Massive allogenic blood transfusion during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) increased the risk of major complications and reduced overall survival in a review of 936 cases at St. George Hospital near Sydney, Australia.

CRS/HIPEC is a long, complex procedure for peritoneal carcinomatosis, pseudomyxoma peritonei, peritoneal mesothelioma, and other abdominal cancers. The abdomen is opened, the cancer is debulked as much as possible, and the cavity is filled with heated chemotherapy drugs. Because CRS/HIPEC often requires multivisceral resection and dissection in multiple abdominal regions, up to 77% of patients require intraoperative transfusions, and up to 37% require massive allogenic blood transfusions (MABT) with five or more units.

Blood transfusions are known to be associated with poorer cancer surgery outcomes, but their effect in CRS/HIPEC hasn’t been much studied, which is “surprising given the extent to which blood products are used in” the procedure, said investigators led by Akshat Saxena, MD, a surgeon at St. George Hospital (J Gastrointest Surg. 2017 May 30. doi: 10.1007/s11605-017-3444-8).

Based on their findings, the researchers concluded that “there is a real need to evaluate new strategies to reduce the rate of MABT during CRS/HIPEC.”

The procedures in the study were performed from 1996 to 2016. The in-hospital mortality rate was 0.3% in patients who did not have MABT but 4.4% among the 337 patients (36%) who did. Even after adjusting for confounders on multivariate analysis, including the fact that MABT patients had more extensive disease and longer surgeries, MABT significantly increased the risk of in-hospital mortality (relative risk, 7.72; P = .021). In patients requiring MABT had a 5-year survival of 5%. In patients not requiring MABT, 5-year survival was at 36%. The difference remained significant on multivariate analysis.

MABT patients also had twice the risk of life-threatening complications and complications requiring surgical, endoscopic, or radiological intervention (62% versus 30%; RR, 2.05; P less than .001). MABT patients were more likely to stay in the ICU for 4 or more days and in the hospital for 28 or more days.

Worse overall survival with MABT was driven at least in part by patients who had CRS/HIPEC for colorectal cancer peritoneal carcinomatosis and pseudomyxoma peritonei. MABT did not seem to contribute to lower survival in patients who had the procedure for appendiceal or ovarian cancer. “It seems that the impact of long-term immunomodulation induced by blood transfusion” – the suspected mechanism through which transfusions cause problems – “varies according to the disease subtype. This warrants further investigation,” the investigators said.

Several strategies have been tried to reduce the need for transfusions during CRS/HIPEC. The study team previously reported that preemptive clotting factor replacement helps. Others have had success with preemptive tranexamic acid and cryoprecipitate to address low serum fibrinogen levels during CRS/HIPEC. “Further evaluation of both these strategies is warranted,” the researchers said.

Funding source and disclosure information were not included in the study report.
 

[email protected]

Massive allogenic blood transfusion during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) increased the risk of major complications and reduced overall survival in a review of 936 cases at St. George Hospital near Sydney, Australia.

CRS/HIPEC is a long, complex procedure for peritoneal carcinomatosis, pseudomyxoma peritonei, peritoneal mesothelioma, and other abdominal cancers. The abdomen is opened, the cancer is debulked as much as possible, and the cavity is filled with heated chemotherapy drugs. Because CRS/HIPEC often requires multivisceral resection and dissection in multiple abdominal regions, up to 77% of patients require intraoperative transfusions, and up to 37% require massive allogenic blood transfusions (MABT) with five or more units.

Blood transfusions are known to be associated with poorer cancer surgery outcomes, but their effect in CRS/HIPEC hasn’t been much studied, which is “surprising given the extent to which blood products are used in” the procedure, said investigators led by Akshat Saxena, MD, a surgeon at St. George Hospital (J Gastrointest Surg. 2017 May 30. doi: 10.1007/s11605-017-3444-8).

Based on their findings, the researchers concluded that “there is a real need to evaluate new strategies to reduce the rate of MABT during CRS/HIPEC.”

The procedures in the study were performed from 1996 to 2016. The in-hospital mortality rate was 0.3% in patients who did not have MABT but 4.4% among the 337 patients (36%) who did. Even after adjusting for confounders on multivariate analysis, including the fact that MABT patients had more extensive disease and longer surgeries, MABT significantly increased the risk of in-hospital mortality (relative risk, 7.72; P = .021). In patients requiring MABT had a 5-year survival of 5%. In patients not requiring MABT, 5-year survival was at 36%. The difference remained significant on multivariate analysis.

MABT patients also had twice the risk of life-threatening complications and complications requiring surgical, endoscopic, or radiological intervention (62% versus 30%; RR, 2.05; P less than .001). MABT patients were more likely to stay in the ICU for 4 or more days and in the hospital for 28 or more days.

Worse overall survival with MABT was driven at least in part by patients who had CRS/HIPEC for colorectal cancer peritoneal carcinomatosis and pseudomyxoma peritonei. MABT did not seem to contribute to lower survival in patients who had the procedure for appendiceal or ovarian cancer. “It seems that the impact of long-term immunomodulation induced by blood transfusion” – the suspected mechanism through which transfusions cause problems – “varies according to the disease subtype. This warrants further investigation,” the investigators said.

Several strategies have been tried to reduce the need for transfusions during CRS/HIPEC. The study team previously reported that preemptive clotting factor replacement helps. Others have had success with preemptive tranexamic acid and cryoprecipitate to address low serum fibrinogen levels during CRS/HIPEC. “Further evaluation of both these strategies is warranted,” the researchers said.

Funding source and disclosure information were not included in the study report.
 

[email protected]

Massive allogenic blood transfusion during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) increased the risk of major complications and reduced overall survival in a review of 936 cases at St. George Hospital near Sydney, Australia.

CRS/HIPEC is a long, complex procedure for peritoneal carcinomatosis, pseudomyxoma peritonei, peritoneal mesothelioma, and other abdominal cancers. The abdomen is opened, the cancer is debulked as much as possible, and the cavity is filled with heated chemotherapy drugs. Because CRS/HIPEC often requires multivisceral resection and dissection in multiple abdominal regions, up to 77% of patients require intraoperative transfusions, and up to 37% require massive allogenic blood transfusions (MABT) with five or more units.

Blood transfusions are known to be associated with poorer cancer surgery outcomes, but their effect in CRS/HIPEC hasn’t been much studied, which is “surprising given the extent to which blood products are used in” the procedure, said investigators led by Akshat Saxena, MD, a surgeon at St. George Hospital (J Gastrointest Surg. 2017 May 30. doi: 10.1007/s11605-017-3444-8).

Based on their findings, the researchers concluded that “there is a real need to evaluate new strategies to reduce the rate of MABT during CRS/HIPEC.”

The procedures in the study were performed from 1996 to 2016. The in-hospital mortality rate was 0.3% in patients who did not have MABT but 4.4% among the 337 patients (36%) who did. Even after adjusting for confounders on multivariate analysis, including the fact that MABT patients had more extensive disease and longer surgeries, MABT significantly increased the risk of in-hospital mortality (relative risk, 7.72; P = .021). In patients requiring MABT had a 5-year survival of 5%. In patients not requiring MABT, 5-year survival was at 36%. The difference remained significant on multivariate analysis.

MABT patients also had twice the risk of life-threatening complications and complications requiring surgical, endoscopic, or radiological intervention (62% versus 30%; RR, 2.05; P less than .001). MABT patients were more likely to stay in the ICU for 4 or more days and in the hospital for 28 or more days.

Worse overall survival with MABT was driven at least in part by patients who had CRS/HIPEC for colorectal cancer peritoneal carcinomatosis and pseudomyxoma peritonei. MABT did not seem to contribute to lower survival in patients who had the procedure for appendiceal or ovarian cancer. “It seems that the impact of long-term immunomodulation induced by blood transfusion” – the suspected mechanism through which transfusions cause problems – “varies according to the disease subtype. This warrants further investigation,” the investigators said.

Several strategies have been tried to reduce the need for transfusions during CRS/HIPEC. The study team previously reported that preemptive clotting factor replacement helps. Others have had success with preemptive tranexamic acid and cryoprecipitate to address low serum fibrinogen levels during CRS/HIPEC. “Further evaluation of both these strategies is warranted,” the researchers said.

Funding source and disclosure information were not included in the study report.
 

[email protected]

BACKGROUND: Medicare patients account for approximately 50% of hospital days. Hospitalization in older adults often results in poor outcomes.

OBJECTIVE: To test the feasibility and impact of using Assessing Care of Vulnerable Elders (ACOVE) quality indicators (QIs) as a therapeutic intervention to improve care of hospitalized older adults.

Also in JHM

Use of simulation to assess incoming interns’ recognition of opportunities to choose wisely
AUTHORS: Kathleen M. Wiest, Jeanne M. Farnan, MD, MHPE, Ellen Byrne, Lukas Matern, Melissa Cappaert, MA, Kristen Hirsch, Vineet M. Arora, MD, MAPP

Clinician attitudes regarding ICD deactivation in DNR/DNI patients
AUTHORS: Andrew J. Bradley, MD, Adam D. Marks, MD, MPH

Using standardized patients to assess hospitalist communication skills
AUTHORS: Dennis T. Chang, MD, Micah Mann, MD, Terry Sommer, BFA, Robert Fallar, PhD, Alan Weinberg, MS, Erica Friedman, MD

Techniques and behaviors associated with exemplary inpatient general medicine teaching: An exploratory qualitative study
AUTHORS: Nathan Houchens, MD, Molly Harrod, PhD, Stephanie Moody, PhD, Karen E. Fowler, MPH, Sanjay Saint, MD, MPH

A simple algorithm for predicting bacteremia using food consumption and shaking chills: A prospective observational study
AUTHORS: Takayuki Komatsu, MD, PhD, Erika Takahashi, MD, Kentaro Mishima, MD, Takeo Toyoda, MD, Fumihiro Saitoh, MD, Akari Yasuda, RN, Joe Matsuoka, PhD, Manabu Sugita, MD, PhD, Joel Branch, MD, Makoto Aoki, MD, Lawrence M. Tierney Jr., MD, Kenji Inoue, MD, PhD

For more articles and subscription information, visit www.journalofhospitalmedicine.com.

BACKGROUND: Medicare patients account for approximately 50% of hospital days. Hospitalization in older adults often results in poor outcomes.

OBJECTIVE: To test the feasibility and impact of using Assessing Care of Vulnerable Elders (ACOVE) quality indicators (QIs) as a therapeutic intervention to improve care of hospitalized older adults.

Also in JHM

Use of simulation to assess incoming interns’ recognition of opportunities to choose wisely
AUTHORS: Kathleen M. Wiest, Jeanne M. Farnan, MD, MHPE, Ellen Byrne, Lukas Matern, Melissa Cappaert, MA, Kristen Hirsch, Vineet M. Arora, MD, MAPP

Clinician attitudes regarding ICD deactivation in DNR/DNI patients
AUTHORS: Andrew J. Bradley, MD, Adam D. Marks, MD, MPH

Using standardized patients to assess hospitalist communication skills
AUTHORS: Dennis T. Chang, MD, Micah Mann, MD, Terry Sommer, BFA, Robert Fallar, PhD, Alan Weinberg, MS, Erica Friedman, MD

Techniques and behaviors associated with exemplary inpatient general medicine teaching: An exploratory qualitative study
AUTHORS: Nathan Houchens, MD, Molly Harrod, PhD, Stephanie Moody, PhD, Karen E. Fowler, MPH, Sanjay Saint, MD, MPH

A simple algorithm for predicting bacteremia using food consumption and shaking chills: A prospective observational study
AUTHORS: Takayuki Komatsu, MD, PhD, Erika Takahashi, MD, Kentaro Mishima, MD, Takeo Toyoda, MD, Fumihiro Saitoh, MD, Akari Yasuda, RN, Joe Matsuoka, PhD, Manabu Sugita, MD, PhD, Joel Branch, MD, Makoto Aoki, MD, Lawrence M. Tierney Jr., MD, Kenji Inoue, MD, PhD

For more articles and subscription information, visit www.journalofhospitalmedicine.com.

BACKGROUND: Medicare patients account for approximately 50% of hospital days. Hospitalization in older adults often results in poor outcomes.

OBJECTIVE: To test the feasibility and impact of using Assessing Care of Vulnerable Elders (ACOVE) quality indicators (QIs) as a therapeutic intervention to improve care of hospitalized older adults.

Also in JHM

Use of simulation to assess incoming interns’ recognition of opportunities to choose wisely
AUTHORS: Kathleen M. Wiest, Jeanne M. Farnan, MD, MHPE, Ellen Byrne, Lukas Matern, Melissa Cappaert, MA, Kristen Hirsch, Vineet M. Arora, MD, MAPP

Clinician attitudes regarding ICD deactivation in DNR/DNI patients
AUTHORS: Andrew J. Bradley, MD, Adam D. Marks, MD, MPH

Using standardized patients to assess hospitalist communication skills
AUTHORS: Dennis T. Chang, MD, Micah Mann, MD, Terry Sommer, BFA, Robert Fallar, PhD, Alan Weinberg, MS, Erica Friedman, MD

Techniques and behaviors associated with exemplary inpatient general medicine teaching: An exploratory qualitative study
AUTHORS: Nathan Houchens, MD, Molly Harrod, PhD, Stephanie Moody, PhD, Karen E. Fowler, MPH, Sanjay Saint, MD, MPH

A simple algorithm for predicting bacteremia using food consumption and shaking chills: A prospective observational study
AUTHORS: Takayuki Komatsu, MD, PhD, Erika Takahashi, MD, Kentaro Mishima, MD, Takeo Toyoda, MD, Fumihiro Saitoh, MD, Akari Yasuda, RN, Joe Matsuoka, PhD, Manabu Sugita, MD, PhD, Joel Branch, MD, Makoto Aoki, MD, Lawrence M. Tierney Jr., MD, Kenji Inoue, MD, PhD

For more articles and subscription information, visit www.journalofhospitalmedicine.com.

Take-Home Points

• Torn, displaced, and entrapped UCL is a Stener lesion.
• Hyperabduction injury with pain and joint laxity on examination.
• MRI and ultrasound are useful in evaluating UCL tears.
• Ultrasound offers dynamic evaluation.
• Must be treated appropriately to avoid pain, instability, and osteoarthritis.

In the literature, hyperabduction injuries to the thumb metacarpophalangeal (MCP) joint have been referred to interchangeably as gamekeeper’s thumb and skier’s thumb. Historically, though, gamekeeper’s thumb was initially described in hunters with chronic injury to the ulnar collateral ligament (UCL),¹ and skier’s thumb typically has been described as an acute hyperabduction injury of the UCL.^2-5 The proximal portion of a torn UCL may retract with further abduction and displace dorsally, becoming entrapped by the adductor pollicis aponeurosis insertion, known as a Stener lesion.⁶

The first MCP joint is stabilized by static and dynamic structures that contribute in varying degrees in flexion and extension of the joint. The static stabilizers include the proper and accessory radial and UCLs, the palmar plate, and the dorsal capsule. The UCL originates at the dorsal ulnar aspect of the first metacarpal head at the metacarpal tubercle about 5 mm proximal to the articular surface. The UCL courses distally in the palmar direction to insert volar and proximal to the medial tubercle of the proximal phalanx about 3 mm distal to the articular surface.⁷ In flexion, the proper collateral ligament is taut and is the primary static stabilizer. In extension, the accessory collateral ligament, which inserts on the palmar plate, is taut and is the primary static stabilizer.^8-11

The dynamic stabilizers include the extrinsic muscles (flexor pollicis longus, extensor pollicis longus and brevis) and the intrinsic muscles (abductor pollicis brevis, adductor pollicis, flexor pollicis brevis) inserting on the thumb at the distal phalanx and proximal phalanx and at the base of the first metacarpal.^8-10

Clinical Findings

A 33-year-old healthy man had persistent left hand pain and grip weakness after performing a handstand. He presented to the orthopedic hand clinic 20 days after injury, having failed nonoperative management (use of nonsteroidal anti-inflammatory drugs and soft thumb spica splint). Physical examination revealed soft-tissue swelling and focal tenderness to palpation at the ulnar aspect of the thumb MCP joint. Despite bilateral first MCP joint laxity on varus and valgus stress without identification of a firm endpoint, pain was elicited only on valgus stress of the left first MCP joint. Given the laxity and the left thumb soft-tissue swelling with pain, plain radiographs, ultrasound, and MRI were used to evaluate for severity of presumed left thumb UCL injury.

Imaging Findings

Plain radiographs showed normal bony anatomy without fracture, normal joint space, and mild soft-tissue swelling at the left thumb MCP level (Figures 3A, 3B).

Surgical Findings

Given laxity with pain at the UCL on stress testing, MRI and ultrasound findings, and continued pain and instability of the thumb with pinching and grasping during activities of daily living, the patient and orthopedic hand surgeon proceeded with surgical intervention. Preoperative examination under anesthesia confirmed significant laxity on valgus stress without a palpable endpoint (Figures 5A, 5B).

Discussion

Hyperabduction injuries to the thumb may rupture the UCL of the MCP joint of the thumb or cause a bony avulsion of the base of the proximal phalanx. Injury to the UCL, most often at its distal portion,^4,14,15 may result in a sprain or full-thickness tear of the ligament.

It is vital for the radiologist to identify a Stener lesion because a nondisplaced tear of the UCL is often treated nonsurgically, but UCL tears displaced more than 3 mm and Stener lesions usually must be operated on to avoid chronic instability, pain, and osteoarthritis.^2-5,8,12-23 Sensitivity and specificity of MRI in evaluating UCL injuries are reported to be almost 100%, with resolution of 1 mm using current surface coils.²³ There are various UCL injury patterns, including partial tears, displaced and nondisplaced complete tears, and even complex injuries, such as an incomplete tear with the torn portion retracted as a Stener lesion.²² MRI is needed to establish the extent of injury, as 90% of complete tears that are displaced at least 3 mm, and all tears with retraction proximal and superficial to the aponeurosis (true Stener lesions), failed immobilization and required surgical treatment.²³Although they vary in the literature, mean sensitivity and specificity of ultrasound in detecting UCL tears in level I studies have been reported as 76% and 81%, respectively.²⁴ When Melville and colleagues²¹ applied their ultrasound criteria—including absence of normal UCL fibers traversing the first MCP joint as well as heterogeneous masslike tissue at least partially proximal to the apex of the metacarpal lateral tubercle—they were able to distinguish displaced full-thickness tears from nondisplaced full-thickness tears with 100% accuracy. Hergan and colleagues²⁵ found that the diagnostic accuracy of MRI was superior to that of ultrasound; while MRI accuracy was perfect, 12% of patients were incorrectly diagnosed with ultrasound, with false-positive or false-negative tendon-edge displacement. In our experience, ultrasound is uniquely useful in its ability to characterize the real-time dynamic interaction of the UCL with the adductor aponeurosis. It has been observed that passive flexion of the first interphalangeal joint moves the adductor aponeurosis in isolation, allowing differentiation from the subjacent UCL.²¹ Had a partial tear been in the differential diagnosis of our patient’s Stener lesion, such a maneuver under ultrasound visualization would have solved the dilemma. In addition, ultrasound allows for comparison with the contralateral ligament at the time of examination should a diagnostic dilemma arise.

As many have reported both bony avulsion of the base of the proximal phalanx and concomitant injury to the UCL, identification of a bony avulsion does not exclude a ligamentous injury and the possibility of a Stener lesion (Figure 7).^16,19

Conclusion

A Stener lesion—retraction of a completely torn UCL becoming entrapped dorsally and proximally to the adductor insertion—can cause pain, instability, and ultimately osteoarthritis if not treated appropriately. The orthopedic surgeon should have a high index of suspicion for a Stener lesion in the appropriate clinical scenario and consider all imaging modalities for diagnosis. Likewise, it is of utmost importance for the radiologist to identify imaging findings of a Stener lesion, as physical examination alone may be limited in its ability to characterize injury severity. Both MRI and ultrasound are useful in evaluating UCL tears, and ultrasound provides the additional benefit of dynamic visualization and comparison with the contralateral side.

Am J Orthop. 2017;46(3):E195-E199. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Torn, displaced, and entrapped UCL is a Stener lesion.
• Hyperabduction injury with pain and joint laxity on examination.
• MRI and ultrasound are useful in evaluating UCL tears.
• Ultrasound offers dynamic evaluation.
• Must be treated appropriately to avoid pain, instability, and osteoarthritis.

In the literature, hyperabduction injuries to the thumb metacarpophalangeal (MCP) joint have been referred to interchangeably as gamekeeper’s thumb and skier’s thumb. Historically, though, gamekeeper’s thumb was initially described in hunters with chronic injury to the ulnar collateral ligament (UCL),¹ and skier’s thumb typically has been described as an acute hyperabduction injury of the UCL.^2-5 The proximal portion of a torn UCL may retract with further abduction and displace dorsally, becoming entrapped by the adductor pollicis aponeurosis insertion, known as a Stener lesion.⁶

The first MCP joint is stabilized by static and dynamic structures that contribute in varying degrees in flexion and extension of the joint. The static stabilizers include the proper and accessory radial and UCLs, the palmar plate, and the dorsal capsule. The UCL originates at the dorsal ulnar aspect of the first metacarpal head at the metacarpal tubercle about 5 mm proximal to the articular surface. The UCL courses distally in the palmar direction to insert volar and proximal to the medial tubercle of the proximal phalanx about 3 mm distal to the articular surface.⁷ In flexion, the proper collateral ligament is taut and is the primary static stabilizer. In extension, the accessory collateral ligament, which inserts on the palmar plate, is taut and is the primary static stabilizer.^8-11

The dynamic stabilizers include the extrinsic muscles (flexor pollicis longus, extensor pollicis longus and brevis) and the intrinsic muscles (abductor pollicis brevis, adductor pollicis, flexor pollicis brevis) inserting on the thumb at the distal phalanx and proximal phalanx and at the base of the first metacarpal.^8-10

Clinical Findings

A 33-year-old healthy man had persistent left hand pain and grip weakness after performing a handstand. He presented to the orthopedic hand clinic 20 days after injury, having failed nonoperative management (use of nonsteroidal anti-inflammatory drugs and soft thumb spica splint). Physical examination revealed soft-tissue swelling and focal tenderness to palpation at the ulnar aspect of the thumb MCP joint. Despite bilateral first MCP joint laxity on varus and valgus stress without identification of a firm endpoint, pain was elicited only on valgus stress of the left first MCP joint. Given the laxity and the left thumb soft-tissue swelling with pain, plain radiographs, ultrasound, and MRI were used to evaluate for severity of presumed left thumb UCL injury.

Imaging Findings

Plain radiographs showed normal bony anatomy without fracture, normal joint space, and mild soft-tissue swelling at the left thumb MCP level (Figures 3A, 3B).

Surgical Findings

Given laxity with pain at the UCL on stress testing, MRI and ultrasound findings, and continued pain and instability of the thumb with pinching and grasping during activities of daily living, the patient and orthopedic hand surgeon proceeded with surgical intervention. Preoperative examination under anesthesia confirmed significant laxity on valgus stress without a palpable endpoint (Figures 5A, 5B).

Discussion

Hyperabduction injuries to the thumb may rupture the UCL of the MCP joint of the thumb or cause a bony avulsion of the base of the proximal phalanx. Injury to the UCL, most often at its distal portion,^4,14,15 may result in a sprain or full-thickness tear of the ligament.

It is vital for the radiologist to identify a Stener lesion because a nondisplaced tear of the UCL is often treated nonsurgically, but UCL tears displaced more than 3 mm and Stener lesions usually must be operated on to avoid chronic instability, pain, and osteoarthritis.^2-5,8,12-23 Sensitivity and specificity of MRI in evaluating UCL injuries are reported to be almost 100%, with resolution of 1 mm using current surface coils.²³ There are various UCL injury patterns, including partial tears, displaced and nondisplaced complete tears, and even complex injuries, such as an incomplete tear with the torn portion retracted as a Stener lesion.²² MRI is needed to establish the extent of injury, as 90% of complete tears that are displaced at least 3 mm, and all tears with retraction proximal and superficial to the aponeurosis (true Stener lesions), failed immobilization and required surgical treatment.²³Although they vary in the literature, mean sensitivity and specificity of ultrasound in detecting UCL tears in level I studies have been reported as 76% and 81%, respectively.²⁴ When Melville and colleagues²¹ applied their ultrasound criteria—including absence of normal UCL fibers traversing the first MCP joint as well as heterogeneous masslike tissue at least partially proximal to the apex of the metacarpal lateral tubercle—they were able to distinguish displaced full-thickness tears from nondisplaced full-thickness tears with 100% accuracy. Hergan and colleagues²⁵ found that the diagnostic accuracy of MRI was superior to that of ultrasound; while MRI accuracy was perfect, 12% of patients were incorrectly diagnosed with ultrasound, with false-positive or false-negative tendon-edge displacement. In our experience, ultrasound is uniquely useful in its ability to characterize the real-time dynamic interaction of the UCL with the adductor aponeurosis. It has been observed that passive flexion of the first interphalangeal joint moves the adductor aponeurosis in isolation, allowing differentiation from the subjacent UCL.²¹ Had a partial tear been in the differential diagnosis of our patient’s Stener lesion, such a maneuver under ultrasound visualization would have solved the dilemma. In addition, ultrasound allows for comparison with the contralateral ligament at the time of examination should a diagnostic dilemma arise.

As many have reported both bony avulsion of the base of the proximal phalanx and concomitant injury to the UCL, identification of a bony avulsion does not exclude a ligamentous injury and the possibility of a Stener lesion (Figure 7).^16,19

Conclusion

A Stener lesion—retraction of a completely torn UCL becoming entrapped dorsally and proximally to the adductor insertion—can cause pain, instability, and ultimately osteoarthritis if not treated appropriately. The orthopedic surgeon should have a high index of suspicion for a Stener lesion in the appropriate clinical scenario and consider all imaging modalities for diagnosis. Likewise, it is of utmost importance for the radiologist to identify imaging findings of a Stener lesion, as physical examination alone may be limited in its ability to characterize injury severity. Both MRI and ultrasound are useful in evaluating UCL tears, and ultrasound provides the additional benefit of dynamic visualization and comparison with the contralateral side.

Am J Orthop. 2017;46(3):E195-E199. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Torn, displaced, and entrapped UCL is a Stener lesion.
• Hyperabduction injury with pain and joint laxity on examination.
• MRI and ultrasound are useful in evaluating UCL tears.
• Ultrasound offers dynamic evaluation.
• Must be treated appropriately to avoid pain, instability, and osteoarthritis.

In the literature, hyperabduction injuries to the thumb metacarpophalangeal (MCP) joint have been referred to interchangeably as gamekeeper’s thumb and skier’s thumb. Historically, though, gamekeeper’s thumb was initially described in hunters with chronic injury to the ulnar collateral ligament (UCL),¹ and skier’s thumb typically has been described as an acute hyperabduction injury of the UCL.^2-5 The proximal portion of a torn UCL may retract with further abduction and displace dorsally, becoming entrapped by the adductor pollicis aponeurosis insertion, known as a Stener lesion.⁶

The first MCP joint is stabilized by static and dynamic structures that contribute in varying degrees in flexion and extension of the joint. The static stabilizers include the proper and accessory radial and UCLs, the palmar plate, and the dorsal capsule. The UCL originates at the dorsal ulnar aspect of the first metacarpal head at the metacarpal tubercle about 5 mm proximal to the articular surface. The UCL courses distally in the palmar direction to insert volar and proximal to the medial tubercle of the proximal phalanx about 3 mm distal to the articular surface.⁷ In flexion, the proper collateral ligament is taut and is the primary static stabilizer. In extension, the accessory collateral ligament, which inserts on the palmar plate, is taut and is the primary static stabilizer.^8-11

The dynamic stabilizers include the extrinsic muscles (flexor pollicis longus, extensor pollicis longus and brevis) and the intrinsic muscles (abductor pollicis brevis, adductor pollicis, flexor pollicis brevis) inserting on the thumb at the distal phalanx and proximal phalanx and at the base of the first metacarpal.^8-10

Clinical Findings

A 33-year-old healthy man had persistent left hand pain and grip weakness after performing a handstand. He presented to the orthopedic hand clinic 20 days after injury, having failed nonoperative management (use of nonsteroidal anti-inflammatory drugs and soft thumb spica splint). Physical examination revealed soft-tissue swelling and focal tenderness to palpation at the ulnar aspect of the thumb MCP joint. Despite bilateral first MCP joint laxity on varus and valgus stress without identification of a firm endpoint, pain was elicited only on valgus stress of the left first MCP joint. Given the laxity and the left thumb soft-tissue swelling with pain, plain radiographs, ultrasound, and MRI were used to evaluate for severity of presumed left thumb UCL injury.

Imaging Findings

Plain radiographs showed normal bony anatomy without fracture, normal joint space, and mild soft-tissue swelling at the left thumb MCP level (Figures 3A, 3B).

Surgical Findings

Given laxity with pain at the UCL on stress testing, MRI and ultrasound findings, and continued pain and instability of the thumb with pinching and grasping during activities of daily living, the patient and orthopedic hand surgeon proceeded with surgical intervention. Preoperative examination under anesthesia confirmed significant laxity on valgus stress without a palpable endpoint (Figures 5A, 5B).

Discussion

Hyperabduction injuries to the thumb may rupture the UCL of the MCP joint of the thumb or cause a bony avulsion of the base of the proximal phalanx. Injury to the UCL, most often at its distal portion,^4,14,15 may result in a sprain or full-thickness tear of the ligament.

It is vital for the radiologist to identify a Stener lesion because a nondisplaced tear of the UCL is often treated nonsurgically, but UCL tears displaced more than 3 mm and Stener lesions usually must be operated on to avoid chronic instability, pain, and osteoarthritis.^2-5,8,12-23 Sensitivity and specificity of MRI in evaluating UCL injuries are reported to be almost 100%, with resolution of 1 mm using current surface coils.²³ There are various UCL injury patterns, including partial tears, displaced and nondisplaced complete tears, and even complex injuries, such as an incomplete tear with the torn portion retracted as a Stener lesion.²² MRI is needed to establish the extent of injury, as 90% of complete tears that are displaced at least 3 mm, and all tears with retraction proximal and superficial to the aponeurosis (true Stener lesions), failed immobilization and required surgical treatment.²³Although they vary in the literature, mean sensitivity and specificity of ultrasound in detecting UCL tears in level I studies have been reported as 76% and 81%, respectively.²⁴ When Melville and colleagues²¹ applied their ultrasound criteria—including absence of normal UCL fibers traversing the first MCP joint as well as heterogeneous masslike tissue at least partially proximal to the apex of the metacarpal lateral tubercle—they were able to distinguish displaced full-thickness tears from nondisplaced full-thickness tears with 100% accuracy. Hergan and colleagues²⁵ found that the diagnostic accuracy of MRI was superior to that of ultrasound; while MRI accuracy was perfect, 12% of patients were incorrectly diagnosed with ultrasound, with false-positive or false-negative tendon-edge displacement. In our experience, ultrasound is uniquely useful in its ability to characterize the real-time dynamic interaction of the UCL with the adductor aponeurosis. It has been observed that passive flexion of the first interphalangeal joint moves the adductor aponeurosis in isolation, allowing differentiation from the subjacent UCL.²¹ Had a partial tear been in the differential diagnosis of our patient’s Stener lesion, such a maneuver under ultrasound visualization would have solved the dilemma. In addition, ultrasound allows for comparison with the contralateral ligament at the time of examination should a diagnostic dilemma arise.

As many have reported both bony avulsion of the base of the proximal phalanx and concomitant injury to the UCL, identification of a bony avulsion does not exclude a ligamentous injury and the possibility of a Stener lesion (Figure 7).^16,19

Conclusion

A Stener lesion—retraction of a completely torn UCL becoming entrapped dorsally and proximally to the adductor insertion—can cause pain, instability, and ultimately osteoarthritis if not treated appropriately. The orthopedic surgeon should have a high index of suspicion for a Stener lesion in the appropriate clinical scenario and consider all imaging modalities for diagnosis. Likewise, it is of utmost importance for the radiologist to identify imaging findings of a Stener lesion, as physical examination alone may be limited in its ability to characterize injury severity. Both MRI and ultrasound are useful in evaluating UCL tears, and ultrasound provides the additional benefit of dynamic visualization and comparison with the contralateral side.

Am J Orthop. 2017;46(3):E195-E199. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

In the Madigan Intrepid Spirit Transitions (MIST) program, holistic treatment for traumatic brain injuries (TBIs) includes traditional and nontraditional therapies as well as a little help from friends.

MIST is a 6-week intensive outpatient group for service members who have TBIs and other traumatic injuries, along with coexisting conditions, such as chronic pain or posttraumatic stress. Coexisting conditions can make cases more complex, said U.S. Army Colonel Beverly Scott, medical and program director of Madigan Army Medical Center’s Traumatic Brain Injury Program and Intrepid Spirit Program in an interview with Health.mil News. But she adds, “It’s never too late to help [patients] address a number of issues they may be having following a traumatic brain injury, dealing with pain, dealing with behavior health issues.”

Related: Let’s Dance: A Holistic Approach to Treating Veterans With Posttraumatic Stress Disorder

The MIST program serves only active-duty service members with referral from their primary care managers and other specialty services at Madigan or throughout the Regional Health Command-Pacific. Commanders must sign memoranda of understanding that patients will be off duty rosters for the duration of the program. “They’re making a commitment to help that service member get better,” Scott said.

The MIST program enrolls 8 to 12 service members at a time. The holistic focus allows patients to address chronic pain, insomnia, and cognitive issues through traditional means as well as less traditional means that include mindfulness training; art; such as creating symbolic masks; and yoga. The variety of approaches lets them “cherry pick the methods they believe will help them the most,” the Health.mil News article reports, or what one member called “customizing their own multitool.”

Participants are encouraged to continue individual care within the TBI/Intrepid Spirit program. The MIST program aims to introduce them to the resources they can use going forward. Giving them tools they can use after they complete the program is an acknowledgment that the recovery process is ongoing. “We recognize it is a transition,” Scott said.

Related: Ideas for Helping TBI Patients

The MIST program has graduated 2 groups. Scott says, “We’ve seen incredible success,” both in wellness and in other areas, such as improved interpersonal relationships. Some of the credit goes to the peer support that MIST promotes. The curriculum is evidence based, but Scott says some “significant success is clearly related to soldiers helping soldiers.”

In the Madigan Intrepid Spirit Transitions (MIST) program, holistic treatment for traumatic brain injuries (TBIs) includes traditional and nontraditional therapies as well as a little help from friends.

MIST is a 6-week intensive outpatient group for service members who have TBIs and other traumatic injuries, along with coexisting conditions, such as chronic pain or posttraumatic stress. Coexisting conditions can make cases more complex, said U.S. Army Colonel Beverly Scott, medical and program director of Madigan Army Medical Center’s Traumatic Brain Injury Program and Intrepid Spirit Program in an interview with Health.mil News. But she adds, “It’s never too late to help [patients] address a number of issues they may be having following a traumatic brain injury, dealing with pain, dealing with behavior health issues.”

Related: Let’s Dance: A Holistic Approach to Treating Veterans With Posttraumatic Stress Disorder

The MIST program serves only active-duty service members with referral from their primary care managers and other specialty services at Madigan or throughout the Regional Health Command-Pacific. Commanders must sign memoranda of understanding that patients will be off duty rosters for the duration of the program. “They’re making a commitment to help that service member get better,” Scott said.

The MIST program enrolls 8 to 12 service members at a time. The holistic focus allows patients to address chronic pain, insomnia, and cognitive issues through traditional means as well as less traditional means that include mindfulness training; art; such as creating symbolic masks; and yoga. The variety of approaches lets them “cherry pick the methods they believe will help them the most,” the Health.mil News article reports, or what one member called “customizing their own multitool.”

Participants are encouraged to continue individual care within the TBI/Intrepid Spirit program. The MIST program aims to introduce them to the resources they can use going forward. Giving them tools they can use after they complete the program is an acknowledgment that the recovery process is ongoing. “We recognize it is a transition,” Scott said.

Related: Ideas for Helping TBI Patients

The MIST program has graduated 2 groups. Scott says, “We’ve seen incredible success,” both in wellness and in other areas, such as improved interpersonal relationships. Some of the credit goes to the peer support that MIST promotes. The curriculum is evidence based, but Scott says some “significant success is clearly related to soldiers helping soldiers.”

In the Madigan Intrepid Spirit Transitions (MIST) program, holistic treatment for traumatic brain injuries (TBIs) includes traditional and nontraditional therapies as well as a little help from friends.

MIST is a 6-week intensive outpatient group for service members who have TBIs and other traumatic injuries, along with coexisting conditions, such as chronic pain or posttraumatic stress. Coexisting conditions can make cases more complex, said U.S. Army Colonel Beverly Scott, medical and program director of Madigan Army Medical Center’s Traumatic Brain Injury Program and Intrepid Spirit Program in an interview with Health.mil News. But she adds, “It’s never too late to help [patients] address a number of issues they may be having following a traumatic brain injury, dealing with pain, dealing with behavior health issues.”

Related: Let’s Dance: A Holistic Approach to Treating Veterans With Posttraumatic Stress Disorder

The MIST program serves only active-duty service members with referral from their primary care managers and other specialty services at Madigan or throughout the Regional Health Command-Pacific. Commanders must sign memoranda of understanding that patients will be off duty rosters for the duration of the program. “They’re making a commitment to help that service member get better,” Scott said.

The MIST program enrolls 8 to 12 service members at a time. The holistic focus allows patients to address chronic pain, insomnia, and cognitive issues through traditional means as well as less traditional means that include mindfulness training; art; such as creating symbolic masks; and yoga. The variety of approaches lets them “cherry pick the methods they believe will help them the most,” the Health.mil News article reports, or what one member called “customizing their own multitool.”

Participants are encouraged to continue individual care within the TBI/Intrepid Spirit program. The MIST program aims to introduce them to the resources they can use going forward. Giving them tools they can use after they complete the program is an acknowledgment that the recovery process is ongoing. “We recognize it is a transition,” Scott said.

Related: Ideas for Helping TBI Patients

The MIST program has graduated 2 groups. Scott says, “We’ve seen incredible success,” both in wellness and in other areas, such as improved interpersonal relationships. Some of the credit goes to the peer support that MIST promotes. The curriculum is evidence based, but Scott says some “significant success is clearly related to soldiers helping soldiers.”

Natriuretic peptides have been shown to be valuable biomarkers for guiding diagnosis and treatment for cardiovascular disease. Recently, they also have been reported to inhibit progression of several cancers. The link is likely to be inflammation—which is usually a precursor to malignant changes, say researchers from Tokushima University and the National Cerebral and Cardiovascular Center Research Institute, both in Japan. To find out how reliable brain natriuretic peptide and C-reactive protein (CRP) levels might be in cancer, the researchers retrospectively studied 2,923 patients at their hospital who had had brain natriuretic peptide (BNP) measured to rule out heart disease.

Related: The Link Between Low-Density Lipoproteins and Chronic Lymphocytic Leukemia

Of 234 patients included in the final analysis, 80 were diagnosed with cancer. No patients with clinically evident heart failure and cardiac disease requiring medical treatment were included in the study. Both the plasma BNP and serum CRP levels were significantly higher in the patients with cancer (66.4 vs 44.0 pg/mL, and 0.99 vs 0.18 mg/dL, respectively). There were no significant differences in the echocardiographic parameters.

In 28 cured patients with solid cancers who underwent a radical surgery, the plasma BNP levels dropped significantly, from 70.7 to 45.0 pg/mL. However, the levels did not change after surgery in 7 relapsed or “insufficiently treated” patients with solid cancers. And although plasma BNP levels “tended to decrease” after chemotherapy in patients with hematologic cancers, in 13 patients plasma BNP levels did not change significantly.

Related: Novel Neuroendocrine Tumor in Multiple Endocrine Neoplasia Type 1

BNP levels were significantly higher in the patients with stage IV cancer, compared with those who had stages I, II, or III. This might be accompanied by systemic inflammation, the researchers say.

As far as the researchers know, no studies have shown that cancer cells generate BNP. Therefore, they think a higher plasma BNP level may reflect the elevated production from cardiomyocytes in association with inflammation in cancer patients.

Related: Pneumatic Tube-Induced Reverse Pseudohyperkalemia in a Patient With Chronic Lymphocytic Leukemia

Their findings suggest that it’s a good idea to consider the effect of cancer on the BNP levels when using BNP as an indicator of heart failure. Asymptomatic cancer patients with higher BNP levels should be diagnosed whether the elevated BNP is due to asymptomatic heart failure or cancer.

Source:

Bando S, Soeki T, Matsuura T, et al. PLoS One. 2017;12(6):e0178607

Natriuretic peptides have been shown to be valuable biomarkers for guiding diagnosis and treatment for cardiovascular disease. Recently, they also have been reported to inhibit progression of several cancers. The link is likely to be inflammation—which is usually a precursor to malignant changes, say researchers from Tokushima University and the National Cerebral and Cardiovascular Center Research Institute, both in Japan. To find out how reliable brain natriuretic peptide and C-reactive protein (CRP) levels might be in cancer, the researchers retrospectively studied 2,923 patients at their hospital who had had brain natriuretic peptide (BNP) measured to rule out heart disease.

Related: The Link Between Low-Density Lipoproteins and Chronic Lymphocytic Leukemia

Of 234 patients included in the final analysis, 80 were diagnosed with cancer. No patients with clinically evident heart failure and cardiac disease requiring medical treatment were included in the study. Both the plasma BNP and serum CRP levels were significantly higher in the patients with cancer (66.4 vs 44.0 pg/mL, and 0.99 vs 0.18 mg/dL, respectively). There were no significant differences in the echocardiographic parameters.

In 28 cured patients with solid cancers who underwent a radical surgery, the plasma BNP levels dropped significantly, from 70.7 to 45.0 pg/mL. However, the levels did not change after surgery in 7 relapsed or “insufficiently treated” patients with solid cancers. And although plasma BNP levels “tended to decrease” after chemotherapy in patients with hematologic cancers, in 13 patients plasma BNP levels did not change significantly.

Related: Novel Neuroendocrine Tumor in Multiple Endocrine Neoplasia Type 1

BNP levels were significantly higher in the patients with stage IV cancer, compared with those who had stages I, II, or III. This might be accompanied by systemic inflammation, the researchers say.

As far as the researchers know, no studies have shown that cancer cells generate BNP. Therefore, they think a higher plasma BNP level may reflect the elevated production from cardiomyocytes in association with inflammation in cancer patients.

Related: Pneumatic Tube-Induced Reverse Pseudohyperkalemia in a Patient With Chronic Lymphocytic Leukemia

Their findings suggest that it’s a good idea to consider the effect of cancer on the BNP levels when using BNP as an indicator of heart failure. Asymptomatic cancer patients with higher BNP levels should be diagnosed whether the elevated BNP is due to asymptomatic heart failure or cancer.

Source:

Bando S, Soeki T, Matsuura T, et al. PLoS One. 2017;12(6):e0178607

Natriuretic peptides have been shown to be valuable biomarkers for guiding diagnosis and treatment for cardiovascular disease. Recently, they also have been reported to inhibit progression of several cancers. The link is likely to be inflammation—which is usually a precursor to malignant changes, say researchers from Tokushima University and the National Cerebral and Cardiovascular Center Research Institute, both in Japan. To find out how reliable brain natriuretic peptide and C-reactive protein (CRP) levels might be in cancer, the researchers retrospectively studied 2,923 patients at their hospital who had had brain natriuretic peptide (BNP) measured to rule out heart disease.

Related: The Link Between Low-Density Lipoproteins and Chronic Lymphocytic Leukemia

Of 234 patients included in the final analysis, 80 were diagnosed with cancer. No patients with clinically evident heart failure and cardiac disease requiring medical treatment were included in the study. Both the plasma BNP and serum CRP levels were significantly higher in the patients with cancer (66.4 vs 44.0 pg/mL, and 0.99 vs 0.18 mg/dL, respectively). There were no significant differences in the echocardiographic parameters.

In 28 cured patients with solid cancers who underwent a radical surgery, the plasma BNP levels dropped significantly, from 70.7 to 45.0 pg/mL. However, the levels did not change after surgery in 7 relapsed or “insufficiently treated” patients with solid cancers. And although plasma BNP levels “tended to decrease” after chemotherapy in patients with hematologic cancers, in 13 patients plasma BNP levels did not change significantly.

Related: Novel Neuroendocrine Tumor in Multiple Endocrine Neoplasia Type 1

BNP levels were significantly higher in the patients with stage IV cancer, compared with those who had stages I, II, or III. This might be accompanied by systemic inflammation, the researchers say.

As far as the researchers know, no studies have shown that cancer cells generate BNP. Therefore, they think a higher plasma BNP level may reflect the elevated production from cardiomyocytes in association with inflammation in cancer patients.

Related: Pneumatic Tube-Induced Reverse Pseudohyperkalemia in a Patient With Chronic Lymphocytic Leukemia

Their findings suggest that it’s a good idea to consider the effect of cancer on the BNP levels when using BNP as an indicator of heart failure. Asymptomatic cancer patients with higher BNP levels should be diagnosed whether the elevated BNP is due to asymptomatic heart failure or cancer.

Source:

Bando S, Soeki T, Matsuura T, et al. PLoS One. 2017;12(6):e0178607

AML cells

Update as of June 21:  The US Food and Drug Administration (FDA) has placed the Investigational New Drug (IND) application for vadastuximab talirine on hold. No clinical trial may resume under the IND until the FDA lifts the clinical hold.

On the advice of the Independent Data Monitoring Committee, Seattle Genetics is discontinuing the phase 3 CASCADE clinical trial of vadastuximab talirine as frontline treatment in older patients with acute myeloid leukemia (AML).

The company is also suspending patient enrollment and treatment in all its vadastuximab trials, including the ongoing phase 1/2 trial in frontline high-risk myelodysplastic syndromes (MDS).

In December last year, the US Food and Drug Administration (FDA) had placed the trials of vadastuximab on full and partial clinical holds due to the potential risk of hepatotoxicity.

The FDA lifted the hold in March of this year. However, concerns regarding a higher rate of deaths, including fatal infections but not liver toxicity, in the vadastuximab arm compared to control prompted the company to discontinue the phase 3 trial.

Vadastuximab talirene is an antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blasts. The ADC technology links anti-cancer compounds with targeting antibodies to precisely kill cancer cells and spare healthy ones.

Seattle Genetics’ ADC for Hodgkin lymphoma, brentuximab vedotin, was granted accelerated approval by the FDA in 2011.

The CASCADE trial was evaluating vadastuximab in combination with the hypomethylating agents (HMAs) azacytidine or decitabine compared to an HMA alone in older patients with newly diagnosed AML.

In addition to the MDS trial, the company is stopping enrollment onto the trial of vadastuximab in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients and vadastuximab given prior to or after allogeneic hematopoietic stem cell transplant in AML patients.

Calling the decision “disappointing and unexpected,” Clay Siegall, PhD, president and CEO of Seattle Genetics, said, “Patient safety is our highest priority, and we will closely review the data and evaluate next steps.” 

AML cells

Update as of June 21:  The US Food and Drug Administration (FDA) has placed the Investigational New Drug (IND) application for vadastuximab talirine on hold. No clinical trial may resume under the IND until the FDA lifts the clinical hold.

On the advice of the Independent Data Monitoring Committee, Seattle Genetics is discontinuing the phase 3 CASCADE clinical trial of vadastuximab talirine as frontline treatment in older patients with acute myeloid leukemia (AML).

The company is also suspending patient enrollment and treatment in all its vadastuximab trials, including the ongoing phase 1/2 trial in frontline high-risk myelodysplastic syndromes (MDS).

In December last year, the US Food and Drug Administration (FDA) had placed the trials of vadastuximab on full and partial clinical holds due to the potential risk of hepatotoxicity.

The FDA lifted the hold in March of this year. However, concerns regarding a higher rate of deaths, including fatal infections but not liver toxicity, in the vadastuximab arm compared to control prompted the company to discontinue the phase 3 trial.

Vadastuximab talirene is an antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blasts. The ADC technology links anti-cancer compounds with targeting antibodies to precisely kill cancer cells and spare healthy ones.

Seattle Genetics’ ADC for Hodgkin lymphoma, brentuximab vedotin, was granted accelerated approval by the FDA in 2011.

The CASCADE trial was evaluating vadastuximab in combination with the hypomethylating agents (HMAs) azacytidine or decitabine compared to an HMA alone in older patients with newly diagnosed AML.

In addition to the MDS trial, the company is stopping enrollment onto the trial of vadastuximab in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients and vadastuximab given prior to or after allogeneic hematopoietic stem cell transplant in AML patients.

Calling the decision “disappointing and unexpected,” Clay Siegall, PhD, president and CEO of Seattle Genetics, said, “Patient safety is our highest priority, and we will closely review the data and evaluate next steps.” 

AML cells

Update as of June 21:  The US Food and Drug Administration (FDA) has placed the Investigational New Drug (IND) application for vadastuximab talirine on hold. No clinical trial may resume under the IND until the FDA lifts the clinical hold.

On the advice of the Independent Data Monitoring Committee, Seattle Genetics is discontinuing the phase 3 CASCADE clinical trial of vadastuximab talirine as frontline treatment in older patients with acute myeloid leukemia (AML).

The company is also suspending patient enrollment and treatment in all its vadastuximab trials, including the ongoing phase 1/2 trial in frontline high-risk myelodysplastic syndromes (MDS).

In December last year, the US Food and Drug Administration (FDA) had placed the trials of vadastuximab on full and partial clinical holds due to the potential risk of hepatotoxicity.

The FDA lifted the hold in March of this year. However, concerns regarding a higher rate of deaths, including fatal infections but not liver toxicity, in the vadastuximab arm compared to control prompted the company to discontinue the phase 3 trial.

Vadastuximab talirene is an antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blasts. The ADC technology links anti-cancer compounds with targeting antibodies to precisely kill cancer cells and spare healthy ones.

Seattle Genetics’ ADC for Hodgkin lymphoma, brentuximab vedotin, was granted accelerated approval by the FDA in 2011.

The CASCADE trial was evaluating vadastuximab in combination with the hypomethylating agents (HMAs) azacytidine or decitabine compared to an HMA alone in older patients with newly diagnosed AML.

In addition to the MDS trial, the company is stopping enrollment onto the trial of vadastuximab in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients and vadastuximab given prior to or after allogeneic hematopoietic stem cell transplant in AML patients.

Calling the decision “disappointing and unexpected,” Clay Siegall, PhD, president and CEO of Seattle Genetics, said, “Patient safety is our highest priority, and we will closely review the data and evaluate next steps.” 

Photo by Linda Bartlett

The European Commission (EC) has approved the Sandoz biosimilar rituximab (Rixathon^®) for use in the European Economic Area.

Rixathon is approved for all indications of the reference medicine, MabThera®, including follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and immunologic diseases such as rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.

This approval allows Rixathon to be marketed in the member states of the European Union and Iceland, Liechtenstein, and Norway, members of the European Free Trade Association.

The approval “represents a big win for patients in Europe with blood cancers or immunological diseases,” according to Carol Lynch, global head of Biopharmaceuticals at Sandoz.

“Rixathon will be one of the 5 major launches we plan in the next 4 years,” she said.

Earlier in the year, the European Medicines Agency’s Committee for Medicinal Products for Human Use had recommended marketing authorization for Rixathon.

The EC based its approval on a comprehensive development program generating analytical, preclinical, and clinical data.  Clinical studies included ASSIST-RA and ASSIST-FL.

ASSIST-RA demonstrated that the biosimilar product has equivalent pharmacokinetic and pharmacodynamic profiles to the reference medicine, with no clinically meaningful differences in safety, tolerability, or immunogenicity in patients with rheumatoid arthritis.

ASSIST-FL was a phase 3 study confirming efficacy and safety. The study met its primary endpoint of equivalence in overall response rate between the biosimilar product and the reference medicine after 6 months.

ASSIST-FL also confirmed the comparable safety profiles of the 2 medicines.

Sandoz is a division of the Swiss pharmaceutical company Novartis. MabThera is a registered trademark of F. Hoffmann-La-Roche AG.

Another Sandoz biosimilar rituximab has been approved in the EU as Riximyo® under a duplicate marketing authorization. 

Photo by Linda Bartlett

The European Commission (EC) has approved the Sandoz biosimilar rituximab (Rixathon^®) for use in the European Economic Area.

Rixathon is approved for all indications of the reference medicine, MabThera®, including follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and immunologic diseases such as rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.

This approval allows Rixathon to be marketed in the member states of the European Union and Iceland, Liechtenstein, and Norway, members of the European Free Trade Association.

The approval “represents a big win for patients in Europe with blood cancers or immunological diseases,” according to Carol Lynch, global head of Biopharmaceuticals at Sandoz.

“Rixathon will be one of the 5 major launches we plan in the next 4 years,” she said.

Earlier in the year, the European Medicines Agency’s Committee for Medicinal Products for Human Use had recommended marketing authorization for Rixathon.

The EC based its approval on a comprehensive development program generating analytical, preclinical, and clinical data.  Clinical studies included ASSIST-RA and ASSIST-FL.

ASSIST-RA demonstrated that the biosimilar product has equivalent pharmacokinetic and pharmacodynamic profiles to the reference medicine, with no clinically meaningful differences in safety, tolerability, or immunogenicity in patients with rheumatoid arthritis.

ASSIST-FL was a phase 3 study confirming efficacy and safety. The study met its primary endpoint of equivalence in overall response rate between the biosimilar product and the reference medicine after 6 months.

ASSIST-FL also confirmed the comparable safety profiles of the 2 medicines.

Sandoz is a division of the Swiss pharmaceutical company Novartis. MabThera is a registered trademark of F. Hoffmann-La-Roche AG.

Another Sandoz biosimilar rituximab has been approved in the EU as Riximyo® under a duplicate marketing authorization. 

Photo by Linda Bartlett

The European Commission (EC) has approved the Sandoz biosimilar rituximab (Rixathon^®) for use in the European Economic Area.

Rixathon is approved for all indications of the reference medicine, MabThera®, including follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and immunologic diseases such as rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.

This approval allows Rixathon to be marketed in the member states of the European Union and Iceland, Liechtenstein, and Norway, members of the European Free Trade Association.

The approval “represents a big win for patients in Europe with blood cancers or immunological diseases,” according to Carol Lynch, global head of Biopharmaceuticals at Sandoz.

“Rixathon will be one of the 5 major launches we plan in the next 4 years,” she said.

Earlier in the year, the European Medicines Agency’s Committee for Medicinal Products for Human Use had recommended marketing authorization for Rixathon.

The EC based its approval on a comprehensive development program generating analytical, preclinical, and clinical data.  Clinical studies included ASSIST-RA and ASSIST-FL.

ASSIST-RA demonstrated that the biosimilar product has equivalent pharmacokinetic and pharmacodynamic profiles to the reference medicine, with no clinically meaningful differences in safety, tolerability, or immunogenicity in patients with rheumatoid arthritis.

ASSIST-FL was a phase 3 study confirming efficacy and safety. The study met its primary endpoint of equivalence in overall response rate between the biosimilar product and the reference medicine after 6 months.

ASSIST-FL also confirmed the comparable safety profiles of the 2 medicines.

Sandoz is a division of the Swiss pharmaceutical company Novartis. MabThera is a registered trademark of F. Hoffmann-La-Roche AG.

Another Sandoz biosimilar rituximab has been approved in the EU as Riximyo® under a duplicate marketing authorization. 

PARIS – During the most recent pharmaceutical generation, drug development for heart failure largely focused on acute heart failure, and specifically on patients with rest dyspnea as the primary manifestation of their acute heart failure decompensation events.

That has now changed, agreed heart failure experts as they debated the upshot of sobering results from two neutral trials that failed to show a midterm mortality benefit in patients hospitalized for acute heart failure who underwent aggressive management of their congestion using 2 days of intravenous treatment with either of two potent vasodilating drugs. Results first reported in November 2016 failed to show a survival benefit from ularitide in the 2,100-patient TRUE-AHF (Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure) trial (N Engl J Med. 2017 May 18;376[20]:1956-64). And results reported at a meeting of the Heart Failure Association of the ESC failed to show a survival benefit from serelaxin in more than 6,500 acute heart failure patients in the RELAX-AHF-2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF) trial.

The failure of a 2-day infusion of serelaxin to produce a significant reduction in cardiovascular death in RELAX-AHF-2 was especially surprising because the predecessor trial, RELAX-AHF, which randomized only 1,160 patients and used a surrogate endpoint of dyspnea improvement, had shown significant benefit that hinted more clinically meaningful benefits might also result from serelaxin treatment (Lancet. 2013 Jan 5;381[9860]:29-39). The disappointing serelaxin and ularitide results also culminate a series of studies using several different agents or procedures to treat acute decompensated heart failure patients that all failed to produce a reduction in deaths.

Frontline Medical News

The right time to intervene

Meeting attendees offered several hypotheses to explain why the acute ularitide and serelaxin trials both failed to show a mortality benefit, with timing of treatment the most common denominator.

Acute heart failure “is an event, not a disease,” declared Milton Packer, MD, lead investigator of TRUE-AHF, during a session devoted to vasodilator treatment of acute heart failure. Acute heart failure decompensations “are fluctuations in a chronic disease. It doesn’t matter what you do during the episode – it matters what you do between acute episodes. We focus all our attention on which vasodilator and which dose of Lasix [furosemide], but we send patients home on inadequate chronic therapy. It doesn’t matter what you do to the dyspnea, the shortness of breath will get better. Do we need a new drug that makes dyspnea go away an hour sooner and doesn’t cost a fortune? What really matters is what patients do between acute episodes and how to prevent them, ” said Dr. Packer, distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas.

Dr. Packer strongly urged clinicians to put heart failure patients on the full regimen of guideline-directed drugs and at full dosages, a step he thinks would go a long way toward preventing a majority of decompensation episodes. “Chronic heart failure treatment has improved dramatically, but implementation is abysmal,” he said.

Mitchel L. Zoler/Frontlione Medical News

Wrong patients with the wrong presentation

Perhaps just as big a flaw of the acute heart failure trials has been their target patient population, patients with rest dyspnea at the time of admission. “Why do we think that dyspnea is a clinically relevant symptom for acute heart failure?” Dr. Packer asked.

Mitchel L. Zoler/Frontlione Medical News

Acute heart failure remains a target

Despite all the talk of refocusing attention on chronic heart failure and peripheral edema, at least one expert remained steadfast in talking up the importance of new acute interventions.

Mitchel L. Zoler/Frontlione Medical News

[email protected]

On Twitter @mitchelzoler

PARIS – During the most recent pharmaceutical generation, drug development for heart failure largely focused on acute heart failure, and specifically on patients with rest dyspnea as the primary manifestation of their acute heart failure decompensation events.

That has now changed, agreed heart failure experts as they debated the upshot of sobering results from two neutral trials that failed to show a midterm mortality benefit in patients hospitalized for acute heart failure who underwent aggressive management of their congestion using 2 days of intravenous treatment with either of two potent vasodilating drugs. Results first reported in November 2016 failed to show a survival benefit from ularitide in the 2,100-patient TRUE-AHF (Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure) trial (N Engl J Med. 2017 May 18;376[20]:1956-64). And results reported at a meeting of the Heart Failure Association of the ESC failed to show a survival benefit from serelaxin in more than 6,500 acute heart failure patients in the RELAX-AHF-2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF) trial.

The failure of a 2-day infusion of serelaxin to produce a significant reduction in cardiovascular death in RELAX-AHF-2 was especially surprising because the predecessor trial, RELAX-AHF, which randomized only 1,160 patients and used a surrogate endpoint of dyspnea improvement, had shown significant benefit that hinted more clinically meaningful benefits might also result from serelaxin treatment (Lancet. 2013 Jan 5;381[9860]:29-39). The disappointing serelaxin and ularitide results also culminate a series of studies using several different agents or procedures to treat acute decompensated heart failure patients that all failed to produce a reduction in deaths.

Frontline Medical News

The right time to intervene

Meeting attendees offered several hypotheses to explain why the acute ularitide and serelaxin trials both failed to show a mortality benefit, with timing of treatment the most common denominator.

Acute heart failure “is an event, not a disease,” declared Milton Packer, MD, lead investigator of TRUE-AHF, during a session devoted to vasodilator treatment of acute heart failure. Acute heart failure decompensations “are fluctuations in a chronic disease. It doesn’t matter what you do during the episode – it matters what you do between acute episodes. We focus all our attention on which vasodilator and which dose of Lasix [furosemide], but we send patients home on inadequate chronic therapy. It doesn’t matter what you do to the dyspnea, the shortness of breath will get better. Do we need a new drug that makes dyspnea go away an hour sooner and doesn’t cost a fortune? What really matters is what patients do between acute episodes and how to prevent them, ” said Dr. Packer, distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas.

Dr. Packer strongly urged clinicians to put heart failure patients on the full regimen of guideline-directed drugs and at full dosages, a step he thinks would go a long way toward preventing a majority of decompensation episodes. “Chronic heart failure treatment has improved dramatically, but implementation is abysmal,” he said.

Mitchel L. Zoler/Frontlione Medical News

Wrong patients with the wrong presentation

Perhaps just as big a flaw of the acute heart failure trials has been their target patient population, patients with rest dyspnea at the time of admission. “Why do we think that dyspnea is a clinically relevant symptom for acute heart failure?” Dr. Packer asked.

Mitchel L. Zoler/Frontlione Medical News

Acute heart failure remains a target

Despite all the talk of refocusing attention on chronic heart failure and peripheral edema, at least one expert remained steadfast in talking up the importance of new acute interventions.

Mitchel L. Zoler/Frontlione Medical News

[email protected]

On Twitter @mitchelzoler

PARIS – During the most recent pharmaceutical generation, drug development for heart failure largely focused on acute heart failure, and specifically on patients with rest dyspnea as the primary manifestation of their acute heart failure decompensation events.

That has now changed, agreed heart failure experts as they debated the upshot of sobering results from two neutral trials that failed to show a midterm mortality benefit in patients hospitalized for acute heart failure who underwent aggressive management of their congestion using 2 days of intravenous treatment with either of two potent vasodilating drugs. Results first reported in November 2016 failed to show a survival benefit from ularitide in the 2,100-patient TRUE-AHF (Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure) trial (N Engl J Med. 2017 May 18;376[20]:1956-64). And results reported at a meeting of the Heart Failure Association of the ESC failed to show a survival benefit from serelaxin in more than 6,500 acute heart failure patients in the RELAX-AHF-2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF) trial.

The failure of a 2-day infusion of serelaxin to produce a significant reduction in cardiovascular death in RELAX-AHF-2 was especially surprising because the predecessor trial, RELAX-AHF, which randomized only 1,160 patients and used a surrogate endpoint of dyspnea improvement, had shown significant benefit that hinted more clinically meaningful benefits might also result from serelaxin treatment (Lancet. 2013 Jan 5;381[9860]:29-39). The disappointing serelaxin and ularitide results also culminate a series of studies using several different agents or procedures to treat acute decompensated heart failure patients that all failed to produce a reduction in deaths.

Frontline Medical News

The right time to intervene

Meeting attendees offered several hypotheses to explain why the acute ularitide and serelaxin trials both failed to show a mortality benefit, with timing of treatment the most common denominator.

Acute heart failure “is an event, not a disease,” declared Milton Packer, MD, lead investigator of TRUE-AHF, during a session devoted to vasodilator treatment of acute heart failure. Acute heart failure decompensations “are fluctuations in a chronic disease. It doesn’t matter what you do during the episode – it matters what you do between acute episodes. We focus all our attention on which vasodilator and which dose of Lasix [furosemide], but we send patients home on inadequate chronic therapy. It doesn’t matter what you do to the dyspnea, the shortness of breath will get better. Do we need a new drug that makes dyspnea go away an hour sooner and doesn’t cost a fortune? What really matters is what patients do between acute episodes and how to prevent them, ” said Dr. Packer, distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas.

Dr. Packer strongly urged clinicians to put heart failure patients on the full regimen of guideline-directed drugs and at full dosages, a step he thinks would go a long way toward preventing a majority of decompensation episodes. “Chronic heart failure treatment has improved dramatically, but implementation is abysmal,” he said.

Mitchel L. Zoler/Frontlione Medical News

Wrong patients with the wrong presentation

Perhaps just as big a flaw of the acute heart failure trials has been their target patient population, patients with rest dyspnea at the time of admission. “Why do we think that dyspnea is a clinically relevant symptom for acute heart failure?” Dr. Packer asked.

Mitchel L. Zoler/Frontlione Medical News

Acute heart failure remains a target

Despite all the talk of refocusing attention on chronic heart failure and peripheral edema, at least one expert remained steadfast in talking up the importance of new acute interventions.

Mitchel L. Zoler/Frontlione Medical News

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On Twitter @mitchelzoler

The Food and Drug Administration has approved delafloxacin, a fluoroquinolone, for the treatment of acute bacterial skin and skin structure infections, according to an agency announcement June 19.

Delafloxacin, which will be marketed by Melinta Therapeutics as Baxdela, was designated a qualified infectious disease product (QIDP) and granted fast-track and priority review. These classifications are designed to speed approval of antibacterial products to treat serious or life-threatening infections, according to an FDA statement.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

On Twitter @denisefulton

The Food and Drug Administration has approved delafloxacin, a fluoroquinolone, for the treatment of acute bacterial skin and skin structure infections, according to an agency announcement June 19.

Delafloxacin, which will be marketed by Melinta Therapeutics as Baxdela, was designated a qualified infectious disease product (QIDP) and granted fast-track and priority review. These classifications are designed to speed approval of antibacterial products to treat serious or life-threatening infections, according to an FDA statement.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

On Twitter @denisefulton

The Food and Drug Administration has approved delafloxacin, a fluoroquinolone, for the treatment of acute bacterial skin and skin structure infections, according to an agency announcement June 19.

Delafloxacin, which will be marketed by Melinta Therapeutics as Baxdela, was designated a qualified infectious disease product (QIDP) and granted fast-track and priority review. These classifications are designed to speed approval of antibacterial products to treat serious or life-threatening infections, according to an FDA statement.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

On Twitter @denisefulton

A single 60-hour infusion of brexanolone dramatically and rapidly improves severe postpartum depression with minimal adverse effects, a small manufacturer-conducted phase II trial suggests.

Brexanolone is a proprietary formulation of allopregnanolone, the major metabolite of progesterone and a potent modulator of synaptic and extrasynaptic gamma-aminobutyric acid type A (GABAA) receptors that has demonstrated profound benefits for anxiety and depression symptoms in animal models. Plasma levels of allopregnanolone rise to a peak during the third trimester of pregnancy, then abruptly fall after childbirth. “Failure of GABAA receptors to adapt to these changes at parturition has been postulated to have a role in triggering postpartum depression,” said Stephen Kanes, MD, of Sage Therapeutics, Cambridge, Mass., and his associates.

They assessed the drug’s effects in 21 women hospitalized for severe postpartum depression at 11 U.S. medical centers during a 5-month period. The study participants, who had Hamilton Rating Scale for Depression (HAM-D) scores of 26 or higher at baseline, randomized to receive a 60-hour infusion of brexanolone (10 patients) or a matching placebo (11 patients) in a double-blind fashion.

The primary outcome measure – mean reduction in HAM-D score at the end of the 60-hour infusion – was 21.0 points with brexanolone, significantly greater than the 8.8 point reduction seen with placebo. Women in the active-treatment group began showing a marked improvement within 24 hours of beginning the infusion, which was maintained throughout the week of treatment, as well as for the succeeding 30 days of follow-up.

Of the 10 patients, 7 receiving brexanolone (70%), compared with only 1 of those receiving placebo (9%), achieved remission of depression (HAM-D score of 7 or less) by the end of treatment. That remission occurred within 24 hours of beginning the infusion in six of the women in the brexanolone group. Moreover, improvement extended beyond the core depressive symptoms, with women in the active-treatment group also showing rapid and marked improvement on Clinical Global Impression–Improvement Scale scores, the investigators said (Lancet. 2017 Jun 12. doi: 10.1016/S0140-67369(17)31264-3).

Two women who received brexanolone admitted that, at baseline, they’d had active suicidal ideation with a specific plan and intent. Neither was suicidal after treatment.

Brexanolone was well-tolerated, with no serious adverse events or treatment discontinuations. Fewer patients who received active treatment (4) than placebo (8) reported mild adverse events. The most frequently reported adverse effects of brexanolone were dizziness and somnolence.

Among the limitations cited by the investigators was the use of a “very strict definition of postpartum depression” (HAM-D scores greater than or equal to 26).

Dr. Kanes and his associates reported that a phase III study currently underway is looking into the possible use of brexanolone in women with “varying degrees of severity.”

“Our findings provide the first placebo-controlled clinical support for the role of extrasynaptic GABAA receptors in the modulation of mood and affective states in any clinical population. The large effect size seen in this trial contrasts with that observed in studies of currently available and widely used antidepressants, including [selective serotonin reuptake inhibitors], [selective norepinephrine reuptake inhibitors], and tricyclics,” Dr. Kanes and his associates noted.

A single 60-hour infusion of brexanolone dramatically and rapidly improves severe postpartum depression with minimal adverse effects, a small manufacturer-conducted phase II trial suggests.

Brexanolone is a proprietary formulation of allopregnanolone, the major metabolite of progesterone and a potent modulator of synaptic and extrasynaptic gamma-aminobutyric acid type A (GABAA) receptors that has demonstrated profound benefits for anxiety and depression symptoms in animal models. Plasma levels of allopregnanolone rise to a peak during the third trimester of pregnancy, then abruptly fall after childbirth. “Failure of GABAA receptors to adapt to these changes at parturition has been postulated to have a role in triggering postpartum depression,” said Stephen Kanes, MD, of Sage Therapeutics, Cambridge, Mass., and his associates.

They assessed the drug’s effects in 21 women hospitalized for severe postpartum depression at 11 U.S. medical centers during a 5-month period. The study participants, who had Hamilton Rating Scale for Depression (HAM-D) scores of 26 or higher at baseline, randomized to receive a 60-hour infusion of brexanolone (10 patients) or a matching placebo (11 patients) in a double-blind fashion.

The primary outcome measure – mean reduction in HAM-D score at the end of the 60-hour infusion – was 21.0 points with brexanolone, significantly greater than the 8.8 point reduction seen with placebo. Women in the active-treatment group began showing a marked improvement within 24 hours of beginning the infusion, which was maintained throughout the week of treatment, as well as for the succeeding 30 days of follow-up.

Of the 10 patients, 7 receiving brexanolone (70%), compared with only 1 of those receiving placebo (9%), achieved remission of depression (HAM-D score of 7 or less) by the end of treatment. That remission occurred within 24 hours of beginning the infusion in six of the women in the brexanolone group. Moreover, improvement extended beyond the core depressive symptoms, with women in the active-treatment group also showing rapid and marked improvement on Clinical Global Impression–Improvement Scale scores, the investigators said (Lancet. 2017 Jun 12. doi: 10.1016/S0140-67369(17)31264-3).

Two women who received brexanolone admitted that, at baseline, they’d had active suicidal ideation with a specific plan and intent. Neither was suicidal after treatment.

Brexanolone was well-tolerated, with no serious adverse events or treatment discontinuations. Fewer patients who received active treatment (4) than placebo (8) reported mild adverse events. The most frequently reported adverse effects of brexanolone were dizziness and somnolence.

Among the limitations cited by the investigators was the use of a “very strict definition of postpartum depression” (HAM-D scores greater than or equal to 26).

Dr. Kanes and his associates reported that a phase III study currently underway is looking into the possible use of brexanolone in women with “varying degrees of severity.”

“Our findings provide the first placebo-controlled clinical support for the role of extrasynaptic GABAA receptors in the modulation of mood and affective states in any clinical population. The large effect size seen in this trial contrasts with that observed in studies of currently available and widely used antidepressants, including [selective serotonin reuptake inhibitors], [selective norepinephrine reuptake inhibitors], and tricyclics,” Dr. Kanes and his associates noted.

A single 60-hour infusion of brexanolone dramatically and rapidly improves severe postpartum depression with minimal adverse effects, a small manufacturer-conducted phase II trial suggests.

Brexanolone is a proprietary formulation of allopregnanolone, the major metabolite of progesterone and a potent modulator of synaptic and extrasynaptic gamma-aminobutyric acid type A (GABAA) receptors that has demonstrated profound benefits for anxiety and depression symptoms in animal models. Plasma levels of allopregnanolone rise to a peak during the third trimester of pregnancy, then abruptly fall after childbirth. “Failure of GABAA receptors to adapt to these changes at parturition has been postulated to have a role in triggering postpartum depression,” said Stephen Kanes, MD, of Sage Therapeutics, Cambridge, Mass., and his associates.

They assessed the drug’s effects in 21 women hospitalized for severe postpartum depression at 11 U.S. medical centers during a 5-month period. The study participants, who had Hamilton Rating Scale for Depression (HAM-D) scores of 26 or higher at baseline, randomized to receive a 60-hour infusion of brexanolone (10 patients) or a matching placebo (11 patients) in a double-blind fashion.

The primary outcome measure – mean reduction in HAM-D score at the end of the 60-hour infusion – was 21.0 points with brexanolone, significantly greater than the 8.8 point reduction seen with placebo. Women in the active-treatment group began showing a marked improvement within 24 hours of beginning the infusion, which was maintained throughout the week of treatment, as well as for the succeeding 30 days of follow-up.

Of the 10 patients, 7 receiving brexanolone (70%), compared with only 1 of those receiving placebo (9%), achieved remission of depression (HAM-D score of 7 or less) by the end of treatment. That remission occurred within 24 hours of beginning the infusion in six of the women in the brexanolone group. Moreover, improvement extended beyond the core depressive symptoms, with women in the active-treatment group also showing rapid and marked improvement on Clinical Global Impression–Improvement Scale scores, the investigators said (Lancet. 2017 Jun 12. doi: 10.1016/S0140-67369(17)31264-3).

Two women who received brexanolone admitted that, at baseline, they’d had active suicidal ideation with a specific plan and intent. Neither was suicidal after treatment.

Brexanolone was well-tolerated, with no serious adverse events or treatment discontinuations. Fewer patients who received active treatment (4) than placebo (8) reported mild adverse events. The most frequently reported adverse effects of brexanolone were dizziness and somnolence.

Among the limitations cited by the investigators was the use of a “very strict definition of postpartum depression” (HAM-D scores greater than or equal to 26).

Dr. Kanes and his associates reported that a phase III study currently underway is looking into the possible use of brexanolone in women with “varying degrees of severity.”

“Our findings provide the first placebo-controlled clinical support for the role of extrasynaptic GABAA receptors in the modulation of mood and affective states in any clinical population. The large effect size seen in this trial contrasts with that observed in studies of currently available and widely used antidepressants, including [selective serotonin reuptake inhibitors], [selective norepinephrine reuptake inhibitors], and tricyclics,” Dr. Kanes and his associates noted.