Related content on burnout:

• Is burnout on the rise and what are the signs ObGyns should be on the lookout for?
• ObGyn burnout: ACOG takes aim
• Strategies for maintaining resilience to the burnout threat

Related content on burnout:

• Is burnout on the rise and what are the signs ObGyns should be on the lookout for?
• ObGyn burnout: ACOG takes aim
• Strategies for maintaining resilience to the burnout threat

Related content on burnout:

• Is burnout on the rise and what are the signs ObGyns should be on the lookout for?
• ObGyn burnout: ACOG takes aim
• Strategies for maintaining resilience to the burnout threat

In newborns with a borderline hypoplastic aortic arch, the type of operation and surgical approach can be critical in determining the risk of recurrent obstruction, but aortic arch reconstruction through a median sternotomy on bypass may carry a lower risk of recurrence than use of a thoracotomy.

In a study of 183 newborns and infants (median age of 15 days) who had surgery for coarctation and hypoplastic aortic arch over a 17-year period, researchers led by Andreas Tulzer, MD, of Children’s Heart Center, Linz, Austria, found that resection and extended end-to-end anastomosis (REEEA) as well as end-to-side anastomosis (ESA) yielded low mortality. The findings were published in the December 2016 issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152:1506-13).

In the study, 72 patients had a median sternotomy – 71 with cardiopulmonary bypass (CPB) – and the remaining 111 had a lateral thoracotomy. Fifty-two patients (28.4%) had an additional ventricular septal defect closure. In the 71 patients who had median sternotomy with CPB, 41 had REEEA and 30 had ESA.

One patient who had median sternotomy with CPB had complications whereas 10 who had undergone primary repair with REEEA through a lateral thoracotomy had complications, for complications rates of 1.4% and 9%, respectively.

“Access through a median sternotomy with the use of CPB was superior to a lateral thoracotomy in terms of necessary reinterventions,” noted Dr. Tulzer and coauthors.

Of the 131 patients who had isolated repair of coarctation of the aorta with associated hypoplastic aortic arch, 116 had REEEA and 15 had ESA. There were no in-hospital deaths in this group and one patient needed an early reintervention. One patient had a severe neurologic complication.

On long-term follow-up of 139 patients at a median duration of 6.3 years, no late deaths were reported. “The calculated freedom from mortality (early and late) at 10 years for the entire group was 99.27%,” the researchers said. “In none of the patients of the follow-up population did we notice any signs of permanent left laryngeal nerve injury, bronchial compression, or left pulmonary artery stenosis.”

Lateral thoracotomy as access was a significant risk factor for recurrent obstruction at P = .03.

In the study, an experienced pediatric cardiologist and a pediatric cardiac surgeon determined which of three procedures to use – ESA on bypass, REEEA with a median sternotomy on CPB, or REEEA with a lateral thoracotomy without CPB – based on the size and anatomy of the proximal transverse aortic arch. In the early study period, cut-off values were proximal transverse arch diameters of 4 mm or less in newborns and young infants, but in the later study period the cut-off was z scores of –4.5 or less.

Adverse outcomes were minimal. There was one death within 30 days of surgery in the overall population (0.54%). The one severe complication consisted of paraplegia and cerebral hypoxemia after REEEA. At 10 years, 99.27% of all patients survived and 90.12% were free from intervention.

Either approach with REEEA and ESA is safe and effective, Dr. Tulzer and colleagues said, but they did determine a suitable population for the median sternotomy using CPB. “In patients with proximal transverse aortic arch, z scores of less than –4.59, arch repair should be performed through a median sternotomy using CPB, rather than through a lateral thoracotomy to reduce the risk for recurrent arch obstructions,” the researchers concluded.

Dr. Tulzer and coauthors had no financial relationships to disclose.

In newborns with a borderline hypoplastic aortic arch, the type of operation and surgical approach can be critical in determining the risk of recurrent obstruction, but aortic arch reconstruction through a median sternotomy on bypass may carry a lower risk of recurrence than use of a thoracotomy.

In a study of 183 newborns and infants (median age of 15 days) who had surgery for coarctation and hypoplastic aortic arch over a 17-year period, researchers led by Andreas Tulzer, MD, of Children’s Heart Center, Linz, Austria, found that resection and extended end-to-end anastomosis (REEEA) as well as end-to-side anastomosis (ESA) yielded low mortality. The findings were published in the December 2016 issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152:1506-13).

In the study, 72 patients had a median sternotomy – 71 with cardiopulmonary bypass (CPB) – and the remaining 111 had a lateral thoracotomy. Fifty-two patients (28.4%) had an additional ventricular septal defect closure. In the 71 patients who had median sternotomy with CPB, 41 had REEEA and 30 had ESA.

One patient who had median sternotomy with CPB had complications whereas 10 who had undergone primary repair with REEEA through a lateral thoracotomy had complications, for complications rates of 1.4% and 9%, respectively.

“Access through a median sternotomy with the use of CPB was superior to a lateral thoracotomy in terms of necessary reinterventions,” noted Dr. Tulzer and coauthors.

Of the 131 patients who had isolated repair of coarctation of the aorta with associated hypoplastic aortic arch, 116 had REEEA and 15 had ESA. There were no in-hospital deaths in this group and one patient needed an early reintervention. One patient had a severe neurologic complication.

On long-term follow-up of 139 patients at a median duration of 6.3 years, no late deaths were reported. “The calculated freedom from mortality (early and late) at 10 years for the entire group was 99.27%,” the researchers said. “In none of the patients of the follow-up population did we notice any signs of permanent left laryngeal nerve injury, bronchial compression, or left pulmonary artery stenosis.”

Lateral thoracotomy as access was a significant risk factor for recurrent obstruction at P = .03.

In the study, an experienced pediatric cardiologist and a pediatric cardiac surgeon determined which of three procedures to use – ESA on bypass, REEEA with a median sternotomy on CPB, or REEEA with a lateral thoracotomy without CPB – based on the size and anatomy of the proximal transverse aortic arch. In the early study period, cut-off values were proximal transverse arch diameters of 4 mm or less in newborns and young infants, but in the later study period the cut-off was z scores of –4.5 or less.

Adverse outcomes were minimal. There was one death within 30 days of surgery in the overall population (0.54%). The one severe complication consisted of paraplegia and cerebral hypoxemia after REEEA. At 10 years, 99.27% of all patients survived and 90.12% were free from intervention.

Either approach with REEEA and ESA is safe and effective, Dr. Tulzer and colleagues said, but they did determine a suitable population for the median sternotomy using CPB. “In patients with proximal transverse aortic arch, z scores of less than –4.59, arch repair should be performed through a median sternotomy using CPB, rather than through a lateral thoracotomy to reduce the risk for recurrent arch obstructions,” the researchers concluded.

Dr. Tulzer and coauthors had no financial relationships to disclose.

In newborns with a borderline hypoplastic aortic arch, the type of operation and surgical approach can be critical in determining the risk of recurrent obstruction, but aortic arch reconstruction through a median sternotomy on bypass may carry a lower risk of recurrence than use of a thoracotomy.

In a study of 183 newborns and infants (median age of 15 days) who had surgery for coarctation and hypoplastic aortic arch over a 17-year period, researchers led by Andreas Tulzer, MD, of Children’s Heart Center, Linz, Austria, found that resection and extended end-to-end anastomosis (REEEA) as well as end-to-side anastomosis (ESA) yielded low mortality. The findings were published in the December 2016 issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152:1506-13).

In the study, 72 patients had a median sternotomy – 71 with cardiopulmonary bypass (CPB) – and the remaining 111 had a lateral thoracotomy. Fifty-two patients (28.4%) had an additional ventricular septal defect closure. In the 71 patients who had median sternotomy with CPB, 41 had REEEA and 30 had ESA.

One patient who had median sternotomy with CPB had complications whereas 10 who had undergone primary repair with REEEA through a lateral thoracotomy had complications, for complications rates of 1.4% and 9%, respectively.

“Access through a median sternotomy with the use of CPB was superior to a lateral thoracotomy in terms of necessary reinterventions,” noted Dr. Tulzer and coauthors.

Of the 131 patients who had isolated repair of coarctation of the aorta with associated hypoplastic aortic arch, 116 had REEEA and 15 had ESA. There were no in-hospital deaths in this group and one patient needed an early reintervention. One patient had a severe neurologic complication.

On long-term follow-up of 139 patients at a median duration of 6.3 years, no late deaths were reported. “The calculated freedom from mortality (early and late) at 10 years for the entire group was 99.27%,” the researchers said. “In none of the patients of the follow-up population did we notice any signs of permanent left laryngeal nerve injury, bronchial compression, or left pulmonary artery stenosis.”

Lateral thoracotomy as access was a significant risk factor for recurrent obstruction at P = .03.

In the study, an experienced pediatric cardiologist and a pediatric cardiac surgeon determined which of three procedures to use – ESA on bypass, REEEA with a median sternotomy on CPB, or REEEA with a lateral thoracotomy without CPB – based on the size and anatomy of the proximal transverse aortic arch. In the early study period, cut-off values were proximal transverse arch diameters of 4 mm or less in newborns and young infants, but in the later study period the cut-off was z scores of –4.5 or less.

Adverse outcomes were minimal. There was one death within 30 days of surgery in the overall population (0.54%). The one severe complication consisted of paraplegia and cerebral hypoxemia after REEEA. At 10 years, 99.27% of all patients survived and 90.12% were free from intervention.

Either approach with REEEA and ESA is safe and effective, Dr. Tulzer and colleagues said, but they did determine a suitable population for the median sternotomy using CPB. “In patients with proximal transverse aortic arch, z scores of less than –4.59, arch repair should be performed through a median sternotomy using CPB, rather than through a lateral thoracotomy to reduce the risk for recurrent arch obstructions,” the researchers concluded.

Dr. Tulzer and coauthors had no financial relationships to disclose.

SAN DIEGO – A multi-arm clinical trial aims to transform the treatment of acute myeloid leukemia, a deadly blood cancer whose standard of care has remained essentially unchanged for 4 decades.

Launched in October 2016, the multicenter BEAT AML Master Trial is based on a simple but radical goal – turn around genomic tests of bone marrow biopsies within 7 days to allow targeted therapy, said lead investigator Brian Druker, MD, of Oregon Health and Science University Knight Cancer Institute in Portland.

SAN DIEGO – A multi-arm clinical trial aims to transform the treatment of acute myeloid leukemia, a deadly blood cancer whose standard of care has remained essentially unchanged for 4 decades.

Launched in October 2016, the multicenter BEAT AML Master Trial is based on a simple but radical goal – turn around genomic tests of bone marrow biopsies within 7 days to allow targeted therapy, said lead investigator Brian Druker, MD, of Oregon Health and Science University Knight Cancer Institute in Portland.

SAN DIEGO – A multi-arm clinical trial aims to transform the treatment of acute myeloid leukemia, a deadly blood cancer whose standard of care has remained essentially unchanged for 4 decades.

Launched in October 2016, the multicenter BEAT AML Master Trial is based on a simple but radical goal – turn around genomic tests of bone marrow biopsies within 7 days to allow targeted therapy, said lead investigator Brian Druker, MD, of Oregon Health and Science University Knight Cancer Institute in Portland.

In the aftermath of the most acrimonious presidential election of my lifetime, we are left with recriminations, celebrations, and more questions than answers. And, of course, no real answers for the medical field at all. Just as in 2008, we face an unknown future.

Will this be good or bad for us? I have no idea. Some of the health care changes that hit small practices hardest were the requirements to upgrade or be penalized. Many of us, including myself, didn’t have the financial means to do that and elected to take the penalties. It would be nice to see those rolled back. Since all insurers peg their rates to Medicare, I’d be thrilled to see those increase, too. The repeal of the hated Sustainable Growth Rate formula showed that the parties can get something done when they’re actually willing to do the work they were elected to do.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

In the aftermath of the most acrimonious presidential election of my lifetime, we are left with recriminations, celebrations, and more questions than answers. And, of course, no real answers for the medical field at all. Just as in 2008, we face an unknown future.

Will this be good or bad for us? I have no idea. Some of the health care changes that hit small practices hardest were the requirements to upgrade or be penalized. Many of us, including myself, didn’t have the financial means to do that and elected to take the penalties. It would be nice to see those rolled back. Since all insurers peg their rates to Medicare, I’d be thrilled to see those increase, too. The repeal of the hated Sustainable Growth Rate formula showed that the parties can get something done when they’re actually willing to do the work they were elected to do.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

In the aftermath of the most acrimonious presidential election of my lifetime, we are left with recriminations, celebrations, and more questions than answers. And, of course, no real answers for the medical field at all. Just as in 2008, we face an unknown future.

Will this be good or bad for us? I have no idea. Some of the health care changes that hit small practices hardest were the requirements to upgrade or be penalized. Many of us, including myself, didn’t have the financial means to do that and elected to take the penalties. It would be nice to see those rolled back. Since all insurers peg their rates to Medicare, I’d be thrilled to see those increase, too. The repeal of the hated Sustainable Growth Rate formula showed that the parties can get something done when they’re actually willing to do the work they were elected to do.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Women denied an abortion appear to experience more psychological problems in the short term, compared with women who are able to access the procedure, according to findings published in JAMA Psychiatry.

The prospective, longitudinal Turnaway Study involved regular follow-up telephone interviews of 956 women recruited from 30 abortion facilities in 21 states. Of these women, 273 received abortions in the first trimester, 452 received abortions just under the facility’s gestational limit, 161 sought an abortion but were turned away because they were just past the limit and later gave birth (turnaway-births), and 70 were turned away but either miscarried or obtained an abortion elsewhere (turnaway-no-births).

KatarzynaBialasiewicz/Thinkstock

Women denied an abortion appear to experience more psychological problems in the short term, compared with women who are able to access the procedure, according to findings published in JAMA Psychiatry.

The prospective, longitudinal Turnaway Study involved regular follow-up telephone interviews of 956 women recruited from 30 abortion facilities in 21 states. Of these women, 273 received abortions in the first trimester, 452 received abortions just under the facility’s gestational limit, 161 sought an abortion but were turned away because they were just past the limit and later gave birth (turnaway-births), and 70 were turned away but either miscarried or obtained an abortion elsewhere (turnaway-no-births).

KatarzynaBialasiewicz/Thinkstock

Women denied an abortion appear to experience more psychological problems in the short term, compared with women who are able to access the procedure, according to findings published in JAMA Psychiatry.

The prospective, longitudinal Turnaway Study involved regular follow-up telephone interviews of 956 women recruited from 30 abortion facilities in 21 states. Of these women, 273 received abortions in the first trimester, 452 received abortions just under the facility’s gestational limit, 161 sought an abortion but were turned away because they were just past the limit and later gave birth (turnaway-births), and 70 were turned away but either miscarried or obtained an abortion elsewhere (turnaway-no-births).

KatarzynaBialasiewicz/Thinkstock

VIENNA – Patients with metastatic non–small-cell lung cancer with high levels of PD-L1 who received first-line pembrolizumab treatment had clinically meaningful improvement in their quality of life, compared with patients randomized to chemotherapy, in a prespecified secondary analysis of data from the drug’s pivotal trial.

This boost in quality of life as well as other measures of health status add to the pivotal trial’s primary finding of significantly increased progression-free survival compared with chemotherapy, as well as previously-reported secondary findings of superior overall survival, objective response rate, and safety with pembrolizumab compared with chemotherapy (N Engl J Med. 2016 Nov 10;375[19]:1823-33), Julie R. Brahmer, MD, said at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

The primary endpoint of the Study of Pembrolizumab Compared to Platinum-Based Chemotherapies in Participants With Metastatic Non–Small Cell Lung Cancer (KEYNOTE-024) showed an average 4.3-month increase in progression-free survival with pembrolizumab immunotherapy, compared with a standard chemotherapy regimen.

Improved quality of life on top of improved efficacy and safety is an important added benefit from pembrolizumab that should further spur its widespread adoption as first-line treatment for approved patients, Dr. Brahmer said in a video interview.

“When you talk about improving efficacy by months, patients and physicians want to also see improved quality of life,” said Dr. Brahmer, director of thoracic oncology at the Johns Hopkins Kimmel Cancer Center in Baltimore. “If symptoms are not improved or there are a ton of side effects with the treatment then use might be low.”

Based on its performance in KEYNOTE-024, pembrolizumab (Keytruda) received Food and Drug Administration approval on Oct. 24, 2016, as first-line treatment for patients with metastatic non–small-cell lung cancer that has a tumor proportion score of at least 50% for programmed death ligand 1 (PD-L1). Pembrolizumab is a monoclonal antibody that binds and blocks PD-1, the immune-cell receptor that tumor-cell PD-L1 binds to make immune cells less active. Other new immune checkpoint inhibitor drugs that act by blocking PD-1 or PD-L1 have shown similar quality of life benefits, she noted.

Routine availability of pembrolizumab as initial treatment for patients who have tumors with this level of PD-L1 expression (and also have no EGFR or ALK genomic aberrations) is shifting practice, Dr. Brahmer said.

“It’s catching on. The limitation right now is making sure patients get tested” for their PD-L1 tumor proportion score at the time they are first diagnosed. “Medical oncologists need to educate pathologists that we need this testing automatically, upfront. It’s not there yet,” she said.

Patients also are enthused. “There is a lot of chemo-exhaustion among patients. They are looking for something different, and something that uses their immune system makes sense.” But only about one quarter of patients have tumors with this level of PD-L1 expression; the others must start chemotherapy first before trying immunotherapy, unless they have an EGFR mutation. Out-of-pocket cost for pembrolizumab is also a major issues for many patients, she said.

KEYNOTE-024 randomized 305 patients at 102 international sites and followed patients for a median of 11 months. Dr. Brahmer and her associates made two primary analyses of patient-reported outcomes. One was measurement of global health status at 15 weeks after the start of treatment using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire designed to assess quality of life. Weighted averaging of the EORTC QCQ-C30 scores showed a mean improvement of 7.8 points (P = .002) in the pembrolizumab patients compared with the chemotherapy patients, a difference Dr. Brahmer called “clinically meaningful” as well as statistically significant.

A second analysis of patient-reported outcomes used a second EORTC instrument, the QLC-LC13, which combines assessment of cough, chest pain, and dyspnea. Treatment with pembrolizumab significantly reduced the time to deterioration as measured by this questionnaire by a relative 34%, (P = .029).

A third analysis looked at 15 individual function or symptom domains that make up the QLQ-C30. In general, these showed more improvements with pembrolizumab than with chemotherapy. One notable subcategory was fatigue, which showed significant improvement with pembrolizumab compared with a small worsening with chemotherapy.

[email protected]

On Twitter @mitchelzoler

VIENNA – Patients with metastatic non–small-cell lung cancer with high levels of PD-L1 who received first-line pembrolizumab treatment had clinically meaningful improvement in their quality of life, compared with patients randomized to chemotherapy, in a prespecified secondary analysis of data from the drug’s pivotal trial.

This boost in quality of life as well as other measures of health status add to the pivotal trial’s primary finding of significantly increased progression-free survival compared with chemotherapy, as well as previously-reported secondary findings of superior overall survival, objective response rate, and safety with pembrolizumab compared with chemotherapy (N Engl J Med. 2016 Nov 10;375[19]:1823-33), Julie R. Brahmer, MD, said at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

The primary endpoint of the Study of Pembrolizumab Compared to Platinum-Based Chemotherapies in Participants With Metastatic Non–Small Cell Lung Cancer (KEYNOTE-024) showed an average 4.3-month increase in progression-free survival with pembrolizumab immunotherapy, compared with a standard chemotherapy regimen.

Improved quality of life on top of improved efficacy and safety is an important added benefit from pembrolizumab that should further spur its widespread adoption as first-line treatment for approved patients, Dr. Brahmer said in a video interview.

“When you talk about improving efficacy by months, patients and physicians want to also see improved quality of life,” said Dr. Brahmer, director of thoracic oncology at the Johns Hopkins Kimmel Cancer Center in Baltimore. “If symptoms are not improved or there are a ton of side effects with the treatment then use might be low.”

Based on its performance in KEYNOTE-024, pembrolizumab (Keytruda) received Food and Drug Administration approval on Oct. 24, 2016, as first-line treatment for patients with metastatic non–small-cell lung cancer that has a tumor proportion score of at least 50% for programmed death ligand 1 (PD-L1). Pembrolizumab is a monoclonal antibody that binds and blocks PD-1, the immune-cell receptor that tumor-cell PD-L1 binds to make immune cells less active. Other new immune checkpoint inhibitor drugs that act by blocking PD-1 or PD-L1 have shown similar quality of life benefits, she noted.

Routine availability of pembrolizumab as initial treatment for patients who have tumors with this level of PD-L1 expression (and also have no EGFR or ALK genomic aberrations) is shifting practice, Dr. Brahmer said.

“It’s catching on. The limitation right now is making sure patients get tested” for their PD-L1 tumor proportion score at the time they are first diagnosed. “Medical oncologists need to educate pathologists that we need this testing automatically, upfront. It’s not there yet,” she said.

Patients also are enthused. “There is a lot of chemo-exhaustion among patients. They are looking for something different, and something that uses their immune system makes sense.” But only about one quarter of patients have tumors with this level of PD-L1 expression; the others must start chemotherapy first before trying immunotherapy, unless they have an EGFR mutation. Out-of-pocket cost for pembrolizumab is also a major issues for many patients, she said.

KEYNOTE-024 randomized 305 patients at 102 international sites and followed patients for a median of 11 months. Dr. Brahmer and her associates made two primary analyses of patient-reported outcomes. One was measurement of global health status at 15 weeks after the start of treatment using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire designed to assess quality of life. Weighted averaging of the EORTC QCQ-C30 scores showed a mean improvement of 7.8 points (P = .002) in the pembrolizumab patients compared with the chemotherapy patients, a difference Dr. Brahmer called “clinically meaningful” as well as statistically significant.

A second analysis of patient-reported outcomes used a second EORTC instrument, the QLC-LC13, which combines assessment of cough, chest pain, and dyspnea. Treatment with pembrolizumab significantly reduced the time to deterioration as measured by this questionnaire by a relative 34%, (P = .029).

A third analysis looked at 15 individual function or symptom domains that make up the QLQ-C30. In general, these showed more improvements with pembrolizumab than with chemotherapy. One notable subcategory was fatigue, which showed significant improvement with pembrolizumab compared with a small worsening with chemotherapy.

[email protected]

On Twitter @mitchelzoler

VIENNA – Patients with metastatic non–small-cell lung cancer with high levels of PD-L1 who received first-line pembrolizumab treatment had clinically meaningful improvement in their quality of life, compared with patients randomized to chemotherapy, in a prespecified secondary analysis of data from the drug’s pivotal trial.

This boost in quality of life as well as other measures of health status add to the pivotal trial’s primary finding of significantly increased progression-free survival compared with chemotherapy, as well as previously-reported secondary findings of superior overall survival, objective response rate, and safety with pembrolizumab compared with chemotherapy (N Engl J Med. 2016 Nov 10;375[19]:1823-33), Julie R. Brahmer, MD, said at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

The primary endpoint of the Study of Pembrolizumab Compared to Platinum-Based Chemotherapies in Participants With Metastatic Non–Small Cell Lung Cancer (KEYNOTE-024) showed an average 4.3-month increase in progression-free survival with pembrolizumab immunotherapy, compared with a standard chemotherapy regimen.

Improved quality of life on top of improved efficacy and safety is an important added benefit from pembrolizumab that should further spur its widespread adoption as first-line treatment for approved patients, Dr. Brahmer said in a video interview.

“When you talk about improving efficacy by months, patients and physicians want to also see improved quality of life,” said Dr. Brahmer, director of thoracic oncology at the Johns Hopkins Kimmel Cancer Center in Baltimore. “If symptoms are not improved or there are a ton of side effects with the treatment then use might be low.”

Based on its performance in KEYNOTE-024, pembrolizumab (Keytruda) received Food and Drug Administration approval on Oct. 24, 2016, as first-line treatment for patients with metastatic non–small-cell lung cancer that has a tumor proportion score of at least 50% for programmed death ligand 1 (PD-L1). Pembrolizumab is a monoclonal antibody that binds and blocks PD-1, the immune-cell receptor that tumor-cell PD-L1 binds to make immune cells less active. Other new immune checkpoint inhibitor drugs that act by blocking PD-1 or PD-L1 have shown similar quality of life benefits, she noted.

Routine availability of pembrolizumab as initial treatment for patients who have tumors with this level of PD-L1 expression (and also have no EGFR or ALK genomic aberrations) is shifting practice, Dr. Brahmer said.

“It’s catching on. The limitation right now is making sure patients get tested” for their PD-L1 tumor proportion score at the time they are first diagnosed. “Medical oncologists need to educate pathologists that we need this testing automatically, upfront. It’s not there yet,” she said.

Patients also are enthused. “There is a lot of chemo-exhaustion among patients. They are looking for something different, and something that uses their immune system makes sense.” But only about one quarter of patients have tumors with this level of PD-L1 expression; the others must start chemotherapy first before trying immunotherapy, unless they have an EGFR mutation. Out-of-pocket cost for pembrolizumab is also a major issues for many patients, she said.

KEYNOTE-024 randomized 305 patients at 102 international sites and followed patients for a median of 11 months. Dr. Brahmer and her associates made two primary analyses of patient-reported outcomes. One was measurement of global health status at 15 weeks after the start of treatment using the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire designed to assess quality of life. Weighted averaging of the EORTC QCQ-C30 scores showed a mean improvement of 7.8 points (P = .002) in the pembrolizumab patients compared with the chemotherapy patients, a difference Dr. Brahmer called “clinically meaningful” as well as statistically significant.

A second analysis of patient-reported outcomes used a second EORTC instrument, the QLC-LC13, which combines assessment of cough, chest pain, and dyspnea. Treatment with pembrolizumab significantly reduced the time to deterioration as measured by this questionnaire by a relative 34%, (P = .029).

A third analysis looked at 15 individual function or symptom domains that make up the QLQ-C30. In general, these showed more improvements with pembrolizumab than with chemotherapy. One notable subcategory was fatigue, which showed significant improvement with pembrolizumab compared with a small worsening with chemotherapy.

[email protected]

On Twitter @mitchelzoler

Healing after rotator cuff repair (RCR) can be challenging, especially in cases of large and massive tears, revision repairs, and tendons with poor tissue quality.^1-3 Poor tissue quality is associated with increased risk for recurrent tears, independent of age and tear size.³ Various techniques have been used to improve tendon fixation strength in these difficult situations, including augmented suture configurations (eg, massive cuff stitches, rip-stop stitches) and tissue grafts (eg, acellular dermal matrix).^4-9 Clinical studies have found improved healing rates for larger tears and revision repairs using acellular dermal matrix grafts.^6,10 Synthetic patches are another option for RCR augmentation, but limited clinical data and biomechanical evidence support use of synthetic grafts as an augment for RCRs.^11-13

Polyhydroxyalkanoates (PHAs) are a class of biodegradable polymers that have been used as orthopedic devices, tissue scaffolds, patches, and other applications with increasing frequency over the past decade.¹⁴ In the laboratory, these implanted materials have been shown to support cell migration and growth.¹⁵ The PHA family of polymers typically degrades by hydrolytic and bacterial depolymerase mechanisms over 52-plus weeks in vivo.¹⁴PHA grafts have been studied in the setting of RCR. An expanded polytetrafluoroethylene scaffold was shown to improve repair mechanics when used as a bursal side graft in an in vitro ovine model.¹¹ The graft increased tendon footprint contact pressure and failure loads by almost 180 N. In clinical studies, poly-L-lactic acid augmentations have been used to reinforce massive RCRs. Lenart and colleagues¹⁶ found that 38% of 16 patients with such tears had an intact rotator cuff at 1.2-year follow-up, and improvement in clinical scores. Proctor¹³ reported on use of a poly-L-lactic acid retrograde patch for reinforcement of massive tears with both single- and double-row repairs in 18 patients. The cohort had more favorable rates of intact cuffs at 12 months (83%) and 42 months (78%), and ASES (American Shoulder and Elbow Surgeons) scores improved from 25 before surgery to 82 at latest follow-up after surgery.

RCR augmentation traditionally has been performed with an open or mini-open technique.⁶ Recently, several authors have reported on arthroscopic techniques for augmentation with either acellular dermal matrix or synthetic grafts.^13,17,18 Most techniques have involved “bridging” with a graft or patch used to stress-shield a single-row repair.^8,9,13 This bridging typically involves placing several sutures medial to where the anchor repair stitches pass through the tendon. An alternative is to pass the repair stitches through both the tendon and the graft.^17-19 The overall volume of tissue incorporated into the repair stitches (rotator cuff plus graft) is increased with the augmented technique relative to the bridging technique. Both can be technically challenging, but the augmented technique may be easier to perform arthroscopically.^9,19 Regardless, these techniques are complicated and require a higher level of arthroscopic skills compared with those required in arthroscopic RCR without a graft. Simplifying arthroscopic graft augmentation likely will increase its utility because, even for skilled surgeons, adding a graft can increase operative time by 20 to 30 minutes. Simplification will also extend use of the technique to surgeons with less experience and proficiency with arthroscopic repair.

We developed a simple method for augmenting single-row RCR with a strip of bioresorbable soft-tissue scaffold. We also conducted a study to evaluate the initial biomechanical properties of single-row RCR in cadaveric shoulder specimens augmented with PHA mesh (BioFiber; Tornier) graft as compared with single-row RCR without augmentation. Both cyclic gap formation and ultimate failure loads and displacement were quantified. We hypothesized that the augmented RCRs would have decreased gap formation and increased ultimate failure loads compared with nonaugmented RCRs. This study was exempt from having to obtain Institutional Review Board approval.

Methods

Eight pairs of fresh-frozen cadaver humeri (6 male, 2 female; mean [SD] age, 61 [9] years) were dissected of all soft tissue (except rotator cuff) by Dr. Tashjian, a board-certified, fellowship-trained orthopedic surgeon. There were no qualitative differences in tendon condition between tendons within a pair. The supraspinatus muscle and tendon were separated from the other rotator cuff muscles. The infraspinatus, subscapularis, and teres minor were removed from the humerus. Last, the supraspinatus was resected at its insertion. Humeral pairs were then randomized into augmented and nonaugmented RCRs within each pair.

In the nonaugmented group, the supraspinatus was reattached to its insertion in a single-row RCR with 2 triple-loaded suture anchors (5.5-mm Insite FT Ti, No. 2 Force Fiber suture; Tornier) and 6 simple stitches (Figure 1A). Anchors were placed midway between the articular margin and the lateral edge of the greater tuberosity at about 45° to the bone surface.

21

Statistical Analysis

Paired t tests were used to compare the matched pairs of constructs. For all tests, significance was set at P ≤ .05. Post hoc power was calculated for significant results using G*Power Version 3.1.6.²³ All data are presented as means (SDs).

Results

After 1000 cycles of displacement, mean (SD) gapping was 3.8 (0.9) mm for the nonaugmented repairs and 3.9 (1.1) mm for the PHA mesh–augmented repairs (P = .879) (Figure 4).

For the nonaugmented repairs, mean (SD) failure displacement was 6.3 (1.7) mm, and mean (SD) ultimate failure load was 472.1 (120.3) N. For the PHA-augmented repairs, failure displacement was 5.5 (1.9) mm, and ultimate failure load was 571.2 (173.0) N. There was no difference in failure displacement (P = .393), but there was a difference in ultimate failure load (P = .042; power = 0.57). During failure testing, mean (SD) tissue deformation was higher (P = .012; power = 0.83) for the PHA-augmented repairs, 1.2 (0.7) mm, than for the nonaugmented repairs, 0.8 (0.5) mm. Failures, which were consistent within pairs, were caused by tissue failure, with sutures pulling through the tissue (4 pairs) or single anchor pullout before ultimate tissue failure (4 pairs). Of the 4 failures with anchor pullout, 3 had anterior anchor pullout, and 1 had posterior anchor pullout. In all specimens with anchor pullout, the second anchor remained stable, and ultimate failure occurred with tissue tearing at the suture interface. There were no significant differences in any metrics between specimens that failed with intact anchors and specimens with single anchor pullout (P ≥ .122). Therefore, both groups were pooled for the failure analysis.

Discussion

RCR augmentation with a synthetic graft is a viable option for improving fixation strength of supraspinatus repairs, as shown in otherwise healthy tendon in the present study. Our hypothesis that there would be decreased gap formation with graft augmentation was not supported, whereas the hypothesis of increased failure loads with graft augmentation was supported. These findings may also be applicable in cases of large tears, revisions, and tendons with poor tissue quality. Simplification of graft application techniques will allow quick and easy arthroscopic augmentation.

Studies of RCRs for large or massive tears have reported retear rates of 25% to 79%.^24-26 Latissimus dorsi tendon transfers also show promise in posterosuperior RCRs, with failure rates near 10%.^27,28 Although use of PHA patches in RCR augmentation is relatively new, short-term and midterm failure rates are in the range of 20% to 60% in the few small cohorts currently being studied.^13,16 It is possible that these rates may improve as indications, surgical experience, and techniques for use of PHA patches are further refined. Regardless, with PHA currently being used in practice, it is important to quantify the biomechanics of the augmentation as a baseline for its performance in reinforcing the tendon–suture interface.

We determined that the initial fixation strength of single-row repairs was higher with the addition of PHA synthetic grafts using a very simple technique. Single-row triple-loaded anchor repairs already provide high initial mechanical strength, and our results are similar to those of another study of this technique.²⁹ Despite the already high mechanical strength of a triple-loaded anchor repair, PHA mesh increased ultimate strength by about 100 N (~25%). Of note, tissue elongation during failure was higher (P = .012; power = 0.83) in the PHA-augmented group (1.2 mm) than in the nonaugmented group (0.8 mm). This was not surprising—failure loads were almost 100 N higher in the PHA-augmented group than in the nonaugmented group. Consequently, much higher forces were placed on the muscle belly, likely resulting in additional elongation of the intact tissue medial to the repair construct.

The ultimate failure loads in our study compare favorably with the biomechanical strength of augmented repairs reported by others.^8,9,18 Barber and colleagues¹⁸ evaluated an augmented single-row repair with 2 double-loaded suture anchors and an acellular dermal matrix graft. The ultimate failure load of the augmented repairs was 325 N. In contrast, Omae and colleagues⁸ tested a bridging single-row repair using 2 double-loaded suture anchors and an acellular dermal matrix graft. Ultimate failure load of the augmented repairs was 560 N, similar to our finding. Last, Shea and colleagues⁹ evaluated a bridging single-row repair using 2 double-loaded suture anchors and an acellular dermal matrix graft, with ultimate failure load of 429 N. The techniques in all 3 studies can be performed arthroscopically but are challenging and require multiple extra sutures and anchors that need management and tying. Our technique provides similar initial fixation strength, has no requirement for extra sutures or anchors, and is very simple to perform.

The supraspinatus tendon is estimated to fail between 800 N and 1000 N.^30,31 Biomechanical shoulder simulators use supraspinatus forces in the range of 20 N to 200 N for scapular plane abduction.^32-36 Therefore, the single-row repair failures in our study fell between functional and full-thickness failure loads. Studies on the mechanics of degenerated human supraspinatus tendon are limited, but there is evidence the mechanical properties of these tissues are inferior to those of healthy tendon.³⁷ A 100-N increase in failure loads with PHA augmentation may prove highly significant in reinforcing the suture–tendon interface in degenerated tendons.

Adding the mesh did not have any effect on gapping at the repair site after cyclic loading. This finding suggests that construct gapping under cyclic loading is not a function of a reinforced knot–tendon interface but is instead caused by microtearing and cinching of the suture constructs in relation to the underlying bone. Tissue elongation likely was not a strong contributor to overall cyclic gapping, as elongation did not differ between the nonaugmented and augmented repairs (0.5 mm vs 0.7 mm; P = .276) and was small relative to the nearly 4 mm of construct gapping. Gapping may be affected by healing and integration of the mesh into the repaired tendon over time, but this effect could not be captured in the present study. Patients are initially immobilized and passive shoulder motion gradually introduced, in stark contrast to the immediate loading protocol in the present study. Regardless, the 25% increase in overall strength may be clinically important, especially in cases of difficult repair or poor tissue quality.

Our technique simplifies arthroscopic augmentation—stitches are passed through the rotator cuff in simple fashion. Before being tied, the limbs that were passed through the rotator cuff are removed through a cannula and then passed through the synthetic graft.

Study Limitations

This study had several limitations. First, it was a cadaveric biomechanical study that evaluated only time-zero biomechanical properties. Loads were normalized to tendon size, specimens were randomized between sides, and paired specimens were used to minimize the effects of tendon and bone quality on outcome metrics. In addition, donor tendons were representative of otherwise healthy tissue. Chronic tears and associated resorption/atrophy could have affected the magnitude of forces and gapping detected in this study. Theoretically, over time the tendon tissue will adhere to and grow into the mesh, which could minimize potential differences. Studies are needed to determine the effects of healing on long-term repair strength in affected patients. Last, all constructs were performed in open fashion to improve repeatability of construct placement and provide accessibility for Instron testing. Our technique did not directly replicate the arthroscopic approach, but, unlike other augmentation techniques, it is so simple that transition to all-arthroscopic augmentation is realistic.

Patch augmentation increases the cost of materials and operative time and should be considered a limitation of its utility. We do not recommend augmentation in all RCRs, as it likely is cost-ineffective. Instead, we recommend augmentation in cases of poor tissue quality, which could lead to healing failure, revision surgery, and higher overall patient costs beyond the cost of adding augmentation. Similarly, we recommend augmentation for revision cases in which tendon healing has failed and tissue quality is poor. The goal is to prevent another failure.

Conclusion

PHA graft augmentation of single-row triple-loaded anchor repairs of the supraspinatus tendon improves the overall ultimate load to failure by 25%. There was no difference in gap formation after cyclic loading between augmented and nonaugmented repairs. This technique for arthroscopic augmentation can be used to improve initial biomechanical repair strength in tears at risk for failure.

Am J Orthop. 2016;45(7):E527-E533. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Healing after rotator cuff repair (RCR) can be challenging, especially in cases of large and massive tears, revision repairs, and tendons with poor tissue quality.^1-3 Poor tissue quality is associated with increased risk for recurrent tears, independent of age and tear size.³ Various techniques have been used to improve tendon fixation strength in these difficult situations, including augmented suture configurations (eg, massive cuff stitches, rip-stop stitches) and tissue grafts (eg, acellular dermal matrix).^4-9 Clinical studies have found improved healing rates for larger tears and revision repairs using acellular dermal matrix grafts.^6,10 Synthetic patches are another option for RCR augmentation, but limited clinical data and biomechanical evidence support use of synthetic grafts as an augment for RCRs.^11-13

Polyhydroxyalkanoates (PHAs) are a class of biodegradable polymers that have been used as orthopedic devices, tissue scaffolds, patches, and other applications with increasing frequency over the past decade.¹⁴ In the laboratory, these implanted materials have been shown to support cell migration and growth.¹⁵ The PHA family of polymers typically degrades by hydrolytic and bacterial depolymerase mechanisms over 52-plus weeks in vivo.¹⁴PHA grafts have been studied in the setting of RCR. An expanded polytetrafluoroethylene scaffold was shown to improve repair mechanics when used as a bursal side graft in an in vitro ovine model.¹¹ The graft increased tendon footprint contact pressure and failure loads by almost 180 N. In clinical studies, poly-L-lactic acid augmentations have been used to reinforce massive RCRs. Lenart and colleagues¹⁶ found that 38% of 16 patients with such tears had an intact rotator cuff at 1.2-year follow-up, and improvement in clinical scores. Proctor¹³ reported on use of a poly-L-lactic acid retrograde patch for reinforcement of massive tears with both single- and double-row repairs in 18 patients. The cohort had more favorable rates of intact cuffs at 12 months (83%) and 42 months (78%), and ASES (American Shoulder and Elbow Surgeons) scores improved from 25 before surgery to 82 at latest follow-up after surgery.

RCR augmentation traditionally has been performed with an open or mini-open technique.⁶ Recently, several authors have reported on arthroscopic techniques for augmentation with either acellular dermal matrix or synthetic grafts.^13,17,18 Most techniques have involved “bridging” with a graft or patch used to stress-shield a single-row repair.^8,9,13 This bridging typically involves placing several sutures medial to where the anchor repair stitches pass through the tendon. An alternative is to pass the repair stitches through both the tendon and the graft.^17-19 The overall volume of tissue incorporated into the repair stitches (rotator cuff plus graft) is increased with the augmented technique relative to the bridging technique. Both can be technically challenging, but the augmented technique may be easier to perform arthroscopically.^9,19 Regardless, these techniques are complicated and require a higher level of arthroscopic skills compared with those required in arthroscopic RCR without a graft. Simplifying arthroscopic graft augmentation likely will increase its utility because, even for skilled surgeons, adding a graft can increase operative time by 20 to 30 minutes. Simplification will also extend use of the technique to surgeons with less experience and proficiency with arthroscopic repair.

We developed a simple method for augmenting single-row RCR with a strip of bioresorbable soft-tissue scaffold. We also conducted a study to evaluate the initial biomechanical properties of single-row RCR in cadaveric shoulder specimens augmented with PHA mesh (BioFiber; Tornier) graft as compared with single-row RCR without augmentation. Both cyclic gap formation and ultimate failure loads and displacement were quantified. We hypothesized that the augmented RCRs would have decreased gap formation and increased ultimate failure loads compared with nonaugmented RCRs. This study was exempt from having to obtain Institutional Review Board approval.

Methods

Eight pairs of fresh-frozen cadaver humeri (6 male, 2 female; mean [SD] age, 61 [9] years) were dissected of all soft tissue (except rotator cuff) by Dr. Tashjian, a board-certified, fellowship-trained orthopedic surgeon. There were no qualitative differences in tendon condition between tendons within a pair. The supraspinatus muscle and tendon were separated from the other rotator cuff muscles. The infraspinatus, subscapularis, and teres minor were removed from the humerus. Last, the supraspinatus was resected at its insertion. Humeral pairs were then randomized into augmented and nonaugmented RCRs within each pair.

In the nonaugmented group, the supraspinatus was reattached to its insertion in a single-row RCR with 2 triple-loaded suture anchors (5.5-mm Insite FT Ti, No. 2 Force Fiber suture; Tornier) and 6 simple stitches (Figure 1A). Anchors were placed midway between the articular margin and the lateral edge of the greater tuberosity at about 45° to the bone surface.

21

Statistical Analysis

Paired t tests were used to compare the matched pairs of constructs. For all tests, significance was set at P ≤ .05. Post hoc power was calculated for significant results using G*Power Version 3.1.6.²³ All data are presented as means (SDs).

Results

After 1000 cycles of displacement, mean (SD) gapping was 3.8 (0.9) mm for the nonaugmented repairs and 3.9 (1.1) mm for the PHA mesh–augmented repairs (P = .879) (Figure 4).

For the nonaugmented repairs, mean (SD) failure displacement was 6.3 (1.7) mm, and mean (SD) ultimate failure load was 472.1 (120.3) N. For the PHA-augmented repairs, failure displacement was 5.5 (1.9) mm, and ultimate failure load was 571.2 (173.0) N. There was no difference in failure displacement (P = .393), but there was a difference in ultimate failure load (P = .042; power = 0.57). During failure testing, mean (SD) tissue deformation was higher (P = .012; power = 0.83) for the PHA-augmented repairs, 1.2 (0.7) mm, than for the nonaugmented repairs, 0.8 (0.5) mm. Failures, which were consistent within pairs, were caused by tissue failure, with sutures pulling through the tissue (4 pairs) or single anchor pullout before ultimate tissue failure (4 pairs). Of the 4 failures with anchor pullout, 3 had anterior anchor pullout, and 1 had posterior anchor pullout. In all specimens with anchor pullout, the second anchor remained stable, and ultimate failure occurred with tissue tearing at the suture interface. There were no significant differences in any metrics between specimens that failed with intact anchors and specimens with single anchor pullout (P ≥ .122). Therefore, both groups were pooled for the failure analysis.

Discussion

RCR augmentation with a synthetic graft is a viable option for improving fixation strength of supraspinatus repairs, as shown in otherwise healthy tendon in the present study. Our hypothesis that there would be decreased gap formation with graft augmentation was not supported, whereas the hypothesis of increased failure loads with graft augmentation was supported. These findings may also be applicable in cases of large tears, revisions, and tendons with poor tissue quality. Simplification of graft application techniques will allow quick and easy arthroscopic augmentation.

Studies of RCRs for large or massive tears have reported retear rates of 25% to 79%.^24-26 Latissimus dorsi tendon transfers also show promise in posterosuperior RCRs, with failure rates near 10%.^27,28 Although use of PHA patches in RCR augmentation is relatively new, short-term and midterm failure rates are in the range of 20% to 60% in the few small cohorts currently being studied.^13,16 It is possible that these rates may improve as indications, surgical experience, and techniques for use of PHA patches are further refined. Regardless, with PHA currently being used in practice, it is important to quantify the biomechanics of the augmentation as a baseline for its performance in reinforcing the tendon–suture interface.

We determined that the initial fixation strength of single-row repairs was higher with the addition of PHA synthetic grafts using a very simple technique. Single-row triple-loaded anchor repairs already provide high initial mechanical strength, and our results are similar to those of another study of this technique.²⁹ Despite the already high mechanical strength of a triple-loaded anchor repair, PHA mesh increased ultimate strength by about 100 N (~25%). Of note, tissue elongation during failure was higher (P = .012; power = 0.83) in the PHA-augmented group (1.2 mm) than in the nonaugmented group (0.8 mm). This was not surprising—failure loads were almost 100 N higher in the PHA-augmented group than in the nonaugmented group. Consequently, much higher forces were placed on the muscle belly, likely resulting in additional elongation of the intact tissue medial to the repair construct.

The ultimate failure loads in our study compare favorably with the biomechanical strength of augmented repairs reported by others.^8,9,18 Barber and colleagues¹⁸ evaluated an augmented single-row repair with 2 double-loaded suture anchors and an acellular dermal matrix graft. The ultimate failure load of the augmented repairs was 325 N. In contrast, Omae and colleagues⁸ tested a bridging single-row repair using 2 double-loaded suture anchors and an acellular dermal matrix graft. Ultimate failure load of the augmented repairs was 560 N, similar to our finding. Last, Shea and colleagues⁹ evaluated a bridging single-row repair using 2 double-loaded suture anchors and an acellular dermal matrix graft, with ultimate failure load of 429 N. The techniques in all 3 studies can be performed arthroscopically but are challenging and require multiple extra sutures and anchors that need management and tying. Our technique provides similar initial fixation strength, has no requirement for extra sutures or anchors, and is very simple to perform.

The supraspinatus tendon is estimated to fail between 800 N and 1000 N.^30,31 Biomechanical shoulder simulators use supraspinatus forces in the range of 20 N to 200 N for scapular plane abduction.^32-36 Therefore, the single-row repair failures in our study fell between functional and full-thickness failure loads. Studies on the mechanics of degenerated human supraspinatus tendon are limited, but there is evidence the mechanical properties of these tissues are inferior to those of healthy tendon.³⁷ A 100-N increase in failure loads with PHA augmentation may prove highly significant in reinforcing the suture–tendon interface in degenerated tendons.

Adding the mesh did not have any effect on gapping at the repair site after cyclic loading. This finding suggests that construct gapping under cyclic loading is not a function of a reinforced knot–tendon interface but is instead caused by microtearing and cinching of the suture constructs in relation to the underlying bone. Tissue elongation likely was not a strong contributor to overall cyclic gapping, as elongation did not differ between the nonaugmented and augmented repairs (0.5 mm vs 0.7 mm; P = .276) and was small relative to the nearly 4 mm of construct gapping. Gapping may be affected by healing and integration of the mesh into the repaired tendon over time, but this effect could not be captured in the present study. Patients are initially immobilized and passive shoulder motion gradually introduced, in stark contrast to the immediate loading protocol in the present study. Regardless, the 25% increase in overall strength may be clinically important, especially in cases of difficult repair or poor tissue quality.

Our technique simplifies arthroscopic augmentation—stitches are passed through the rotator cuff in simple fashion. Before being tied, the limbs that were passed through the rotator cuff are removed through a cannula and then passed through the synthetic graft.

Study Limitations

This study had several limitations. First, it was a cadaveric biomechanical study that evaluated only time-zero biomechanical properties. Loads were normalized to tendon size, specimens were randomized between sides, and paired specimens were used to minimize the effects of tendon and bone quality on outcome metrics. In addition, donor tendons were representative of otherwise healthy tissue. Chronic tears and associated resorption/atrophy could have affected the magnitude of forces and gapping detected in this study. Theoretically, over time the tendon tissue will adhere to and grow into the mesh, which could minimize potential differences. Studies are needed to determine the effects of healing on long-term repair strength in affected patients. Last, all constructs were performed in open fashion to improve repeatability of construct placement and provide accessibility for Instron testing. Our technique did not directly replicate the arthroscopic approach, but, unlike other augmentation techniques, it is so simple that transition to all-arthroscopic augmentation is realistic.

Patch augmentation increases the cost of materials and operative time and should be considered a limitation of its utility. We do not recommend augmentation in all RCRs, as it likely is cost-ineffective. Instead, we recommend augmentation in cases of poor tissue quality, which could lead to healing failure, revision surgery, and higher overall patient costs beyond the cost of adding augmentation. Similarly, we recommend augmentation for revision cases in which tendon healing has failed and tissue quality is poor. The goal is to prevent another failure.

Conclusion

PHA graft augmentation of single-row triple-loaded anchor repairs of the supraspinatus tendon improves the overall ultimate load to failure by 25%. There was no difference in gap formation after cyclic loading between augmented and nonaugmented repairs. This technique for arthroscopic augmentation can be used to improve initial biomechanical repair strength in tears at risk for failure.

Am J Orthop. 2016;45(7):E527-E533. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Healing after rotator cuff repair (RCR) can be challenging, especially in cases of large and massive tears, revision repairs, and tendons with poor tissue quality.^1-3 Poor tissue quality is associated with increased risk for recurrent tears, independent of age and tear size.³ Various techniques have been used to improve tendon fixation strength in these difficult situations, including augmented suture configurations (eg, massive cuff stitches, rip-stop stitches) and tissue grafts (eg, acellular dermal matrix).^4-9 Clinical studies have found improved healing rates for larger tears and revision repairs using acellular dermal matrix grafts.^6,10 Synthetic patches are another option for RCR augmentation, but limited clinical data and biomechanical evidence support use of synthetic grafts as an augment for RCRs.^11-13

Polyhydroxyalkanoates (PHAs) are a class of biodegradable polymers that have been used as orthopedic devices, tissue scaffolds, patches, and other applications with increasing frequency over the past decade.¹⁴ In the laboratory, these implanted materials have been shown to support cell migration and growth.¹⁵ The PHA family of polymers typically degrades by hydrolytic and bacterial depolymerase mechanisms over 52-plus weeks in vivo.¹⁴PHA grafts have been studied in the setting of RCR. An expanded polytetrafluoroethylene scaffold was shown to improve repair mechanics when used as a bursal side graft in an in vitro ovine model.¹¹ The graft increased tendon footprint contact pressure and failure loads by almost 180 N. In clinical studies, poly-L-lactic acid augmentations have been used to reinforce massive RCRs. Lenart and colleagues¹⁶ found that 38% of 16 patients with such tears had an intact rotator cuff at 1.2-year follow-up, and improvement in clinical scores. Proctor¹³ reported on use of a poly-L-lactic acid retrograde patch for reinforcement of massive tears with both single- and double-row repairs in 18 patients. The cohort had more favorable rates of intact cuffs at 12 months (83%) and 42 months (78%), and ASES (American Shoulder and Elbow Surgeons) scores improved from 25 before surgery to 82 at latest follow-up after surgery.

RCR augmentation traditionally has been performed with an open or mini-open technique.⁶ Recently, several authors have reported on arthroscopic techniques for augmentation with either acellular dermal matrix or synthetic grafts.^13,17,18 Most techniques have involved “bridging” with a graft or patch used to stress-shield a single-row repair.^8,9,13 This bridging typically involves placing several sutures medial to where the anchor repair stitches pass through the tendon. An alternative is to pass the repair stitches through both the tendon and the graft.^17-19 The overall volume of tissue incorporated into the repair stitches (rotator cuff plus graft) is increased with the augmented technique relative to the bridging technique. Both can be technically challenging, but the augmented technique may be easier to perform arthroscopically.^9,19 Regardless, these techniques are complicated and require a higher level of arthroscopic skills compared with those required in arthroscopic RCR without a graft. Simplifying arthroscopic graft augmentation likely will increase its utility because, even for skilled surgeons, adding a graft can increase operative time by 20 to 30 minutes. Simplification will also extend use of the technique to surgeons with less experience and proficiency with arthroscopic repair.

We developed a simple method for augmenting single-row RCR with a strip of bioresorbable soft-tissue scaffold. We also conducted a study to evaluate the initial biomechanical properties of single-row RCR in cadaveric shoulder specimens augmented with PHA mesh (BioFiber; Tornier) graft as compared with single-row RCR without augmentation. Both cyclic gap formation and ultimate failure loads and displacement were quantified. We hypothesized that the augmented RCRs would have decreased gap formation and increased ultimate failure loads compared with nonaugmented RCRs. This study was exempt from having to obtain Institutional Review Board approval.

Methods

Eight pairs of fresh-frozen cadaver humeri (6 male, 2 female; mean [SD] age, 61 [9] years) were dissected of all soft tissue (except rotator cuff) by Dr. Tashjian, a board-certified, fellowship-trained orthopedic surgeon. There were no qualitative differences in tendon condition between tendons within a pair. The supraspinatus muscle and tendon were separated from the other rotator cuff muscles. The infraspinatus, subscapularis, and teres minor were removed from the humerus. Last, the supraspinatus was resected at its insertion. Humeral pairs were then randomized into augmented and nonaugmented RCRs within each pair.

In the nonaugmented group, the supraspinatus was reattached to its insertion in a single-row RCR with 2 triple-loaded suture anchors (5.5-mm Insite FT Ti, No. 2 Force Fiber suture; Tornier) and 6 simple stitches (Figure 1A). Anchors were placed midway between the articular margin and the lateral edge of the greater tuberosity at about 45° to the bone surface.

21

Statistical Analysis

Paired t tests were used to compare the matched pairs of constructs. For all tests, significance was set at P ≤ .05. Post hoc power was calculated for significant results using G*Power Version 3.1.6.²³ All data are presented as means (SDs).

Results

After 1000 cycles of displacement, mean (SD) gapping was 3.8 (0.9) mm for the nonaugmented repairs and 3.9 (1.1) mm for the PHA mesh–augmented repairs (P = .879) (Figure 4).

For the nonaugmented repairs, mean (SD) failure displacement was 6.3 (1.7) mm, and mean (SD) ultimate failure load was 472.1 (120.3) N. For the PHA-augmented repairs, failure displacement was 5.5 (1.9) mm, and ultimate failure load was 571.2 (173.0) N. There was no difference in failure displacement (P = .393), but there was a difference in ultimate failure load (P = .042; power = 0.57). During failure testing, mean (SD) tissue deformation was higher (P = .012; power = 0.83) for the PHA-augmented repairs, 1.2 (0.7) mm, than for the nonaugmented repairs, 0.8 (0.5) mm. Failures, which were consistent within pairs, were caused by tissue failure, with sutures pulling through the tissue (4 pairs) or single anchor pullout before ultimate tissue failure (4 pairs). Of the 4 failures with anchor pullout, 3 had anterior anchor pullout, and 1 had posterior anchor pullout. In all specimens with anchor pullout, the second anchor remained stable, and ultimate failure occurred with tissue tearing at the suture interface. There were no significant differences in any metrics between specimens that failed with intact anchors and specimens with single anchor pullout (P ≥ .122). Therefore, both groups were pooled for the failure analysis.

Discussion

RCR augmentation with a synthetic graft is a viable option for improving fixation strength of supraspinatus repairs, as shown in otherwise healthy tendon in the present study. Our hypothesis that there would be decreased gap formation with graft augmentation was not supported, whereas the hypothesis of increased failure loads with graft augmentation was supported. These findings may also be applicable in cases of large tears, revisions, and tendons with poor tissue quality. Simplification of graft application techniques will allow quick and easy arthroscopic augmentation.

Studies of RCRs for large or massive tears have reported retear rates of 25% to 79%.^24-26 Latissimus dorsi tendon transfers also show promise in posterosuperior RCRs, with failure rates near 10%.^27,28 Although use of PHA patches in RCR augmentation is relatively new, short-term and midterm failure rates are in the range of 20% to 60% in the few small cohorts currently being studied.^13,16 It is possible that these rates may improve as indications, surgical experience, and techniques for use of PHA patches are further refined. Regardless, with PHA currently being used in practice, it is important to quantify the biomechanics of the augmentation as a baseline for its performance in reinforcing the tendon–suture interface.

We determined that the initial fixation strength of single-row repairs was higher with the addition of PHA synthetic grafts using a very simple technique. Single-row triple-loaded anchor repairs already provide high initial mechanical strength, and our results are similar to those of another study of this technique.²⁹ Despite the already high mechanical strength of a triple-loaded anchor repair, PHA mesh increased ultimate strength by about 100 N (~25%). Of note, tissue elongation during failure was higher (P = .012; power = 0.83) in the PHA-augmented group (1.2 mm) than in the nonaugmented group (0.8 mm). This was not surprising—failure loads were almost 100 N higher in the PHA-augmented group than in the nonaugmented group. Consequently, much higher forces were placed on the muscle belly, likely resulting in additional elongation of the intact tissue medial to the repair construct.

The ultimate failure loads in our study compare favorably with the biomechanical strength of augmented repairs reported by others.^8,9,18 Barber and colleagues¹⁸ evaluated an augmented single-row repair with 2 double-loaded suture anchors and an acellular dermal matrix graft. The ultimate failure load of the augmented repairs was 325 N. In contrast, Omae and colleagues⁸ tested a bridging single-row repair using 2 double-loaded suture anchors and an acellular dermal matrix graft. Ultimate failure load of the augmented repairs was 560 N, similar to our finding. Last, Shea and colleagues⁹ evaluated a bridging single-row repair using 2 double-loaded suture anchors and an acellular dermal matrix graft, with ultimate failure load of 429 N. The techniques in all 3 studies can be performed arthroscopically but are challenging and require multiple extra sutures and anchors that need management and tying. Our technique provides similar initial fixation strength, has no requirement for extra sutures or anchors, and is very simple to perform.

The supraspinatus tendon is estimated to fail between 800 N and 1000 N.^30,31 Biomechanical shoulder simulators use supraspinatus forces in the range of 20 N to 200 N for scapular plane abduction.^32-36 Therefore, the single-row repair failures in our study fell between functional and full-thickness failure loads. Studies on the mechanics of degenerated human supraspinatus tendon are limited, but there is evidence the mechanical properties of these tissues are inferior to those of healthy tendon.³⁷ A 100-N increase in failure loads with PHA augmentation may prove highly significant in reinforcing the suture–tendon interface in degenerated tendons.

Adding the mesh did not have any effect on gapping at the repair site after cyclic loading. This finding suggests that construct gapping under cyclic loading is not a function of a reinforced knot–tendon interface but is instead caused by microtearing and cinching of the suture constructs in relation to the underlying bone. Tissue elongation likely was not a strong contributor to overall cyclic gapping, as elongation did not differ between the nonaugmented and augmented repairs (0.5 mm vs 0.7 mm; P = .276) and was small relative to the nearly 4 mm of construct gapping. Gapping may be affected by healing and integration of the mesh into the repaired tendon over time, but this effect could not be captured in the present study. Patients are initially immobilized and passive shoulder motion gradually introduced, in stark contrast to the immediate loading protocol in the present study. Regardless, the 25% increase in overall strength may be clinically important, especially in cases of difficult repair or poor tissue quality.

Our technique simplifies arthroscopic augmentation—stitches are passed through the rotator cuff in simple fashion. Before being tied, the limbs that were passed through the rotator cuff are removed through a cannula and then passed through the synthetic graft.

Study Limitations

This study had several limitations. First, it was a cadaveric biomechanical study that evaluated only time-zero biomechanical properties. Loads were normalized to tendon size, specimens were randomized between sides, and paired specimens were used to minimize the effects of tendon and bone quality on outcome metrics. In addition, donor tendons were representative of otherwise healthy tissue. Chronic tears and associated resorption/atrophy could have affected the magnitude of forces and gapping detected in this study. Theoretically, over time the tendon tissue will adhere to and grow into the mesh, which could minimize potential differences. Studies are needed to determine the effects of healing on long-term repair strength in affected patients. Last, all constructs were performed in open fashion to improve repeatability of construct placement and provide accessibility for Instron testing. Our technique did not directly replicate the arthroscopic approach, but, unlike other augmentation techniques, it is so simple that transition to all-arthroscopic augmentation is realistic.

Patch augmentation increases the cost of materials and operative time and should be considered a limitation of its utility. We do not recommend augmentation in all RCRs, as it likely is cost-ineffective. Instead, we recommend augmentation in cases of poor tissue quality, which could lead to healing failure, revision surgery, and higher overall patient costs beyond the cost of adding augmentation. Similarly, we recommend augmentation for revision cases in which tendon healing has failed and tissue quality is poor. The goal is to prevent another failure.

Conclusion

PHA graft augmentation of single-row triple-loaded anchor repairs of the supraspinatus tendon improves the overall ultimate load to failure by 25%. There was no difference in gap formation after cyclic loading between augmented and nonaugmented repairs. This technique for arthroscopic augmentation can be used to improve initial biomechanical repair strength in tears at risk for failure.

Am J Orthop. 2016;45(7):E527-E533. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Follow-up telephone calls can significantly improve the collection of long-term patient-reported outcomes following ventral hernia repair, according to a study published online in the Oct. 20 edition of the Journal of the American College of Surgeons.

Nishant Ganesh Kumar, a medical student, and his colleagues at Vanderbilt University, Nashville, Tenn., wrote that while ventral hernia repair is one of the most common surgical procedures in the world, reliable long-term, prospective data on outcomes has been extremely difficult to collect.

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Follow-up telephone calls can significantly improve the collection of long-term patient-reported outcomes following ventral hernia repair, according to a study published online in the Oct. 20 edition of the Journal of the American College of Surgeons.

Nishant Ganesh Kumar, a medical student, and his colleagues at Vanderbilt University, Nashville, Tenn., wrote that while ventral hernia repair is one of the most common surgical procedures in the world, reliable long-term, prospective data on outcomes has been extremely difficult to collect.

copyright Dron - Fotolia.com

Follow-up telephone calls can significantly improve the collection of long-term patient-reported outcomes following ventral hernia repair, according to a study published online in the Oct. 20 edition of the Journal of the American College of Surgeons.

Nishant Ganesh Kumar, a medical student, and his colleagues at Vanderbilt University, Nashville, Tenn., wrote that while ventral hernia repair is one of the most common surgical procedures in the world, reliable long-term, prospective data on outcomes has been extremely difficult to collect.

copyright Dron - Fotolia.com

SAN DIEGO – Lenalidomide, a mainstay of maintenance therapy for multiple myeloma, is now making inroads into maintenance therapy following first- and second-line therapy for chronic lymphocytic leukemia (CLL), investigators reported in two phase III studies.

Among patients with previously untreated CLL who were at high risk for early disease progression following standard chemotherapy, lenalidomide (Revlimid) maintenance therapy was associated with an 80% reduction in the relative risk for disease progression compared with placebo, reported Anna Fink, MD, of the University of Cologne, Germany, and her colleagues in the German CLL Study Group.

Similarly, lenalidomide maintenance significantly improved progression-free survival (PFS) compared with placebo among patients with CLL who had at least partial responses to second-line therapy, reported Anna Schuh, MD, of the University of Oxford, England, and her colleagues in the CONTINUUM trial.

“Lenalidomide maintenance therapy significantly improved progression-free survival, from just about 9 months to almost 40 months when given to patients with CLL who responded to second-line therapy,” Dr. Schuh said at the American Society of Hematology annual meeting.

Both studies were unblinded because of the superiority of lenalidomide after prespecified analyses, on the recommendation of the respective data safety monitoring boards (DSMBs).

The PFS advantage with lenalidomide seen in each study did not translate into differences in overall survival in either study, however.
 

Maintenance after first-line therapy

In the CLLM1 trial, Dr. Fink and her colleagues enrolled physically fit, previously untreated patients with CLL and delivered chemoimmunotherapy at the investigator’s choice: either FCR (fludarabine, cyclophosphamide, and rituximab), FR (fludarabine and rituximab), FC (fludarabine and cyclophosphamide), or BR (bendamustine and rituximab).

Patients who had at least a partial response after a minimum of four cycles were identified as being at high risk for progression if they had minimal residual disease (MRD) levels of at least 10^-2 cells, or MRD levels from 10^-4 to less than 10^-2 combined with either an unmutated IGHV gene status, del(17p) or TP53 mutation at baseline.

Of 468 screened patients, 89 were deemed to have high risk disease, and these patients were randomly assigned on a 2:1 basis to maintenance with lenalidomide given 5 mg orally for the first cycle and escalated to a target dose of 15 mg by the seventh cycle, or to placebo.

Additional dose escalations could be performed based on MRD assessments every 6 months, with the drug continued until progression or unacceptable toxicity. Patients also were assigned to daily low-dose aspirin or to an anticoagulation agent depending on their individual risk for thromboembolic events.

The study was stopped and unblinded after a planned interim analysis showed that the difference in PFS met the stopping boundary for efficacy.

Ultimately, 56 patients assigned to lenalidomide received study treatment, as did 29 assigned to placebo.

At a median follow-up of 17.5 months, the median PFS according to independent review was not reached for lenalidomide, vs. 13.3 months for placebo. Lenalidomide was associated with a hazard ratio (HR) for progression of 0.148 (P less than .00001), and a relative risk reduction of 80%.

Lenalidomide was also significantly better for PFS in analysis by MRD at baseline, with a PFS of 19.4 months for placebo vs. not reached among patients with less than 10^-2 but more than 10^-4 cells (HR, 0.125) and 3.7 vs. 32.3 months, respectively, for patients with MRD greater than 10^-2 (HR 0.165).

There were three deaths (two in patients on placebo), and at the last analysis there was no difference in overall survival. In all, 42.9% of patients on lenalidomide discontinued because of adverse events, compared with 72.4% of those on placebo.
 

Maintenance after second-line therapy

In CONTINUUM, patients with at least a partial response after two prior lines of therapy and an Eastern Cooperative Oncology Group performance score of 0-2 were enrolled and randomized to receive either lenalidomide (160 patients) at a starting dose of 2.5 mg/day for the first 28-day cycle, 5 mg/day from cycle 2, and, if well tolerated, up to 10 mg/day from cycle 7 on, or to placebo (154 patients).

This study, as noted before, was also unblinded at the time of the primary analysis as recommended by the DSMB, after a prespecified number of events had occurred.

At a median follow-up of 31.5 months, the median PFS, a co-primary endpoint with OS, was 33.9 months in the lenalidomide arm, compared with 9.2 months in the placebo arm, translating into a HR for lenalidomide of 0.40 (P less than .001).

The lenalidomide advantage also was seen in a subgroup analysis by age, prior response to chemotherapy, and number of factors for poor prognosis. Of note, among patients older than age 70, the PFS with lenalidomide was 52.5 months, compared with 7.3 months for placebo (HR 0.34, P = .005).

In a second PFS analysis conducted after 71 months of follow-up, lenalidomide remained superior, with a median PFS of 57.5 months vs. 32.7 months in the placebo arm. As noted, there was no difference in overall survival in this study.

Grade 3 or greater adverse events occurring more frequently with lenalidomide were neutropenia, thrombocytopenia, diarrhea, pneumonia, fatigue, hypokalemia, pulmonary embolism, and sepsis. There was no difference in the incidence of second primary malignancies, however.

CLLM1 was sponsored by the German CLL Study Group with support from Celgene. CONTINUUM was supported by Celgene. Dr. Fink disclosed research funding from the company, and travel grants and honoraria from others. Dr. Schuh disclosed honoraria from and consulting with Celgene and other companies.

[email protected]

SAN DIEGO – Lenalidomide, a mainstay of maintenance therapy for multiple myeloma, is now making inroads into maintenance therapy following first- and second-line therapy for chronic lymphocytic leukemia (CLL), investigators reported in two phase III studies.

Among patients with previously untreated CLL who were at high risk for early disease progression following standard chemotherapy, lenalidomide (Revlimid) maintenance therapy was associated with an 80% reduction in the relative risk for disease progression compared with placebo, reported Anna Fink, MD, of the University of Cologne, Germany, and her colleagues in the German CLL Study Group.

Similarly, lenalidomide maintenance significantly improved progression-free survival (PFS) compared with placebo among patients with CLL who had at least partial responses to second-line therapy, reported Anna Schuh, MD, of the University of Oxford, England, and her colleagues in the CONTINUUM trial.

“Lenalidomide maintenance therapy significantly improved progression-free survival, from just about 9 months to almost 40 months when given to patients with CLL who responded to second-line therapy,” Dr. Schuh said at the American Society of Hematology annual meeting.

Both studies were unblinded because of the superiority of lenalidomide after prespecified analyses, on the recommendation of the respective data safety monitoring boards (DSMBs).

The PFS advantage with lenalidomide seen in each study did not translate into differences in overall survival in either study, however.
 

Maintenance after first-line therapy

In the CLLM1 trial, Dr. Fink and her colleagues enrolled physically fit, previously untreated patients with CLL and delivered chemoimmunotherapy at the investigator’s choice: either FCR (fludarabine, cyclophosphamide, and rituximab), FR (fludarabine and rituximab), FC (fludarabine and cyclophosphamide), or BR (bendamustine and rituximab).

Patients who had at least a partial response after a minimum of four cycles were identified as being at high risk for progression if they had minimal residual disease (MRD) levels of at least 10^-2 cells, or MRD levels from 10^-4 to less than 10^-2 combined with either an unmutated IGHV gene status, del(17p) or TP53 mutation at baseline.

Of 468 screened patients, 89 were deemed to have high risk disease, and these patients were randomly assigned on a 2:1 basis to maintenance with lenalidomide given 5 mg orally for the first cycle and escalated to a target dose of 15 mg by the seventh cycle, or to placebo.

Additional dose escalations could be performed based on MRD assessments every 6 months, with the drug continued until progression or unacceptable toxicity. Patients also were assigned to daily low-dose aspirin or to an anticoagulation agent depending on their individual risk for thromboembolic events.

The study was stopped and unblinded after a planned interim analysis showed that the difference in PFS met the stopping boundary for efficacy.

Ultimately, 56 patients assigned to lenalidomide received study treatment, as did 29 assigned to placebo.

At a median follow-up of 17.5 months, the median PFS according to independent review was not reached for lenalidomide, vs. 13.3 months for placebo. Lenalidomide was associated with a hazard ratio (HR) for progression of 0.148 (P less than .00001), and a relative risk reduction of 80%.

Lenalidomide was also significantly better for PFS in analysis by MRD at baseline, with a PFS of 19.4 months for placebo vs. not reached among patients with less than 10^-2 but more than 10^-4 cells (HR, 0.125) and 3.7 vs. 32.3 months, respectively, for patients with MRD greater than 10^-2 (HR 0.165).

There were three deaths (two in patients on placebo), and at the last analysis there was no difference in overall survival. In all, 42.9% of patients on lenalidomide discontinued because of adverse events, compared with 72.4% of those on placebo.
 

Maintenance after second-line therapy

In CONTINUUM, patients with at least a partial response after two prior lines of therapy and an Eastern Cooperative Oncology Group performance score of 0-2 were enrolled and randomized to receive either lenalidomide (160 patients) at a starting dose of 2.5 mg/day for the first 28-day cycle, 5 mg/day from cycle 2, and, if well tolerated, up to 10 mg/day from cycle 7 on, or to placebo (154 patients).

This study, as noted before, was also unblinded at the time of the primary analysis as recommended by the DSMB, after a prespecified number of events had occurred.

At a median follow-up of 31.5 months, the median PFS, a co-primary endpoint with OS, was 33.9 months in the lenalidomide arm, compared with 9.2 months in the placebo arm, translating into a HR for lenalidomide of 0.40 (P less than .001).

The lenalidomide advantage also was seen in a subgroup analysis by age, prior response to chemotherapy, and number of factors for poor prognosis. Of note, among patients older than age 70, the PFS with lenalidomide was 52.5 months, compared with 7.3 months for placebo (HR 0.34, P = .005).

In a second PFS analysis conducted after 71 months of follow-up, lenalidomide remained superior, with a median PFS of 57.5 months vs. 32.7 months in the placebo arm. As noted, there was no difference in overall survival in this study.

Grade 3 or greater adverse events occurring more frequently with lenalidomide were neutropenia, thrombocytopenia, diarrhea, pneumonia, fatigue, hypokalemia, pulmonary embolism, and sepsis. There was no difference in the incidence of second primary malignancies, however.

CLLM1 was sponsored by the German CLL Study Group with support from Celgene. CONTINUUM was supported by Celgene. Dr. Fink disclosed research funding from the company, and travel grants and honoraria from others. Dr. Schuh disclosed honoraria from and consulting with Celgene and other companies.

[email protected]

SAN DIEGO – Lenalidomide, a mainstay of maintenance therapy for multiple myeloma, is now making inroads into maintenance therapy following first- and second-line therapy for chronic lymphocytic leukemia (CLL), investigators reported in two phase III studies.

Among patients with previously untreated CLL who were at high risk for early disease progression following standard chemotherapy, lenalidomide (Revlimid) maintenance therapy was associated with an 80% reduction in the relative risk for disease progression compared with placebo, reported Anna Fink, MD, of the University of Cologne, Germany, and her colleagues in the German CLL Study Group.

Similarly, lenalidomide maintenance significantly improved progression-free survival (PFS) compared with placebo among patients with CLL who had at least partial responses to second-line therapy, reported Anna Schuh, MD, of the University of Oxford, England, and her colleagues in the CONTINUUM trial.

“Lenalidomide maintenance therapy significantly improved progression-free survival, from just about 9 months to almost 40 months when given to patients with CLL who responded to second-line therapy,” Dr. Schuh said at the American Society of Hematology annual meeting.

Both studies were unblinded because of the superiority of lenalidomide after prespecified analyses, on the recommendation of the respective data safety monitoring boards (DSMBs).

The PFS advantage with lenalidomide seen in each study did not translate into differences in overall survival in either study, however.
 

Maintenance after first-line therapy

In the CLLM1 trial, Dr. Fink and her colleagues enrolled physically fit, previously untreated patients with CLL and delivered chemoimmunotherapy at the investigator’s choice: either FCR (fludarabine, cyclophosphamide, and rituximab), FR (fludarabine and rituximab), FC (fludarabine and cyclophosphamide), or BR (bendamustine and rituximab).

Patients who had at least a partial response after a minimum of four cycles were identified as being at high risk for progression if they had minimal residual disease (MRD) levels of at least 10^-2 cells, or MRD levels from 10^-4 to less than 10^-2 combined with either an unmutated IGHV gene status, del(17p) or TP53 mutation at baseline.

Of 468 screened patients, 89 were deemed to have high risk disease, and these patients were randomly assigned on a 2:1 basis to maintenance with lenalidomide given 5 mg orally for the first cycle and escalated to a target dose of 15 mg by the seventh cycle, or to placebo.

Additional dose escalations could be performed based on MRD assessments every 6 months, with the drug continued until progression or unacceptable toxicity. Patients also were assigned to daily low-dose aspirin or to an anticoagulation agent depending on their individual risk for thromboembolic events.

The study was stopped and unblinded after a planned interim analysis showed that the difference in PFS met the stopping boundary for efficacy.

Ultimately, 56 patients assigned to lenalidomide received study treatment, as did 29 assigned to placebo.

At a median follow-up of 17.5 months, the median PFS according to independent review was not reached for lenalidomide, vs. 13.3 months for placebo. Lenalidomide was associated with a hazard ratio (HR) for progression of 0.148 (P less than .00001), and a relative risk reduction of 80%.

Lenalidomide was also significantly better for PFS in analysis by MRD at baseline, with a PFS of 19.4 months for placebo vs. not reached among patients with less than 10^-2 but more than 10^-4 cells (HR, 0.125) and 3.7 vs. 32.3 months, respectively, for patients with MRD greater than 10^-2 (HR 0.165).

There were three deaths (two in patients on placebo), and at the last analysis there was no difference in overall survival. In all, 42.9% of patients on lenalidomide discontinued because of adverse events, compared with 72.4% of those on placebo.
 

Maintenance after second-line therapy

In CONTINUUM, patients with at least a partial response after two prior lines of therapy and an Eastern Cooperative Oncology Group performance score of 0-2 were enrolled and randomized to receive either lenalidomide (160 patients) at a starting dose of 2.5 mg/day for the first 28-day cycle, 5 mg/day from cycle 2, and, if well tolerated, up to 10 mg/day from cycle 7 on, or to placebo (154 patients).

This study, as noted before, was also unblinded at the time of the primary analysis as recommended by the DSMB, after a prespecified number of events had occurred.

At a median follow-up of 31.5 months, the median PFS, a co-primary endpoint with OS, was 33.9 months in the lenalidomide arm, compared with 9.2 months in the placebo arm, translating into a HR for lenalidomide of 0.40 (P less than .001).

The lenalidomide advantage also was seen in a subgroup analysis by age, prior response to chemotherapy, and number of factors for poor prognosis. Of note, among patients older than age 70, the PFS with lenalidomide was 52.5 months, compared with 7.3 months for placebo (HR 0.34, P = .005).

In a second PFS analysis conducted after 71 months of follow-up, lenalidomide remained superior, with a median PFS of 57.5 months vs. 32.7 months in the placebo arm. As noted, there was no difference in overall survival in this study.

Grade 3 or greater adverse events occurring more frequently with lenalidomide were neutropenia, thrombocytopenia, diarrhea, pneumonia, fatigue, hypokalemia, pulmonary embolism, and sepsis. There was no difference in the incidence of second primary malignancies, however.

CLLM1 was sponsored by the German CLL Study Group with support from Celgene. CONTINUUM was supported by Celgene. Dr. Fink disclosed research funding from the company, and travel grants and honoraria from others. Dr. Schuh disclosed honoraria from and consulting with Celgene and other companies.

[email protected]

WASHINGTON – Adding respiratory rate and suspected blunt chest injury to a trauma assessment in the field significantly improved the appropriate triaging of level III trauma patients.

When the assessment specifically evaluated for tachypnea in the setting of blunt chest injury, undertriaging improved by 1.2%, John Yonge, MD, said at the annual clinical congress of the American College of Surgeons.
 

“When we applied this new criteria to our 10-year study, we identified 661 patients who should have been activated as a level I or level II,” but instead were assessed as less critically injured, Dr. Yonge said in an interview. This initial misstep significantly extended the time before patients could have critical surgical procedures and was related to higher mortality among them.

Dr. Yonge, a surgical fellow at Oregon Health & Science University, Portland, and his mentor Martin Schreiber, MD, conducted the retrospective study of 7,880 trauma patients admitted at level III activation from 2004 to 2014. The OHSU trauma system has three activation levels.

• Level I activations are reserved for the most critically injured patients; attending trauma surgeon and anesthesiologist presence is mandatory.

• Level II activations capture moderate to severe injuries; trauma surgeon and respiratory therapist presence is mandated.

• Level III activations are designed to capture patients who do not require an immediate lifesaving intervention; the presence of the trauma surgery chief resident and attending emergency medicine physician is mandatory.

Patients were considered undertriaged if they were admitted as level III activations, but then required a critical intervention (chest tube placement, intubation, needle thoracostomy, or intracranial pressure monitoring) in the emergency department or ultimately met level I or II activation criteria.

Among all the level III patients, 466 (6%) were undertriaged: 390 were undertriaged based on the existing level I or II activation criteria, and 76 were considered undertriaged based on the need for a critical intervention.

Most of the undertriaged patients (65%) met criteria for level I activation; the rest should have been triaged as level II patients. Compared with appropriately staged level III patients, mortality among the undertriaged patients was significantly higher (3.2% vs. 0.6%). Undertriaged patients also experienced longer delays before initiation of major emergency surgery: a mean of 147 minutes, compared with 106 minutes for appropriately triaged level I patients and 62 minutes for appropriately triaged level II patients.

Dr. Yonge then looked for clinical measures that would improve triage. Tachypnea (respiratory rate of more than 20 breaths per minute) in the field stood out as a significant factor. Tachypneic patients who had a suspected chest injury were 70% more likely to be undertriaged than were those with a normal respiratory rate. Tachypnea was significantly associated with a diagnosis of flail chest, emergency department intubation, and chest tube placement.

The team then constructed a new triage criterion for patients with suspected chest injury – tachypnea combined with suspected blunt thoracic injury. By applying that model to their study population of level III patients, they determined that the level III undertriage rate would be reduced by 1.2%.

Tying the physiologic marker of tachypnea to a suspected clinical diagnosis is a key factor, Dr. Yonge noted. “Just adding tachypnea doesn’t help us. In fact, it would overwhelm us, because a trauma patient could very well be tachypneic because he’s experiencing panic. But tying it to a suspected clinical diagnosis gives us a meaningful result.”

He confirmed this linkage with an additional analysis. “We looked to see how severely injured these patients were and found that 71% of them had an Abbreviated Injury Score (AIS) to the chest of 3 or more, indicating a severe chest injury. Only 29% had an AIS of 2 or less. So this proves that respiratory rate is a valid triage criterion and can be used to identify patients who need a higher level of trauma care.”

The challenge now, Dr. Yonge said, is incorporating the marker into clinical practice. “It doesn’t matter how many statistics you do, if you can’t educate the prehospital providers in this, it’s useless. They are the crux of the trauma system.”

Although national guidelines do recommend assessing respiratory rate as part of field triage, it often isn’t recorded or is only estimated, Dr. Yonge said. That’s one reason he used the 20-breaths-per-minute cutoff rate. “It doesn’t even take a full minute to assess this, but it can make a big improvement in care.”

Neither he nor Dr. Schreiber had any financial disclosures.

[email protected]

On Twitter @alz_gal

WASHINGTON – Adding respiratory rate and suspected blunt chest injury to a trauma assessment in the field significantly improved the appropriate triaging of level III trauma patients.

When the assessment specifically evaluated for tachypnea in the setting of blunt chest injury, undertriaging improved by 1.2%, John Yonge, MD, said at the annual clinical congress of the American College of Surgeons.
 

“When we applied this new criteria to our 10-year study, we identified 661 patients who should have been activated as a level I or level II,” but instead were assessed as less critically injured, Dr. Yonge said in an interview. This initial misstep significantly extended the time before patients could have critical surgical procedures and was related to higher mortality among them.

Dr. Yonge, a surgical fellow at Oregon Health & Science University, Portland, and his mentor Martin Schreiber, MD, conducted the retrospective study of 7,880 trauma patients admitted at level III activation from 2004 to 2014. The OHSU trauma system has three activation levels.

• Level I activations are reserved for the most critically injured patients; attending trauma surgeon and anesthesiologist presence is mandatory.

• Level II activations capture moderate to severe injuries; trauma surgeon and respiratory therapist presence is mandated.

• Level III activations are designed to capture patients who do not require an immediate lifesaving intervention; the presence of the trauma surgery chief resident and attending emergency medicine physician is mandatory.

Patients were considered undertriaged if they were admitted as level III activations, but then required a critical intervention (chest tube placement, intubation, needle thoracostomy, or intracranial pressure monitoring) in the emergency department or ultimately met level I or II activation criteria.

Among all the level III patients, 466 (6%) were undertriaged: 390 were undertriaged based on the existing level I or II activation criteria, and 76 were considered undertriaged based on the need for a critical intervention.

Most of the undertriaged patients (65%) met criteria for level I activation; the rest should have been triaged as level II patients. Compared with appropriately staged level III patients, mortality among the undertriaged patients was significantly higher (3.2% vs. 0.6%). Undertriaged patients also experienced longer delays before initiation of major emergency surgery: a mean of 147 minutes, compared with 106 minutes for appropriately triaged level I patients and 62 minutes for appropriately triaged level II patients.

Dr. Yonge then looked for clinical measures that would improve triage. Tachypnea (respiratory rate of more than 20 breaths per minute) in the field stood out as a significant factor. Tachypneic patients who had a suspected chest injury were 70% more likely to be undertriaged than were those with a normal respiratory rate. Tachypnea was significantly associated with a diagnosis of flail chest, emergency department intubation, and chest tube placement.

The team then constructed a new triage criterion for patients with suspected chest injury – tachypnea combined with suspected blunt thoracic injury. By applying that model to their study population of level III patients, they determined that the level III undertriage rate would be reduced by 1.2%.

Tying the physiologic marker of tachypnea to a suspected clinical diagnosis is a key factor, Dr. Yonge noted. “Just adding tachypnea doesn’t help us. In fact, it would overwhelm us, because a trauma patient could very well be tachypneic because he’s experiencing panic. But tying it to a suspected clinical diagnosis gives us a meaningful result.”

He confirmed this linkage with an additional analysis. “We looked to see how severely injured these patients were and found that 71% of them had an Abbreviated Injury Score (AIS) to the chest of 3 or more, indicating a severe chest injury. Only 29% had an AIS of 2 or less. So this proves that respiratory rate is a valid triage criterion and can be used to identify patients who need a higher level of trauma care.”

The challenge now, Dr. Yonge said, is incorporating the marker into clinical practice. “It doesn’t matter how many statistics you do, if you can’t educate the prehospital providers in this, it’s useless. They are the crux of the trauma system.”

Although national guidelines do recommend assessing respiratory rate as part of field triage, it often isn’t recorded or is only estimated, Dr. Yonge said. That’s one reason he used the 20-breaths-per-minute cutoff rate. “It doesn’t even take a full minute to assess this, but it can make a big improvement in care.”

Neither he nor Dr. Schreiber had any financial disclosures.

[email protected]

On Twitter @alz_gal

WASHINGTON – Adding respiratory rate and suspected blunt chest injury to a trauma assessment in the field significantly improved the appropriate triaging of level III trauma patients.

When the assessment specifically evaluated for tachypnea in the setting of blunt chest injury, undertriaging improved by 1.2%, John Yonge, MD, said at the annual clinical congress of the American College of Surgeons.
 

“When we applied this new criteria to our 10-year study, we identified 661 patients who should have been activated as a level I or level II,” but instead were assessed as less critically injured, Dr. Yonge said in an interview. This initial misstep significantly extended the time before patients could have critical surgical procedures and was related to higher mortality among them.

Dr. Yonge, a surgical fellow at Oregon Health & Science University, Portland, and his mentor Martin Schreiber, MD, conducted the retrospective study of 7,880 trauma patients admitted at level III activation from 2004 to 2014. The OHSU trauma system has three activation levels.

• Level I activations are reserved for the most critically injured patients; attending trauma surgeon and anesthesiologist presence is mandatory.

• Level II activations capture moderate to severe injuries; trauma surgeon and respiratory therapist presence is mandated.

• Level III activations are designed to capture patients who do not require an immediate lifesaving intervention; the presence of the trauma surgery chief resident and attending emergency medicine physician is mandatory.

Patients were considered undertriaged if they were admitted as level III activations, but then required a critical intervention (chest tube placement, intubation, needle thoracostomy, or intracranial pressure monitoring) in the emergency department or ultimately met level I or II activation criteria.

Among all the level III patients, 466 (6%) were undertriaged: 390 were undertriaged based on the existing level I or II activation criteria, and 76 were considered undertriaged based on the need for a critical intervention.

Most of the undertriaged patients (65%) met criteria for level I activation; the rest should have been triaged as level II patients. Compared with appropriately staged level III patients, mortality among the undertriaged patients was significantly higher (3.2% vs. 0.6%). Undertriaged patients also experienced longer delays before initiation of major emergency surgery: a mean of 147 minutes, compared with 106 minutes for appropriately triaged level I patients and 62 minutes for appropriately triaged level II patients.

Dr. Yonge then looked for clinical measures that would improve triage. Tachypnea (respiratory rate of more than 20 breaths per minute) in the field stood out as a significant factor. Tachypneic patients who had a suspected chest injury were 70% more likely to be undertriaged than were those with a normal respiratory rate. Tachypnea was significantly associated with a diagnosis of flail chest, emergency department intubation, and chest tube placement.

The team then constructed a new triage criterion for patients with suspected chest injury – tachypnea combined with suspected blunt thoracic injury. By applying that model to their study population of level III patients, they determined that the level III undertriage rate would be reduced by 1.2%.

Tying the physiologic marker of tachypnea to a suspected clinical diagnosis is a key factor, Dr. Yonge noted. “Just adding tachypnea doesn’t help us. In fact, it would overwhelm us, because a trauma patient could very well be tachypneic because he’s experiencing panic. But tying it to a suspected clinical diagnosis gives us a meaningful result.”

He confirmed this linkage with an additional analysis. “We looked to see how severely injured these patients were and found that 71% of them had an Abbreviated Injury Score (AIS) to the chest of 3 or more, indicating a severe chest injury. Only 29% had an AIS of 2 or less. So this proves that respiratory rate is a valid triage criterion and can be used to identify patients who need a higher level of trauma care.”

The challenge now, Dr. Yonge said, is incorporating the marker into clinical practice. “It doesn’t matter how many statistics you do, if you can’t educate the prehospital providers in this, it’s useless. They are the crux of the trauma system.”

Although national guidelines do recommend assessing respiratory rate as part of field triage, it often isn’t recorded or is only estimated, Dr. Yonge said. That’s one reason he used the 20-breaths-per-minute cutoff rate. “It doesn’t even take a full minute to assess this, but it can make a big improvement in care.”

Neither he nor Dr. Schreiber had any financial disclosures.

[email protected]

On Twitter @alz_gal