibitors or HER-2 blockade, the 10-year incidence of ipsilateral breast tumor recurrence ranged from 3.5% to 6.5% in the breast cancer population at large.

In addition, the incidence of contralateral breast cancers has been declining at a rate of approximately 3% per year, thanks to the use of adjuvant systemic therapies.

We have known since the 1960s, thanks to our colleagues in pathology, that somewhere between 30% and 60% of breast cancers that appear to be localized have microscopic subclinical disease which is treated with breast irradiation. More recently, we have recognized that we can leave behind cancer in the axilla in anywhere from 13% to 27% of patients who are not receiving direct axillary radiation, and see failure rates of 1% or less.

In the context, then, of our current understanding of breast cancer biology, what outcomes could MRI be expected to improve, since the purpose of a test is to improve patient outcomes?

We know that MRI will not improve survival, because 30 years ago randomized trials showed us that survival was equal between breast conservation and mastectomy.

MRI has no apparent effect on reducing local recurrences either, as shown in an analysis of data on 3,180 patients published in 2014 (J Clin Oncol. 2014;32:292).

Regarding contralateral breast cancer, a 2007 study (N Engl J Med. 2007;356:1295-303) showed that among 969 women, MRI found unsuspected cancer in the contralateral breast within 1 year of diagnosis in 3.1%, a finding used to support the argument that all women with breast cancer should have an MRI. But a second study using Surveillance, Epidemiology and End Results (SEER) data on 339,790 women with 2.5 million person-years of follow-up found that the 10-year rate of contralateral cancers was 2%-3% of women with estrogen-receptor–positive tumors, and in 5%-6% of those with estrogen-receptor–negative tumors, strongly suggesting that MRI leads to detection and treatment of disease that would never become clinically evident.

Finally, I would point to evidence that MRI does not improve short-term surgical outcomes, as shown in a meta-analysis my colleagues and I conducted of two randomized controlled trials and seven cohort studies, involving a total of 3,112 patients (Ann Surg. 2013;257:249-55).

We found that after adjustment for age, having an MRI was associated with a three-fold greater chance of having a mastectomy, and MRI did not significantly reduce either the need for re-excision or unexpected conversion to mastectomy. We also performed a subanalysis of infiltrating lobular cancers, and found that there was no statistically significant benefit for MRI in these patients.

The overall rate of mastectomy was 25.5% among patients who had an MRI, vs. 18.2% for those who did not.

So to summarize: MRI finds two to three times more cancer than observed rates of local recurrence, leading to unnecessary mastectomies and does not improve short-term surgical outcomes, and there is no evidence indicating that MRI decreases local recurrence.

Monica Morrow, MD, FACS, is chief of the breast service in the department of surgery and holds the Anne Burnett Windfohr Chair of Clinical Oncology at Memorial Sloan Kettering Cancer Center in New York.

Six years after promising a plan to “repeal and replace” the federal health law, House Republicans are finally ready to deliver.

The 37-page white paper, called “A Better Way,” includes virtually every idea on health care proposed by Republicans going back at least 2 decades. It would bring back “high-risk pools” for people with very high medical expenses, end open-ended funding for the Medicaid program, and encourage small businesses to band together to get better bargaining power in “Association Health Plans.”

What the plan does not include, however, is any idea of how much it would cost, or how it would be financed. Also unclear is how many of the 20 million Americans who have gained coverage since the law took effect would be able to remain insured.

“It’s a framework,” a senior House Republican leadership aide said on a conference call with reporters Tuesday, with the specifics to be determined next year by congressional committees, assuming the GOP maintains its majority. He likened the document to the white paper issued just after President Barack Obama’s election by then–Senate Finance Committee Chairman Max Baucus (D-Mont.). That document foreshadowed many of the key elements of the Affordable Care Act.

The plan starts with repeal of the health law and its requirements and taxes, but it would then put back many of its most popular elements: Allowing young adults to stay on their parents’ health plan to age 26; banning insurers from charging people with preexisting health problems higher premiums; and forbidding insurers from dropping coverage if a policyholder gets sick.

It would repeal the current scheme of exchanges where consumers buy insurance and government tax credits to help moderate-income Americans pay their premiums if they don’t have an employer to help. Instead, everyone buying policies in the individual market would receive tax credits. Older people charged more by insurers would receive larger credits, though the House Republicans don’t specify how much.

But the GOP plan also would likely make insurance more expensive for older people by proposing a broader range for premiums based on age. Current premiums can vary only threefold based on age, which is “driving out younger and healthier patients” who can’t afford them, the GOP aide said.

Under the plan, insurance companies could not charge higher rates to people with preexisting conditions so long as they maintain continuous coverage, whether from an employer or in a policy they purchase themselves. The new high-risk pools would be available for those who have a break in coverage, or who fail to purchase during a one-time open enrollment under the plan.

The plan would get rid of most of the coverage requirements under the Medicaid program for the poor, so states could make them more or less generous than they are currently. It would also limit funding. States could opt for either a per-person cap or a block grant to spend much as they wish.

On Medicare, the proposal would encourage the existing movement of patients from the program’s traditional fee-for-service program to managed care plans, and would transition from the existing financing structure based on benefits to a controversial structure called “premium support” that puts cost-controlling responsibilities more on private insurance companies. That change has been pushed by House Speaker Paul Ryan (R-Wisc.) for nearly a decade.

Backers of the existing health law were quick to criticize the GOP outline.

“The proposal introduced by Speaker Ryan is nothing more than vague and recycled ideas to take health insurance away from millions and increase costs for seniors and hardworking families,” said White House Assistant Press Secretary Katie Hill.

Families USA Executive Director Ron Pollack, who pushed hard for passage of the Affordable Care Act, said: “Make no mistake, Ryan’s approach is not a better way forward, but a bitter path backward that returns us to the bad old days when vast swaths of Americans were left to the tender mercies of the insurance industry and could not afford needed care.”

This story appears courtesy of Kaiser Health News, a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.

Six years after promising a plan to “repeal and replace” the federal health law, House Republicans are finally ready to deliver.

The 37-page white paper, called “A Better Way,” includes virtually every idea on health care proposed by Republicans going back at least 2 decades. It would bring back “high-risk pools” for people with very high medical expenses, end open-ended funding for the Medicaid program, and encourage small businesses to band together to get better bargaining power in “Association Health Plans.”

What the plan does not include, however, is any idea of how much it would cost, or how it would be financed. Also unclear is how many of the 20 million Americans who have gained coverage since the law took effect would be able to remain insured.

“It’s a framework,” a senior House Republican leadership aide said on a conference call with reporters Tuesday, with the specifics to be determined next year by congressional committees, assuming the GOP maintains its majority. He likened the document to the white paper issued just after President Barack Obama’s election by then–Senate Finance Committee Chairman Max Baucus (D-Mont.). That document foreshadowed many of the key elements of the Affordable Care Act.

The plan starts with repeal of the health law and its requirements and taxes, but it would then put back many of its most popular elements: Allowing young adults to stay on their parents’ health plan to age 26; banning insurers from charging people with preexisting health problems higher premiums; and forbidding insurers from dropping coverage if a policyholder gets sick.

It would repeal the current scheme of exchanges where consumers buy insurance and government tax credits to help moderate-income Americans pay their premiums if they don’t have an employer to help. Instead, everyone buying policies in the individual market would receive tax credits. Older people charged more by insurers would receive larger credits, though the House Republicans don’t specify how much.

But the GOP plan also would likely make insurance more expensive for older people by proposing a broader range for premiums based on age. Current premiums can vary only threefold based on age, which is “driving out younger and healthier patients” who can’t afford them, the GOP aide said.

Under the plan, insurance companies could not charge higher rates to people with preexisting conditions so long as they maintain continuous coverage, whether from an employer or in a policy they purchase themselves. The new high-risk pools would be available for those who have a break in coverage, or who fail to purchase during a one-time open enrollment under the plan.

The plan would get rid of most of the coverage requirements under the Medicaid program for the poor, so states could make them more or less generous than they are currently. It would also limit funding. States could opt for either a per-person cap or a block grant to spend much as they wish.

On Medicare, the proposal would encourage the existing movement of patients from the program’s traditional fee-for-service program to managed care plans, and would transition from the existing financing structure based on benefits to a controversial structure called “premium support” that puts cost-controlling responsibilities more on private insurance companies. That change has been pushed by House Speaker Paul Ryan (R-Wisc.) for nearly a decade.

Backers of the existing health law were quick to criticize the GOP outline.

“The proposal introduced by Speaker Ryan is nothing more than vague and recycled ideas to take health insurance away from millions and increase costs for seniors and hardworking families,” said White House Assistant Press Secretary Katie Hill.

Families USA Executive Director Ron Pollack, who pushed hard for passage of the Affordable Care Act, said: “Make no mistake, Ryan’s approach is not a better way forward, but a bitter path backward that returns us to the bad old days when vast swaths of Americans were left to the tender mercies of the insurance industry and could not afford needed care.”

This story appears courtesy of Kaiser Health News, a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.

Six years after promising a plan to “repeal and replace” the federal health law, House Republicans are finally ready to deliver.

The 37-page white paper, called “A Better Way,” includes virtually every idea on health care proposed by Republicans going back at least 2 decades. It would bring back “high-risk pools” for people with very high medical expenses, end open-ended funding for the Medicaid program, and encourage small businesses to band together to get better bargaining power in “Association Health Plans.”

What the plan does not include, however, is any idea of how much it would cost, or how it would be financed. Also unclear is how many of the 20 million Americans who have gained coverage since the law took effect would be able to remain insured.

“It’s a framework,” a senior House Republican leadership aide said on a conference call with reporters Tuesday, with the specifics to be determined next year by congressional committees, assuming the GOP maintains its majority. He likened the document to the white paper issued just after President Barack Obama’s election by then–Senate Finance Committee Chairman Max Baucus (D-Mont.). That document foreshadowed many of the key elements of the Affordable Care Act.

The plan starts with repeal of the health law and its requirements and taxes, but it would then put back many of its most popular elements: Allowing young adults to stay on their parents’ health plan to age 26; banning insurers from charging people with preexisting health problems higher premiums; and forbidding insurers from dropping coverage if a policyholder gets sick.

It would repeal the current scheme of exchanges where consumers buy insurance and government tax credits to help moderate-income Americans pay their premiums if they don’t have an employer to help. Instead, everyone buying policies in the individual market would receive tax credits. Older people charged more by insurers would receive larger credits, though the House Republicans don’t specify how much.

But the GOP plan also would likely make insurance more expensive for older people by proposing a broader range for premiums based on age. Current premiums can vary only threefold based on age, which is “driving out younger and healthier patients” who can’t afford them, the GOP aide said.

Under the plan, insurance companies could not charge higher rates to people with preexisting conditions so long as they maintain continuous coverage, whether from an employer or in a policy they purchase themselves. The new high-risk pools would be available for those who have a break in coverage, or who fail to purchase during a one-time open enrollment under the plan.

The plan would get rid of most of the coverage requirements under the Medicaid program for the poor, so states could make them more or less generous than they are currently. It would also limit funding. States could opt for either a per-person cap or a block grant to spend much as they wish.

On Medicare, the proposal would encourage the existing movement of patients from the program’s traditional fee-for-service program to managed care plans, and would transition from the existing financing structure based on benefits to a controversial structure called “premium support” that puts cost-controlling responsibilities more on private insurance companies. That change has been pushed by House Speaker Paul Ryan (R-Wisc.) for nearly a decade.

Backers of the existing health law were quick to criticize the GOP outline.

“The proposal introduced by Speaker Ryan is nothing more than vague and recycled ideas to take health insurance away from millions and increase costs for seniors and hardworking families,” said White House Assistant Press Secretary Katie Hill.

Families USA Executive Director Ron Pollack, who pushed hard for passage of the Affordable Care Act, said: “Make no mistake, Ryan’s approach is not a better way forward, but a bitter path backward that returns us to the bad old days when vast swaths of Americans were left to the tender mercies of the insurance industry and could not afford needed care.”

This story appears courtesy of Kaiser Health News, a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices unanimously voted to recommend that all HIV-infected persons aged 2 months and older receive the meningococcal ACWY (MenACWY) vaccine.

Guidance for this recommendation states that persons 2 months and older with HIV who have not been vaccinated previously should receive a two-dose, primary series of MenACWY; and that HIV-infected persons who have been vaccinated previously with one dose of MenACWY should receive a second dose at the earliest opportunity, with an 8-week minimum interval between doses. After that, boosters are to be given at the appropriate intervals.

Courtesy CDC

Committee members voted in favor of immunizing earlier rather than waiting until 11 years of age or older, in part because human complement (hSBA) antibody titers following up to two doses of MenACWY vaccine in HIV-infected children ages 2-10 years is higher than in those ages 11-24 years. Also, the agreed upon recommended policy for earlier immunization is in step with current ACIP recommendations for use of the vaccine in persons with functional/anatomic asplenia or complement component deficiencies.

Despite an overall decline in the risk of meningococcal disease in the United States, there was a 13-fold increased risk in HIV-infected persons aged 25-64 years between 2000 and 2008, according to surveillance data presented to ACIP by Ms. Jessica MacNeil, MPH, an epidemiologist at the National Center for Immunization and Respiratory Diseases at the CDC in Atlanta. A ten-fold increase in risk was recorded in New York City alone in this population between 2000 and 2011.

Although fatality data are mixed, the infections were due primarily to serogroups C, W, and Y, for which the immune response wanes rapidly, according to Ms. MacNeil.

There are no safety or immunogenicity data currently available for the use of serogroup B meningococcal vaccines in HIV-infected persons, she said.

ACIP members also unanimously recommended this vaccine be covered under the Vaccines for Children program.

No information about disclosures was available at press time.

[email protected]

On Twitter @whitneymcknight

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices unanimously voted to recommend that all HIV-infected persons aged 2 months and older receive the meningococcal ACWY (MenACWY) vaccine.

Guidance for this recommendation states that persons 2 months and older with HIV who have not been vaccinated previously should receive a two-dose, primary series of MenACWY; and that HIV-infected persons who have been vaccinated previously with one dose of MenACWY should receive a second dose at the earliest opportunity, with an 8-week minimum interval between doses. After that, boosters are to be given at the appropriate intervals.

Courtesy CDC

Committee members voted in favor of immunizing earlier rather than waiting until 11 years of age or older, in part because human complement (hSBA) antibody titers following up to two doses of MenACWY vaccine in HIV-infected children ages 2-10 years is higher than in those ages 11-24 years. Also, the agreed upon recommended policy for earlier immunization is in step with current ACIP recommendations for use of the vaccine in persons with functional/anatomic asplenia or complement component deficiencies.

Despite an overall decline in the risk of meningococcal disease in the United States, there was a 13-fold increased risk in HIV-infected persons aged 25-64 years between 2000 and 2008, according to surveillance data presented to ACIP by Ms. Jessica MacNeil, MPH, an epidemiologist at the National Center for Immunization and Respiratory Diseases at the CDC in Atlanta. A ten-fold increase in risk was recorded in New York City alone in this population between 2000 and 2011.

Although fatality data are mixed, the infections were due primarily to serogroups C, W, and Y, for which the immune response wanes rapidly, according to Ms. MacNeil.

There are no safety or immunogenicity data currently available for the use of serogroup B meningococcal vaccines in HIV-infected persons, she said.

ACIP members also unanimously recommended this vaccine be covered under the Vaccines for Children program.

No information about disclosures was available at press time.

[email protected]

On Twitter @whitneymcknight

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices unanimously voted to recommend that all HIV-infected persons aged 2 months and older receive the meningococcal ACWY (MenACWY) vaccine.

Guidance for this recommendation states that persons 2 months and older with HIV who have not been vaccinated previously should receive a two-dose, primary series of MenACWY; and that HIV-infected persons who have been vaccinated previously with one dose of MenACWY should receive a second dose at the earliest opportunity, with an 8-week minimum interval between doses. After that, boosters are to be given at the appropriate intervals.

Courtesy CDC

Committee members voted in favor of immunizing earlier rather than waiting until 11 years of age or older, in part because human complement (hSBA) antibody titers following up to two doses of MenACWY vaccine in HIV-infected children ages 2-10 years is higher than in those ages 11-24 years. Also, the agreed upon recommended policy for earlier immunization is in step with current ACIP recommendations for use of the vaccine in persons with functional/anatomic asplenia or complement component deficiencies.

Despite an overall decline in the risk of meningococcal disease in the United States, there was a 13-fold increased risk in HIV-infected persons aged 25-64 years between 2000 and 2008, according to surveillance data presented to ACIP by Ms. Jessica MacNeil, MPH, an epidemiologist at the National Center for Immunization and Respiratory Diseases at the CDC in Atlanta. A ten-fold increase in risk was recorded in New York City alone in this population between 2000 and 2011.

Although fatality data are mixed, the infections were due primarily to serogroups C, W, and Y, for which the immune response wanes rapidly, according to Ms. MacNeil.

There are no safety or immunogenicity data currently available for the use of serogroup B meningococcal vaccines in HIV-infected persons, she said.

ACIP members also unanimously recommended this vaccine be covered under the Vaccines for Children program.

No information about disclosures was available at press time.

[email protected]

On Twitter @whitneymcknight

The Medicare Trust Fund is projected to become insolvent in 2028, 2 years earlier than projected this time last year.

The change is based on two key factors: an expected reduction in payroll taxes and a slowdown in declining rate of inpatient utilization, Andy Slavitt, acting administrator of the Centers for Medicare & Medicaid Services said at a June 22 press conference to review the annual Medicare Trustees report.

©MADDRAT/thinkstockphotos.com

“The good news is inpatient utilization is still declining, it’s just declining at a slightly lower rate,” Mr. Slavitt said.

He also highlighted the continuing rising cost of prescription medications, which he called “a major driver” in Medicare spending growth.

“For the second year in a row, we saw spending growth for prescription drugs dramatically outpace cost growth for other Medicare services,” Mr. Slavitt said. “Through 2025, Medicare Part D expenditures per enrollee are estimated to increase nearly 50% higher than the estimated increase in GDP per capita and higher than the combined per enrollee growth rate of Medicare Part A and Medicare Part B combined.”

Overall, total Medicare expenditures “are slightly lower than estimated last year,” Mr. Slavitt said, adding that over the next decade, “Medicare per-enrollee spending is projected to continue to grow slower than historical rates, at 4.3%, lower than the growth in overall per capita national health expenditures.”

The growth rate is not projected to trigger the activation of the Independent Payment Advisory Board, according to the report.

In 2015, Medicare covered 55.3 million people, including 46.3 million aged 65 and older, and 9 million disabled individuals.

[email protected]

The Medicare Trust Fund is projected to become insolvent in 2028, 2 years earlier than projected this time last year.

The change is based on two key factors: an expected reduction in payroll taxes and a slowdown in declining rate of inpatient utilization, Andy Slavitt, acting administrator of the Centers for Medicare & Medicaid Services said at a June 22 press conference to review the annual Medicare Trustees report.

©MADDRAT/thinkstockphotos.com

“The good news is inpatient utilization is still declining, it’s just declining at a slightly lower rate,” Mr. Slavitt said.

He also highlighted the continuing rising cost of prescription medications, which he called “a major driver” in Medicare spending growth.

“For the second year in a row, we saw spending growth for prescription drugs dramatically outpace cost growth for other Medicare services,” Mr. Slavitt said. “Through 2025, Medicare Part D expenditures per enrollee are estimated to increase nearly 50% higher than the estimated increase in GDP per capita and higher than the combined per enrollee growth rate of Medicare Part A and Medicare Part B combined.”

Overall, total Medicare expenditures “are slightly lower than estimated last year,” Mr. Slavitt said, adding that over the next decade, “Medicare per-enrollee spending is projected to continue to grow slower than historical rates, at 4.3%, lower than the growth in overall per capita national health expenditures.”

The growth rate is not projected to trigger the activation of the Independent Payment Advisory Board, according to the report.

In 2015, Medicare covered 55.3 million people, including 46.3 million aged 65 and older, and 9 million disabled individuals.

[email protected]

The Medicare Trust Fund is projected to become insolvent in 2028, 2 years earlier than projected this time last year.

The change is based on two key factors: an expected reduction in payroll taxes and a slowdown in declining rate of inpatient utilization, Andy Slavitt, acting administrator of the Centers for Medicare & Medicaid Services said at a June 22 press conference to review the annual Medicare Trustees report.

©MADDRAT/thinkstockphotos.com

“The good news is inpatient utilization is still declining, it’s just declining at a slightly lower rate,” Mr. Slavitt said.

He also highlighted the continuing rising cost of prescription medications, which he called “a major driver” in Medicare spending growth.

“For the second year in a row, we saw spending growth for prescription drugs dramatically outpace cost growth for other Medicare services,” Mr. Slavitt said. “Through 2025, Medicare Part D expenditures per enrollee are estimated to increase nearly 50% higher than the estimated increase in GDP per capita and higher than the combined per enrollee growth rate of Medicare Part A and Medicare Part B combined.”

Overall, total Medicare expenditures “are slightly lower than estimated last year,” Mr. Slavitt said, adding that over the next decade, “Medicare per-enrollee spending is projected to continue to grow slower than historical rates, at 4.3%, lower than the growth in overall per capita national health expenditures.”

The growth rate is not projected to trigger the activation of the Independent Payment Advisory Board, according to the report.

In 2015, Medicare covered 55.3 million people, including 46.3 million aged 65 and older, and 9 million disabled individuals.

[email protected]

CHICAGO – Dealing with disruptive behavior by staff and colleagues isn’t just about knowing what to do – it’s also about knowing what not to do.

Often, mishandling disruptive behavior can make matters worse and lead to further conflict among physicians and employees, health law experts warn. At a conference held by the American Bar Association, attorneys offered guidance on the dos and don’ts of disruptive behavior management.

Don’t discipline for the wrong reasons

Know what disruptive behavior is not, advised Margo S. Struthers, a Minneapolis-based health law attorney. Criticism offered in good faith with the aim of improving patient care should not be considered disruptive, she said.

Courtesy Margo Struthers

“This is a problem that comes up a lot because, often, there is some element of criticism that is offered by the supposed disruptive physician, which may or may not be justified, may or may have been done in good faith, and may or may not have been in a respectful manner.”

An isolated incident of behavior that is not reflective of a pattern of inappropriate, deep-seated, and habitual behavior should not be construed as disruptive, Ms. Struthers added. In addition, disruptive behavior is not respectful disagreement with leadership, presentation of controversial ideas, or the respectful complaining about processes that endanger patient care.

Do address behavior that is truly disruptive

According to the American Medical Association, disruptive behavior is defined as personal conduct, whether verbal or physical, that negatively affects or that potentially may negatively affect patient care, including conduct that interferes the ability to work with members of the health care team. Such behavior can be passive, such as ignoring calls or frequently missing meetings; passive-aggressive, such as excessive sarcasm or veiled threats; or aggressive, such as yelling or bullying.

Don’t focus solely on the behavior

Most disruptive behavior has a root cause, and efforts should be made to get to the bottom of the conduct, according to Sidney Welch, an Atlanta-based health law attorney.

“Often, there’s an underlying frustration in terms of clinical care or what they’re being told to do or the systems and processes [in play],” she said “Where is the sources of the tension that is creating the behavior?”

Do identify contributing factors

Personality characteristics that could lead to hostile behavior include self-centeredness, immaturity, resentfulness, or a need for power and control. Systemic factors could include increased productivity demands, cost-containment requirements, embedded hierarchies, fear of litigation, ineffective or absent conflict-resolution processes, competition between hospitals and medical staff, new care settings, and marketplace demands. Shortages of staff and high work burdens also could fuel disruptive behavior, Ms. Welch said.

“There are situations where there [is] a psychiatric disorder or a personality disorder that’s the root cause of the disruption,” she said. But “sometimes it’s just a stressful situation. A lot of these cases [in which] the physician is the disruption, we’re seeing them in high stakes emergency departments or situations where decisions have to be made very quickly, or fatigue and external stresses may be the source.”

Don’t apply corrective actions inconsistently

Make expectations clear by having a code of conduct supported by policies that apply to every employee, Ms. Welch noted. A lack of fairness among employees can create greater tension and generate increased conflict during a disruptive situation. Ensure that physicians are not be treated differently than nurses or administrators when addressing complaints, she said.

Do implement a graduated set of responses

A tiered response system (informal, formal, disciplinary, regulatory) helps manage disruptive situations based on the extent of conduct, Ms. Welch said.

“The process and disciplinary process [should] to be multileveled so that people know the rules of the road, and the parameters and the bumpers so to speak, are defined.”

Don’t necessarily involve HR

Be cautious of allowing human resource (HR) departments to direct potential disruptive physician issues, Ms. Struthers said.

“I have some concerns about HR getting involved for a couple of reasons,” she said. “If you get nonphysicians involved, it seems to exacerbate the level of tension.”

In addition, if a hospital has a significant number of both employed and independent physicians, HR can sometimes apply different standards and varied courses of action depending on employment status, she said. Of course, if the alleged disrupter is a nonphysician, HR is generally the only route for remedy within a hospital setting, Ms. Welch noted.

Do address the issue through internal processes

Every medical staff should develop and adopt bylaw provisions or policies for intervening in situations in which a physician’s behavior is identified as disruptive, according to AMA policy. Medical staff bylaw provisions or policies should contain procedural safeguards that protect due process.

For doctors in groups or small practices, employment policies and procedures should address protocols when disruption matters arise, Ms. Struthers said.

“The dynamics in a small clinic is that some doctors may more have power than others, so it may be harder in some contexts to treat everyone the same,” she said in an interview. “But that’s a really important thing to do. Any well-advised clinics would have a code of conduct or conduct policy, really to protect the clinic from employee lawsuits.”

Don’t let policies collect dust

“As we all know, you can write the policies, you can put them on the shelf, but if people aren’t reading them and understanding them and aren’t educated on them, then it really does no good,” Ms. Welch said.

Do ensure everyone knows how disruptive behavior is handled

Make certain that all staff review disruptive behavior policies and are adequately trained in how the process works, Ms. Welch added. Employees should know where to seek help if experiencing a disruption matter. Consider having staff members sign or acknowledge a code of conduct upon credentialing or hiring.

“Obviously, disruptive behavior can impact patient care, and it can come from a lot of differ directions; It’s not just physicians,” Ms. Struthers said. “Hospitals [and practices] like other places of business, need to have comprehensive polices and procedures, and they need to follow them.”

[email protected]

On Twitter @legal_med

CHICAGO – Dealing with disruptive behavior by staff and colleagues isn’t just about knowing what to do – it’s also about knowing what not to do.

Often, mishandling disruptive behavior can make matters worse and lead to further conflict among physicians and employees, health law experts warn. At a conference held by the American Bar Association, attorneys offered guidance on the dos and don’ts of disruptive behavior management.

Don’t discipline for the wrong reasons

Know what disruptive behavior is not, advised Margo S. Struthers, a Minneapolis-based health law attorney. Criticism offered in good faith with the aim of improving patient care should not be considered disruptive, she said.

Courtesy Margo Struthers

“This is a problem that comes up a lot because, often, there is some element of criticism that is offered by the supposed disruptive physician, which may or may not be justified, may or may have been done in good faith, and may or may not have been in a respectful manner.”

An isolated incident of behavior that is not reflective of a pattern of inappropriate, deep-seated, and habitual behavior should not be construed as disruptive, Ms. Struthers added. In addition, disruptive behavior is not respectful disagreement with leadership, presentation of controversial ideas, or the respectful complaining about processes that endanger patient care.

Do address behavior that is truly disruptive

According to the American Medical Association, disruptive behavior is defined as personal conduct, whether verbal or physical, that negatively affects or that potentially may negatively affect patient care, including conduct that interferes the ability to work with members of the health care team. Such behavior can be passive, such as ignoring calls or frequently missing meetings; passive-aggressive, such as excessive sarcasm or veiled threats; or aggressive, such as yelling or bullying.

Don’t focus solely on the behavior

Most disruptive behavior has a root cause, and efforts should be made to get to the bottom of the conduct, according to Sidney Welch, an Atlanta-based health law attorney.

“Often, there’s an underlying frustration in terms of clinical care or what they’re being told to do or the systems and processes [in play],” she said “Where is the sources of the tension that is creating the behavior?”

Do identify contributing factors

Personality characteristics that could lead to hostile behavior include self-centeredness, immaturity, resentfulness, or a need for power and control. Systemic factors could include increased productivity demands, cost-containment requirements, embedded hierarchies, fear of litigation, ineffective or absent conflict-resolution processes, competition between hospitals and medical staff, new care settings, and marketplace demands. Shortages of staff and high work burdens also could fuel disruptive behavior, Ms. Welch said.

“There are situations where there [is] a psychiatric disorder or a personality disorder that’s the root cause of the disruption,” she said. But “sometimes it’s just a stressful situation. A lot of these cases [in which] the physician is the disruption, we’re seeing them in high stakes emergency departments or situations where decisions have to be made very quickly, or fatigue and external stresses may be the source.”

Don’t apply corrective actions inconsistently

Make expectations clear by having a code of conduct supported by policies that apply to every employee, Ms. Welch noted. A lack of fairness among employees can create greater tension and generate increased conflict during a disruptive situation. Ensure that physicians are not be treated differently than nurses or administrators when addressing complaints, she said.

Do implement a graduated set of responses

A tiered response system (informal, formal, disciplinary, regulatory) helps manage disruptive situations based on the extent of conduct, Ms. Welch said.

“The process and disciplinary process [should] to be multileveled so that people know the rules of the road, and the parameters and the bumpers so to speak, are defined.”

Don’t necessarily involve HR

Be cautious of allowing human resource (HR) departments to direct potential disruptive physician issues, Ms. Struthers said.

“I have some concerns about HR getting involved for a couple of reasons,” she said. “If you get nonphysicians involved, it seems to exacerbate the level of tension.”

In addition, if a hospital has a significant number of both employed and independent physicians, HR can sometimes apply different standards and varied courses of action depending on employment status, she said. Of course, if the alleged disrupter is a nonphysician, HR is generally the only route for remedy within a hospital setting, Ms. Welch noted.

Do address the issue through internal processes

Every medical staff should develop and adopt bylaw provisions or policies for intervening in situations in which a physician’s behavior is identified as disruptive, according to AMA policy. Medical staff bylaw provisions or policies should contain procedural safeguards that protect due process.

For doctors in groups or small practices, employment policies and procedures should address protocols when disruption matters arise, Ms. Struthers said.

“The dynamics in a small clinic is that some doctors may more have power than others, so it may be harder in some contexts to treat everyone the same,” she said in an interview. “But that’s a really important thing to do. Any well-advised clinics would have a code of conduct or conduct policy, really to protect the clinic from employee lawsuits.”

Don’t let policies collect dust

“As we all know, you can write the policies, you can put them on the shelf, but if people aren’t reading them and understanding them and aren’t educated on them, then it really does no good,” Ms. Welch said.

Do ensure everyone knows how disruptive behavior is handled

Make certain that all staff review disruptive behavior policies and are adequately trained in how the process works, Ms. Welch added. Employees should know where to seek help if experiencing a disruption matter. Consider having staff members sign or acknowledge a code of conduct upon credentialing or hiring.

“Obviously, disruptive behavior can impact patient care, and it can come from a lot of differ directions; It’s not just physicians,” Ms. Struthers said. “Hospitals [and practices] like other places of business, need to have comprehensive polices and procedures, and they need to follow them.”

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On Twitter @legal_med

CHICAGO – Dealing with disruptive behavior by staff and colleagues isn’t just about knowing what to do – it’s also about knowing what not to do.

Often, mishandling disruptive behavior can make matters worse and lead to further conflict among physicians and employees, health law experts warn. At a conference held by the American Bar Association, attorneys offered guidance on the dos and don’ts of disruptive behavior management.

Don’t discipline for the wrong reasons

Know what disruptive behavior is not, advised Margo S. Struthers, a Minneapolis-based health law attorney. Criticism offered in good faith with the aim of improving patient care should not be considered disruptive, she said.

Courtesy Margo Struthers

“This is a problem that comes up a lot because, often, there is some element of criticism that is offered by the supposed disruptive physician, which may or may not be justified, may or may have been done in good faith, and may or may not have been in a respectful manner.”

An isolated incident of behavior that is not reflective of a pattern of inappropriate, deep-seated, and habitual behavior should not be construed as disruptive, Ms. Struthers added. In addition, disruptive behavior is not respectful disagreement with leadership, presentation of controversial ideas, or the respectful complaining about processes that endanger patient care.

Do address behavior that is truly disruptive

According to the American Medical Association, disruptive behavior is defined as personal conduct, whether verbal or physical, that negatively affects or that potentially may negatively affect patient care, including conduct that interferes the ability to work with members of the health care team. Such behavior can be passive, such as ignoring calls or frequently missing meetings; passive-aggressive, such as excessive sarcasm or veiled threats; or aggressive, such as yelling or bullying.

Don’t focus solely on the behavior

Most disruptive behavior has a root cause, and efforts should be made to get to the bottom of the conduct, according to Sidney Welch, an Atlanta-based health law attorney.

“Often, there’s an underlying frustration in terms of clinical care or what they’re being told to do or the systems and processes [in play],” she said “Where is the sources of the tension that is creating the behavior?”

Do identify contributing factors

Personality characteristics that could lead to hostile behavior include self-centeredness, immaturity, resentfulness, or a need for power and control. Systemic factors could include increased productivity demands, cost-containment requirements, embedded hierarchies, fear of litigation, ineffective or absent conflict-resolution processes, competition between hospitals and medical staff, new care settings, and marketplace demands. Shortages of staff and high work burdens also could fuel disruptive behavior, Ms. Welch said.

“There are situations where there [is] a psychiatric disorder or a personality disorder that’s the root cause of the disruption,” she said. But “sometimes it’s just a stressful situation. A lot of these cases [in which] the physician is the disruption, we’re seeing them in high stakes emergency departments or situations where decisions have to be made very quickly, or fatigue and external stresses may be the source.”

Don’t apply corrective actions inconsistently

Make expectations clear by having a code of conduct supported by policies that apply to every employee, Ms. Welch noted. A lack of fairness among employees can create greater tension and generate increased conflict during a disruptive situation. Ensure that physicians are not be treated differently than nurses or administrators when addressing complaints, she said.

Do implement a graduated set of responses

A tiered response system (informal, formal, disciplinary, regulatory) helps manage disruptive situations based on the extent of conduct, Ms. Welch said.

“The process and disciplinary process [should] to be multileveled so that people know the rules of the road, and the parameters and the bumpers so to speak, are defined.”

Don’t necessarily involve HR

Be cautious of allowing human resource (HR) departments to direct potential disruptive physician issues, Ms. Struthers said.

“I have some concerns about HR getting involved for a couple of reasons,” she said. “If you get nonphysicians involved, it seems to exacerbate the level of tension.”

In addition, if a hospital has a significant number of both employed and independent physicians, HR can sometimes apply different standards and varied courses of action depending on employment status, she said. Of course, if the alleged disrupter is a nonphysician, HR is generally the only route for remedy within a hospital setting, Ms. Welch noted.

Do address the issue through internal processes

Every medical staff should develop and adopt bylaw provisions or policies for intervening in situations in which a physician’s behavior is identified as disruptive, according to AMA policy. Medical staff bylaw provisions or policies should contain procedural safeguards that protect due process.

For doctors in groups or small practices, employment policies and procedures should address protocols when disruption matters arise, Ms. Struthers said.

“The dynamics in a small clinic is that some doctors may more have power than others, so it may be harder in some contexts to treat everyone the same,” she said in an interview. “But that’s a really important thing to do. Any well-advised clinics would have a code of conduct or conduct policy, really to protect the clinic from employee lawsuits.”

Don’t let policies collect dust

“As we all know, you can write the policies, you can put them on the shelf, but if people aren’t reading them and understanding them and aren’t educated on them, then it really does no good,” Ms. Welch said.

Do ensure everyone knows how disruptive behavior is handled

Make certain that all staff review disruptive behavior policies and are adequately trained in how the process works, Ms. Welch added. Employees should know where to seek help if experiencing a disruption matter. Consider having staff members sign or acknowledge a code of conduct upon credentialing or hiring.

“Obviously, disruptive behavior can impact patient care, and it can come from a lot of differ directions; It’s not just physicians,” Ms. Struthers said. “Hospitals [and practices] like other places of business, need to have comprehensive polices and procedures, and they need to follow them.”

[email protected]

On Twitter @legal_med

DENVER – Obstructive sleep apnea diagnosed later in life is associated with an increased likelihood of subsequent Alzheimer’s disease, Dr. Omonigho Bubu reported at the annual meeting of the Associated Professional Sleep Societies.

He presented a retrospective cohort study in which a dose-reponse relationship was apparent. The more severe an individual’s obstructive sleep apnea (OSA) as reflected in a higher apnea-hypopnea index on polysomnography, the greater the risk of later being diagnosed with Alzheimer’s disease, compared with matched controls during up to 13 years of follow-up.

Bruce Jancin/Frontline Medical News

The study also identified several possible contributing factors for the observed OSA/Alzheimer’s relationship. Those OSA patients with more severe sleep fragmentation, nocturnal hypoxia, and abnormal sleep duration were significantly more likely to subsequently develop Alzheimer’s disease than were OSA patients with less severely disrupted sleep measures, added Dr. Bubu of the University of South Florida, Tampa.

The study included 756 patients aged 65 years and older with no history of cognitive decline when diagnosed with OSA by polysomnography at Tampa General Hospital during 2001-2005. They were matched by age, race, sex, body mass index, and zip code to two control groups totaling 3,780 subjects. The controls, drawn from outpatient medical clinics at the hospital, had a variety of medical problems but no sleep disorders or cognitive impairment.

During a mean 10.5-year follow-up period, 513 subjects were diagnosed with Alzheimer’s disease, according to Medicare data. In a Cox proportional hazards analysis adjusted for age, sex, race, body mass index, and education level, OSA was independently associated with a 2.2-fold increased risk. Further adjustment for alcohol intake, smoking, use of sleep medications, and chronic medical conditions didn’t substantially change the results.

However, the investigators were not able to control for apolipoprotein E (APOE)–epsilon 4 allele status, which is a known risk factor for both OSA and Alzheimer’s disease, so it makes one wonder whether the association is “all related to APOE,” said Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic, Scottsdale, Ariz., when asked to comment on the study.

Time to onset of Alzheimer’s disease was shorter in the OSA patients: The mean time to diagnosis was 60.8 months after diagnosis of OSA, compared with 73 and 78 months in members of the two control groups who developed the dementia.

When the risk of developing Alzheimer’s disease was stratified according to baseline OSA severity, a dose-response effect was seen. Mild OSA, defined as 5-14 apnea-hypopnea events per hour of sleep, was associated with a 1.67-fold greater risk than in controls. The moderate OSA group, who had 15-29 events per hour, had a 1.81-fold increased risk. Patients with severe OSA, with 30 or more events per hour, had a 2.63-fold increased risk.

Gender, race, and education modified the relationship between OSA and Alzheimer’s disease, Dr. Bubu said. Women with OSA had a 2.28-fold greater risk of later developing the disease, compared with controls; men had a 1.42-fold increased risk. African-Americans with OSA were at 2.56-fold greater risk than were controls, while Hispanics with OSA were at 1.8-fold increased risk and non-Hispanic whites were at 1.87-fold increased risk. OSA patients with a high school education or less were at 2.73 times greater risk of Alzheimer’s disease than were controls, those with at least some college or technical school were at 1.82-fold risk, and OSA patients who’d been to graduate school had a 1.31-fold increased risk.

“Our results definitely show that OSA precedes the onset of Alzheimer’s disease. But we cannot say that’s causation. That will be left to future research examining the potential mechanisms we’ve identified,” Dr. Bubu said in an interview.

A key missing link in establishing a causal relationship is the lack of data on how many of the older patients diagnosed with OSA accepted treatment for the condition, and what their response rates were. In other words, it remains to be seen whether OSA occurring later in life is a modifiable risk factor for Alzheimer’s disease as opposed to an early expression of the dementing disease process whereby treatment of the sleep disorder doesn’t affect the progressive cognitive decline.

Both short sleep duration of less than 6 hours as well as a mean total sleep time greater than 9 hours in patients with OSA were associated with significantly increased risk of Alzheimer’s disease, compared with a sleep time of 6-9 hours. Patients with a high sleep-onset latency in the sleep lab, a high REM latency from sleep onset, a low percentage of time spent in REM, an oxygen saturation level of less than 90% for at least 1% of sleep time, and/or a high number of arousals per hour of sleep were also at increased risk of subsequent Alzheimer’s disease.

The study was supported by the Byrd Alzheimer’s Institute. Dr. Bubu reported having no financial conflicts.

DENVER – Obstructive sleep apnea diagnosed later in life is associated with an increased likelihood of subsequent Alzheimer’s disease, Dr. Omonigho Bubu reported at the annual meeting of the Associated Professional Sleep Societies.

He presented a retrospective cohort study in which a dose-reponse relationship was apparent. The more severe an individual’s obstructive sleep apnea (OSA) as reflected in a higher apnea-hypopnea index on polysomnography, the greater the risk of later being diagnosed with Alzheimer’s disease, compared with matched controls during up to 13 years of follow-up.

Bruce Jancin/Frontline Medical News

The study also identified several possible contributing factors for the observed OSA/Alzheimer’s relationship. Those OSA patients with more severe sleep fragmentation, nocturnal hypoxia, and abnormal sleep duration were significantly more likely to subsequently develop Alzheimer’s disease than were OSA patients with less severely disrupted sleep measures, added Dr. Bubu of the University of South Florida, Tampa.

The study included 756 patients aged 65 years and older with no history of cognitive decline when diagnosed with OSA by polysomnography at Tampa General Hospital during 2001-2005. They were matched by age, race, sex, body mass index, and zip code to two control groups totaling 3,780 subjects. The controls, drawn from outpatient medical clinics at the hospital, had a variety of medical problems but no sleep disorders or cognitive impairment.

During a mean 10.5-year follow-up period, 513 subjects were diagnosed with Alzheimer’s disease, according to Medicare data. In a Cox proportional hazards analysis adjusted for age, sex, race, body mass index, and education level, OSA was independently associated with a 2.2-fold increased risk. Further adjustment for alcohol intake, smoking, use of sleep medications, and chronic medical conditions didn’t substantially change the results.

However, the investigators were not able to control for apolipoprotein E (APOE)–epsilon 4 allele status, which is a known risk factor for both OSA and Alzheimer’s disease, so it makes one wonder whether the association is “all related to APOE,” said Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic, Scottsdale, Ariz., when asked to comment on the study.

Time to onset of Alzheimer’s disease was shorter in the OSA patients: The mean time to diagnosis was 60.8 months after diagnosis of OSA, compared with 73 and 78 months in members of the two control groups who developed the dementia.

When the risk of developing Alzheimer’s disease was stratified according to baseline OSA severity, a dose-response effect was seen. Mild OSA, defined as 5-14 apnea-hypopnea events per hour of sleep, was associated with a 1.67-fold greater risk than in controls. The moderate OSA group, who had 15-29 events per hour, had a 1.81-fold increased risk. Patients with severe OSA, with 30 or more events per hour, had a 2.63-fold increased risk.

Gender, race, and education modified the relationship between OSA and Alzheimer’s disease, Dr. Bubu said. Women with OSA had a 2.28-fold greater risk of later developing the disease, compared with controls; men had a 1.42-fold increased risk. African-Americans with OSA were at 2.56-fold greater risk than were controls, while Hispanics with OSA were at 1.8-fold increased risk and non-Hispanic whites were at 1.87-fold increased risk. OSA patients with a high school education or less were at 2.73 times greater risk of Alzheimer’s disease than were controls, those with at least some college or technical school were at 1.82-fold risk, and OSA patients who’d been to graduate school had a 1.31-fold increased risk.

“Our results definitely show that OSA precedes the onset of Alzheimer’s disease. But we cannot say that’s causation. That will be left to future research examining the potential mechanisms we’ve identified,” Dr. Bubu said in an interview.

A key missing link in establishing a causal relationship is the lack of data on how many of the older patients diagnosed with OSA accepted treatment for the condition, and what their response rates were. In other words, it remains to be seen whether OSA occurring later in life is a modifiable risk factor for Alzheimer’s disease as opposed to an early expression of the dementing disease process whereby treatment of the sleep disorder doesn’t affect the progressive cognitive decline.

Both short sleep duration of less than 6 hours as well as a mean total sleep time greater than 9 hours in patients with OSA were associated with significantly increased risk of Alzheimer’s disease, compared with a sleep time of 6-9 hours. Patients with a high sleep-onset latency in the sleep lab, a high REM latency from sleep onset, a low percentage of time spent in REM, an oxygen saturation level of less than 90% for at least 1% of sleep time, and/or a high number of arousals per hour of sleep were also at increased risk of subsequent Alzheimer’s disease.

The study was supported by the Byrd Alzheimer’s Institute. Dr. Bubu reported having no financial conflicts.

DENVER – Obstructive sleep apnea diagnosed later in life is associated with an increased likelihood of subsequent Alzheimer’s disease, Dr. Omonigho Bubu reported at the annual meeting of the Associated Professional Sleep Societies.

He presented a retrospective cohort study in which a dose-reponse relationship was apparent. The more severe an individual’s obstructive sleep apnea (OSA) as reflected in a higher apnea-hypopnea index on polysomnography, the greater the risk of later being diagnosed with Alzheimer’s disease, compared with matched controls during up to 13 years of follow-up.

Bruce Jancin/Frontline Medical News

The study also identified several possible contributing factors for the observed OSA/Alzheimer’s relationship. Those OSA patients with more severe sleep fragmentation, nocturnal hypoxia, and abnormal sleep duration were significantly more likely to subsequently develop Alzheimer’s disease than were OSA patients with less severely disrupted sleep measures, added Dr. Bubu of the University of South Florida, Tampa.

The study included 756 patients aged 65 years and older with no history of cognitive decline when diagnosed with OSA by polysomnography at Tampa General Hospital during 2001-2005. They were matched by age, race, sex, body mass index, and zip code to two control groups totaling 3,780 subjects. The controls, drawn from outpatient medical clinics at the hospital, had a variety of medical problems but no sleep disorders or cognitive impairment.

During a mean 10.5-year follow-up period, 513 subjects were diagnosed with Alzheimer’s disease, according to Medicare data. In a Cox proportional hazards analysis adjusted for age, sex, race, body mass index, and education level, OSA was independently associated with a 2.2-fold increased risk. Further adjustment for alcohol intake, smoking, use of sleep medications, and chronic medical conditions didn’t substantially change the results.

However, the investigators were not able to control for apolipoprotein E (APOE)–epsilon 4 allele status, which is a known risk factor for both OSA and Alzheimer’s disease, so it makes one wonder whether the association is “all related to APOE,” said Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic, Scottsdale, Ariz., when asked to comment on the study.

Time to onset of Alzheimer’s disease was shorter in the OSA patients: The mean time to diagnosis was 60.8 months after diagnosis of OSA, compared with 73 and 78 months in members of the two control groups who developed the dementia.

When the risk of developing Alzheimer’s disease was stratified according to baseline OSA severity, a dose-response effect was seen. Mild OSA, defined as 5-14 apnea-hypopnea events per hour of sleep, was associated with a 1.67-fold greater risk than in controls. The moderate OSA group, who had 15-29 events per hour, had a 1.81-fold increased risk. Patients with severe OSA, with 30 or more events per hour, had a 2.63-fold increased risk.

Gender, race, and education modified the relationship between OSA and Alzheimer’s disease, Dr. Bubu said. Women with OSA had a 2.28-fold greater risk of later developing the disease, compared with controls; men had a 1.42-fold increased risk. African-Americans with OSA were at 2.56-fold greater risk than were controls, while Hispanics with OSA were at 1.8-fold increased risk and non-Hispanic whites were at 1.87-fold increased risk. OSA patients with a high school education or less were at 2.73 times greater risk of Alzheimer’s disease than were controls, those with at least some college or technical school were at 1.82-fold risk, and OSA patients who’d been to graduate school had a 1.31-fold increased risk.

“Our results definitely show that OSA precedes the onset of Alzheimer’s disease. But we cannot say that’s causation. That will be left to future research examining the potential mechanisms we’ve identified,” Dr. Bubu said in an interview.

A key missing link in establishing a causal relationship is the lack of data on how many of the older patients diagnosed with OSA accepted treatment for the condition, and what their response rates were. In other words, it remains to be seen whether OSA occurring later in life is a modifiable risk factor for Alzheimer’s disease as opposed to an early expression of the dementing disease process whereby treatment of the sleep disorder doesn’t affect the progressive cognitive decline.

Both short sleep duration of less than 6 hours as well as a mean total sleep time greater than 9 hours in patients with OSA were associated with significantly increased risk of Alzheimer’s disease, compared with a sleep time of 6-9 hours. Patients with a high sleep-onset latency in the sleep lab, a high REM latency from sleep onset, a low percentage of time spent in REM, an oxygen saturation level of less than 90% for at least 1% of sleep time, and/or a high number of arousals per hour of sleep were also at increased risk of subsequent Alzheimer’s disease.

The study was supported by the Byrd Alzheimer’s Institute. Dr. Bubu reported having no financial conflicts.