Hormone therapy, in the form of estrogen combined with progestin, is not recommended to prevent chronic conditions such as heart disease and diabetes in postmenopausal women, according to updated draft recommendations from the U.S. Preventive Services Task Force. They also recommended against the use of estrogen alone in postmenopausal women who have had a hysterectomy.

The updated recommendations were published online May 16 on the U.S. Preventive Services Task Force website.

After considering new evidence in the last several years, the recommendations are essentially unchanged from the final recommendations published in 2012, according to a Task Force statement published with the recommendations. “The benefits of using menopausal hormone therapy to prevent chronic conditions like heart disease and diabetes do not outweigh the harms in women who have gone through menopause,” Maureen G. Phipps, MD, MPH, a task force member, said in the statement.

The draft recommendations were based on a review of 17 randomized clinical trials published through Aug. 1, 2016, that included data from the Women’s Health Initiative.

Women taking estrogen/progestin reported a significantly lower risk (per 10,000 women approximately 5 years) of colorectal cancer, diabetes, and fractures, compared with women on a placebo, wrote Gerald Gartlehner, MD, and his colleagues at the RTI International–University of North Carolina Evidence-Based Practice Center in Research Triangle Park, NC, in the evidence report accompanying the draft recommendations.

However, the risks for several other conditions were significantly higher among women on hormone therapy, compared with placebo, including invasive breast cancer (52 more cases), coronary heart disease (41 more cases) probable dementia (88 more cases), gallbladder disease (259 more cases), stroke (53 more cases), and venous thromboembolism (120 more cases). Additionally, urinary incontinence rates were higher after a 1-year follow up among women on hormone therapy (876 more cases/10,000 women).

Some evidence suggests that women who began hormone therapy closer to menopause might have a lower risk for developing cardiovascular complications, but the evidence is insufficient for firm conclusions, the researchers wrote.

The recommendations against hormone therapy do not apply to women younger than 50 years who have undergone oophorectomies or premature menopause, or to those considering hormone therapy to manage menopausal symptoms, according to the Task Force.

Public comments on the draft recommendations may be submitted on the Task Force website until June 12. The researchers had no financial conflicts to disclose.

View the recommendations online at uspreventiveservicestaskforce.org.

[email protected]

Hormone therapy, in the form of estrogen combined with progestin, is not recommended to prevent chronic conditions such as heart disease and diabetes in postmenopausal women, according to updated draft recommendations from the U.S. Preventive Services Task Force. They also recommended against the use of estrogen alone in postmenopausal women who have had a hysterectomy.

The updated recommendations were published online May 16 on the U.S. Preventive Services Task Force website.

After considering new evidence in the last several years, the recommendations are essentially unchanged from the final recommendations published in 2012, according to a Task Force statement published with the recommendations. “The benefits of using menopausal hormone therapy to prevent chronic conditions like heart disease and diabetes do not outweigh the harms in women who have gone through menopause,” Maureen G. Phipps, MD, MPH, a task force member, said in the statement.

The draft recommendations were based on a review of 17 randomized clinical trials published through Aug. 1, 2016, that included data from the Women’s Health Initiative.

Women taking estrogen/progestin reported a significantly lower risk (per 10,000 women approximately 5 years) of colorectal cancer, diabetes, and fractures, compared with women on a placebo, wrote Gerald Gartlehner, MD, and his colleagues at the RTI International–University of North Carolina Evidence-Based Practice Center in Research Triangle Park, NC, in the evidence report accompanying the draft recommendations.

However, the risks for several other conditions were significantly higher among women on hormone therapy, compared with placebo, including invasive breast cancer (52 more cases), coronary heart disease (41 more cases) probable dementia (88 more cases), gallbladder disease (259 more cases), stroke (53 more cases), and venous thromboembolism (120 more cases). Additionally, urinary incontinence rates were higher after a 1-year follow up among women on hormone therapy (876 more cases/10,000 women).

Some evidence suggests that women who began hormone therapy closer to menopause might have a lower risk for developing cardiovascular complications, but the evidence is insufficient for firm conclusions, the researchers wrote.

The recommendations against hormone therapy do not apply to women younger than 50 years who have undergone oophorectomies or premature menopause, or to those considering hormone therapy to manage menopausal symptoms, according to the Task Force.

Public comments on the draft recommendations may be submitted on the Task Force website until June 12. The researchers had no financial conflicts to disclose.

View the recommendations online at uspreventiveservicestaskforce.org.

[email protected]

Hormone therapy, in the form of estrogen combined with progestin, is not recommended to prevent chronic conditions such as heart disease and diabetes in postmenopausal women, according to updated draft recommendations from the U.S. Preventive Services Task Force. They also recommended against the use of estrogen alone in postmenopausal women who have had a hysterectomy.

The updated recommendations were published online May 16 on the U.S. Preventive Services Task Force website.

After considering new evidence in the last several years, the recommendations are essentially unchanged from the final recommendations published in 2012, according to a Task Force statement published with the recommendations. “The benefits of using menopausal hormone therapy to prevent chronic conditions like heart disease and diabetes do not outweigh the harms in women who have gone through menopause,” Maureen G. Phipps, MD, MPH, a task force member, said in the statement.

The draft recommendations were based on a review of 17 randomized clinical trials published through Aug. 1, 2016, that included data from the Women’s Health Initiative.

Women taking estrogen/progestin reported a significantly lower risk (per 10,000 women approximately 5 years) of colorectal cancer, diabetes, and fractures, compared with women on a placebo, wrote Gerald Gartlehner, MD, and his colleagues at the RTI International–University of North Carolina Evidence-Based Practice Center in Research Triangle Park, NC, in the evidence report accompanying the draft recommendations.

However, the risks for several other conditions were significantly higher among women on hormone therapy, compared with placebo, including invasive breast cancer (52 more cases), coronary heart disease (41 more cases) probable dementia (88 more cases), gallbladder disease (259 more cases), stroke (53 more cases), and venous thromboembolism (120 more cases). Additionally, urinary incontinence rates were higher after a 1-year follow up among women on hormone therapy (876 more cases/10,000 women).

Some evidence suggests that women who began hormone therapy closer to menopause might have a lower risk for developing cardiovascular complications, but the evidence is insufficient for firm conclusions, the researchers wrote.

The recommendations against hormone therapy do not apply to women younger than 50 years who have undergone oophorectomies or premature menopause, or to those considering hormone therapy to manage menopausal symptoms, according to the Task Force.

Public comments on the draft recommendations may be submitted on the Task Force website until June 12. The researchers had no financial conflicts to disclose.

View the recommendations online at uspreventiveservicestaskforce.org.

[email protected]

SAN DIEGO – Women who have preeclampsia are at increased risk for later cardiovascular disease, yet internists performing well-woman exams were unlikely to have asked their patients about a history of preeclampsia, a small study showed.

Just 21 of 89 women were asked about preeclampsia during a well-woman exam, while 88 of 89 were asked about diabetes or smoking history, and all 89 were asked about hypertension (P = .0002 for comparing preeclampsia to each individual comorbidity).

“There is a screening gap leading to missed opportunities to identify women at risk for cardiovascular disease,” Irene Lewnard, MD, said at the annual meeting of the American College of Obstetricians and Gynecologists.

[email protected]

On Twitter @karioakes

SAN DIEGO – Women who have preeclampsia are at increased risk for later cardiovascular disease, yet internists performing well-woman exams were unlikely to have asked their patients about a history of preeclampsia, a small study showed.

Just 21 of 89 women were asked about preeclampsia during a well-woman exam, while 88 of 89 were asked about diabetes or smoking history, and all 89 were asked about hypertension (P = .0002 for comparing preeclampsia to each individual comorbidity).

“There is a screening gap leading to missed opportunities to identify women at risk for cardiovascular disease,” Irene Lewnard, MD, said at the annual meeting of the American College of Obstetricians and Gynecologists.

[email protected]

On Twitter @karioakes

SAN DIEGO – Women who have preeclampsia are at increased risk for later cardiovascular disease, yet internists performing well-woman exams were unlikely to have asked their patients about a history of preeclampsia, a small study showed.

Just 21 of 89 women were asked about preeclampsia during a well-woman exam, while 88 of 89 were asked about diabetes or smoking history, and all 89 were asked about hypertension (P = .0002 for comparing preeclampsia to each individual comorbidity).

“There is a screening gap leading to missed opportunities to identify women at risk for cardiovascular disease,” Irene Lewnard, MD, said at the annual meeting of the American College of Obstetricians and Gynecologists.

[email protected]

On Twitter @karioakes

High-dose oral iron therapy doesn’t improve exercise capacity in the estimated 50% of patients with symptomatic heart failure who also have iron deficiency, according to a report published online May 16 in JAMA.

Iron deficiency in patients with HF, regardless of their hemoglobin status, is associated with reduced functional capacity, poorer quality of life, and increased mortality. Iron plays a crucial role in the delivery and utilization of oxygen, and “cells with high-energy demands, including skeletal and cardiac myocytes, are particularly sensitive to depleted iron stores,” said Gregory D. Lewis, MD, of the pulmonary critical care unit of Massachusetts General Hospital, Boston, and his associates.

Saipg/iStockphoto

High-dose oral iron therapy doesn’t improve exercise capacity in the estimated 50% of patients with symptomatic heart failure who also have iron deficiency, according to a report published online May 16 in JAMA.

Iron deficiency in patients with HF, regardless of their hemoglobin status, is associated with reduced functional capacity, poorer quality of life, and increased mortality. Iron plays a crucial role in the delivery and utilization of oxygen, and “cells with high-energy demands, including skeletal and cardiac myocytes, are particularly sensitive to depleted iron stores,” said Gregory D. Lewis, MD, of the pulmonary critical care unit of Massachusetts General Hospital, Boston, and his associates.

Saipg/iStockphoto

High-dose oral iron therapy doesn’t improve exercise capacity in the estimated 50% of patients with symptomatic heart failure who also have iron deficiency, according to a report published online May 16 in JAMA.

Iron deficiency in patients with HF, regardless of their hemoglobin status, is associated with reduced functional capacity, poorer quality of life, and increased mortality. Iron plays a crucial role in the delivery and utilization of oxygen, and “cells with high-energy demands, including skeletal and cardiac myocytes, are particularly sensitive to depleted iron stores,” said Gregory D. Lewis, MD, of the pulmonary critical care unit of Massachusetts General Hospital, Boston, and his associates.

Saipg/iStockphoto

As psychiatrists, we are the advocates for inserting the biological thread into the tapestry of understanding human behavior. Try as they may, other mental health professionals are not biologists at heart. Accordingly, psychiatrists bring important thoughtfulness to any consideration about mental health and wellness and about the treatment and prevention of problematic thoughts, feelings, and behaviors.

Throughout my career, my main focus has been on identifying strategies and treatments that can prevent mental illness. For example, I wrote a column about prevention for Clinical Psychiatry News from 2004 to 2011, and, as a member of the publication’s Editorial Advisory Board, I continue to try to steer our attention to biological aspects of prevention.

Dr. Bell is a staff psychiatrist at Jackson Park Hospital Family Medicine Clinic in Chicago, clinical psychiatrist emeritus in the department of psychiatry at the University of Illinois at Chicago, former president/CEO of Community Mental Health Council, and former director of the Institute for Juvenile Research (birthplace of child psychiatry), also in Chicago.

As psychiatrists, we are the advocates for inserting the biological thread into the tapestry of understanding human behavior. Try as they may, other mental health professionals are not biologists at heart. Accordingly, psychiatrists bring important thoughtfulness to any consideration about mental health and wellness and about the treatment and prevention of problematic thoughts, feelings, and behaviors.

Throughout my career, my main focus has been on identifying strategies and treatments that can prevent mental illness. For example, I wrote a column about prevention for Clinical Psychiatry News from 2004 to 2011, and, as a member of the publication’s Editorial Advisory Board, I continue to try to steer our attention to biological aspects of prevention.

Dr. Bell is a staff psychiatrist at Jackson Park Hospital Family Medicine Clinic in Chicago, clinical psychiatrist emeritus in the department of psychiatry at the University of Illinois at Chicago, former president/CEO of Community Mental Health Council, and former director of the Institute for Juvenile Research (birthplace of child psychiatry), also in Chicago.

As psychiatrists, we are the advocates for inserting the biological thread into the tapestry of understanding human behavior. Try as they may, other mental health professionals are not biologists at heart. Accordingly, psychiatrists bring important thoughtfulness to any consideration about mental health and wellness and about the treatment and prevention of problematic thoughts, feelings, and behaviors.

Throughout my career, my main focus has been on identifying strategies and treatments that can prevent mental illness. For example, I wrote a column about prevention for Clinical Psychiatry News from 2004 to 2011, and, as a member of the publication’s Editorial Advisory Board, I continue to try to steer our attention to biological aspects of prevention.

Dr. Bell is a staff psychiatrist at Jackson Park Hospital Family Medicine Clinic in Chicago, clinical psychiatrist emeritus in the department of psychiatry at the University of Illinois at Chicago, former president/CEO of Community Mental Health Council, and former director of the Institute for Juvenile Research (birthplace of child psychiatry), also in Chicago.

AMSTERDAM – Determining the ratio of neutrophils to leukocytes in the blood could help identify patients with alcoholic hepatitis that would and would not benefit from steroid treatment.

Patients who had a neutrophil to lymphocyte ratio (NLR) of between 5 and 8 before being treated with the corticosteroid prednisolone appeared to obtain a benefit versus no-steroid treatment (P = .007) while those with higher and lower NLR values did not, in an analysis presented at the International Liver Congress.

Martynasfoto/Thinkstock

[email protected]

AMSTERDAM – Determining the ratio of neutrophils to leukocytes in the blood could help identify patients with alcoholic hepatitis that would and would not benefit from steroid treatment.

Patients who had a neutrophil to lymphocyte ratio (NLR) of between 5 and 8 before being treated with the corticosteroid prednisolone appeared to obtain a benefit versus no-steroid treatment (P = .007) while those with higher and lower NLR values did not, in an analysis presented at the International Liver Congress.

Martynasfoto/Thinkstock

[email protected]

AMSTERDAM – Determining the ratio of neutrophils to leukocytes in the blood could help identify patients with alcoholic hepatitis that would and would not benefit from steroid treatment.

Patients who had a neutrophil to lymphocyte ratio (NLR) of between 5 and 8 before being treated with the corticosteroid prednisolone appeared to obtain a benefit versus no-steroid treatment (P = .007) while those with higher and lower NLR values did not, in an analysis presented at the International Liver Congress.

Martynasfoto/Thinkstock

[email protected]

Fort Belvoir Community Hospital surgeons have performed the first small-incision lenticule extraction (SMILE) in the DoD, according to Health.mil News. The procedure to reduce or eliminate nearsightedness has been performed since 2011; the FDA recently approved it for the U.S.

The very fast and short-pulsed (femtosecond) laser creates a thin disc within the cornea, which is removed through a cut on the corneal surface. Removing the tissue changes the shape of the cornea.

The procedure takes 15 to 20 minutes with the laser activated for about 90 seconds per eye. Both eyes can be treated in the same session. With SMILE, unlike LASIK, no tissue is vaporized, meaning wound recovery time is faster, and with no corneal flap created, there is no risk of flap dislocation.

A clinical study found complications were rare, and by month 12 postsurgery there were only 4 reports of moderate or severe glare and 1 of moderate or severe halos. The most commonly reported effects were starbursts, blurred vision, and difficulty judging distance or depth perception, but at 12 months, more patients reported improvement than worsening. At the 6-month follow-up, 287 of 328 patients were seeing 20/20 or better without glasses.

“We are thrilled to extend this treatment option to active duty service members under the Warfighter Refractive Eye Surgery Program,” said U.S. Army Lt. Col. Bruce Rivers, director of the program at Belvoir Hospital.

The surgery will make a difference for patients. One of the first to have it done, Navy Petty Officer 1st Class Christopher Mahmood, a submarine mechanic, said, “On a submarine we have to be able to put our breathing equipment on in approximately 30 seconds, in case of emergency. Glasses make this difficult. Getting this surgery means I have one less thing to worry about while deployed and can focus 100 percent on the mission.”

The SMILE procedure will be available at Belvoir Hospital, San Diego Naval Medical Center, and Wilford Hall in San Antonio.

Fort Belvoir Community Hospital surgeons have performed the first small-incision lenticule extraction (SMILE) in the DoD, according to Health.mil News. The procedure to reduce or eliminate nearsightedness has been performed since 2011; the FDA recently approved it for the U.S.

The very fast and short-pulsed (femtosecond) laser creates a thin disc within the cornea, which is removed through a cut on the corneal surface. Removing the tissue changes the shape of the cornea.

The procedure takes 15 to 20 minutes with the laser activated for about 90 seconds per eye. Both eyes can be treated in the same session. With SMILE, unlike LASIK, no tissue is vaporized, meaning wound recovery time is faster, and with no corneal flap created, there is no risk of flap dislocation.

A clinical study found complications were rare, and by month 12 postsurgery there were only 4 reports of moderate or severe glare and 1 of moderate or severe halos. The most commonly reported effects were starbursts, blurred vision, and difficulty judging distance or depth perception, but at 12 months, more patients reported improvement than worsening. At the 6-month follow-up, 287 of 328 patients were seeing 20/20 or better without glasses.

“We are thrilled to extend this treatment option to active duty service members under the Warfighter Refractive Eye Surgery Program,” said U.S. Army Lt. Col. Bruce Rivers, director of the program at Belvoir Hospital.

The surgery will make a difference for patients. One of the first to have it done, Navy Petty Officer 1st Class Christopher Mahmood, a submarine mechanic, said, “On a submarine we have to be able to put our breathing equipment on in approximately 30 seconds, in case of emergency. Glasses make this difficult. Getting this surgery means I have one less thing to worry about while deployed and can focus 100 percent on the mission.”

The SMILE procedure will be available at Belvoir Hospital, San Diego Naval Medical Center, and Wilford Hall in San Antonio.

Fort Belvoir Community Hospital surgeons have performed the first small-incision lenticule extraction (SMILE) in the DoD, according to Health.mil News. The procedure to reduce or eliminate nearsightedness has been performed since 2011; the FDA recently approved it for the U.S.

The very fast and short-pulsed (femtosecond) laser creates a thin disc within the cornea, which is removed through a cut on the corneal surface. Removing the tissue changes the shape of the cornea.

The procedure takes 15 to 20 minutes with the laser activated for about 90 seconds per eye. Both eyes can be treated in the same session. With SMILE, unlike LASIK, no tissue is vaporized, meaning wound recovery time is faster, and with no corneal flap created, there is no risk of flap dislocation.

A clinical study found complications were rare, and by month 12 postsurgery there were only 4 reports of moderate or severe glare and 1 of moderate or severe halos. The most commonly reported effects were starbursts, blurred vision, and difficulty judging distance or depth perception, but at 12 months, more patients reported improvement than worsening. At the 6-month follow-up, 287 of 328 patients were seeing 20/20 or better without glasses.

“We are thrilled to extend this treatment option to active duty service members under the Warfighter Refractive Eye Surgery Program,” said U.S. Army Lt. Col. Bruce Rivers, director of the program at Belvoir Hospital.

The surgery will make a difference for patients. One of the first to have it done, Navy Petty Officer 1st Class Christopher Mahmood, a submarine mechanic, said, “On a submarine we have to be able to put our breathing equipment on in approximately 30 seconds, in case of emergency. Glasses make this difficult. Getting this surgery means I have one less thing to worry about while deployed and can focus 100 percent on the mission.”

The SMILE procedure will be available at Belvoir Hospital, San Diego Naval Medical Center, and Wilford Hall in San Antonio.

Pyogenic flexor tenosynovitis (PFT) is a common closed space infection of the flexor tendon sheaths of the hand and remains one of the most challenging problems encountered in orthopedic and hand surgery (Figure 1). PFT also is known as septic flexor tenosynovitis and suppurative flexor tenosynovitis.

Kanavel¹ initially described 4 cardinal signs that characterize infection of the flexor tendon sheath: symmetric fusiform swelling of the entire digit, exquisite tenderness to palpation along the course of the tendon sheath, semiflexed posture at rest, and pain with attempted passive extension of the digit. The prevalence of this infection ranges from 2.5% to 9.4%.² Once the infection is established in a patient, it can cause significant morbidity and disability and produce an economic burden. It can also present a significant treatment dilemma for the treating surgeon, as there is no standardized protocol for managing this common but challenging hand infection. For treatment, many surgeons combine surgical decompression, sheath irrigation, and empiric intravenous (IV) antibiotic administration. However, despite prompt treatment, and regardless of the protocol used, complication rates as high as 38% have been reported.³ Moreover, even after infection eradication, a significant proportion of patients continue to have pain, swelling, stiffness, loss of composite flexion, weakness, and recurrence that potentially requires amputation.

1. What Causes Pyogenic Flexor Tenosynovitis?

PFT can result from hematogenous spread, but local inoculation by a laceration, a puncture, or a bite also is common^4-7 (Figure 1). As a consequence of these mechanisms of injury, the most common source of PFT is skin flora. Staphylococcus aureus has been found in up to 75% of positive cultures in several studies.^2,5,6,8,9 Methicillin-resistant S aureus (MRSA) has been found in up to 29% of cases, and the incidence continues to increase, particularly in urban areas.^2,9-12 Other common bacteria are Staphylococcus epidermidis, β-hemolytic Streptococcus species, and Pseudomonas aeruginosa.^5,6,10 Infection by more than 1 species of bacteria is also fairly prevalent. Of 62 patients in a study, 38% had infections with 1 organism, and 62% with 2 or more.⁶ Twenty-six percent of cultures grew mixed anaerobic and aerobic organisms.⁶ PFT is seldom caused by Eikenella corrodens from a human bite or Pasteurella multocida from an animal bite.¹⁰ Other rare causes of PFT are Listeria monocytogenes¹³ and Clostridium difficile from a gastrointestinal source.¹⁴Neisseria gonorrhea can cause acute tenosynovitis, usually in the setting of disseminated gonococcal infection.^15,16 Also reported is mycobacterial tenosynovitis, most commonly caused by Mycobacterium kansasii and Mycobacterium marinum.¹⁷

2. Which Antibiotics Are Best Suited to Empirical Management of PFT?

Management of PFT, regardless of the pathogen, includes prompt administration of empiric IV antibiotics, usually followed by surgical drainage.^7,18-20 While cultures are being tested, antibiotics should be selected—including antibiotics for empiric coverage against common gram-positive organisms, including Staphylococcus and Streptococcus species.¹² The Centers for Disease Control and Prevention recommends empiric coverage for MRSA if the local prevalence exceeds 10% to 15%. Recommended empiric antibiotics are trimethoprim-sulfamethoxazole (TMP-SMX) and clindamycin (both oral) and clindamycin, vancomycin, and daptomycin (all IV).

In addition, institutional and local antibiotic resistance patterns of bacteria should guide treatment and antibiotic selection. First-generation cephalosporins have long been the cornerstone of treatment for infections caused by S aureus, but increasing methicillin resistance has reduced their role in the treatment, particularly the empiric treatment, of MRSA infections. Methicillin resistance first appeared as nosocomial S aureus infections in 1961, only 1 year after the introduction of the semisynthetic penicillin class that includes methicillin. Over the past 2 decades, MRSA has emerged in the community in otherwise young and healthy individuals with no healthcare-associated risk factors. Fortunately, several readily available antibiotics have maintained their efficacy in managing these “community-acquired” MRSA hand infections. TMP-SMX provides adequate coverage for MRSA and is a relatively inexpensive medication, and clindamycin is an equally effective and cost-effective alternative.

Presumptive antibiotics should also cover gram-negative rods and anaerobes, including Clostridium species, especially in immunocompromised patients.^7,9 These patients may require additional antibiotics for presumptive coverage of other rarer bacterial causes, especially when unique mechanisms of injury (eg, aquatic injury, farm injury) are involved. Once culture results are ready, antibiotic regimens should be narrowed to cover the specific organisms identified.

3. What Are the Timing and Indications for Surgery?

Nonoperative treatment may be appropriate for PFT patients who present early, typically within 48 hours after penetrating trauma to the hand.²¹ In a 4-patient series, Neviaser and Gunther¹⁹ successfully treated PFT nonoperatively, with IV antibiotics, splinting, and elevation. During nonoperative treatment, the affected hand should be regularly examined. If this treatment is to be successful, clinical symptoms should improve within 48 hours; if they do not, surgical irrigation and débridement should be performed.

Regardless of timing and type of irrigation, surgical treatment remains the treatment of choice for the majority of PFT cases. Michon²² developed a 3-tier PFT classification system that is based on intraoperative findings (Table).

4. What Are the Surgical Techniques for PFT Drainage?

Several surgical methods have been developed to decompress and irrigate the flexor sheaths of the hand. However, debates about optimal timing of surgical intervention, surgery type (open surgery or closed catheter irrigation only), and irrigation method continue.

Open Irrigation and Débridement

Open irrigation and débridement procedures were originally described for surgical management of PFT.¹ Midaxial and palmar (Bruner zigzag) incisions can be used to expose and open the entire sheath for complete drainage and washout. Both incisions afford good access to the flexor sheath, but the midaxial approach may provide more coverage of the sheath after surgery. Open irrigation and débridement is the treatment of choice for the most advanced cases of PFT and for atypical or chronic tenosynovial infections.^4,23,24 The Bruner zigzag incision affords ease of surgical dissection, extension, and more exposure of the flexor tendon sheath at the expense of possible difficulty in closure or flap necrosis in the setting of a swollen digit. Alternatively, the midaxial incision has the advantage of a large, more robust skin flap for more reliable closure.

Closed Tendon Sheath Irrigation

In 1943, Dickson-Wright²⁵ first described catheter irrigation of tendon sheath infections. Later, Neviaser⁴ described this technique in detail. A proximal incision is made over the metacarpal neck. The tendon sheath is cut transversely at the proximal edge of the A1 pulley. An angiocatheter is inserted 1 cm to 2 cm antegrade into the flexor tendon sheath. Then, a distal midaxial incision is made dorsal to the neurovascular bundle at the level of the distal interphalangeal joint on the ulnar aspect of the finger or the radial aspect of the thumb. The distal edge of the flexor sheath is exposed and resected distal to the distal-most pulley. A Penrose drain can be threaded into the tendon sheath beneath the A4 pulley to keep the wound open and allow for fluid drainage. The sheath is flushed gently in the operating room. After surgery, intermittent bedside irrigation can be continued on the floor.

Neviaser⁴ reported excellent initial results with this technique; 18 of 20 patients regained complete active and passive range of motion (ROM) by 1 week after surgery. Similarly, Juliano and Eglseder,²⁶ using a similar method, reported 100% excellent results for mild PFT and 88.4% excellent results for more severe infection.

Gutowski and colleagues²³ reviewed 47 PFT cases to determine if there is a difference in outcomes between PFT treated with open irrigation and débridement and PFT treated with closed catheter irrigation. Between these groups, they found no significant differences in early postoperative outcomes, including resolution of infection, need for additional surgery, and hospital length of stay.

There are also many differing opinions regarding the best irrigation method. Some authors have asserted that normal saline is sufficient,^4,5,23 and others that local antibiotics provide added benefit.^27-29 Recently, Draeger and colleagues³⁰ reported promising results with local injection of antibiotics into the tendon sheath and the addition of locally administered corticosteroids in the treatment of PFT in an animal model.

Continuous Closed Irrigation

A continuous closed irrigation system with inlet and outlet tubes has yielded successful results.^8,31,32 This system consists of 2 fenestrated tubes placed within the infected space, with the tip of the smaller caliber inlet tube positioned just inside the larger outlet tube. Advantages of this system include the patient’s ability to participate in hand therapy with the system in place and avoidance of pain caused by the high pressures involved in intermittent closed irrigation. Duration of this system has ranged from 2 days to 3 weeks, and results have been good.^5,8

Postoperative Irrigation

Use of postoperative irrigation on the floor or at home is controversial, as leaving an indwelling catheter in the tendon sheath can lead to complications. Catheters may increase digital stiffness by decreasing the patient’s ability to participate in therapy or may cause additional injury and irritation to the sheath itself if left in place too long. Lille and colleagues⁶ retrospectively compared the results of intraoperative closed tendon sheath irrigation alone with those of intraoperative and postoperative closed tendon sheath irrigation. There were no significant differences in mean hospital length of stay, follow-up complication rates, or postoperative ROM—which suggests that postoperative intermittent or continuous irrigation is not necessary.

Our Preferred Technique

We recommend a palmar approach that begins with outlining a Bruner zigzag incision along the entire finger. Then, only the distal-most and proximal-most incision lines are opened, thereby exposing the A5 and A1 pulleys, respectively (Figure 2).

5. What Are the Long-Term Outcomes of PFT?

The principal complication associated with PFT is stiffness with loss of ROM, which can be caused by flexor tendon adhesions, joint capsular thickening, or destruction of the sheath and pulley system.²⁴ In several studies, up to one-fourth of patients with PFT did not obtain full ROM, despite adequate treatment.^4-6,27 Therefore, full active ROM exercises should be initiated immediately after surgery to counteract the development of stiffness.

The most severe complication of PFT is amputation of the affected digit (Figures 3A, 3B).

Conclusion

PFT is a common hand infection that can cause significant morbidity. Early treatment is crucial: this requires use of IV antibiotics, or surgical irrigation and débridement in more advanced cases. However, despite prompt and thorough treatment, severe infection can lead to long-term impaired function and even amputation of the affected digit. More research is needed to determine optimal timing and technique for surgical intervention and to elucidate the role of local antibiotics and corticosteroids in treating this infection and potentially preventing the morbid outcomes we currently see.

Am J Orthop. 2017;46(3):E207-E212. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Pyogenic flexor tenosynovitis (PFT) is a common closed space infection of the flexor tendon sheaths of the hand and remains one of the most challenging problems encountered in orthopedic and hand surgery (Figure 1). PFT also is known as septic flexor tenosynovitis and suppurative flexor tenosynovitis.

Kanavel¹ initially described 4 cardinal signs that characterize infection of the flexor tendon sheath: symmetric fusiform swelling of the entire digit, exquisite tenderness to palpation along the course of the tendon sheath, semiflexed posture at rest, and pain with attempted passive extension of the digit. The prevalence of this infection ranges from 2.5% to 9.4%.² Once the infection is established in a patient, it can cause significant morbidity and disability and produce an economic burden. It can also present a significant treatment dilemma for the treating surgeon, as there is no standardized protocol for managing this common but challenging hand infection. For treatment, many surgeons combine surgical decompression, sheath irrigation, and empiric intravenous (IV) antibiotic administration. However, despite prompt treatment, and regardless of the protocol used, complication rates as high as 38% have been reported.³ Moreover, even after infection eradication, a significant proportion of patients continue to have pain, swelling, stiffness, loss of composite flexion, weakness, and recurrence that potentially requires amputation.

1. What Causes Pyogenic Flexor Tenosynovitis?

PFT can result from hematogenous spread, but local inoculation by a laceration, a puncture, or a bite also is common^4-7 (Figure 1). As a consequence of these mechanisms of injury, the most common source of PFT is skin flora. Staphylococcus aureus has been found in up to 75% of positive cultures in several studies.^2,5,6,8,9 Methicillin-resistant S aureus (MRSA) has been found in up to 29% of cases, and the incidence continues to increase, particularly in urban areas.^2,9-12 Other common bacteria are Staphylococcus epidermidis, β-hemolytic Streptococcus species, and Pseudomonas aeruginosa.^5,6,10 Infection by more than 1 species of bacteria is also fairly prevalent. Of 62 patients in a study, 38% had infections with 1 organism, and 62% with 2 or more.⁶ Twenty-six percent of cultures grew mixed anaerobic and aerobic organisms.⁶ PFT is seldom caused by Eikenella corrodens from a human bite or Pasteurella multocida from an animal bite.¹⁰ Other rare causes of PFT are Listeria monocytogenes¹³ and Clostridium difficile from a gastrointestinal source.¹⁴Neisseria gonorrhea can cause acute tenosynovitis, usually in the setting of disseminated gonococcal infection.^15,16 Also reported is mycobacterial tenosynovitis, most commonly caused by Mycobacterium kansasii and Mycobacterium marinum.¹⁷

2. Which Antibiotics Are Best Suited to Empirical Management of PFT?

Management of PFT, regardless of the pathogen, includes prompt administration of empiric IV antibiotics, usually followed by surgical drainage.^7,18-20 While cultures are being tested, antibiotics should be selected—including antibiotics for empiric coverage against common gram-positive organisms, including Staphylococcus and Streptococcus species.¹² The Centers for Disease Control and Prevention recommends empiric coverage for MRSA if the local prevalence exceeds 10% to 15%. Recommended empiric antibiotics are trimethoprim-sulfamethoxazole (TMP-SMX) and clindamycin (both oral) and clindamycin, vancomycin, and daptomycin (all IV).

In addition, institutional and local antibiotic resistance patterns of bacteria should guide treatment and antibiotic selection. First-generation cephalosporins have long been the cornerstone of treatment for infections caused by S aureus, but increasing methicillin resistance has reduced their role in the treatment, particularly the empiric treatment, of MRSA infections. Methicillin resistance first appeared as nosocomial S aureus infections in 1961, only 1 year after the introduction of the semisynthetic penicillin class that includes methicillin. Over the past 2 decades, MRSA has emerged in the community in otherwise young and healthy individuals with no healthcare-associated risk factors. Fortunately, several readily available antibiotics have maintained their efficacy in managing these “community-acquired” MRSA hand infections. TMP-SMX provides adequate coverage for MRSA and is a relatively inexpensive medication, and clindamycin is an equally effective and cost-effective alternative.

Presumptive antibiotics should also cover gram-negative rods and anaerobes, including Clostridium species, especially in immunocompromised patients.^7,9 These patients may require additional antibiotics for presumptive coverage of other rarer bacterial causes, especially when unique mechanisms of injury (eg, aquatic injury, farm injury) are involved. Once culture results are ready, antibiotic regimens should be narrowed to cover the specific organisms identified.

3. What Are the Timing and Indications for Surgery?

Nonoperative treatment may be appropriate for PFT patients who present early, typically within 48 hours after penetrating trauma to the hand.²¹ In a 4-patient series, Neviaser and Gunther¹⁹ successfully treated PFT nonoperatively, with IV antibiotics, splinting, and elevation. During nonoperative treatment, the affected hand should be regularly examined. If this treatment is to be successful, clinical symptoms should improve within 48 hours; if they do not, surgical irrigation and débridement should be performed.

Regardless of timing and type of irrigation, surgical treatment remains the treatment of choice for the majority of PFT cases. Michon²² developed a 3-tier PFT classification system that is based on intraoperative findings (Table).

4. What Are the Surgical Techniques for PFT Drainage?

Several surgical methods have been developed to decompress and irrigate the flexor sheaths of the hand. However, debates about optimal timing of surgical intervention, surgery type (open surgery or closed catheter irrigation only), and irrigation method continue.

Open Irrigation and Débridement

Open irrigation and débridement procedures were originally described for surgical management of PFT.¹ Midaxial and palmar (Bruner zigzag) incisions can be used to expose and open the entire sheath for complete drainage and washout. Both incisions afford good access to the flexor sheath, but the midaxial approach may provide more coverage of the sheath after surgery. Open irrigation and débridement is the treatment of choice for the most advanced cases of PFT and for atypical or chronic tenosynovial infections.^4,23,24 The Bruner zigzag incision affords ease of surgical dissection, extension, and more exposure of the flexor tendon sheath at the expense of possible difficulty in closure or flap necrosis in the setting of a swollen digit. Alternatively, the midaxial incision has the advantage of a large, more robust skin flap for more reliable closure.

Closed Tendon Sheath Irrigation

In 1943, Dickson-Wright²⁵ first described catheter irrigation of tendon sheath infections. Later, Neviaser⁴ described this technique in detail. A proximal incision is made over the metacarpal neck. The tendon sheath is cut transversely at the proximal edge of the A1 pulley. An angiocatheter is inserted 1 cm to 2 cm antegrade into the flexor tendon sheath. Then, a distal midaxial incision is made dorsal to the neurovascular bundle at the level of the distal interphalangeal joint on the ulnar aspect of the finger or the radial aspect of the thumb. The distal edge of the flexor sheath is exposed and resected distal to the distal-most pulley. A Penrose drain can be threaded into the tendon sheath beneath the A4 pulley to keep the wound open and allow for fluid drainage. The sheath is flushed gently in the operating room. After surgery, intermittent bedside irrigation can be continued on the floor.

Neviaser⁴ reported excellent initial results with this technique; 18 of 20 patients regained complete active and passive range of motion (ROM) by 1 week after surgery. Similarly, Juliano and Eglseder,²⁶ using a similar method, reported 100% excellent results for mild PFT and 88.4% excellent results for more severe infection.

Gutowski and colleagues²³ reviewed 47 PFT cases to determine if there is a difference in outcomes between PFT treated with open irrigation and débridement and PFT treated with closed catheter irrigation. Between these groups, they found no significant differences in early postoperative outcomes, including resolution of infection, need for additional surgery, and hospital length of stay.

There are also many differing opinions regarding the best irrigation method. Some authors have asserted that normal saline is sufficient,^4,5,23 and others that local antibiotics provide added benefit.^27-29 Recently, Draeger and colleagues³⁰ reported promising results with local injection of antibiotics into the tendon sheath and the addition of locally administered corticosteroids in the treatment of PFT in an animal model.

Continuous Closed Irrigation

A continuous closed irrigation system with inlet and outlet tubes has yielded successful results.^8,31,32 This system consists of 2 fenestrated tubes placed within the infected space, with the tip of the smaller caliber inlet tube positioned just inside the larger outlet tube. Advantages of this system include the patient’s ability to participate in hand therapy with the system in place and avoidance of pain caused by the high pressures involved in intermittent closed irrigation. Duration of this system has ranged from 2 days to 3 weeks, and results have been good.^5,8

Postoperative Irrigation

Use of postoperative irrigation on the floor or at home is controversial, as leaving an indwelling catheter in the tendon sheath can lead to complications. Catheters may increase digital stiffness by decreasing the patient’s ability to participate in therapy or may cause additional injury and irritation to the sheath itself if left in place too long. Lille and colleagues⁶ retrospectively compared the results of intraoperative closed tendon sheath irrigation alone with those of intraoperative and postoperative closed tendon sheath irrigation. There were no significant differences in mean hospital length of stay, follow-up complication rates, or postoperative ROM—which suggests that postoperative intermittent or continuous irrigation is not necessary.

Our Preferred Technique

We recommend a palmar approach that begins with outlining a Bruner zigzag incision along the entire finger. Then, only the distal-most and proximal-most incision lines are opened, thereby exposing the A5 and A1 pulleys, respectively (Figure 2).

5. What Are the Long-Term Outcomes of PFT?

The principal complication associated with PFT is stiffness with loss of ROM, which can be caused by flexor tendon adhesions, joint capsular thickening, or destruction of the sheath and pulley system.²⁴ In several studies, up to one-fourth of patients with PFT did not obtain full ROM, despite adequate treatment.^4-6,27 Therefore, full active ROM exercises should be initiated immediately after surgery to counteract the development of stiffness.

The most severe complication of PFT is amputation of the affected digit (Figures 3A, 3B).

Conclusion

PFT is a common hand infection that can cause significant morbidity. Early treatment is crucial: this requires use of IV antibiotics, or surgical irrigation and débridement in more advanced cases. However, despite prompt and thorough treatment, severe infection can lead to long-term impaired function and even amputation of the affected digit. More research is needed to determine optimal timing and technique for surgical intervention and to elucidate the role of local antibiotics and corticosteroids in treating this infection and potentially preventing the morbid outcomes we currently see.

Am J Orthop. 2017;46(3):E207-E212. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Pyogenic flexor tenosynovitis (PFT) is a common closed space infection of the flexor tendon sheaths of the hand and remains one of the most challenging problems encountered in orthopedic and hand surgery (Figure 1). PFT also is known as septic flexor tenosynovitis and suppurative flexor tenosynovitis.

Kanavel¹ initially described 4 cardinal signs that characterize infection of the flexor tendon sheath: symmetric fusiform swelling of the entire digit, exquisite tenderness to palpation along the course of the tendon sheath, semiflexed posture at rest, and pain with attempted passive extension of the digit. The prevalence of this infection ranges from 2.5% to 9.4%.² Once the infection is established in a patient, it can cause significant morbidity and disability and produce an economic burden. It can also present a significant treatment dilemma for the treating surgeon, as there is no standardized protocol for managing this common but challenging hand infection. For treatment, many surgeons combine surgical decompression, sheath irrigation, and empiric intravenous (IV) antibiotic administration. However, despite prompt treatment, and regardless of the protocol used, complication rates as high as 38% have been reported.³ Moreover, even after infection eradication, a significant proportion of patients continue to have pain, swelling, stiffness, loss of composite flexion, weakness, and recurrence that potentially requires amputation.

1. What Causes Pyogenic Flexor Tenosynovitis?

PFT can result from hematogenous spread, but local inoculation by a laceration, a puncture, or a bite also is common^4-7 (Figure 1). As a consequence of these mechanisms of injury, the most common source of PFT is skin flora. Staphylococcus aureus has been found in up to 75% of positive cultures in several studies.^2,5,6,8,9 Methicillin-resistant S aureus (MRSA) has been found in up to 29% of cases, and the incidence continues to increase, particularly in urban areas.^2,9-12 Other common bacteria are Staphylococcus epidermidis, β-hemolytic Streptococcus species, and Pseudomonas aeruginosa.^5,6,10 Infection by more than 1 species of bacteria is also fairly prevalent. Of 62 patients in a study, 38% had infections with 1 organism, and 62% with 2 or more.⁶ Twenty-six percent of cultures grew mixed anaerobic and aerobic organisms.⁶ PFT is seldom caused by Eikenella corrodens from a human bite or Pasteurella multocida from an animal bite.¹⁰ Other rare causes of PFT are Listeria monocytogenes¹³ and Clostridium difficile from a gastrointestinal source.¹⁴Neisseria gonorrhea can cause acute tenosynovitis, usually in the setting of disseminated gonococcal infection.^15,16 Also reported is mycobacterial tenosynovitis, most commonly caused by Mycobacterium kansasii and Mycobacterium marinum.¹⁷

2. Which Antibiotics Are Best Suited to Empirical Management of PFT?

Management of PFT, regardless of the pathogen, includes prompt administration of empiric IV antibiotics, usually followed by surgical drainage.^7,18-20 While cultures are being tested, antibiotics should be selected—including antibiotics for empiric coverage against common gram-positive organisms, including Staphylococcus and Streptococcus species.¹² The Centers for Disease Control and Prevention recommends empiric coverage for MRSA if the local prevalence exceeds 10% to 15%. Recommended empiric antibiotics are trimethoprim-sulfamethoxazole (TMP-SMX) and clindamycin (both oral) and clindamycin, vancomycin, and daptomycin (all IV).

In addition, institutional and local antibiotic resistance patterns of bacteria should guide treatment and antibiotic selection. First-generation cephalosporins have long been the cornerstone of treatment for infections caused by S aureus, but increasing methicillin resistance has reduced their role in the treatment, particularly the empiric treatment, of MRSA infections. Methicillin resistance first appeared as nosocomial S aureus infections in 1961, only 1 year after the introduction of the semisynthetic penicillin class that includes methicillin. Over the past 2 decades, MRSA has emerged in the community in otherwise young and healthy individuals with no healthcare-associated risk factors. Fortunately, several readily available antibiotics have maintained their efficacy in managing these “community-acquired” MRSA hand infections. TMP-SMX provides adequate coverage for MRSA and is a relatively inexpensive medication, and clindamycin is an equally effective and cost-effective alternative.

Presumptive antibiotics should also cover gram-negative rods and anaerobes, including Clostridium species, especially in immunocompromised patients.^7,9 These patients may require additional antibiotics for presumptive coverage of other rarer bacterial causes, especially when unique mechanisms of injury (eg, aquatic injury, farm injury) are involved. Once culture results are ready, antibiotic regimens should be narrowed to cover the specific organisms identified.

3. What Are the Timing and Indications for Surgery?

Nonoperative treatment may be appropriate for PFT patients who present early, typically within 48 hours after penetrating trauma to the hand.²¹ In a 4-patient series, Neviaser and Gunther¹⁹ successfully treated PFT nonoperatively, with IV antibiotics, splinting, and elevation. During nonoperative treatment, the affected hand should be regularly examined. If this treatment is to be successful, clinical symptoms should improve within 48 hours; if they do not, surgical irrigation and débridement should be performed.

Regardless of timing and type of irrigation, surgical treatment remains the treatment of choice for the majority of PFT cases. Michon²² developed a 3-tier PFT classification system that is based on intraoperative findings (Table).

4. What Are the Surgical Techniques for PFT Drainage?

Several surgical methods have been developed to decompress and irrigate the flexor sheaths of the hand. However, debates about optimal timing of surgical intervention, surgery type (open surgery or closed catheter irrigation only), and irrigation method continue.

Open Irrigation and Débridement

Open irrigation and débridement procedures were originally described for surgical management of PFT.¹ Midaxial and palmar (Bruner zigzag) incisions can be used to expose and open the entire sheath for complete drainage and washout. Both incisions afford good access to the flexor sheath, but the midaxial approach may provide more coverage of the sheath after surgery. Open irrigation and débridement is the treatment of choice for the most advanced cases of PFT and for atypical or chronic tenosynovial infections.^4,23,24 The Bruner zigzag incision affords ease of surgical dissection, extension, and more exposure of the flexor tendon sheath at the expense of possible difficulty in closure or flap necrosis in the setting of a swollen digit. Alternatively, the midaxial incision has the advantage of a large, more robust skin flap for more reliable closure.

Closed Tendon Sheath Irrigation

In 1943, Dickson-Wright²⁵ first described catheter irrigation of tendon sheath infections. Later, Neviaser⁴ described this technique in detail. A proximal incision is made over the metacarpal neck. The tendon sheath is cut transversely at the proximal edge of the A1 pulley. An angiocatheter is inserted 1 cm to 2 cm antegrade into the flexor tendon sheath. Then, a distal midaxial incision is made dorsal to the neurovascular bundle at the level of the distal interphalangeal joint on the ulnar aspect of the finger or the radial aspect of the thumb. The distal edge of the flexor sheath is exposed and resected distal to the distal-most pulley. A Penrose drain can be threaded into the tendon sheath beneath the A4 pulley to keep the wound open and allow for fluid drainage. The sheath is flushed gently in the operating room. After surgery, intermittent bedside irrigation can be continued on the floor.

Neviaser⁴ reported excellent initial results with this technique; 18 of 20 patients regained complete active and passive range of motion (ROM) by 1 week after surgery. Similarly, Juliano and Eglseder,²⁶ using a similar method, reported 100% excellent results for mild PFT and 88.4% excellent results for more severe infection.

Gutowski and colleagues²³ reviewed 47 PFT cases to determine if there is a difference in outcomes between PFT treated with open irrigation and débridement and PFT treated with closed catheter irrigation. Between these groups, they found no significant differences in early postoperative outcomes, including resolution of infection, need for additional surgery, and hospital length of stay.

There are also many differing opinions regarding the best irrigation method. Some authors have asserted that normal saline is sufficient,^4,5,23 and others that local antibiotics provide added benefit.^27-29 Recently, Draeger and colleagues³⁰ reported promising results with local injection of antibiotics into the tendon sheath and the addition of locally administered corticosteroids in the treatment of PFT in an animal model.

Continuous Closed Irrigation

A continuous closed irrigation system with inlet and outlet tubes has yielded successful results.^8,31,32 This system consists of 2 fenestrated tubes placed within the infected space, with the tip of the smaller caliber inlet tube positioned just inside the larger outlet tube. Advantages of this system include the patient’s ability to participate in hand therapy with the system in place and avoidance of pain caused by the high pressures involved in intermittent closed irrigation. Duration of this system has ranged from 2 days to 3 weeks, and results have been good.^5,8

Postoperative Irrigation

Use of postoperative irrigation on the floor or at home is controversial, as leaving an indwelling catheter in the tendon sheath can lead to complications. Catheters may increase digital stiffness by decreasing the patient’s ability to participate in therapy or may cause additional injury and irritation to the sheath itself if left in place too long. Lille and colleagues⁶ retrospectively compared the results of intraoperative closed tendon sheath irrigation alone with those of intraoperative and postoperative closed tendon sheath irrigation. There were no significant differences in mean hospital length of stay, follow-up complication rates, or postoperative ROM—which suggests that postoperative intermittent or continuous irrigation is not necessary.

Our Preferred Technique

We recommend a palmar approach that begins with outlining a Bruner zigzag incision along the entire finger. Then, only the distal-most and proximal-most incision lines are opened, thereby exposing the A5 and A1 pulleys, respectively (Figure 2).

5. What Are the Long-Term Outcomes of PFT?

The principal complication associated with PFT is stiffness with loss of ROM, which can be caused by flexor tendon adhesions, joint capsular thickening, or destruction of the sheath and pulley system.²⁴ In several studies, up to one-fourth of patients with PFT did not obtain full ROM, despite adequate treatment.^4-6,27 Therefore, full active ROM exercises should be initiated immediately after surgery to counteract the development of stiffness.

The most severe complication of PFT is amputation of the affected digit (Figures 3A, 3B).

Conclusion

PFT is a common hand infection that can cause significant morbidity. Early treatment is crucial: this requires use of IV antibiotics, or surgical irrigation and débridement in more advanced cases. However, despite prompt and thorough treatment, severe infection can lead to long-term impaired function and even amputation of the affected digit. More research is needed to determine optimal timing and technique for surgical intervention and to elucidate the role of local antibiotics and corticosteroids in treating this infection and potentially preventing the morbid outcomes we currently see.

Am J Orthop. 2017;46(3):E207-E212. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Photo by Rhoda Baer

A new study suggests that patients with double-hit lymphoma (DHL) in first remission only benefit from an autologous hematopoietic stem cell transplant (auto-HSCT) if they received standard frontline chemotherapy.

Researchers looked at long-term outcomes for DHL patients who achieved remission and, overall, found that auto-HSCT did not significantly prolong remission or survival.

However, patients who received standard chemotherapy as frontline treatment did appear to benefit from auto-HSCT, as these patients had worse outcomes than patients who received intensive frontline chemotherapy.

This finding led the researchers to recommend that DHL patients receive intensive chemotherapy upfront and forgo subsequent auto-HSCT.

Daniel J. Landsburg, MD, of the University of Pennsylvania in Philadelphia, and his colleagues made these recommendations in the Journal of Clinical Oncology.

“A major dilemma for oncologists who treat [DHL] was whether or not to recommend the potentially harmful therapy of auto-[H]SCT to patients with this disease as a strategy to help keep them in remission,” Dr Landsburg said.

To gain some insight into the issue, Dr Landsburg and his colleagues looked at data on 159 patients from 19 academic medical centers across the US.

Patients were diagnosed with DHL between 2006 and 2015, and all achieved remission following frontline chemotherapy.

Thirty-five patients received standard frontline therapy—R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

The remaining patients received intensive frontline chemotherapy:

• 81 received DA-EPOCH-R (etoposide, prednisone, vincristine, cyclophos­phamide, doxorubicin, and rituximab)
• 32 received R-hyperCVAD (rituximab, cyclophos­phamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine)
• 11 received R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high-dose cytarabine).

Sixty-two patients underwent auto-HSCT, and 97 patients did not. There were no significant differences between these 2 patient groups at baseline.

“Our result is not explained by differences in patients’ overall health or disease features,” Dr Landsburg said. “The transplant and non-transplant arms of this study were very well-matched.”

Relapse and survival

For the entire patient cohort, the 3-year relapse-free survival (RFS) rate was 80%, and the 3-year overall survival (OS) rate was 87%.

There was no significant difference in RFS or OS between patients who underwent auto-HSCT and those who did not.

The RFS rate was 89% in patients who underwent auto-HSCT and 75% in patients who did not (P=0.12). The OS rate was 91% and 85%, respectively (P=0.74).

“Once these patients achieve remission, the data show they are likely to stay in remission,” Dr Landsburg said.

“In the absence of a large, randomized, controlled trial, which would be very challenging to carry out in this case, this is the best evidence we have, and it shows there’s no clear benefit to these patients undergoing auto-[H]SCT.”

Impact of frontline therapy

Patients who received R-CHOP upfront had worse RFS and OS than those who received intensive chemotherapy, although the OS difference was not significant.

RFS rates were 56% in patients who received R-CHOP, 88% in those who received DA-EPOCH-R, 87% in those who received R-hyperCVAD, and 91% in those who received R-CODOX-M/IVAC (P=0.003).

OS rates were 77% in patients who received R-CHOP, 87% in those who received DA-EPOCH-R, 90% in those who received R-hyperCVAD, and 100% in those who received R-CODOX-M/IVAC, respectively (P=0.36).

When the 3 intensive regimens were combined, the RFS rate was 88% (vs 56% for R-CHOP, P=0.002), and the OS rate was 90% (vs 77% for R-CHOP, P=0.13).

Frontline therapy and HSCT

Patients who received R-CHOP upfront benefited from auto-HSCT, but patients who received intensive chemotherapy did not.

The RFS was 51% for patients who received R-CHOP and did not undergo auto-HSCT, and it was 75% for patients who received R-CHOP followed by auto-HSCT.

The OS was 75% for patients who received R-CHOP and did not undergo auto-HSCT, and it was 83% for patients who received R-CHOP followed by auto-HSCT.

The RFS was 86% for patients who received intensive chemotherapy and did not undergo auto-HSCT, and it was 91% for patients who received intensive chemotherapy followed by auto-HSCT.

The OS was 89% for patients who received intensive chemotherapy and did not undergo auto-HSCT, and it was 92% for patients who received intensive chemotherapy followed by auto-HSCT.

An intergroup comparison showed a significant difference in RFS (P=0.003), which was driven by a significantly lower rate of RFS for patients who received R-CHOP without auto-HSCT, compared with patients who received intensive chemotherapy without auto-HSCT (P=0.003) or intensive chemotherapy with auto-HSCT (P=0.001).

“[I]f patients do go into remission with R-CHOP, it appears to be less durable, so, in these cases, going forward with auto-[H]SCT may still make sense,” Dr Landsburg said.

On the other hand, there was no significant difference between the groups with regard to OS (P=0.50).

Dr Landsburg said the next step for this research will be to study features of patients who don’t go into remission in order to understand why their disease is resistant to therapy and if that can be overcome with different treatment strategies. He also said it’s important to try to find more effective therapies for DHL patients who relapse. 

Photo by Rhoda Baer

A new study suggests that patients with double-hit lymphoma (DHL) in first remission only benefit from an autologous hematopoietic stem cell transplant (auto-HSCT) if they received standard frontline chemotherapy.

Researchers looked at long-term outcomes for DHL patients who achieved remission and, overall, found that auto-HSCT did not significantly prolong remission or survival.

However, patients who received standard chemotherapy as frontline treatment did appear to benefit from auto-HSCT, as these patients had worse outcomes than patients who received intensive frontline chemotherapy.

This finding led the researchers to recommend that DHL patients receive intensive chemotherapy upfront and forgo subsequent auto-HSCT.

Daniel J. Landsburg, MD, of the University of Pennsylvania in Philadelphia, and his colleagues made these recommendations in the Journal of Clinical Oncology.

“A major dilemma for oncologists who treat [DHL] was whether or not to recommend the potentially harmful therapy of auto-[H]SCT to patients with this disease as a strategy to help keep them in remission,” Dr Landsburg said.

To gain some insight into the issue, Dr Landsburg and his colleagues looked at data on 159 patients from 19 academic medical centers across the US.

Patients were diagnosed with DHL between 2006 and 2015, and all achieved remission following frontline chemotherapy.

Thirty-five patients received standard frontline therapy—R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

The remaining patients received intensive frontline chemotherapy:

• 81 received DA-EPOCH-R (etoposide, prednisone, vincristine, cyclophos­phamide, doxorubicin, and rituximab)
• 32 received R-hyperCVAD (rituximab, cyclophos­phamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine)
• 11 received R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high-dose cytarabine).

Sixty-two patients underwent auto-HSCT, and 97 patients did not. There were no significant differences between these 2 patient groups at baseline.

“Our result is not explained by differences in patients’ overall health or disease features,” Dr Landsburg said. “The transplant and non-transplant arms of this study were very well-matched.”

Relapse and survival

For the entire patient cohort, the 3-year relapse-free survival (RFS) rate was 80%, and the 3-year overall survival (OS) rate was 87%.

There was no significant difference in RFS or OS between patients who underwent auto-HSCT and those who did not.

The RFS rate was 89% in patients who underwent auto-HSCT and 75% in patients who did not (P=0.12). The OS rate was 91% and 85%, respectively (P=0.74).

“Once these patients achieve remission, the data show they are likely to stay in remission,” Dr Landsburg said.

“In the absence of a large, randomized, controlled trial, which would be very challenging to carry out in this case, this is the best evidence we have, and it shows there’s no clear benefit to these patients undergoing auto-[H]SCT.”

Impact of frontline therapy

Patients who received R-CHOP upfront had worse RFS and OS than those who received intensive chemotherapy, although the OS difference was not significant.

RFS rates were 56% in patients who received R-CHOP, 88% in those who received DA-EPOCH-R, 87% in those who received R-hyperCVAD, and 91% in those who received R-CODOX-M/IVAC (P=0.003).

OS rates were 77% in patients who received R-CHOP, 87% in those who received DA-EPOCH-R, 90% in those who received R-hyperCVAD, and 100% in those who received R-CODOX-M/IVAC, respectively (P=0.36).

When the 3 intensive regimens were combined, the RFS rate was 88% (vs 56% for R-CHOP, P=0.002), and the OS rate was 90% (vs 77% for R-CHOP, P=0.13).

Frontline therapy and HSCT

Patients who received R-CHOP upfront benefited from auto-HSCT, but patients who received intensive chemotherapy did not.

The RFS was 51% for patients who received R-CHOP and did not undergo auto-HSCT, and it was 75% for patients who received R-CHOP followed by auto-HSCT.

The OS was 75% for patients who received R-CHOP and did not undergo auto-HSCT, and it was 83% for patients who received R-CHOP followed by auto-HSCT.

The RFS was 86% for patients who received intensive chemotherapy and did not undergo auto-HSCT, and it was 91% for patients who received intensive chemotherapy followed by auto-HSCT.

The OS was 89% for patients who received intensive chemotherapy and did not undergo auto-HSCT, and it was 92% for patients who received intensive chemotherapy followed by auto-HSCT.

An intergroup comparison showed a significant difference in RFS (P=0.003), which was driven by a significantly lower rate of RFS for patients who received R-CHOP without auto-HSCT, compared with patients who received intensive chemotherapy without auto-HSCT (P=0.003) or intensive chemotherapy with auto-HSCT (P=0.001).

“[I]f patients do go into remission with R-CHOP, it appears to be less durable, so, in these cases, going forward with auto-[H]SCT may still make sense,” Dr Landsburg said.

On the other hand, there was no significant difference between the groups with regard to OS (P=0.50).

Dr Landsburg said the next step for this research will be to study features of patients who don’t go into remission in order to understand why their disease is resistant to therapy and if that can be overcome with different treatment strategies. He also said it’s important to try to find more effective therapies for DHL patients who relapse. 

Photo by Rhoda Baer

A new study suggests that patients with double-hit lymphoma (DHL) in first remission only benefit from an autologous hematopoietic stem cell transplant (auto-HSCT) if they received standard frontline chemotherapy.

Researchers looked at long-term outcomes for DHL patients who achieved remission and, overall, found that auto-HSCT did not significantly prolong remission or survival.

However, patients who received standard chemotherapy as frontline treatment did appear to benefit from auto-HSCT, as these patients had worse outcomes than patients who received intensive frontline chemotherapy.

This finding led the researchers to recommend that DHL patients receive intensive chemotherapy upfront and forgo subsequent auto-HSCT.

Daniel J. Landsburg, MD, of the University of Pennsylvania in Philadelphia, and his colleagues made these recommendations in the Journal of Clinical Oncology.

“A major dilemma for oncologists who treat [DHL] was whether or not to recommend the potentially harmful therapy of auto-[H]SCT to patients with this disease as a strategy to help keep them in remission,” Dr Landsburg said.

To gain some insight into the issue, Dr Landsburg and his colleagues looked at data on 159 patients from 19 academic medical centers across the US.

Patients were diagnosed with DHL between 2006 and 2015, and all achieved remission following frontline chemotherapy.

Thirty-five patients received standard frontline therapy—R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

The remaining patients received intensive frontline chemotherapy:

• 81 received DA-EPOCH-R (etoposide, prednisone, vincristine, cyclophos­phamide, doxorubicin, and rituximab)
• 32 received R-hyperCVAD (rituximab, cyclophos­phamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine)
• 11 received R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high-dose cytarabine).

Sixty-two patients underwent auto-HSCT, and 97 patients did not. There were no significant differences between these 2 patient groups at baseline.

“Our result is not explained by differences in patients’ overall health or disease features,” Dr Landsburg said. “The transplant and non-transplant arms of this study were very well-matched.”

Relapse and survival

For the entire patient cohort, the 3-year relapse-free survival (RFS) rate was 80%, and the 3-year overall survival (OS) rate was 87%.

There was no significant difference in RFS or OS between patients who underwent auto-HSCT and those who did not.

The RFS rate was 89% in patients who underwent auto-HSCT and 75% in patients who did not (P=0.12). The OS rate was 91% and 85%, respectively (P=0.74).

“Once these patients achieve remission, the data show they are likely to stay in remission,” Dr Landsburg said.

“In the absence of a large, randomized, controlled trial, which would be very challenging to carry out in this case, this is the best evidence we have, and it shows there’s no clear benefit to these patients undergoing auto-[H]SCT.”

Impact of frontline therapy

Patients who received R-CHOP upfront had worse RFS and OS than those who received intensive chemotherapy, although the OS difference was not significant.

RFS rates were 56% in patients who received R-CHOP, 88% in those who received DA-EPOCH-R, 87% in those who received R-hyperCVAD, and 91% in those who received R-CODOX-M/IVAC (P=0.003).

OS rates were 77% in patients who received R-CHOP, 87% in those who received DA-EPOCH-R, 90% in those who received R-hyperCVAD, and 100% in those who received R-CODOX-M/IVAC, respectively (P=0.36).

When the 3 intensive regimens were combined, the RFS rate was 88% (vs 56% for R-CHOP, P=0.002), and the OS rate was 90% (vs 77% for R-CHOP, P=0.13).

Frontline therapy and HSCT

Patients who received R-CHOP upfront benefited from auto-HSCT, but patients who received intensive chemotherapy did not.

The RFS was 51% for patients who received R-CHOP and did not undergo auto-HSCT, and it was 75% for patients who received R-CHOP followed by auto-HSCT.

The OS was 75% for patients who received R-CHOP and did not undergo auto-HSCT, and it was 83% for patients who received R-CHOP followed by auto-HSCT.

The RFS was 86% for patients who received intensive chemotherapy and did not undergo auto-HSCT, and it was 91% for patients who received intensive chemotherapy followed by auto-HSCT.

The OS was 89% for patients who received intensive chemotherapy and did not undergo auto-HSCT, and it was 92% for patients who received intensive chemotherapy followed by auto-HSCT.

An intergroup comparison showed a significant difference in RFS (P=0.003), which was driven by a significantly lower rate of RFS for patients who received R-CHOP without auto-HSCT, compared with patients who received intensive chemotherapy without auto-HSCT (P=0.003) or intensive chemotherapy with auto-HSCT (P=0.001).

“[I]f patients do go into remission with R-CHOP, it appears to be less durable, so, in these cases, going forward with auto-[H]SCT may still make sense,” Dr Landsburg said.

On the other hand, there was no significant difference between the groups with regard to OS (P=0.50).

Dr Landsburg said the next step for this research will be to study features of patients who don’t go into remission in order to understand why their disease is resistant to therapy and if that can be overcome with different treatment strategies. He also said it’s important to try to find more effective therapies for DHL patients who relapse. 

Micrograph showing B-ALL

Endoglin may be a promising therapeutic target in acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL), according to researchers.

The group identified endoglin expression on the majority of blasts from patients with AML and B-ALL.

The team also found that an endoglin antibody, TRC105 (carotuximab), exhibited activity against AML and B-ALL in vivo, and combining the drug with chemotherapeutic agents enhanced this activity.

Rita Perlingeiro, PhD, of the University of Minnesota in Minneapolis, and her colleagues reported these findings in Blood.

The researchers first discovered that endoglin, which is also known as CD105, was “highly expressed” in leukemic blasts.

In samples from AML patients, 47.6% to 98.5% of blasts were CD105+. In samples from B-ALL patients, 92.6% to 99% of blasts were CD105+.

“We have been studying the function of endoglin in hematopoiesis for more than a decade, and the consistent expression of this receptor in the majority of acute leukemias was intriguing,” Dr Perlingeiro said.

She and her colleagues also found that CD105+ blasts had superior leukemogenic activity and reduced survival in mice when compared to CD105- blasts.

Mice injected with AML CD105+ blasts had all died at day 110 after injection, but mice injected with CD105- AML blasts survived until day 140.

Mice injected with CD105+ ALL blasts died 3 months after injection, but mice injected with CD105- ALL blasts were still alive and showed no signs of disease at the time of sacrifice, which was 5 months after injection.

TRC105 monotherapy

Several experiments showed that TRC105 could reduce leukemic activity in vivo.

TRC105 reduced blast counts in the peripheral blood of mice that had been injected with AML blasts. The drug also reduced blasts in the bone marrow initially, though blast counts were comparable in treated mice and controls by week 12.

On the other hand, mice treated with TRC105 did not experience the weight loss and splenomegaly observed in control mice. And TRC105 suppressed the ability of AML blasts to give rise to leukemia in secondary recipient mice.

In mice injected with ALL blasts, TRC105 initially decreased blast counts. However, by week 8, blast counts in the peripheral blood, bone marrow, and spleen of treated mice were similar to those observed in controls. The researchers said this suggests that TRC105 only slows the development of ALL.

The team then evaluated the effects of TRC105 after disease had been established. Mice with established AML received TRC105 for 8 weeks, and mice with established ALL received TRC105 for 4 weeks.

In mice with AML, TRC105 reduced blasts in the peripheral blood and spleen but not the bone marrow. The treatment also prevented splenomegaly and weight loss and prolonged survival.

“Our hypothesis that endoglin expression was linked to leukemia-forming activity was proven to be true, and it was even more rewarding to witness the robust anti-leukemogenic effect of blocking endoglin signaling with TRC105, even when leukemia had already been established in the mouse,” Dr Perlingeiro said.

However, in mice with established ALL, TRC105 had no effect on leukemia progression.

The researchers said this could be due to expression of soluble endoglin (sENG), which would titrate the TRC105 antibody, limiting its ability to bind to membrane-bound endoglin on leukemic cells. Results of additional experiments supported this idea.

TRC105 in combination

The researchers also tested TRC105 in combination with chemotherapy in the mouse models. The team combined the antibody with cytarabine to treat AML and cyclophosphamide to treat ALL.

In mice with AML, cytarabine and TRC105 significantly reduced levels of leukemic cells in the peripheral blood.

In mice with ALL, cyclophosphamide and TRC105 suppressed leukemia development more effectively and more quickly than cyclophosphamide alone.

The researchers detected high levels of sENG in untreated mice with ALL, but levels were lower in the TRC105-treated mice. And there was “no significant detection” of sENG in mice that received cyclophosphamide and TRC105 or cyclophosphamide alone.

Dr Perlingeiro and her colleagues said this suggests the inhibitory effects of sENG can be circumvented by suppressing tumor burden, which results in the combination therapy demonstrating potent antileukemic activity. 

Micrograph showing B-ALL

Endoglin may be a promising therapeutic target in acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL), according to researchers.

The group identified endoglin expression on the majority of blasts from patients with AML and B-ALL.

The team also found that an endoglin antibody, TRC105 (carotuximab), exhibited activity against AML and B-ALL in vivo, and combining the drug with chemotherapeutic agents enhanced this activity.

Rita Perlingeiro, PhD, of the University of Minnesota in Minneapolis, and her colleagues reported these findings in Blood.

The researchers first discovered that endoglin, which is also known as CD105, was “highly expressed” in leukemic blasts.

In samples from AML patients, 47.6% to 98.5% of blasts were CD105+. In samples from B-ALL patients, 92.6% to 99% of blasts were CD105+.

“We have been studying the function of endoglin in hematopoiesis for more than a decade, and the consistent expression of this receptor in the majority of acute leukemias was intriguing,” Dr Perlingeiro said.

She and her colleagues also found that CD105+ blasts had superior leukemogenic activity and reduced survival in mice when compared to CD105- blasts.

Mice injected with AML CD105+ blasts had all died at day 110 after injection, but mice injected with CD105- AML blasts survived until day 140.

Mice injected with CD105+ ALL blasts died 3 months after injection, but mice injected with CD105- ALL blasts were still alive and showed no signs of disease at the time of sacrifice, which was 5 months after injection.

TRC105 monotherapy

Several experiments showed that TRC105 could reduce leukemic activity in vivo.

TRC105 reduced blast counts in the peripheral blood of mice that had been injected with AML blasts. The drug also reduced blasts in the bone marrow initially, though blast counts were comparable in treated mice and controls by week 12.

On the other hand, mice treated with TRC105 did not experience the weight loss and splenomegaly observed in control mice. And TRC105 suppressed the ability of AML blasts to give rise to leukemia in secondary recipient mice.

In mice injected with ALL blasts, TRC105 initially decreased blast counts. However, by week 8, blast counts in the peripheral blood, bone marrow, and spleen of treated mice were similar to those observed in controls. The researchers said this suggests that TRC105 only slows the development of ALL.

The team then evaluated the effects of TRC105 after disease had been established. Mice with established AML received TRC105 for 8 weeks, and mice with established ALL received TRC105 for 4 weeks.

In mice with AML, TRC105 reduced blasts in the peripheral blood and spleen but not the bone marrow. The treatment also prevented splenomegaly and weight loss and prolonged survival.

“Our hypothesis that endoglin expression was linked to leukemia-forming activity was proven to be true, and it was even more rewarding to witness the robust anti-leukemogenic effect of blocking endoglin signaling with TRC105, even when leukemia had already been established in the mouse,” Dr Perlingeiro said.

However, in mice with established ALL, TRC105 had no effect on leukemia progression.

The researchers said this could be due to expression of soluble endoglin (sENG), which would titrate the TRC105 antibody, limiting its ability to bind to membrane-bound endoglin on leukemic cells. Results of additional experiments supported this idea.

TRC105 in combination

The researchers also tested TRC105 in combination with chemotherapy in the mouse models. The team combined the antibody with cytarabine to treat AML and cyclophosphamide to treat ALL.

In mice with AML, cytarabine and TRC105 significantly reduced levels of leukemic cells in the peripheral blood.

In mice with ALL, cyclophosphamide and TRC105 suppressed leukemia development more effectively and more quickly than cyclophosphamide alone.

The researchers detected high levels of sENG in untreated mice with ALL, but levels were lower in the TRC105-treated mice. And there was “no significant detection” of sENG in mice that received cyclophosphamide and TRC105 or cyclophosphamide alone.

Dr Perlingeiro and her colleagues said this suggests the inhibitory effects of sENG can be circumvented by suppressing tumor burden, which results in the combination therapy demonstrating potent antileukemic activity. 

Micrograph showing B-ALL

Endoglin may be a promising therapeutic target in acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL), according to researchers.

The group identified endoglin expression on the majority of blasts from patients with AML and B-ALL.

The team also found that an endoglin antibody, TRC105 (carotuximab), exhibited activity against AML and B-ALL in vivo, and combining the drug with chemotherapeutic agents enhanced this activity.

Rita Perlingeiro, PhD, of the University of Minnesota in Minneapolis, and her colleagues reported these findings in Blood.

The researchers first discovered that endoglin, which is also known as CD105, was “highly expressed” in leukemic blasts.

In samples from AML patients, 47.6% to 98.5% of blasts were CD105+. In samples from B-ALL patients, 92.6% to 99% of blasts were CD105+.

“We have been studying the function of endoglin in hematopoiesis for more than a decade, and the consistent expression of this receptor in the majority of acute leukemias was intriguing,” Dr Perlingeiro said.

She and her colleagues also found that CD105+ blasts had superior leukemogenic activity and reduced survival in mice when compared to CD105- blasts.

Mice injected with AML CD105+ blasts had all died at day 110 after injection, but mice injected with CD105- AML blasts survived until day 140.

Mice injected with CD105+ ALL blasts died 3 months after injection, but mice injected with CD105- ALL blasts were still alive and showed no signs of disease at the time of sacrifice, which was 5 months after injection.

TRC105 monotherapy

Several experiments showed that TRC105 could reduce leukemic activity in vivo.

TRC105 reduced blast counts in the peripheral blood of mice that had been injected with AML blasts. The drug also reduced blasts in the bone marrow initially, though blast counts were comparable in treated mice and controls by week 12.

On the other hand, mice treated with TRC105 did not experience the weight loss and splenomegaly observed in control mice. And TRC105 suppressed the ability of AML blasts to give rise to leukemia in secondary recipient mice.

In mice injected with ALL blasts, TRC105 initially decreased blast counts. However, by week 8, blast counts in the peripheral blood, bone marrow, and spleen of treated mice were similar to those observed in controls. The researchers said this suggests that TRC105 only slows the development of ALL.

The team then evaluated the effects of TRC105 after disease had been established. Mice with established AML received TRC105 for 8 weeks, and mice with established ALL received TRC105 for 4 weeks.

In mice with AML, TRC105 reduced blasts in the peripheral blood and spleen but not the bone marrow. The treatment also prevented splenomegaly and weight loss and prolonged survival.

“Our hypothesis that endoglin expression was linked to leukemia-forming activity was proven to be true, and it was even more rewarding to witness the robust anti-leukemogenic effect of blocking endoglin signaling with TRC105, even when leukemia had already been established in the mouse,” Dr Perlingeiro said.

However, in mice with established ALL, TRC105 had no effect on leukemia progression.

The researchers said this could be due to expression of soluble endoglin (sENG), which would titrate the TRC105 antibody, limiting its ability to bind to membrane-bound endoglin on leukemic cells. Results of additional experiments supported this idea.

TRC105 in combination

The researchers also tested TRC105 in combination with chemotherapy in the mouse models. The team combined the antibody with cytarabine to treat AML and cyclophosphamide to treat ALL.

In mice with AML, cytarabine and TRC105 significantly reduced levels of leukemic cells in the peripheral blood.

In mice with ALL, cyclophosphamide and TRC105 suppressed leukemia development more effectively and more quickly than cyclophosphamide alone.

The researchers detected high levels of sENG in untreated mice with ALL, but levels were lower in the TRC105-treated mice. And there was “no significant detection” of sENG in mice that received cyclophosphamide and TRC105 or cyclophosphamide alone.

Dr Perlingeiro and her colleagues said this suggests the inhibitory effects of sENG can be circumvented by suppressing tumor burden, which results in the combination therapy demonstrating potent antileukemic activity.