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Woman Awakens With Rapid Heart Rate
ANSWER
The correct interpretation of this ECG is atrial flutter with a 2:1 block. Careful inspection of lead I reveals a P wave at the terminal portion of the QRS complex, in addition to the P wave seen with a consistent PR interval of 150 ms. This results in two P waves for each QRS complex. Given the presence of the flutter waves, an accurate assessment of the ST segment is not possible.
ANSWER
The correct interpretation of this ECG is atrial flutter with a 2:1 block. Careful inspection of lead I reveals a P wave at the terminal portion of the QRS complex, in addition to the P wave seen with a consistent PR interval of 150 ms. This results in two P waves for each QRS complex. Given the presence of the flutter waves, an accurate assessment of the ST segment is not possible.
ANSWER
The correct interpretation of this ECG is atrial flutter with a 2:1 block. Careful inspection of lead I reveals a P wave at the terminal portion of the QRS complex, in addition to the P wave seen with a consistent PR interval of 150 ms. This results in two P waves for each QRS complex. Given the presence of the flutter waves, an accurate assessment of the ST segment is not possible.
Three nights ago, a 44-year-old woman awoke with a regular, rapid heart rate that lasted about 15 minutes before abruptly terminating. The next morning, at the hospital where she works as an emergency department (ED) nurse, she had a colleague perform an undocumented ECG that, by the patient’s account, was normal. Early this morning, she was again awakened by a similar regular but rapid heart rate. Not wanting anyone at her facility to know about the problem, she presents to your ED instead. She denies chest pain but admits that she is slightly short of breath, adding that her symptoms remind her of how she feels when finishing a 10K run. The patient has been in excellent health with no underlying medical problems and no prior cardiac history. She is an avid runner, averaging three miles a day, and does not smoke. She does report drinking two or three glasses of wine in the evenings and admits she likes to party on the weekends, frequently consuming three or four margaritas with her coworkers on Saturday nights. She experimented with cannabis in college but hasn’t used illicit or recreational drugs since graduating. The patient is divorced, has a steady boyfriend, and has no children or siblings. Her parents are alive and well, with no history of arrhythmias, cardiovascular disease, or diabetes. She has no known drug allergies. Her medications include an oral contraceptive and occasional ibuprofen for soreness following exercise. The review of systems is remarkable for menses, which began yesterday. She denies that she is pregnant. Her vision is corrected with contact lenses. Physical examination reveals a thin, athletic-appearing woman who seems anxious. Her height is 67 in and her weight, 132 lb. Vital signs include a blood pressure of 118/68 mm Hg; pulse, 150 beats/min; respiratory rate, 14 breaths/min-1; and temperature, 37.8°C. The HEENT exam is normal with the presence of contact lenses. There is no thyromegaly. The lungs are clear in all fields. Her cardiac exam reveals a regular, rapid rate of 150 beats/min, without murmurs, rubs, or extra heart sounds. The abdomen is soft and nontender without palpable masses. The peripheral pulses are strong and equal bilaterally. There is no peripheral edema. The neurologic exam is intact. Laboratory tests, including a complete blood count, thyroid panel, and chemistry panel, are performed. All values are within normal limits. An ECG reveals a ventricular rate of 149 beats/min; PR interval, 150 ms; QRS interval, 102 ms; QT/QTc interval, 270/425 ms; P axis, 103°; R axis, 78°; and T axis, –18°. What is your interpretation of this ECG?
Left Arm Pain, Numbness, and Weakness
ANSWER
The radiograph shows no evidence of a fracture. However, there is a 2-cm focal sclerotic area noted within the juncture of the humeral neck and head. This finding could represent an enchondroma, a bone cyst, or a bone infarct. Additional imaging, including MRI and bone scan, is warranted, as is orthopedic evaluation. This finding is likely incidental, as the patient’s clinical exam is suggestive of a cervical radiculitis referable to the herniated disc in her neck.
ANSWER
The radiograph shows no evidence of a fracture. However, there is a 2-cm focal sclerotic area noted within the juncture of the humeral neck and head. This finding could represent an enchondroma, a bone cyst, or a bone infarct. Additional imaging, including MRI and bone scan, is warranted, as is orthopedic evaluation. This finding is likely incidental, as the patient’s clinical exam is suggestive of a cervical radiculitis referable to the herniated disc in her neck.
ANSWER
The radiograph shows no evidence of a fracture. However, there is a 2-cm focal sclerotic area noted within the juncture of the humeral neck and head. This finding could represent an enchondroma, a bone cyst, or a bone infarct. Additional imaging, including MRI and bone scan, is warranted, as is orthopedic evaluation. This finding is likely incidental, as the patient’s clinical exam is suggestive of a cervical radiculitis referable to the herniated disc in her neck.
A 40-year-old woman presents to the urgent care clinic complaining of left arm pain with associated numbness and weakness. She denies any injury or trauma, adding that the pain manifested several months ago but has recently progressed. She has already undergone outpatient MRI of her neck; she was told she had some “herniated discs” and would need to see a specialist. Her medical history is significant for hypertension. On physical examination, the patient appears uncomfortable but in no obvious distress. Vital signs are normal. Tenderness is present at the left trapezius and the left shoulder. Mild weakness is present in the left arm; strength is 4/5 and grip strength, 3/5. Pulses are normal, and sensation is intact. Available medical records include a report from her recent MRI of the cervical spine. Findings include a moderate left-sided disc osteophyte at the C6-C7 level and resultant cervical stenosis. A radiograph of the left shoulder is obtained. What is your impression?
Lesions’ Pattern Helps Line Up Diagnosis
ANSWER
The correct answer is lichen nitidus (choice “b”), a harmless, self-limited condition of unknown origin. The lesions’ flat-topped (planar) surfaces and tendency to form in linear configurations along lines of trauma (so-called Koebner phenomenon) are also features seen in lichen planus (choice “d”) lesions; however, the latter are almost always pruritic and purple in color. Ironically, the histologic pattern seen in both is almost identical.
An extremely common condition, molluscum contagiosum (choice “a”) presents with multiple tiny papules. But these are not planar, and most will have an umbilicated center. See the Discussion for ways to distinguish it from lichen nitidus.
Flat warts (choice “c”), known as verruca plana, can strongly resemble lichen nitidus, but they are not as flat-topped and do not appear white. They do Koebnerize, however, which occasionally makes the distinction difficult.
DISCUSSION
Lichen nitidus (LN) is an unusual but benign condition primarily affecting children and young adults. Due to the contrast, the white planar papules are easier to see on darker skin. As is the case with many dermatologic diagnoses, LN is easily identified if you’ve heard of it and therefore know what to expect—but much more difficult if you haven’t.
LN’s unique manifestation distinguishes it from other items in the differential. For example, molluscum and LN can easily be confused, especially since both primarily affect children. But the pathognomic central umbilication of molluscum lesions is the key distinguishing feature; the best way to highlight it is with a short blast of liquid nitrogen. (Usually, though, the planar surfaces of LN are sufficient to distinguish it from other conditions.)
In the United States, the term Koebner phenomenon refers to the tendency for lesions to form along areas of trauma, usually in a linear configuration. All four items in our differential can present in this way. However, the term auto-inoculation might be more properly applied to conditions such as warts and molluscum, since the trauma has merely inoculated the organism into the skin. Inflammatory conditions such as LN and lichen planus are not truly “spread” by the trauma.
Linearly configured lesions are sufficiently unusual in dermatology to warrant their own differential. Among those that can present in this manner are psoriasis, lichen sclerosus et atrophicus, and vitiligo.
TREATMENT/PROGNOSIS
Our LN patient did not require any treatment, nor was any possible. The condition is quite likely to clear on its own, leaving little if any evidence in its wake.
I often show affected patients and/or their parents pictures of these types of conditions from our textbooks, for added reassurance. And in this day and age, I direct them to websites where they can do more investigation on their own time.
The effective practice of dermatology (and of all medicine, for that matter) includes more than merely making a correct diagnosis: I believe we’re obliged to “sell” it as well.
ANSWER
The correct answer is lichen nitidus (choice “b”), a harmless, self-limited condition of unknown origin. The lesions’ flat-topped (planar) surfaces and tendency to form in linear configurations along lines of trauma (so-called Koebner phenomenon) are also features seen in lichen planus (choice “d”) lesions; however, the latter are almost always pruritic and purple in color. Ironically, the histologic pattern seen in both is almost identical.
An extremely common condition, molluscum contagiosum (choice “a”) presents with multiple tiny papules. But these are not planar, and most will have an umbilicated center. See the Discussion for ways to distinguish it from lichen nitidus.
Flat warts (choice “c”), known as verruca plana, can strongly resemble lichen nitidus, but they are not as flat-topped and do not appear white. They do Koebnerize, however, which occasionally makes the distinction difficult.
DISCUSSION
Lichen nitidus (LN) is an unusual but benign condition primarily affecting children and young adults. Due to the contrast, the white planar papules are easier to see on darker skin. As is the case with many dermatologic diagnoses, LN is easily identified if you’ve heard of it and therefore know what to expect—but much more difficult if you haven’t.
LN’s unique manifestation distinguishes it from other items in the differential. For example, molluscum and LN can easily be confused, especially since both primarily affect children. But the pathognomic central umbilication of molluscum lesions is the key distinguishing feature; the best way to highlight it is with a short blast of liquid nitrogen. (Usually, though, the planar surfaces of LN are sufficient to distinguish it from other conditions.)
In the United States, the term Koebner phenomenon refers to the tendency for lesions to form along areas of trauma, usually in a linear configuration. All four items in our differential can present in this way. However, the term auto-inoculation might be more properly applied to conditions such as warts and molluscum, since the trauma has merely inoculated the organism into the skin. Inflammatory conditions such as LN and lichen planus are not truly “spread” by the trauma.
Linearly configured lesions are sufficiently unusual in dermatology to warrant their own differential. Among those that can present in this manner are psoriasis, lichen sclerosus et atrophicus, and vitiligo.
TREATMENT/PROGNOSIS
Our LN patient did not require any treatment, nor was any possible. The condition is quite likely to clear on its own, leaving little if any evidence in its wake.
I often show affected patients and/or their parents pictures of these types of conditions from our textbooks, for added reassurance. And in this day and age, I direct them to websites where they can do more investigation on their own time.
The effective practice of dermatology (and of all medicine, for that matter) includes more than merely making a correct diagnosis: I believe we’re obliged to “sell” it as well.
ANSWER
The correct answer is lichen nitidus (choice “b”), a harmless, self-limited condition of unknown origin. The lesions’ flat-topped (planar) surfaces and tendency to form in linear configurations along lines of trauma (so-called Koebner phenomenon) are also features seen in lichen planus (choice “d”) lesions; however, the latter are almost always pruritic and purple in color. Ironically, the histologic pattern seen in both is almost identical.
An extremely common condition, molluscum contagiosum (choice “a”) presents with multiple tiny papules. But these are not planar, and most will have an umbilicated center. See the Discussion for ways to distinguish it from lichen nitidus.
Flat warts (choice “c”), known as verruca plana, can strongly resemble lichen nitidus, but they are not as flat-topped and do not appear white. They do Koebnerize, however, which occasionally makes the distinction difficult.
DISCUSSION
Lichen nitidus (LN) is an unusual but benign condition primarily affecting children and young adults. Due to the contrast, the white planar papules are easier to see on darker skin. As is the case with many dermatologic diagnoses, LN is easily identified if you’ve heard of it and therefore know what to expect—but much more difficult if you haven’t.
LN’s unique manifestation distinguishes it from other items in the differential. For example, molluscum and LN can easily be confused, especially since both primarily affect children. But the pathognomic central umbilication of molluscum lesions is the key distinguishing feature; the best way to highlight it is with a short blast of liquid nitrogen. (Usually, though, the planar surfaces of LN are sufficient to distinguish it from other conditions.)
In the United States, the term Koebner phenomenon refers to the tendency for lesions to form along areas of trauma, usually in a linear configuration. All four items in our differential can present in this way. However, the term auto-inoculation might be more properly applied to conditions such as warts and molluscum, since the trauma has merely inoculated the organism into the skin. Inflammatory conditions such as LN and lichen planus are not truly “spread” by the trauma.
Linearly configured lesions are sufficiently unusual in dermatology to warrant their own differential. Among those that can present in this manner are psoriasis, lichen sclerosus et atrophicus, and vitiligo.
TREATMENT/PROGNOSIS
Our LN patient did not require any treatment, nor was any possible. The condition is quite likely to clear on its own, leaving little if any evidence in its wake.
I often show affected patients and/or their parents pictures of these types of conditions from our textbooks, for added reassurance. And in this day and age, I direct them to websites where they can do more investigation on their own time.
The effective practice of dermatology (and of all medicine, for that matter) includes more than merely making a correct diagnosis: I believe we’re obliged to “sell” it as well.
Six months ago, a 6-year-old boy developed asymptomatic lesions on his elbows, then his knees. They slowly spread to other areas, including his forearms. One primary care provider diagnosed probable warts; another, molluscum. The prescribed treatments—liquid nitrogen and tretinoin, respectively—had no effect. The boy’s mother became alarmed when the lesions started to form in long lines on his arms. At that point, she decided to bring him to dermatology for evaluation. Aside from his skin condition, the child is healthy, according to both his mother and the records provided by his primary care provider’s office. The lesions are particularly numerous over the extensor surfaces of the legs—especially the knees—but are also seen on the extensor forearms and elbows. The lesions are exquisitely discrete, identical, tiny white pinpoint papules, all with flat tops. None are umbilicated. In several areas of the arms, linear collections of lesions, some extending as long as 6 cm, are noted. The rest of his exposed type V skin is unremarkable.
Breaking down midurethral sling approaches
It has been nearly 20 years since the first minimally invasive midurethral sling was introduced. This development was followed 5 years later with the introduction of the transobturator midurethral sling. The advent of both ambulatory techniques has essentially changed the landscape in the surgical treatment of stress urinary incontinence; midurethral slings are certainly considered the procedure of choice for many women.
The midurethral sling has continued to evolve. Not only does the surgeon have the choice of placing a retropubic midurethral sling (bottom to top or top to bottom) and the transobturator midurethral sling (inside-out or outside-in), but, as of late, single incision midurethral slings (mini-slings or mini-tape) as well.
In the previous Master Class on urinary incontinence, Dr. Eric Sokol discussed issues of sling selection and the evidence in favor of various types of retropubic and transobturator slings. This month, we’ll discuss the technique behind these two approaches. I have elicited the assistance of Dr. Sokol, as well as Dr. Charles Rardin.
Dr. Sokol is an associate professor of obstetrics and gynecology, associate professor of urology (by courtesy), and cochief of the division of urogynecology and pelvic reconstructive surgery at Stanford (Calif.) University. He has published many articles regarding urogynecology and minimally invasive surgery. Dr. Sokol has been awarded numerous teaching awards, and he is a reviewer for multiple prestigious, peer-reviewed journals.
Dr. Rardin is the director of the robotic surgery program at Women & Infants Hospital of Rhode Island, Providence, a surgeon in the division of urogynecology and reconstructive pelvic surgery, and is the director of the hospital’s fellowship in urogynecology and reconstructive pelvic surgery. He is also an assistant professor at Brown University, also in Providence. He has published numerous articles in peer-reviewed journals.
Dr. Miller is clinical associate professor at the University of Illinois at Chicago, immediate past president of the International Society for Gynecologic Endoscopy (ISGE), and a past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in private practice in Naperville, Ill., and Schaumburg, Ill.; the director of minimally invasive gynecologic surgery and the director of the AAGL/SRS fellowship in minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column, Master Class. Dr. Miller is a consultant and on the speaker’s bureau for Ethicon.
It has been nearly 20 years since the first minimally invasive midurethral sling was introduced. This development was followed 5 years later with the introduction of the transobturator midurethral sling. The advent of both ambulatory techniques has essentially changed the landscape in the surgical treatment of stress urinary incontinence; midurethral slings are certainly considered the procedure of choice for many women.
The midurethral sling has continued to evolve. Not only does the surgeon have the choice of placing a retropubic midurethral sling (bottom to top or top to bottom) and the transobturator midurethral sling (inside-out or outside-in), but, as of late, single incision midurethral slings (mini-slings or mini-tape) as well.
In the previous Master Class on urinary incontinence, Dr. Eric Sokol discussed issues of sling selection and the evidence in favor of various types of retropubic and transobturator slings. This month, we’ll discuss the technique behind these two approaches. I have elicited the assistance of Dr. Sokol, as well as Dr. Charles Rardin.
Dr. Sokol is an associate professor of obstetrics and gynecology, associate professor of urology (by courtesy), and cochief of the division of urogynecology and pelvic reconstructive surgery at Stanford (Calif.) University. He has published many articles regarding urogynecology and minimally invasive surgery. Dr. Sokol has been awarded numerous teaching awards, and he is a reviewer for multiple prestigious, peer-reviewed journals.
Dr. Rardin is the director of the robotic surgery program at Women & Infants Hospital of Rhode Island, Providence, a surgeon in the division of urogynecology and reconstructive pelvic surgery, and is the director of the hospital’s fellowship in urogynecology and reconstructive pelvic surgery. He is also an assistant professor at Brown University, also in Providence. He has published numerous articles in peer-reviewed journals.
Dr. Miller is clinical associate professor at the University of Illinois at Chicago, immediate past president of the International Society for Gynecologic Endoscopy (ISGE), and a past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in private practice in Naperville, Ill., and Schaumburg, Ill.; the director of minimally invasive gynecologic surgery and the director of the AAGL/SRS fellowship in minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column, Master Class. Dr. Miller is a consultant and on the speaker’s bureau for Ethicon.
It has been nearly 20 years since the first minimally invasive midurethral sling was introduced. This development was followed 5 years later with the introduction of the transobturator midurethral sling. The advent of both ambulatory techniques has essentially changed the landscape in the surgical treatment of stress urinary incontinence; midurethral slings are certainly considered the procedure of choice for many women.
The midurethral sling has continued to evolve. Not only does the surgeon have the choice of placing a retropubic midurethral sling (bottom to top or top to bottom) and the transobturator midurethral sling (inside-out or outside-in), but, as of late, single incision midurethral slings (mini-slings or mini-tape) as well.
In the previous Master Class on urinary incontinence, Dr. Eric Sokol discussed issues of sling selection and the evidence in favor of various types of retropubic and transobturator slings. This month, we’ll discuss the technique behind these two approaches. I have elicited the assistance of Dr. Sokol, as well as Dr. Charles Rardin.
Dr. Sokol is an associate professor of obstetrics and gynecology, associate professor of urology (by courtesy), and cochief of the division of urogynecology and pelvic reconstructive surgery at Stanford (Calif.) University. He has published many articles regarding urogynecology and minimally invasive surgery. Dr. Sokol has been awarded numerous teaching awards, and he is a reviewer for multiple prestigious, peer-reviewed journals.
Dr. Rardin is the director of the robotic surgery program at Women & Infants Hospital of Rhode Island, Providence, a surgeon in the division of urogynecology and reconstructive pelvic surgery, and is the director of the hospital’s fellowship in urogynecology and reconstructive pelvic surgery. He is also an assistant professor at Brown University, also in Providence. He has published numerous articles in peer-reviewed journals.
Dr. Miller is clinical associate professor at the University of Illinois at Chicago, immediate past president of the International Society for Gynecologic Endoscopy (ISGE), and a past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in private practice in Naperville, Ill., and Schaumburg, Ill.; the director of minimally invasive gynecologic surgery and the director of the AAGL/SRS fellowship in minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column, Master Class. Dr. Miller is a consultant and on the speaker’s bureau for Ethicon.
Expert tips on retropubic vs. transobturator sling approaches
Midurethral slings – both retropubic and transobturator – have been extensively studied and have evolved to become standard therapies for the treatment of stress urinary incontinence. The two approaches utilize different routes for sling delivery, but in many other respects, they are similar. Improvements in technique are continually being developed. In this column, Dr. Sokol and Dr. Rardin share key parts of their technique and give their pearls of advice for midurethral sling surgery.
Dr. Sokol’s retropubic approach
I use newer retropubic midurethral slings with smaller trocars that have evolved from first-generation tension-free vaginal tape (TVT) slings. The slings I prefer are placed in a bottom-up fashion, with curved needles passed from a small vaginal incision up through the retropubic space to exit through two suprapubic incisions.
I find it helpful to place patients in a high lithotomy position with the legs supported in candy cane stirrups rather than Allen-type stirrups; sling placement is a short procedure with minimal to no risk of neuropathy.
To precisely identify the midurethral point, I use a 16-FR Foley catheter. When the catheter balloon is filled with 10 mm of fluid and gently pulled back, the urethrovesical junction can be identified. Then, by looking at the urethral meatus relative to the bladder neck, I can mark the midpoint between the two.
The suprapubic exit points are marked at two finger-widths lateral to the midline, just above the pubic symphysis. For precise identification of these points, the Foley catheter may be pulled up exactly midline (with the collection bag detached), and the two finger-widths measured on either side. I also aim for the ipsilateral shoulder, imagining a straight line from the urethral meatus to the ipsilateral shoulder on each side. Together, these measurements and visual cues serve as a good safety check.
With two Allis clamps, the vaginal wall on either side of the midline is grasped transversely at the level of the midurethral mark. The clamps will sit a couple of centimeters apart so that the midurethral point can be visualized. This helps to stabilize and elevate the midurethra.
To safely and efficiently develop a paraurethral passage, I perform a hydrodissection and hemostatic injection at the level of the midurethra using a control top 10-cc syringe with a 22-gauge needle. I find that dilute vasopressin saline solution affords better hemostasis than does a dilute lidocaine epinephrine solution, though I use dilute lidocaine if the sling is being done under local anesthesia.
The needle is inserted into a full thickness of skin, to a point shy of the urethra, and 10 cc is rapidly injected. The vaginal epithelium will appear blanched and will balloon out, like a white marble. The process basically lifts the vaginal skin away from the urethra itself, not only creating hemostasis but also providing a zone of safety to help avoid a urethral injury.
With a second syringe identical to the first, I inject 5 cc on each side of the midurethral point, aiming precisely at the underside of the pubic bone toward the ipsilateral shoulder. This creates a hydrodissected tunnel around each side of the midurethra. With a final syringe, I then inject 5 cc on each side suprapubically at my marked exit points.
With a #15 blade scalpel, I make two very small “poke” incisions transversely at the suprapubic sites. The suburethral incision is larger – just over a centimeter – and is made through a full thickness of skin under the area of hydrodissection, but not so deep as to injure the urethra. To finish development of the paraurethral passage, I pass standard Metzenbaum scissors through each hydrodissected tunnel until I feel the underside of the pubic bone, but no further.
For sling placement (after ensuring the bladder is completely empty), I lower the table such that my arm will be at a right angle to pass the sling while standing.
With my index finger underneath the pubic bone, the trocar tip, with the attached sling, is advanced with my thumb directly toward the ipsilateral shoulder just until it pops through the retropubic space. The depth of the trocar tip can be palpated with the index finger of the same hand, which is positioned just below the pelvic bone.
After the sling “pops” into the retropubic space, I remove my hand from the vagina and place it on the abdominal wall at the ipsilateral suprapubic poke site. In one smooth pass, I hug the pubic bone and advance the sling, again aiming directly and consistently at the shoulder. The trocar handle stays steady, never deviating in any direction. Cystoscopy is performed after the sling is placed on both sides to ensure bladder and urethral integrity.
For tensioning, I raise the table back up and, after reinserting the Foley catheter and a Sims retractor, I place my finger in the middle of the sling and pull the suprapubic ends of the sling up until my finger rests right under the urethra.
I then remove the vaginal clamps and use Metzenbaum scissors as a spacer between the sling and the urethra. With the scissors parallel to and right under the Foley catheter, at the same angle as the urethra, I tighten the sling and remove the plastic sheaths.
Dr. Sokol’s transobturator (TOT) approach
I most often use an outside-in sling. I utilize the same patient positioning and identify the midurethral point in the same way as with the retropubic approach.
On the thigh, I identify the adductor longus tendon as well as a little soft spot or depression just beneath the tendon and lateral to the descending ischial pubic ramus. With my thumb on the soft spot, I can actually grasp the adductor longus tendon between my thumb and index finger. This spot, which is also approximately at the level of the clitoris, marks the entry point for sling placement. It is the thinnest point between the groin and the vagina at the level of the midurethra.
I perform a similar hydrodissection under the urethra as I do in a retropubic procedure, though instead of injecting 5 cc’s to the underside of the pubic symphysis on each side, I instead inject toward the obturator internus muscles. I then inject my final syringe of dilute vasopressin saline solution at the groin poke incision sites, directed toward the projected trocar path, as opposed to suprapubically.
After the full-thickness vaginal incision is made with the scalpel, the dissection is performed sharply with Metzenbaum scissors and is more like the dissection done for cystocele repair than for a retropubic sling. Rather than a poke, the midurethral incision is long enough – about 1.5 cm – for me to reach a finger behind the obturator internus muscle after having sharply dissected the suburethral tissue and fascia. The angle of the dissection is more lateral than for a retropubic sling, toward the underside of the descending ischiopubic ramus and obturator internus muscle.
To place the sling, I have one hand with an index finger in the midurethral tunnel under the obturator internus muscle to protect the urethra. The thumb of that same hand is used to push the helical trocar straight through the thigh poke incision with the handle starting at a 35-degree angle from vertical. The trocar tip is pushed until it can no longer go straight and is ready to be tightly turned around the descending ischiopubic ramus with the opposite hand. A distinct pop can be felt as the trocar tip advances through the obturator membrane and muscles. As the tip is advanced, the angle of the trocar is rotated from 35 degrees to vertical, almost perpendicular to the floor. At this point, the tip of the trocar should be guided out of the midurethral tunnel against the opposite index finger.
I utilize the same technique for tensioning a TOT sling as I do the retropubic sling.
Dr. Rardin’s retropubic approach
I continue to use the original TVT sling with a 5-mm stainless steel, mechanically cut trocar and reusable handle. The newer slender needles may advance with less pressure, but I worry about them bending during passage. I feel more assured and comfortable using the older trocars.
I perform retropubic hydrodissection with a spinal needle using a top-down approach. With 40 cc of a very dilute solution of bupivacaine (Marcaine) with epinephrine on each side of the urethra, I create columns of hydrodissected space. Studies are inconsistent about the benefits of hydrodissection, but theoretically, it decreases the risk of bladder injury by pushing the bladder away from the pubic bone, creates effective hemostasis, and can provide analgesia that will be on board when the patient wakes up.
I bring the spinal needle down behind the pubic bone to the location of the urethral incision site, with my finger in the vagina, so I can feel the tip of the needle next to the urethra/Foley catheter. For each side, I will inject 20 cc of the solution in this location, and the other 20 cc as I withdraw the needle upward.
For trocar passage, some surgeons are taught to advance the trocar until a pop is felt, then drop the handle and push upward. I view the maneuver as a consistent, smooth arch; for every degree that I advance the trocar, I drop the handle slightly in order to maintain contact with the back of the pubic bone throughout the pass. I continuously and simultaneously drop the handle and advance the trocar. Contact with the back of the pubic bone is maintained with a slight pulling on the back end of the trocar handle, while the forward hand pushes the trocar upward.
The target that I visualize for a retropubic pass is the patient’s ipsilateral shoulder. A cadaver study showed that if you aim as far lateral as the patient’s outstretched elbow, you can enter the iliac vasculature (Obstet. Gynecol. 2003;101:933-6).
If the patient is draped such that I cannot see the ipsilateral shoulder, I ask the anesthesia team to show me. I have also identified and marked the suprapubic points about 2-3 cm from each other on either side of the midline just about the pubic symphysis, but I consider the broader anatomic picture and purposeful visualization toward the ipsilateral shoulder to be an essential part of safe technique. In general, it is safer to be more medial than more lateral for the needle passage.
I continue to use a rigid catheter guide to deflect the bladder neck while passing the needles.
Cystoscopy is performed after both needles are placed but not yet pulled through. I fill the bladder until the ureteral orifices appear flattened, which confirms that the bladder is under enough distension to preclude any mucosal wrinkles.
The technique I utilize for adjusting the tension of the TVT sling was taught to me by Dr. Peter L. Rosenblatt of Mt. Auburn Hospital in Cambridge, Mass. At the midline of the sling, I advance the sheaths just enough so that I can grasp a 2-3 mm “knuckle” of the midportion of the sling with a Babcock clamp. I then pull the sling ends until the Babcock comes into gentle contact with the suburethral tissue. The sheaths encasing the sling are then removed and the Babcock clamp is released to assure a tension-free deployment.
The amount of tape that is pinched with the Babcock – the size of the “knuckle” – determines the tension. For a patient with a more profound problem, such as intrinsic sphincter deficiency or a lack or urethral hypermobility, I will grasp a smaller knuckle.
These steps ensure that the midportion of the tape will not tighten or become deformed under tension. Rather than use a spacer, I like to protect the midportion of the tape and prevent it from being stretched. I find that the approach is reproducible and results in a reliable amount of space between the urethra and sling when the procedure is completed.
Dr. Rardin’s TOT approach
I employ an inside-out technique to the TOT procedure, and I utilize devices with segment of mesh that is shorter – only about 13 cm in length – than the original full-length mesh used in many TOT procedures. Once placed, the ends of the mesh penetrate the obturator membrane and obturator externus but not the adductor compartment of the thigh and groin.
In a study we presented last year at the annual meeting of the Society of Gynecologic Surgeons meeting, the shortened tape reduced postoperative groin pain, compared with full-length TOT tape without any reduction in subjective benefit. It appears that with shortened tape, we are anchoring the sling in tissues that provide critical support while avoiding the muscles that relate to the inner thigh/groin pain experienced by some patients. Effectiveness was not reduced, compared with full-length TOT slings.
These shortened slings are distinct from a single-incision sling, which is basically pushed into place. We still pass the needle all the way through a vaginal incision and out through the obturator foramen, and we pull the sling into place as we would any other TOT sling. The difference is that we’re not leaving any mesh in the groin.
I prefer an inside-out approach for two reasons: I always feel that I have more control over where a needle enters than where it exits, and precision is important with suburethral slings. Secondly, the dissection tunnel created for an inside-out pass is much smaller than the tunnel that must be dissected for an outside-in approach. In theory, less dissection means less devascularization, less denervation, and less opportunity for erosion.
Hydrodissection for TOT slings is more minimal and involves less fluid than does hydrodissection for retropubic slings, mainly because we do not want to anesthetize the obturator nerve. I pass the spinal needle from the outside in. At the start, prior to making any incisions, it is important to identify the arcus tendineus, a linear thickening of the superior fascia that is sometimes called the “white line.” This is where the sulcus is affixed to the sidewall. I will be sure to penetrate the sidewall at or above the level of the arcus.
With the TOT approach, the likelihood of bladder injury is so low that I usually drive the trocars all the way through prior to cystoscopy, as opposed to leaving the needles in place as I do with the retropubic approach.
Tensioning is achieved in the same manner, by using the Babcock clamp to avoid distortion of the critical part of the mesh while creating the space needed given the patient’s clinical scenario. It is worth remembering, at this point, that overall risks for retention appear to be lower for obturator slings, compared with retropubic slings.
I place most of my patients receiving retropubic slings in dorsal lithotomy position; but for obturator sling placement, I favor a few degrees into higher lithotomy because this pulls the obturator neurovascular bundle a little further out of the path of the needle.
Dr. Sokol reported that he owns stock in Pelvalon and is a clinical adviser to that company. He also is a national principal investigator for American Medical Systems and the recipient of research grants from Acell and several other companies. Dr. Rardin reported that he has no relevant financial disclosures. To view a video related to this article, go to SurgeryU at aagl.org/obgyn-news.
Midurethral slings – both retropubic and transobturator – have been extensively studied and have evolved to become standard therapies for the treatment of stress urinary incontinence. The two approaches utilize different routes for sling delivery, but in many other respects, they are similar. Improvements in technique are continually being developed. In this column, Dr. Sokol and Dr. Rardin share key parts of their technique and give their pearls of advice for midurethral sling surgery.
Dr. Sokol’s retropubic approach
I use newer retropubic midurethral slings with smaller trocars that have evolved from first-generation tension-free vaginal tape (TVT) slings. The slings I prefer are placed in a bottom-up fashion, with curved needles passed from a small vaginal incision up through the retropubic space to exit through two suprapubic incisions.
I find it helpful to place patients in a high lithotomy position with the legs supported in candy cane stirrups rather than Allen-type stirrups; sling placement is a short procedure with minimal to no risk of neuropathy.
To precisely identify the midurethral point, I use a 16-FR Foley catheter. When the catheter balloon is filled with 10 mm of fluid and gently pulled back, the urethrovesical junction can be identified. Then, by looking at the urethral meatus relative to the bladder neck, I can mark the midpoint between the two.
The suprapubic exit points are marked at two finger-widths lateral to the midline, just above the pubic symphysis. For precise identification of these points, the Foley catheter may be pulled up exactly midline (with the collection bag detached), and the two finger-widths measured on either side. I also aim for the ipsilateral shoulder, imagining a straight line from the urethral meatus to the ipsilateral shoulder on each side. Together, these measurements and visual cues serve as a good safety check.
With two Allis clamps, the vaginal wall on either side of the midline is grasped transversely at the level of the midurethral mark. The clamps will sit a couple of centimeters apart so that the midurethral point can be visualized. This helps to stabilize and elevate the midurethra.
To safely and efficiently develop a paraurethral passage, I perform a hydrodissection and hemostatic injection at the level of the midurethra using a control top 10-cc syringe with a 22-gauge needle. I find that dilute vasopressin saline solution affords better hemostasis than does a dilute lidocaine epinephrine solution, though I use dilute lidocaine if the sling is being done under local anesthesia.
The needle is inserted into a full thickness of skin, to a point shy of the urethra, and 10 cc is rapidly injected. The vaginal epithelium will appear blanched and will balloon out, like a white marble. The process basically lifts the vaginal skin away from the urethra itself, not only creating hemostasis but also providing a zone of safety to help avoid a urethral injury.
With a second syringe identical to the first, I inject 5 cc on each side of the midurethral point, aiming precisely at the underside of the pubic bone toward the ipsilateral shoulder. This creates a hydrodissected tunnel around each side of the midurethra. With a final syringe, I then inject 5 cc on each side suprapubically at my marked exit points.
With a #15 blade scalpel, I make two very small “poke” incisions transversely at the suprapubic sites. The suburethral incision is larger – just over a centimeter – and is made through a full thickness of skin under the area of hydrodissection, but not so deep as to injure the urethra. To finish development of the paraurethral passage, I pass standard Metzenbaum scissors through each hydrodissected tunnel until I feel the underside of the pubic bone, but no further.
For sling placement (after ensuring the bladder is completely empty), I lower the table such that my arm will be at a right angle to pass the sling while standing.
With my index finger underneath the pubic bone, the trocar tip, with the attached sling, is advanced with my thumb directly toward the ipsilateral shoulder just until it pops through the retropubic space. The depth of the trocar tip can be palpated with the index finger of the same hand, which is positioned just below the pelvic bone.
After the sling “pops” into the retropubic space, I remove my hand from the vagina and place it on the abdominal wall at the ipsilateral suprapubic poke site. In one smooth pass, I hug the pubic bone and advance the sling, again aiming directly and consistently at the shoulder. The trocar handle stays steady, never deviating in any direction. Cystoscopy is performed after the sling is placed on both sides to ensure bladder and urethral integrity.
For tensioning, I raise the table back up and, after reinserting the Foley catheter and a Sims retractor, I place my finger in the middle of the sling and pull the suprapubic ends of the sling up until my finger rests right under the urethra.
I then remove the vaginal clamps and use Metzenbaum scissors as a spacer between the sling and the urethra. With the scissors parallel to and right under the Foley catheter, at the same angle as the urethra, I tighten the sling and remove the plastic sheaths.
Dr. Sokol’s transobturator (TOT) approach
I most often use an outside-in sling. I utilize the same patient positioning and identify the midurethral point in the same way as with the retropubic approach.
On the thigh, I identify the adductor longus tendon as well as a little soft spot or depression just beneath the tendon and lateral to the descending ischial pubic ramus. With my thumb on the soft spot, I can actually grasp the adductor longus tendon between my thumb and index finger. This spot, which is also approximately at the level of the clitoris, marks the entry point for sling placement. It is the thinnest point between the groin and the vagina at the level of the midurethra.
I perform a similar hydrodissection under the urethra as I do in a retropubic procedure, though instead of injecting 5 cc’s to the underside of the pubic symphysis on each side, I instead inject toward the obturator internus muscles. I then inject my final syringe of dilute vasopressin saline solution at the groin poke incision sites, directed toward the projected trocar path, as opposed to suprapubically.
After the full-thickness vaginal incision is made with the scalpel, the dissection is performed sharply with Metzenbaum scissors and is more like the dissection done for cystocele repair than for a retropubic sling. Rather than a poke, the midurethral incision is long enough – about 1.5 cm – for me to reach a finger behind the obturator internus muscle after having sharply dissected the suburethral tissue and fascia. The angle of the dissection is more lateral than for a retropubic sling, toward the underside of the descending ischiopubic ramus and obturator internus muscle.
To place the sling, I have one hand with an index finger in the midurethral tunnel under the obturator internus muscle to protect the urethra. The thumb of that same hand is used to push the helical trocar straight through the thigh poke incision with the handle starting at a 35-degree angle from vertical. The trocar tip is pushed until it can no longer go straight and is ready to be tightly turned around the descending ischiopubic ramus with the opposite hand. A distinct pop can be felt as the trocar tip advances through the obturator membrane and muscles. As the tip is advanced, the angle of the trocar is rotated from 35 degrees to vertical, almost perpendicular to the floor. At this point, the tip of the trocar should be guided out of the midurethral tunnel against the opposite index finger.
I utilize the same technique for tensioning a TOT sling as I do the retropubic sling.
Dr. Rardin’s retropubic approach
I continue to use the original TVT sling with a 5-mm stainless steel, mechanically cut trocar and reusable handle. The newer slender needles may advance with less pressure, but I worry about them bending during passage. I feel more assured and comfortable using the older trocars.
I perform retropubic hydrodissection with a spinal needle using a top-down approach. With 40 cc of a very dilute solution of bupivacaine (Marcaine) with epinephrine on each side of the urethra, I create columns of hydrodissected space. Studies are inconsistent about the benefits of hydrodissection, but theoretically, it decreases the risk of bladder injury by pushing the bladder away from the pubic bone, creates effective hemostasis, and can provide analgesia that will be on board when the patient wakes up.
I bring the spinal needle down behind the pubic bone to the location of the urethral incision site, with my finger in the vagina, so I can feel the tip of the needle next to the urethra/Foley catheter. For each side, I will inject 20 cc of the solution in this location, and the other 20 cc as I withdraw the needle upward.
For trocar passage, some surgeons are taught to advance the trocar until a pop is felt, then drop the handle and push upward. I view the maneuver as a consistent, smooth arch; for every degree that I advance the trocar, I drop the handle slightly in order to maintain contact with the back of the pubic bone throughout the pass. I continuously and simultaneously drop the handle and advance the trocar. Contact with the back of the pubic bone is maintained with a slight pulling on the back end of the trocar handle, while the forward hand pushes the trocar upward.
The target that I visualize for a retropubic pass is the patient’s ipsilateral shoulder. A cadaver study showed that if you aim as far lateral as the patient’s outstretched elbow, you can enter the iliac vasculature (Obstet. Gynecol. 2003;101:933-6).
If the patient is draped such that I cannot see the ipsilateral shoulder, I ask the anesthesia team to show me. I have also identified and marked the suprapubic points about 2-3 cm from each other on either side of the midline just about the pubic symphysis, but I consider the broader anatomic picture and purposeful visualization toward the ipsilateral shoulder to be an essential part of safe technique. In general, it is safer to be more medial than more lateral for the needle passage.
I continue to use a rigid catheter guide to deflect the bladder neck while passing the needles.
Cystoscopy is performed after both needles are placed but not yet pulled through. I fill the bladder until the ureteral orifices appear flattened, which confirms that the bladder is under enough distension to preclude any mucosal wrinkles.
The technique I utilize for adjusting the tension of the TVT sling was taught to me by Dr. Peter L. Rosenblatt of Mt. Auburn Hospital in Cambridge, Mass. At the midline of the sling, I advance the sheaths just enough so that I can grasp a 2-3 mm “knuckle” of the midportion of the sling with a Babcock clamp. I then pull the sling ends until the Babcock comes into gentle contact with the suburethral tissue. The sheaths encasing the sling are then removed and the Babcock clamp is released to assure a tension-free deployment.
The amount of tape that is pinched with the Babcock – the size of the “knuckle” – determines the tension. For a patient with a more profound problem, such as intrinsic sphincter deficiency or a lack or urethral hypermobility, I will grasp a smaller knuckle.
These steps ensure that the midportion of the tape will not tighten or become deformed under tension. Rather than use a spacer, I like to protect the midportion of the tape and prevent it from being stretched. I find that the approach is reproducible and results in a reliable amount of space between the urethra and sling when the procedure is completed.
Dr. Rardin’s TOT approach
I employ an inside-out technique to the TOT procedure, and I utilize devices with segment of mesh that is shorter – only about 13 cm in length – than the original full-length mesh used in many TOT procedures. Once placed, the ends of the mesh penetrate the obturator membrane and obturator externus but not the adductor compartment of the thigh and groin.
In a study we presented last year at the annual meeting of the Society of Gynecologic Surgeons meeting, the shortened tape reduced postoperative groin pain, compared with full-length TOT tape without any reduction in subjective benefit. It appears that with shortened tape, we are anchoring the sling in tissues that provide critical support while avoiding the muscles that relate to the inner thigh/groin pain experienced by some patients. Effectiveness was not reduced, compared with full-length TOT slings.
These shortened slings are distinct from a single-incision sling, which is basically pushed into place. We still pass the needle all the way through a vaginal incision and out through the obturator foramen, and we pull the sling into place as we would any other TOT sling. The difference is that we’re not leaving any mesh in the groin.
I prefer an inside-out approach for two reasons: I always feel that I have more control over where a needle enters than where it exits, and precision is important with suburethral slings. Secondly, the dissection tunnel created for an inside-out pass is much smaller than the tunnel that must be dissected for an outside-in approach. In theory, less dissection means less devascularization, less denervation, and less opportunity for erosion.
Hydrodissection for TOT slings is more minimal and involves less fluid than does hydrodissection for retropubic slings, mainly because we do not want to anesthetize the obturator nerve. I pass the spinal needle from the outside in. At the start, prior to making any incisions, it is important to identify the arcus tendineus, a linear thickening of the superior fascia that is sometimes called the “white line.” This is where the sulcus is affixed to the sidewall. I will be sure to penetrate the sidewall at or above the level of the arcus.
With the TOT approach, the likelihood of bladder injury is so low that I usually drive the trocars all the way through prior to cystoscopy, as opposed to leaving the needles in place as I do with the retropubic approach.
Tensioning is achieved in the same manner, by using the Babcock clamp to avoid distortion of the critical part of the mesh while creating the space needed given the patient’s clinical scenario. It is worth remembering, at this point, that overall risks for retention appear to be lower for obturator slings, compared with retropubic slings.
I place most of my patients receiving retropubic slings in dorsal lithotomy position; but for obturator sling placement, I favor a few degrees into higher lithotomy because this pulls the obturator neurovascular bundle a little further out of the path of the needle.
Dr. Sokol reported that he owns stock in Pelvalon and is a clinical adviser to that company. He also is a national principal investigator for American Medical Systems and the recipient of research grants from Acell and several other companies. Dr. Rardin reported that he has no relevant financial disclosures. To view a video related to this article, go to SurgeryU at aagl.org/obgyn-news.
Midurethral slings – both retropubic and transobturator – have been extensively studied and have evolved to become standard therapies for the treatment of stress urinary incontinence. The two approaches utilize different routes for sling delivery, but in many other respects, they are similar. Improvements in technique are continually being developed. In this column, Dr. Sokol and Dr. Rardin share key parts of their technique and give their pearls of advice for midurethral sling surgery.
Dr. Sokol’s retropubic approach
I use newer retropubic midurethral slings with smaller trocars that have evolved from first-generation tension-free vaginal tape (TVT) slings. The slings I prefer are placed in a bottom-up fashion, with curved needles passed from a small vaginal incision up through the retropubic space to exit through two suprapubic incisions.
I find it helpful to place patients in a high lithotomy position with the legs supported in candy cane stirrups rather than Allen-type stirrups; sling placement is a short procedure with minimal to no risk of neuropathy.
To precisely identify the midurethral point, I use a 16-FR Foley catheter. When the catheter balloon is filled with 10 mm of fluid and gently pulled back, the urethrovesical junction can be identified. Then, by looking at the urethral meatus relative to the bladder neck, I can mark the midpoint between the two.
The suprapubic exit points are marked at two finger-widths lateral to the midline, just above the pubic symphysis. For precise identification of these points, the Foley catheter may be pulled up exactly midline (with the collection bag detached), and the two finger-widths measured on either side. I also aim for the ipsilateral shoulder, imagining a straight line from the urethral meatus to the ipsilateral shoulder on each side. Together, these measurements and visual cues serve as a good safety check.
With two Allis clamps, the vaginal wall on either side of the midline is grasped transversely at the level of the midurethral mark. The clamps will sit a couple of centimeters apart so that the midurethral point can be visualized. This helps to stabilize and elevate the midurethra.
To safely and efficiently develop a paraurethral passage, I perform a hydrodissection and hemostatic injection at the level of the midurethra using a control top 10-cc syringe with a 22-gauge needle. I find that dilute vasopressin saline solution affords better hemostasis than does a dilute lidocaine epinephrine solution, though I use dilute lidocaine if the sling is being done under local anesthesia.
The needle is inserted into a full thickness of skin, to a point shy of the urethra, and 10 cc is rapidly injected. The vaginal epithelium will appear blanched and will balloon out, like a white marble. The process basically lifts the vaginal skin away from the urethra itself, not only creating hemostasis but also providing a zone of safety to help avoid a urethral injury.
With a second syringe identical to the first, I inject 5 cc on each side of the midurethral point, aiming precisely at the underside of the pubic bone toward the ipsilateral shoulder. This creates a hydrodissected tunnel around each side of the midurethra. With a final syringe, I then inject 5 cc on each side suprapubically at my marked exit points.
With a #15 blade scalpel, I make two very small “poke” incisions transversely at the suprapubic sites. The suburethral incision is larger – just over a centimeter – and is made through a full thickness of skin under the area of hydrodissection, but not so deep as to injure the urethra. To finish development of the paraurethral passage, I pass standard Metzenbaum scissors through each hydrodissected tunnel until I feel the underside of the pubic bone, but no further.
For sling placement (after ensuring the bladder is completely empty), I lower the table such that my arm will be at a right angle to pass the sling while standing.
With my index finger underneath the pubic bone, the trocar tip, with the attached sling, is advanced with my thumb directly toward the ipsilateral shoulder just until it pops through the retropubic space. The depth of the trocar tip can be palpated with the index finger of the same hand, which is positioned just below the pelvic bone.
After the sling “pops” into the retropubic space, I remove my hand from the vagina and place it on the abdominal wall at the ipsilateral suprapubic poke site. In one smooth pass, I hug the pubic bone and advance the sling, again aiming directly and consistently at the shoulder. The trocar handle stays steady, never deviating in any direction. Cystoscopy is performed after the sling is placed on both sides to ensure bladder and urethral integrity.
For tensioning, I raise the table back up and, after reinserting the Foley catheter and a Sims retractor, I place my finger in the middle of the sling and pull the suprapubic ends of the sling up until my finger rests right under the urethra.
I then remove the vaginal clamps and use Metzenbaum scissors as a spacer between the sling and the urethra. With the scissors parallel to and right under the Foley catheter, at the same angle as the urethra, I tighten the sling and remove the plastic sheaths.
Dr. Sokol’s transobturator (TOT) approach
I most often use an outside-in sling. I utilize the same patient positioning and identify the midurethral point in the same way as with the retropubic approach.
On the thigh, I identify the adductor longus tendon as well as a little soft spot or depression just beneath the tendon and lateral to the descending ischial pubic ramus. With my thumb on the soft spot, I can actually grasp the adductor longus tendon between my thumb and index finger. This spot, which is also approximately at the level of the clitoris, marks the entry point for sling placement. It is the thinnest point between the groin and the vagina at the level of the midurethra.
I perform a similar hydrodissection under the urethra as I do in a retropubic procedure, though instead of injecting 5 cc’s to the underside of the pubic symphysis on each side, I instead inject toward the obturator internus muscles. I then inject my final syringe of dilute vasopressin saline solution at the groin poke incision sites, directed toward the projected trocar path, as opposed to suprapubically.
After the full-thickness vaginal incision is made with the scalpel, the dissection is performed sharply with Metzenbaum scissors and is more like the dissection done for cystocele repair than for a retropubic sling. Rather than a poke, the midurethral incision is long enough – about 1.5 cm – for me to reach a finger behind the obturator internus muscle after having sharply dissected the suburethral tissue and fascia. The angle of the dissection is more lateral than for a retropubic sling, toward the underside of the descending ischiopubic ramus and obturator internus muscle.
To place the sling, I have one hand with an index finger in the midurethral tunnel under the obturator internus muscle to protect the urethra. The thumb of that same hand is used to push the helical trocar straight through the thigh poke incision with the handle starting at a 35-degree angle from vertical. The trocar tip is pushed until it can no longer go straight and is ready to be tightly turned around the descending ischiopubic ramus with the opposite hand. A distinct pop can be felt as the trocar tip advances through the obturator membrane and muscles. As the tip is advanced, the angle of the trocar is rotated from 35 degrees to vertical, almost perpendicular to the floor. At this point, the tip of the trocar should be guided out of the midurethral tunnel against the opposite index finger.
I utilize the same technique for tensioning a TOT sling as I do the retropubic sling.
Dr. Rardin’s retropubic approach
I continue to use the original TVT sling with a 5-mm stainless steel, mechanically cut trocar and reusable handle. The newer slender needles may advance with less pressure, but I worry about them bending during passage. I feel more assured and comfortable using the older trocars.
I perform retropubic hydrodissection with a spinal needle using a top-down approach. With 40 cc of a very dilute solution of bupivacaine (Marcaine) with epinephrine on each side of the urethra, I create columns of hydrodissected space. Studies are inconsistent about the benefits of hydrodissection, but theoretically, it decreases the risk of bladder injury by pushing the bladder away from the pubic bone, creates effective hemostasis, and can provide analgesia that will be on board when the patient wakes up.
I bring the spinal needle down behind the pubic bone to the location of the urethral incision site, with my finger in the vagina, so I can feel the tip of the needle next to the urethra/Foley catheter. For each side, I will inject 20 cc of the solution in this location, and the other 20 cc as I withdraw the needle upward.
For trocar passage, some surgeons are taught to advance the trocar until a pop is felt, then drop the handle and push upward. I view the maneuver as a consistent, smooth arch; for every degree that I advance the trocar, I drop the handle slightly in order to maintain contact with the back of the pubic bone throughout the pass. I continuously and simultaneously drop the handle and advance the trocar. Contact with the back of the pubic bone is maintained with a slight pulling on the back end of the trocar handle, while the forward hand pushes the trocar upward.
The target that I visualize for a retropubic pass is the patient’s ipsilateral shoulder. A cadaver study showed that if you aim as far lateral as the patient’s outstretched elbow, you can enter the iliac vasculature (Obstet. Gynecol. 2003;101:933-6).
If the patient is draped such that I cannot see the ipsilateral shoulder, I ask the anesthesia team to show me. I have also identified and marked the suprapubic points about 2-3 cm from each other on either side of the midline just about the pubic symphysis, but I consider the broader anatomic picture and purposeful visualization toward the ipsilateral shoulder to be an essential part of safe technique. In general, it is safer to be more medial than more lateral for the needle passage.
I continue to use a rigid catheter guide to deflect the bladder neck while passing the needles.
Cystoscopy is performed after both needles are placed but not yet pulled through. I fill the bladder until the ureteral orifices appear flattened, which confirms that the bladder is under enough distension to preclude any mucosal wrinkles.
The technique I utilize for adjusting the tension of the TVT sling was taught to me by Dr. Peter L. Rosenblatt of Mt. Auburn Hospital in Cambridge, Mass. At the midline of the sling, I advance the sheaths just enough so that I can grasp a 2-3 mm “knuckle” of the midportion of the sling with a Babcock clamp. I then pull the sling ends until the Babcock comes into gentle contact with the suburethral tissue. The sheaths encasing the sling are then removed and the Babcock clamp is released to assure a tension-free deployment.
The amount of tape that is pinched with the Babcock – the size of the “knuckle” – determines the tension. For a patient with a more profound problem, such as intrinsic sphincter deficiency or a lack or urethral hypermobility, I will grasp a smaller knuckle.
These steps ensure that the midportion of the tape will not tighten or become deformed under tension. Rather than use a spacer, I like to protect the midportion of the tape and prevent it from being stretched. I find that the approach is reproducible and results in a reliable amount of space between the urethra and sling when the procedure is completed.
Dr. Rardin’s TOT approach
I employ an inside-out technique to the TOT procedure, and I utilize devices with segment of mesh that is shorter – only about 13 cm in length – than the original full-length mesh used in many TOT procedures. Once placed, the ends of the mesh penetrate the obturator membrane and obturator externus but not the adductor compartment of the thigh and groin.
In a study we presented last year at the annual meeting of the Society of Gynecologic Surgeons meeting, the shortened tape reduced postoperative groin pain, compared with full-length TOT tape without any reduction in subjective benefit. It appears that with shortened tape, we are anchoring the sling in tissues that provide critical support while avoiding the muscles that relate to the inner thigh/groin pain experienced by some patients. Effectiveness was not reduced, compared with full-length TOT slings.
These shortened slings are distinct from a single-incision sling, which is basically pushed into place. We still pass the needle all the way through a vaginal incision and out through the obturator foramen, and we pull the sling into place as we would any other TOT sling. The difference is that we’re not leaving any mesh in the groin.
I prefer an inside-out approach for two reasons: I always feel that I have more control over where a needle enters than where it exits, and precision is important with suburethral slings. Secondly, the dissection tunnel created for an inside-out pass is much smaller than the tunnel that must be dissected for an outside-in approach. In theory, less dissection means less devascularization, less denervation, and less opportunity for erosion.
Hydrodissection for TOT slings is more minimal and involves less fluid than does hydrodissection for retropubic slings, mainly because we do not want to anesthetize the obturator nerve. I pass the spinal needle from the outside in. At the start, prior to making any incisions, it is important to identify the arcus tendineus, a linear thickening of the superior fascia that is sometimes called the “white line.” This is where the sulcus is affixed to the sidewall. I will be sure to penetrate the sidewall at or above the level of the arcus.
With the TOT approach, the likelihood of bladder injury is so low that I usually drive the trocars all the way through prior to cystoscopy, as opposed to leaving the needles in place as I do with the retropubic approach.
Tensioning is achieved in the same manner, by using the Babcock clamp to avoid distortion of the critical part of the mesh while creating the space needed given the patient’s clinical scenario. It is worth remembering, at this point, that overall risks for retention appear to be lower for obturator slings, compared with retropubic slings.
I place most of my patients receiving retropubic slings in dorsal lithotomy position; but for obturator sling placement, I favor a few degrees into higher lithotomy because this pulls the obturator neurovascular bundle a little further out of the path of the needle.
Dr. Sokol reported that he owns stock in Pelvalon and is a clinical adviser to that company. He also is a national principal investigator for American Medical Systems and the recipient of research grants from Acell and several other companies. Dr. Rardin reported that he has no relevant financial disclosures. To view a video related to this article, go to SurgeryU at aagl.org/obgyn-news.
Team discovers new mechanisms of platelet formation
in the bone marrow
Researchers have found that megakaryocytes can produce platelets via different polyploidization mechanisms.
Experiments suggested that endomitosis is the major megakaryocyte polyploidization mechanism, but megakaryocytes can generate platelets even in the absence of endomitosis—via endocycles and re-replication.
These findings may have implications for treating cancers as well as thrombocytopenia, the researchers said.
They described their discoveries in Developmental Cell.
Marcos Malumbres, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain, and his colleagues performed a genetic analysis of endomitosis, in which megakaryocytes become polyploid by entering mitosis but aborting anaphase.
The team studied mice lacking key proteins involved in mitotic entry (Cdk1 and Cdk2), mitotic progression (Aurora B), or mitotic exit (the anaphase-promoting complex [APC/C] cofactor Cdc20) during megakaryocyte maturation.
They found that Aurora B is not required for megakaryocyte maturation, but Cdc20 is. In mice lacking Cdc20, the researchers observed mitotic arrest and severe thrombocytopenia. The team said this suggests endomitosis is the major megakaryocyte polyploidization mechanism in vivo.
So they were surprised to discover that deleting Cdk1 prevents endomitosis but does not hinder platelet formation.
“Whilst the elimination of the main proteins that regulate megakaryocyte growth generates, as we thought, a reduction in the production of platelets, this didn’t happen when we removed Cdk1,” Dr Malumbres said. “[Even] when Cdk1 was absent, the megakaryocytes were able to grow in size in a similar way to normal cells.”
“[Further] analysis revealed that cells deficient in Cdk1 underwent cellular reprogramming towards a process known as endocycles, which can also be seen in other types of cells, such as certain cells in the placenta,” said Marianna Trakala, also of CNIO.
In endocycles, cells successively replicate their genomes without segregating chromosomes during mitosis.
The researchers uncovered an additional mechanism for megakaryocyte polyploidy when they studied mice lacking both Cdk1 and Cdk2. The deletion of both Cdks resulted in aberrant re-replication, in which the genome is replicated more than once per cell cycle, but platelet levels were not affected.
In fact, the team found that the loss of Cdk1 alone or Cdk1 and Cdk2 together can significantly rescue proplatelet formation and increase platelet levels in Cdc20-null mice.
“We immediately asked ourselves if, by reprogramming the cell cycle towards endocycles, we could correct the thrombocytopenia induced in other models,” Dr Malumbres said.
And when the researchers eliminated Cdk1 in Cdc20-null mice with severe thrombocytopenia, they observed an increase in platelet production. Results were similar when the team ablated Cdk1 and Cdk2 in Cdc20-null mice.
In addition to their implications for treating thrombocytopenia, these results could aid the design of cancer treatments, the researchers said. The findings reveal the different requirements that normal or tumor cells have toward cell-cycle regulators.
Specifically, the research suggests that deleting Cdk1 or other cell-cycle proteins is lethal for tumor cells but does not affect megakaryocytes. So drugs that inhibit these proteins could be used to treat malignancies such as pro-megakaryocytic leukemias. 
in the bone marrow
Researchers have found that megakaryocytes can produce platelets via different polyploidization mechanisms.
Experiments suggested that endomitosis is the major megakaryocyte polyploidization mechanism, but megakaryocytes can generate platelets even in the absence of endomitosis—via endocycles and re-replication.
These findings may have implications for treating cancers as well as thrombocytopenia, the researchers said.
They described their discoveries in Developmental Cell.
Marcos Malumbres, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain, and his colleagues performed a genetic analysis of endomitosis, in which megakaryocytes become polyploid by entering mitosis but aborting anaphase.
The team studied mice lacking key proteins involved in mitotic entry (Cdk1 and Cdk2), mitotic progression (Aurora B), or mitotic exit (the anaphase-promoting complex [APC/C] cofactor Cdc20) during megakaryocyte maturation.
They found that Aurora B is not required for megakaryocyte maturation, but Cdc20 is. In mice lacking Cdc20, the researchers observed mitotic arrest and severe thrombocytopenia. The team said this suggests endomitosis is the major megakaryocyte polyploidization mechanism in vivo.
So they were surprised to discover that deleting Cdk1 prevents endomitosis but does not hinder platelet formation.
“Whilst the elimination of the main proteins that regulate megakaryocyte growth generates, as we thought, a reduction in the production of platelets, this didn’t happen when we removed Cdk1,” Dr Malumbres said. “[Even] when Cdk1 was absent, the megakaryocytes were able to grow in size in a similar way to normal cells.”
“[Further] analysis revealed that cells deficient in Cdk1 underwent cellular reprogramming towards a process known as endocycles, which can also be seen in other types of cells, such as certain cells in the placenta,” said Marianna Trakala, also of CNIO.
In endocycles, cells successively replicate their genomes without segregating chromosomes during mitosis.
The researchers uncovered an additional mechanism for megakaryocyte polyploidy when they studied mice lacking both Cdk1 and Cdk2. The deletion of both Cdks resulted in aberrant re-replication, in which the genome is replicated more than once per cell cycle, but platelet levels were not affected.
In fact, the team found that the loss of Cdk1 alone or Cdk1 and Cdk2 together can significantly rescue proplatelet formation and increase platelet levels in Cdc20-null mice.
“We immediately asked ourselves if, by reprogramming the cell cycle towards endocycles, we could correct the thrombocytopenia induced in other models,” Dr Malumbres said.
And when the researchers eliminated Cdk1 in Cdc20-null mice with severe thrombocytopenia, they observed an increase in platelet production. Results were similar when the team ablated Cdk1 and Cdk2 in Cdc20-null mice.
In addition to their implications for treating thrombocytopenia, these results could aid the design of cancer treatments, the researchers said. The findings reveal the different requirements that normal or tumor cells have toward cell-cycle regulators.
Specifically, the research suggests that deleting Cdk1 or other cell-cycle proteins is lethal for tumor cells but does not affect megakaryocytes. So drugs that inhibit these proteins could be used to treat malignancies such as pro-megakaryocytic leukemias.
in the bone marrow
Researchers have found that megakaryocytes can produce platelets via different polyploidization mechanisms.
Experiments suggested that endomitosis is the major megakaryocyte polyploidization mechanism, but megakaryocytes can generate platelets even in the absence of endomitosis—via endocycles and re-replication.
These findings may have implications for treating cancers as well as thrombocytopenia, the researchers said.
They described their discoveries in Developmental Cell.
Marcos Malumbres, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain, and his colleagues performed a genetic analysis of endomitosis, in which megakaryocytes become polyploid by entering mitosis but aborting anaphase.
The team studied mice lacking key proteins involved in mitotic entry (Cdk1 and Cdk2), mitotic progression (Aurora B), or mitotic exit (the anaphase-promoting complex [APC/C] cofactor Cdc20) during megakaryocyte maturation.
They found that Aurora B is not required for megakaryocyte maturation, but Cdc20 is. In mice lacking Cdc20, the researchers observed mitotic arrest and severe thrombocytopenia. The team said this suggests endomitosis is the major megakaryocyte polyploidization mechanism in vivo.
So they were surprised to discover that deleting Cdk1 prevents endomitosis but does not hinder platelet formation.
“Whilst the elimination of the main proteins that regulate megakaryocyte growth generates, as we thought, a reduction in the production of platelets, this didn’t happen when we removed Cdk1,” Dr Malumbres said. “[Even] when Cdk1 was absent, the megakaryocytes were able to grow in size in a similar way to normal cells.”
“[Further] analysis revealed that cells deficient in Cdk1 underwent cellular reprogramming towards a process known as endocycles, which can also be seen in other types of cells, such as certain cells in the placenta,” said Marianna Trakala, also of CNIO.
In endocycles, cells successively replicate their genomes without segregating chromosomes during mitosis.
The researchers uncovered an additional mechanism for megakaryocyte polyploidy when they studied mice lacking both Cdk1 and Cdk2. The deletion of both Cdks resulted in aberrant re-replication, in which the genome is replicated more than once per cell cycle, but platelet levels were not affected.
In fact, the team found that the loss of Cdk1 alone or Cdk1 and Cdk2 together can significantly rescue proplatelet formation and increase platelet levels in Cdc20-null mice.
“We immediately asked ourselves if, by reprogramming the cell cycle towards endocycles, we could correct the thrombocytopenia induced in other models,” Dr Malumbres said.
And when the researchers eliminated Cdk1 in Cdc20-null mice with severe thrombocytopenia, they observed an increase in platelet production. Results were similar when the team ablated Cdk1 and Cdk2 in Cdc20-null mice.
In addition to their implications for treating thrombocytopenia, these results could aid the design of cancer treatments, the researchers said. The findings reveal the different requirements that normal or tumor cells have toward cell-cycle regulators.
Specifically, the research suggests that deleting Cdk1 or other cell-cycle proteins is lethal for tumor cells but does not affect megakaryocytes. So drugs that inhibit these proteins could be used to treat malignancies such as pro-megakaryocytic leukemias.
Fusion protein fights resistant ALL
In a preclinical study, a fusion protein targeted treatment-resistant leukemia, demonstrating superiority over both chemotherapy and radiation.
The protein, CD19L-sTRAIL, induced apoptosis in radiation-resistant cells from patients with B-precursor acute lymphoblastic leukemia (ALL) and in
mouse models of the disease.
Additionally, mice that received CD19L-sTRAIL had significantly longer event-free survival than mice that received chemotherapy.
An account of this study appears in The Journal of Clinical Investigation.
Study investigators knew that TNF-related apoptosis-inducing ligand (TRAIL) can cause apoptosis in cancer cells by binding to TRAIL-receptor 1 and TRAIL-receptor 2.
“TRAIL is a naturally occurring part of the body’s immune system that kills cancer cells without toxicity to normal cells,” said Faith Uckun, MD, PhD, of Children’s Hospital Los Angeles in California.
“However, earlier clinical trials using TRAIL as a potential anticancer medicine candidate have not been successful, largely because of its propensity to bind, not only to cancer cells, but also to ‘decoy’ receptors.”
But Dr Uckun and her colleagues had discovered CD19-ligand (CD19L), a natural ligand of human CD19 that is expressed by almost all ALL cells. And they hypothesized that fusing CD19L to the portion of TRAIL that can kill cancer cells (known as sTRAIL) would produce a powerful weapon against leukemia cells.
The resulting fusion protein, CD19L-sTRAIL, would seek out, bind, and destroy only leukemia cells carrying CD19 as the target docking site.
In experiments, the investigators showed that their engineering converted sTRAIL into a much more potent “membrane-anchored” form that is capable of triggering apoptosis, even in the most aggressive and therapy-resistant ALL cells.
“Due to its ability to anchor to the surface of cancer cells via CD19, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed more than 99% of aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice,” Dr Uckun said.
At a 2.1 pM concentration, CD19L-sTRAIL caused 84.0±4.7% apoptosis in leukemia cells from patients with B-precursor ALL, whereas radiation with 2 Gy γ-rays caused 45.0±9.0% apoptosis (P<0.0001). Higher concentrations of CD19L-sTRAIL prompted an apoptosis rate of more than 90%.
In cells from mouse models of B-precursor ALL, 2.1 pM of CD19L-sTRAIL caused 91.4±5.4% apoptosis, compared to 16.0±4.6% with 2 Gy γ-rays (P<0.0001).
In addition, administering 2 or 3 doses of CD19L-sTRAIL significantly improved event-free survival in mice challenged with an otherwise fatal dose of leukemia cells.
The median event-free survival was 17 days in control mice; 20 days in mice treated with either vincristine, dexamethasone, and peg-asparaginase or vincristine, doxorubicin, and peg-asparaginase; and 58 days in mice that received 2- to 3-day treatment with CD19L-sTRAIL (P<0.0001 vs controls; P=0.0002 vs chemo).
The investigators said these results support the clinical potential of CD19L-sTRAIL as a new agent against B-precursor ALL.
“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.
In a preclinical study, a fusion protein targeted treatment-resistant leukemia, demonstrating superiority over both chemotherapy and radiation.
The protein, CD19L-sTRAIL, induced apoptosis in radiation-resistant cells from patients with B-precursor acute lymphoblastic leukemia (ALL) and in
mouse models of the disease.
Additionally, mice that received CD19L-sTRAIL had significantly longer event-free survival than mice that received chemotherapy.
An account of this study appears in The Journal of Clinical Investigation.
Study investigators knew that TNF-related apoptosis-inducing ligand (TRAIL) can cause apoptosis in cancer cells by binding to TRAIL-receptor 1 and TRAIL-receptor 2.
“TRAIL is a naturally occurring part of the body’s immune system that kills cancer cells without toxicity to normal cells,” said Faith Uckun, MD, PhD, of Children’s Hospital Los Angeles in California.
“However, earlier clinical trials using TRAIL as a potential anticancer medicine candidate have not been successful, largely because of its propensity to bind, not only to cancer cells, but also to ‘decoy’ receptors.”
But Dr Uckun and her colleagues had discovered CD19-ligand (CD19L), a natural ligand of human CD19 that is expressed by almost all ALL cells. And they hypothesized that fusing CD19L to the portion of TRAIL that can kill cancer cells (known as sTRAIL) would produce a powerful weapon against leukemia cells.
The resulting fusion protein, CD19L-sTRAIL, would seek out, bind, and destroy only leukemia cells carrying CD19 as the target docking site.
In experiments, the investigators showed that their engineering converted sTRAIL into a much more potent “membrane-anchored” form that is capable of triggering apoptosis, even in the most aggressive and therapy-resistant ALL cells.
“Due to its ability to anchor to the surface of cancer cells via CD19, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed more than 99% of aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice,” Dr Uckun said.
At a 2.1 pM concentration, CD19L-sTRAIL caused 84.0±4.7% apoptosis in leukemia cells from patients with B-precursor ALL, whereas radiation with 2 Gy γ-rays caused 45.0±9.0% apoptosis (P<0.0001). Higher concentrations of CD19L-sTRAIL prompted an apoptosis rate of more than 90%.
In cells from mouse models of B-precursor ALL, 2.1 pM of CD19L-sTRAIL caused 91.4±5.4% apoptosis, compared to 16.0±4.6% with 2 Gy γ-rays (P<0.0001).
In addition, administering 2 or 3 doses of CD19L-sTRAIL significantly improved event-free survival in mice challenged with an otherwise fatal dose of leukemia cells.
The median event-free survival was 17 days in control mice; 20 days in mice treated with either vincristine, dexamethasone, and peg-asparaginase or vincristine, doxorubicin, and peg-asparaginase; and 58 days in mice that received 2- to 3-day treatment with CD19L-sTRAIL (P<0.0001 vs controls; P=0.0002 vs chemo).
The investigators said these results support the clinical potential of CD19L-sTRAIL as a new agent against B-precursor ALL.
“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.
In a preclinical study, a fusion protein targeted treatment-resistant leukemia, demonstrating superiority over both chemotherapy and radiation.
The protein, CD19L-sTRAIL, induced apoptosis in radiation-resistant cells from patients with B-precursor acute lymphoblastic leukemia (ALL) and in
mouse models of the disease.
Additionally, mice that received CD19L-sTRAIL had significantly longer event-free survival than mice that received chemotherapy.
An account of this study appears in The Journal of Clinical Investigation.
Study investigators knew that TNF-related apoptosis-inducing ligand (TRAIL) can cause apoptosis in cancer cells by binding to TRAIL-receptor 1 and TRAIL-receptor 2.
“TRAIL is a naturally occurring part of the body’s immune system that kills cancer cells without toxicity to normal cells,” said Faith Uckun, MD, PhD, of Children’s Hospital Los Angeles in California.
“However, earlier clinical trials using TRAIL as a potential anticancer medicine candidate have not been successful, largely because of its propensity to bind, not only to cancer cells, but also to ‘decoy’ receptors.”
But Dr Uckun and her colleagues had discovered CD19-ligand (CD19L), a natural ligand of human CD19 that is expressed by almost all ALL cells. And they hypothesized that fusing CD19L to the portion of TRAIL that can kill cancer cells (known as sTRAIL) would produce a powerful weapon against leukemia cells.
The resulting fusion protein, CD19L-sTRAIL, would seek out, bind, and destroy only leukemia cells carrying CD19 as the target docking site.
In experiments, the investigators showed that their engineering converted sTRAIL into a much more potent “membrane-anchored” form that is capable of triggering apoptosis, even in the most aggressive and therapy-resistant ALL cells.
“Due to its ability to anchor to the surface of cancer cells via CD19, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed more than 99% of aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice,” Dr Uckun said.
At a 2.1 pM concentration, CD19L-sTRAIL caused 84.0±4.7% apoptosis in leukemia cells from patients with B-precursor ALL, whereas radiation with 2 Gy γ-rays caused 45.0±9.0% apoptosis (P<0.0001). Higher concentrations of CD19L-sTRAIL prompted an apoptosis rate of more than 90%.
In cells from mouse models of B-precursor ALL, 2.1 pM of CD19L-sTRAIL caused 91.4±5.4% apoptosis, compared to 16.0±4.6% with 2 Gy γ-rays (P<0.0001).
In addition, administering 2 or 3 doses of CD19L-sTRAIL significantly improved event-free survival in mice challenged with an otherwise fatal dose of leukemia cells.
The median event-free survival was 17 days in control mice; 20 days in mice treated with either vincristine, dexamethasone, and peg-asparaginase or vincristine, doxorubicin, and peg-asparaginase; and 58 days in mice that received 2- to 3-day treatment with CD19L-sTRAIL (P<0.0001 vs controls; P=0.0002 vs chemo).
The investigators said these results support the clinical potential of CD19L-sTRAIL as a new agent against B-precursor ALL.
“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.
Product granted orphan designation for GVHD
Credit: PLOS ONE
The European Medicines Agency (EMA) has granted orphan drug status to ApoCell for the prevention of graft-vs-host disease (GVHD).
ApoCell consists of matched-donor, mononuclear-enriched, early apoptotic cells. It has been shown to immunomodulate macrophages and dendritic cells, both of which are involved in GVHD pathogenesis.
ApoCell showed early promise in a phase 1/2a study, and a phase 2b/3 trial of the product is set to begin this year.
ApoCell, which is under development by Enlivex Therapeutics, received orphan drug designation in the US in 2013.
In the European Union (EU), orphan designation is granted to products intended for the treatment, prevention, or diagnosis of a life-threatening or chronically debilitating disease with a prevalence of no more than 5 in 10,000, with no satisfactory method of diagnosis, prevention, or treatment authorized by the EMA.
Orphan designation in the EU comes with a number of benefits, including protocol assistance and 10-year market exclusivity following regulatory approval.
Phase 1/2a trial of ApoCell
For this study, researchers tested an infusion of ApoCell, in addition to cyclosporine and methotrexate, as prophylaxis for acute GVHD.
The trial enrolled 13 leukemia patients who had a median age of 37 (range, 20-59). All of the patients received an HLA-matched, myeloablative, allogeneic hematopoietic stem cell transplant (HSCT) from a related donor.
All patients engrafted. The median time to neutrophil recovery was 13 days after HSCT (range, 11 to 19), and the median time to platelet recovery was 15 days (range, 11 to 59).
At 100 days post-HSCT, the cumulative incidence of acute grade 2-4 GVHD was 23.1%, and the incidence of acute grade 3-4 GVHD was 15.4%. None of the patients developed acute GVHD beyond day 100.
Among patients who received the 2 higher doses of ApoCell (n=6), the rate of acute grade 2-4 GVHD was 0%.
Ten patients experienced serious adverse events, but 7 were considered unrelated to ApoCell, and 3 were likely unrelated to the treatment.
The nonrelapse mortality rate was 7.7% at both 100 and 180 days after HSCT. The overall survival rate was 92% at 100 days and 85% at 180 days.
The researchers said these results suggest a single infusion of ApoCell is safe and may effectively prevent acute GVHD.
Credit: PLOS ONE
The European Medicines Agency (EMA) has granted orphan drug status to ApoCell for the prevention of graft-vs-host disease (GVHD).
ApoCell consists of matched-donor, mononuclear-enriched, early apoptotic cells. It has been shown to immunomodulate macrophages and dendritic cells, both of which are involved in GVHD pathogenesis.
ApoCell showed early promise in a phase 1/2a study, and a phase 2b/3 trial of the product is set to begin this year.
ApoCell, which is under development by Enlivex Therapeutics, received orphan drug designation in the US in 2013.
In the European Union (EU), orphan designation is granted to products intended for the treatment, prevention, or diagnosis of a life-threatening or chronically debilitating disease with a prevalence of no more than 5 in 10,000, with no satisfactory method of diagnosis, prevention, or treatment authorized by the EMA.
Orphan designation in the EU comes with a number of benefits, including protocol assistance and 10-year market exclusivity following regulatory approval.
Phase 1/2a trial of ApoCell
For this study, researchers tested an infusion of ApoCell, in addition to cyclosporine and methotrexate, as prophylaxis for acute GVHD.
The trial enrolled 13 leukemia patients who had a median age of 37 (range, 20-59). All of the patients received an HLA-matched, myeloablative, allogeneic hematopoietic stem cell transplant (HSCT) from a related donor.
All patients engrafted. The median time to neutrophil recovery was 13 days after HSCT (range, 11 to 19), and the median time to platelet recovery was 15 days (range, 11 to 59).
At 100 days post-HSCT, the cumulative incidence of acute grade 2-4 GVHD was 23.1%, and the incidence of acute grade 3-4 GVHD was 15.4%. None of the patients developed acute GVHD beyond day 100.
Among patients who received the 2 higher doses of ApoCell (n=6), the rate of acute grade 2-4 GVHD was 0%.
Ten patients experienced serious adverse events, but 7 were considered unrelated to ApoCell, and 3 were likely unrelated to the treatment.
The nonrelapse mortality rate was 7.7% at both 100 and 180 days after HSCT. The overall survival rate was 92% at 100 days and 85% at 180 days.
The researchers said these results suggest a single infusion of ApoCell is safe and may effectively prevent acute GVHD.
Credit: PLOS ONE
The European Medicines Agency (EMA) has granted orphan drug status to ApoCell for the prevention of graft-vs-host disease (GVHD).
ApoCell consists of matched-donor, mononuclear-enriched, early apoptotic cells. It has been shown to immunomodulate macrophages and dendritic cells, both of which are involved in GVHD pathogenesis.
ApoCell showed early promise in a phase 1/2a study, and a phase 2b/3 trial of the product is set to begin this year.
ApoCell, which is under development by Enlivex Therapeutics, received orphan drug designation in the US in 2013.
In the European Union (EU), orphan designation is granted to products intended for the treatment, prevention, or diagnosis of a life-threatening or chronically debilitating disease with a prevalence of no more than 5 in 10,000, with no satisfactory method of diagnosis, prevention, or treatment authorized by the EMA.
Orphan designation in the EU comes with a number of benefits, including protocol assistance and 10-year market exclusivity following regulatory approval.
Phase 1/2a trial of ApoCell
For this study, researchers tested an infusion of ApoCell, in addition to cyclosporine and methotrexate, as prophylaxis for acute GVHD.
The trial enrolled 13 leukemia patients who had a median age of 37 (range, 20-59). All of the patients received an HLA-matched, myeloablative, allogeneic hematopoietic stem cell transplant (HSCT) from a related donor.
All patients engrafted. The median time to neutrophil recovery was 13 days after HSCT (range, 11 to 19), and the median time to platelet recovery was 15 days (range, 11 to 59).
At 100 days post-HSCT, the cumulative incidence of acute grade 2-4 GVHD was 23.1%, and the incidence of acute grade 3-4 GVHD was 15.4%. None of the patients developed acute GVHD beyond day 100.
Among patients who received the 2 higher doses of ApoCell (n=6), the rate of acute grade 2-4 GVHD was 0%.
Ten patients experienced serious adverse events, but 7 were considered unrelated to ApoCell, and 3 were likely unrelated to the treatment.
The nonrelapse mortality rate was 7.7% at both 100 and 180 days after HSCT. The overall survival rate was 92% at 100 days and 85% at 180 days.
The researchers said these results suggest a single infusion of ApoCell is safe and may effectively prevent acute GVHD.
NICE recommends rivaroxaban for ACS
Credit: NHS
In its final draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) is recommending rivaroxaban (Xarelto) as an option for preventing adverse outcomes in patients with acute coronary syndromes (ACS).
The agency said it supports use of the factor Xa inhibitor in combination with aspirin and clopidogrel or aspirin alone to prevent atherothrombotic events in ACS patients with elevated cardiac biomarkers.
This includes patients who have had ST-segment-elevation myocardial infarctions (STEMIs) or non-ST-segment myocardial infarctions (NSTEMIs) but not unstable angina. In unstable angina, damage to the heart is not severe enough to result in the release of biomarkers into the blood, so this condition is not included in the guidance.
“Because rivaroxaban is associated with a higher risk of causing bleeding than clopidogrel in combination with aspirin or aspirin alone, the draft guidance recommends that, before starting treatment, doctors should carry out a careful assessment of a person’s bleeding risk,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
“The decision to start treatment should be made after an informed discussion between the doctor and patient about the benefits and risks of rivaroxaban. Also, because there is limited experience of treatment with rivaroxaban up to 24 months, the draft guidance recommends careful consideration should be given to whether treatment is continued beyond 12 months.”
The final draft guidance is now with consultees, who have the opportunity to appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.
Cost and clinical effectiveness
An appraisal committee advising NICE concluded that rivaroxaban given at 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing further cardiovascular deaths and myocardial infarction in patients with ACS and raised cardiac biomarkers.
The committee also found rivaroxaban to be cost-effective. According to Bayer Healthcare (the company co-developing rivaroxaban with Janssen Research & Development, LLC), the base-case incremental cost-effectiveness ratio (ICER) was £6203 per quality-adjusted life-year (QALY) gained. The evidence review group’s preferred base-case estimate was £5622 per QALY gained.
The committee said there is uncertainty about the validity of these results, which were based on the ATLAS-ACS 2-TIMI 51 trial, because of the risk of bias resulting from missing trial data and informative censoring.
However, the committee considered that the ICERs presented were all within the range that could be considered cost-effective, and adjusting for the various types of bias that might have occurred was unlikely to increase the ICER to the extent that it would become unacceptable.
The list price of rivaroxaban is £58.88 per 2.5 mg, 56-capsule pack (excluding value-added tax). The license dose is 2.5 mg twice daily, which equates to a price of £2.10 per day.
Assuming a treatment duration of 12 months, total acquisition costs are £766.50. Costs may vary in different settings because of negotiated procurement discounts.
Credit: NHS
In its final draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) is recommending rivaroxaban (Xarelto) as an option for preventing adverse outcomes in patients with acute coronary syndromes (ACS).
The agency said it supports use of the factor Xa inhibitor in combination with aspirin and clopidogrel or aspirin alone to prevent atherothrombotic events in ACS patients with elevated cardiac biomarkers.
This includes patients who have had ST-segment-elevation myocardial infarctions (STEMIs) or non-ST-segment myocardial infarctions (NSTEMIs) but not unstable angina. In unstable angina, damage to the heart is not severe enough to result in the release of biomarkers into the blood, so this condition is not included in the guidance.
“Because rivaroxaban is associated with a higher risk of causing bleeding than clopidogrel in combination with aspirin or aspirin alone, the draft guidance recommends that, before starting treatment, doctors should carry out a careful assessment of a person’s bleeding risk,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
“The decision to start treatment should be made after an informed discussion between the doctor and patient about the benefits and risks of rivaroxaban. Also, because there is limited experience of treatment with rivaroxaban up to 24 months, the draft guidance recommends careful consideration should be given to whether treatment is continued beyond 12 months.”
The final draft guidance is now with consultees, who have the opportunity to appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.
Cost and clinical effectiveness
An appraisal committee advising NICE concluded that rivaroxaban given at 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing further cardiovascular deaths and myocardial infarction in patients with ACS and raised cardiac biomarkers.
The committee also found rivaroxaban to be cost-effective. According to Bayer Healthcare (the company co-developing rivaroxaban with Janssen Research & Development, LLC), the base-case incremental cost-effectiveness ratio (ICER) was £6203 per quality-adjusted life-year (QALY) gained. The evidence review group’s preferred base-case estimate was £5622 per QALY gained.
The committee said there is uncertainty about the validity of these results, which were based on the ATLAS-ACS 2-TIMI 51 trial, because of the risk of bias resulting from missing trial data and informative censoring.
However, the committee considered that the ICERs presented were all within the range that could be considered cost-effective, and adjusting for the various types of bias that might have occurred was unlikely to increase the ICER to the extent that it would become unacceptable.
The list price of rivaroxaban is £58.88 per 2.5 mg, 56-capsule pack (excluding value-added tax). The license dose is 2.5 mg twice daily, which equates to a price of £2.10 per day.
Assuming a treatment duration of 12 months, total acquisition costs are £766.50. Costs may vary in different settings because of negotiated procurement discounts.
Credit: NHS
In its final draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) is recommending rivaroxaban (Xarelto) as an option for preventing adverse outcomes in patients with acute coronary syndromes (ACS).
The agency said it supports use of the factor Xa inhibitor in combination with aspirin and clopidogrel or aspirin alone to prevent atherothrombotic events in ACS patients with elevated cardiac biomarkers.
This includes patients who have had ST-segment-elevation myocardial infarctions (STEMIs) or non-ST-segment myocardial infarctions (NSTEMIs) but not unstable angina. In unstable angina, damage to the heart is not severe enough to result in the release of biomarkers into the blood, so this condition is not included in the guidance.
“Because rivaroxaban is associated with a higher risk of causing bleeding than clopidogrel in combination with aspirin or aspirin alone, the draft guidance recommends that, before starting treatment, doctors should carry out a careful assessment of a person’s bleeding risk,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
“The decision to start treatment should be made after an informed discussion between the doctor and patient about the benefits and risks of rivaroxaban. Also, because there is limited experience of treatment with rivaroxaban up to 24 months, the draft guidance recommends careful consideration should be given to whether treatment is continued beyond 12 months.”
The final draft guidance is now with consultees, who have the opportunity to appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.
Cost and clinical effectiveness
An appraisal committee advising NICE concluded that rivaroxaban given at 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing further cardiovascular deaths and myocardial infarction in patients with ACS and raised cardiac biomarkers.
The committee also found rivaroxaban to be cost-effective. According to Bayer Healthcare (the company co-developing rivaroxaban with Janssen Research & Development, LLC), the base-case incremental cost-effectiveness ratio (ICER) was £6203 per quality-adjusted life-year (QALY) gained. The evidence review group’s preferred base-case estimate was £5622 per QALY gained.
The committee said there is uncertainty about the validity of these results, which were based on the ATLAS-ACS 2-TIMI 51 trial, because of the risk of bias resulting from missing trial data and informative censoring.
However, the committee considered that the ICERs presented were all within the range that could be considered cost-effective, and adjusting for the various types of bias that might have occurred was unlikely to increase the ICER to the extent that it would become unacceptable.
The list price of rivaroxaban is £58.88 per 2.5 mg, 56-capsule pack (excluding value-added tax). The license dose is 2.5 mg twice daily, which equates to a price of £2.10 per day.
Assuming a treatment duration of 12 months, total acquisition costs are £766.50. Costs may vary in different settings because of negotiated procurement discounts.
Pituitary Incidentaloma
Brian, 46, is referred to endocrinology for evaluation of a pituitary “mass.” The mass was an incidental finding of head and neck CT performed three months ago, when Brian went to an emergency department following a motor vehicle accident. He has fully recovered from the accident and feels well. He describes himself as a “completely healthy” person who has no chronic medical conditions and takes neither prescription nor OTC medications.
Brian denies significant headache, visual disturbance, change in appetite, unexplained weight change, skin rash (wide purple striae) or color changes (hyperpigmentation), polyuria or polydipsia, dizziness, syncopal episodes, low libido, erectile dysfunction, joint pain, and changes in ring or shoe size. He does not wear a hat or cap and is unaware of head size changes. He has not experienced changes in his facial features or trouble with chewing.
He is a happily married engineer with two healthy children and reports that he feels well except for this “brain tumor” finding that has been a shock to him and his family. There is no family history of pituitary adenoma or multiple endocrine neoplasia syndrome.
His vital signs, all within normal ranges, include a blood pressure of 103/65 mm Hg. His height is 6 ft and his weight, 180 lb. His BMI is 24.4.
HOW COMMON IS PITUITARY INCIDENTALOMA?
A pituitary incidentaloma is a lesion in the pituitary gland that was not previously suspected and was found through an imaging study ordered for other reasons. Pituitary incidentaloma is surprisingly common, with an average prevalence of 10.6% (as estimated from combined autopsy data), although it has been found in up to 20% of patients undergoing CT and 38% undergoing MRI.1,2 Most are microadenomas (< 1 cm in size).1
Continue for recommendations from the Endocrine Society >>
SHOULD AN ASYMPTOMATIC PATIENT BE EVALUATED FURTHER?
Endocrine Society guidelines2 recommend that all patients with pituitary incidentaloma, with or without symptoms, should undergo a complete history and physical examination and laboratory evaluation to exclude hypersecretion and hyposecretion of pituitary hormones.
The “classic” presentation of pituitary hormone hypersecretion—in the form of prolactinoma, adrenocorticotropic hormone (ACTH) excess (Cushing disease), growth hormone (GH) excess (gigantism/acromegaly), and TSH excess (secondary hyperthyroidism)—may be readily detectable on history and physical examination. Subtle cases, so-called subclinical disease, however, may exhibit little or no signs and symptoms initially but can be detrimental to the patient’s health if left untreated. For example, the estimated time from onset to diagnosis of acromegaly is approximately seven to 10 years—a delay that can significantly impact the patient’s morbidity and mortality.3
Prolactinoma can be more clinically apparent in premenopausal females due to irregular menstrual cycles (oligomenorrhea/amenorrhea). However, galactorrhea, or “milky” nipple discharge, occurs in only about 50% of women with prolactinoma and is extremely rare in men. Furthermore, the clinical presentation of prolactinoma in men is vague and related to hypogonadism, resulting from increased prolactin levels. Since men are essentially asymptomatic, these tumors can grow extensively (macroadenoma) and cause “mass effect,” such as headaches and visual impairment.
Therefore, without laboratory testing, abnormal pituitary function may go unrecognized.
WHAT LABS SHOULD I ORDER FOR THIS PATIENT?
Guidelines suggest an initial screening panel of prolactin, GH, insulin-like growth factor 1 (IGF-1), ACTH, early-morning cortisol, TSH, free T4, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone.2
Note the use of “suggest” rather than “recommend.” Even among guideline task force members, there were differences in opinion as to whether certain tests (eg, TSH, LH, and FSH) should be included in initial screening. Those tests can be ordered at the clinician’s discretion, according to the level of suspicion, or can be added later if necessary.
Brian’s sample for laboratory testing is drawn at 7:50 am. Results can be found in the table (previous page).
Next page: Caveats and concerns >>
ARE THERE ANY CAVEATS TO THE INTERPRETATION OF LAB VALUES?
It is important to note that in postmenopausal women who are not taking hormone replacement therapy, LH and FSH will be elevated and estradiol may provide an additional clue in the detection of abnormal function. Conversely, low LH and FSH in postmenopausal women should raise a flag for hypopituitarism.
Another caveat is that GH secretion is pulsatile and serum levels are undetectable between pulses. Therefore, low/undetectable GH does not necessarily suggest deficiency. The GH measurement would only be helpful if it is significantly elevated (suggestive of hypersecretion—gigantism/acromegaly). Otherwise, GH has little value as a screening test.
Instead, IGF-1, which is secreted from the liver in response to GH secretion, has a longer half-life and serves as a better screening tool. IGF-1 has age- and sex-adjusted reference ranges, which are often reported by the lab or given as a Z score.
WHAT IS THE PREFERRED IMAGING STUDY FOR THE PITUITARY GLAND?
The best choice is MRI of the pituitary gland (not the whole brain) with gadolinium. If the incidentaloma was initially diagnosed by a CT, additional testing with MRI should be performed, unless contraindicated.2
Brian is referred for MRI with gadolinium. The radiologist’s report describes a 5 x 4 x 4–mm pituitary microadenoma without sellar extension or involvement of the optic chiasm.
AT WHAT POINT SHOULD OPTIC CHIASM BE A CONCERN?
Since the pituitary gland is located directly beneath the optic chiasm, any compressive effect of growth against the optic nerve(s) can cause visual impairment. This includes bitemporal hemianopsia (loss of peripheral vision) or ophthalmoplegia (abnormal movement of the ocular muscle). Since clinical signs and symptoms can be subtle or absent, all patients with evidence of a pituitary lesion abutting or compressing the optic chiasm should have a formal visual field exam.2
Continue for surgical intervention >>
WHO REQUIRES SURGICAL INTERVENTION?
Patients with mass effect (headache, increased intracranial pressure, compromised optic chiasm) and those with hyperfunctioning nonprolactin adenomas, some (but not all) macroprolactinomas, or pituitary apoplexy should be referred for surgery.2 Almost all cases involve macroadenomas rather than microadenomas.
The preferred treatment for GH-secreting tumors and ACTH-secreting tumors is surgery. However, prolactinoma can be well controlled with pharmacologic agents (dopamine agonists) in most cases. For prolactinomas refractory to these medications, surgical resection is recommended. (Detailed treatment approaches are available elsewhere; those for hyperprolactinoma can be found on the Clinician Reviews website: http://bit.ly/1HOb9Jf.)
Pituitary apoplexy, a life-threatening emergency that requires prompt surgical decompression, is an infarction of the gland due to abrupt cessation of the blood supply, caused by either pituitary artery hemorrhage or sudden hypovolemia. Increased blood supply is needed due to the extra tissue and volume of the pituitary mass; this may stress the pituitary arteries, which are not equipped for this increased flow, causing them to rupture. Hemorrhage anywhere else in the body can lead to hypovolemia and decrease the blood supply to the pituitary gland. A classic example would be postpartum hemorrhage causing pituitary infarct, called Sheehan syndrome.
Due to increased estrogen levels, the pituitary gland doubles in size during pregnancy.4 A preexisting mass may further develop and compress the optic chiasm. Therefore, women of childbearing age should be engaged in discussion of the potential risks and benefits of decompression surgery before actively pursuing pregnancy—especially if the lesion is close to the optic chiasm.
Surgery can also be considered for patients with significant growth in adenoma size during monitoring, loss of endocrinologic function due to mass effect on other pituitary cells, or unremitting headache.2
Next: How should patients be monitored?
HOW SHOULD PATIENTS BE MONITORED?
Those who do not meet criteria for surgery can be closely monitored with periodic testing. Imaging can be repeated six months after the first scan for macroadenoma and in one year for microadenoma. If there is no change in the size of the mass, imaging can be done yearly for macroadenoma and for microadenoma, every one to two years for three years and then gradually less often thereafter.2
Unless the lesion is abutting the optic chiasm (seen via imaging) or the patient reports symptoms, visual field testing does not need to be repeated.
Lab testing should be repeated six months after initial testing for macroadenoma and yearly thereafter. No further testing is suggested for nonsecretory microadenoma, unless clinically indicated.2
If there are any changes in status—noted clinically or via imaging—more frequent testing is suggested.
Brian is reassured that pituitary adenoma is not an uncommon finding and that his adenoma is relatively small in size and nonsecretory. Repeat pituitary MRI in one year is recommended.
CONCLUSION
Most pituitary incidentalomas have no consequences to a patient’s health. However, patients often become highly anxious about the “brain tumor” they were told they have. Appropriate patient education and thorough evaluation can reassure patients and alleviate their concerns.
REFERENCES
1. Molitch ME. Nonfunctioning pituitary tumors and pituitary incidentalomas. Endocrinol Metab Clin North Am. 2008;37(1):151-171.
2. Freda PU, Beckers AM, Katznelson L, et al. Pituitary incidentaloma: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96(4):894-904.
3. Katznelson L, Atkinson JL, Cook DM, et al. American Association of Clinical Endocrinologists Medical Guidelines For Clinical Practice For The Diagnosis And Treatment Of Acromegaly–2011 Update. Endocr Pract. 2011;17(suppl 4).
4. Jameson JL. Harrison’s Endocrinology. 2nd ed. China: McGraw-Hill; 2010:16-49.
Clinician Reviews in partnership with
Clinician Reviews in partnership with
Clinician Reviews in partnership with
Brian, 46, is referred to endocrinology for evaluation of a pituitary “mass.” The mass was an incidental finding of head and neck CT performed three months ago, when Brian went to an emergency department following a motor vehicle accident. He has fully recovered from the accident and feels well. He describes himself as a “completely healthy” person who has no chronic medical conditions and takes neither prescription nor OTC medications.
Brian denies significant headache, visual disturbance, change in appetite, unexplained weight change, skin rash (wide purple striae) or color changes (hyperpigmentation), polyuria or polydipsia, dizziness, syncopal episodes, low libido, erectile dysfunction, joint pain, and changes in ring or shoe size. He does not wear a hat or cap and is unaware of head size changes. He has not experienced changes in his facial features or trouble with chewing.
He is a happily married engineer with two healthy children and reports that he feels well except for this “brain tumor” finding that has been a shock to him and his family. There is no family history of pituitary adenoma or multiple endocrine neoplasia syndrome.
His vital signs, all within normal ranges, include a blood pressure of 103/65 mm Hg. His height is 6 ft and his weight, 180 lb. His BMI is 24.4.
HOW COMMON IS PITUITARY INCIDENTALOMA?
A pituitary incidentaloma is a lesion in the pituitary gland that was not previously suspected and was found through an imaging study ordered for other reasons. Pituitary incidentaloma is surprisingly common, with an average prevalence of 10.6% (as estimated from combined autopsy data), although it has been found in up to 20% of patients undergoing CT and 38% undergoing MRI.1,2 Most are microadenomas (< 1 cm in size).1
Continue for recommendations from the Endocrine Society >>
SHOULD AN ASYMPTOMATIC PATIENT BE EVALUATED FURTHER?
Endocrine Society guidelines2 recommend that all patients with pituitary incidentaloma, with or without symptoms, should undergo a complete history and physical examination and laboratory evaluation to exclude hypersecretion and hyposecretion of pituitary hormones.
The “classic” presentation of pituitary hormone hypersecretion—in the form of prolactinoma, adrenocorticotropic hormone (ACTH) excess (Cushing disease), growth hormone (GH) excess (gigantism/acromegaly), and TSH excess (secondary hyperthyroidism)—may be readily detectable on history and physical examination. Subtle cases, so-called subclinical disease, however, may exhibit little or no signs and symptoms initially but can be detrimental to the patient’s health if left untreated. For example, the estimated time from onset to diagnosis of acromegaly is approximately seven to 10 years—a delay that can significantly impact the patient’s morbidity and mortality.3
Prolactinoma can be more clinically apparent in premenopausal females due to irregular menstrual cycles (oligomenorrhea/amenorrhea). However, galactorrhea, or “milky” nipple discharge, occurs in only about 50% of women with prolactinoma and is extremely rare in men. Furthermore, the clinical presentation of prolactinoma in men is vague and related to hypogonadism, resulting from increased prolactin levels. Since men are essentially asymptomatic, these tumors can grow extensively (macroadenoma) and cause “mass effect,” such as headaches and visual impairment.
Therefore, without laboratory testing, abnormal pituitary function may go unrecognized.
WHAT LABS SHOULD I ORDER FOR THIS PATIENT?
Guidelines suggest an initial screening panel of prolactin, GH, insulin-like growth factor 1 (IGF-1), ACTH, early-morning cortisol, TSH, free T4, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone.2
Note the use of “suggest” rather than “recommend.” Even among guideline task force members, there were differences in opinion as to whether certain tests (eg, TSH, LH, and FSH) should be included in initial screening. Those tests can be ordered at the clinician’s discretion, according to the level of suspicion, or can be added later if necessary.
Brian’s sample for laboratory testing is drawn at 7:50 am. Results can be found in the table (previous page).
Next page: Caveats and concerns >>
ARE THERE ANY CAVEATS TO THE INTERPRETATION OF LAB VALUES?
It is important to note that in postmenopausal women who are not taking hormone replacement therapy, LH and FSH will be elevated and estradiol may provide an additional clue in the detection of abnormal function. Conversely, low LH and FSH in postmenopausal women should raise a flag for hypopituitarism.
Another caveat is that GH secretion is pulsatile and serum levels are undetectable between pulses. Therefore, low/undetectable GH does not necessarily suggest deficiency. The GH measurement would only be helpful if it is significantly elevated (suggestive of hypersecretion—gigantism/acromegaly). Otherwise, GH has little value as a screening test.
Instead, IGF-1, which is secreted from the liver in response to GH secretion, has a longer half-life and serves as a better screening tool. IGF-1 has age- and sex-adjusted reference ranges, which are often reported by the lab or given as a Z score.
WHAT IS THE PREFERRED IMAGING STUDY FOR THE PITUITARY GLAND?
The best choice is MRI of the pituitary gland (not the whole brain) with gadolinium. If the incidentaloma was initially diagnosed by a CT, additional testing with MRI should be performed, unless contraindicated.2
Brian is referred for MRI with gadolinium. The radiologist’s report describes a 5 x 4 x 4–mm pituitary microadenoma without sellar extension or involvement of the optic chiasm.
AT WHAT POINT SHOULD OPTIC CHIASM BE A CONCERN?
Since the pituitary gland is located directly beneath the optic chiasm, any compressive effect of growth against the optic nerve(s) can cause visual impairment. This includes bitemporal hemianopsia (loss of peripheral vision) or ophthalmoplegia (abnormal movement of the ocular muscle). Since clinical signs and symptoms can be subtle or absent, all patients with evidence of a pituitary lesion abutting or compressing the optic chiasm should have a formal visual field exam.2
Continue for surgical intervention >>
WHO REQUIRES SURGICAL INTERVENTION?
Patients with mass effect (headache, increased intracranial pressure, compromised optic chiasm) and those with hyperfunctioning nonprolactin adenomas, some (but not all) macroprolactinomas, or pituitary apoplexy should be referred for surgery.2 Almost all cases involve macroadenomas rather than microadenomas.
The preferred treatment for GH-secreting tumors and ACTH-secreting tumors is surgery. However, prolactinoma can be well controlled with pharmacologic agents (dopamine agonists) in most cases. For prolactinomas refractory to these medications, surgical resection is recommended. (Detailed treatment approaches are available elsewhere; those for hyperprolactinoma can be found on the Clinician Reviews website: http://bit.ly/1HOb9Jf.)
Pituitary apoplexy, a life-threatening emergency that requires prompt surgical decompression, is an infarction of the gland due to abrupt cessation of the blood supply, caused by either pituitary artery hemorrhage or sudden hypovolemia. Increased blood supply is needed due to the extra tissue and volume of the pituitary mass; this may stress the pituitary arteries, which are not equipped for this increased flow, causing them to rupture. Hemorrhage anywhere else in the body can lead to hypovolemia and decrease the blood supply to the pituitary gland. A classic example would be postpartum hemorrhage causing pituitary infarct, called Sheehan syndrome.
Due to increased estrogen levels, the pituitary gland doubles in size during pregnancy.4 A preexisting mass may further develop and compress the optic chiasm. Therefore, women of childbearing age should be engaged in discussion of the potential risks and benefits of decompression surgery before actively pursuing pregnancy—especially if the lesion is close to the optic chiasm.
Surgery can also be considered for patients with significant growth in adenoma size during monitoring, loss of endocrinologic function due to mass effect on other pituitary cells, or unremitting headache.2
Next: How should patients be monitored?
HOW SHOULD PATIENTS BE MONITORED?
Those who do not meet criteria for surgery can be closely monitored with periodic testing. Imaging can be repeated six months after the first scan for macroadenoma and in one year for microadenoma. If there is no change in the size of the mass, imaging can be done yearly for macroadenoma and for microadenoma, every one to two years for three years and then gradually less often thereafter.2
Unless the lesion is abutting the optic chiasm (seen via imaging) or the patient reports symptoms, visual field testing does not need to be repeated.
Lab testing should be repeated six months after initial testing for macroadenoma and yearly thereafter. No further testing is suggested for nonsecretory microadenoma, unless clinically indicated.2
If there are any changes in status—noted clinically or via imaging—more frequent testing is suggested.
Brian is reassured that pituitary adenoma is not an uncommon finding and that his adenoma is relatively small in size and nonsecretory. Repeat pituitary MRI in one year is recommended.
CONCLUSION
Most pituitary incidentalomas have no consequences to a patient’s health. However, patients often become highly anxious about the “brain tumor” they were told they have. Appropriate patient education and thorough evaluation can reassure patients and alleviate their concerns.
REFERENCES
1. Molitch ME. Nonfunctioning pituitary tumors and pituitary incidentalomas. Endocrinol Metab Clin North Am. 2008;37(1):151-171.
2. Freda PU, Beckers AM, Katznelson L, et al. Pituitary incidentaloma: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96(4):894-904.
3. Katznelson L, Atkinson JL, Cook DM, et al. American Association of Clinical Endocrinologists Medical Guidelines For Clinical Practice For The Diagnosis And Treatment Of Acromegaly–2011 Update. Endocr Pract. 2011;17(suppl 4).
4. Jameson JL. Harrison’s Endocrinology. 2nd ed. China: McGraw-Hill; 2010:16-49.
Brian, 46, is referred to endocrinology for evaluation of a pituitary “mass.” The mass was an incidental finding of head and neck CT performed three months ago, when Brian went to an emergency department following a motor vehicle accident. He has fully recovered from the accident and feels well. He describes himself as a “completely healthy” person who has no chronic medical conditions and takes neither prescription nor OTC medications.
Brian denies significant headache, visual disturbance, change in appetite, unexplained weight change, skin rash (wide purple striae) or color changes (hyperpigmentation), polyuria or polydipsia, dizziness, syncopal episodes, low libido, erectile dysfunction, joint pain, and changes in ring or shoe size. He does not wear a hat or cap and is unaware of head size changes. He has not experienced changes in his facial features or trouble with chewing.
He is a happily married engineer with two healthy children and reports that he feels well except for this “brain tumor” finding that has been a shock to him and his family. There is no family history of pituitary adenoma or multiple endocrine neoplasia syndrome.
His vital signs, all within normal ranges, include a blood pressure of 103/65 mm Hg. His height is 6 ft and his weight, 180 lb. His BMI is 24.4.
HOW COMMON IS PITUITARY INCIDENTALOMA?
A pituitary incidentaloma is a lesion in the pituitary gland that was not previously suspected and was found through an imaging study ordered for other reasons. Pituitary incidentaloma is surprisingly common, with an average prevalence of 10.6% (as estimated from combined autopsy data), although it has been found in up to 20% of patients undergoing CT and 38% undergoing MRI.1,2 Most are microadenomas (< 1 cm in size).1
Continue for recommendations from the Endocrine Society >>
SHOULD AN ASYMPTOMATIC PATIENT BE EVALUATED FURTHER?
Endocrine Society guidelines2 recommend that all patients with pituitary incidentaloma, with or without symptoms, should undergo a complete history and physical examination and laboratory evaluation to exclude hypersecretion and hyposecretion of pituitary hormones.
The “classic” presentation of pituitary hormone hypersecretion—in the form of prolactinoma, adrenocorticotropic hormone (ACTH) excess (Cushing disease), growth hormone (GH) excess (gigantism/acromegaly), and TSH excess (secondary hyperthyroidism)—may be readily detectable on history and physical examination. Subtle cases, so-called subclinical disease, however, may exhibit little or no signs and symptoms initially but can be detrimental to the patient’s health if left untreated. For example, the estimated time from onset to diagnosis of acromegaly is approximately seven to 10 years—a delay that can significantly impact the patient’s morbidity and mortality.3
Prolactinoma can be more clinically apparent in premenopausal females due to irregular menstrual cycles (oligomenorrhea/amenorrhea). However, galactorrhea, or “milky” nipple discharge, occurs in only about 50% of women with prolactinoma and is extremely rare in men. Furthermore, the clinical presentation of prolactinoma in men is vague and related to hypogonadism, resulting from increased prolactin levels. Since men are essentially asymptomatic, these tumors can grow extensively (macroadenoma) and cause “mass effect,” such as headaches and visual impairment.
Therefore, without laboratory testing, abnormal pituitary function may go unrecognized.
WHAT LABS SHOULD I ORDER FOR THIS PATIENT?
Guidelines suggest an initial screening panel of prolactin, GH, insulin-like growth factor 1 (IGF-1), ACTH, early-morning cortisol, TSH, free T4, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone.2
Note the use of “suggest” rather than “recommend.” Even among guideline task force members, there were differences in opinion as to whether certain tests (eg, TSH, LH, and FSH) should be included in initial screening. Those tests can be ordered at the clinician’s discretion, according to the level of suspicion, or can be added later if necessary.
Brian’s sample for laboratory testing is drawn at 7:50 am. Results can be found in the table (previous page).
Next page: Caveats and concerns >>
ARE THERE ANY CAVEATS TO THE INTERPRETATION OF LAB VALUES?
It is important to note that in postmenopausal women who are not taking hormone replacement therapy, LH and FSH will be elevated and estradiol may provide an additional clue in the detection of abnormal function. Conversely, low LH and FSH in postmenopausal women should raise a flag for hypopituitarism.
Another caveat is that GH secretion is pulsatile and serum levels are undetectable between pulses. Therefore, low/undetectable GH does not necessarily suggest deficiency. The GH measurement would only be helpful if it is significantly elevated (suggestive of hypersecretion—gigantism/acromegaly). Otherwise, GH has little value as a screening test.
Instead, IGF-1, which is secreted from the liver in response to GH secretion, has a longer half-life and serves as a better screening tool. IGF-1 has age- and sex-adjusted reference ranges, which are often reported by the lab or given as a Z score.
WHAT IS THE PREFERRED IMAGING STUDY FOR THE PITUITARY GLAND?
The best choice is MRI of the pituitary gland (not the whole brain) with gadolinium. If the incidentaloma was initially diagnosed by a CT, additional testing with MRI should be performed, unless contraindicated.2
Brian is referred for MRI with gadolinium. The radiologist’s report describes a 5 x 4 x 4–mm pituitary microadenoma without sellar extension or involvement of the optic chiasm.
AT WHAT POINT SHOULD OPTIC CHIASM BE A CONCERN?
Since the pituitary gland is located directly beneath the optic chiasm, any compressive effect of growth against the optic nerve(s) can cause visual impairment. This includes bitemporal hemianopsia (loss of peripheral vision) or ophthalmoplegia (abnormal movement of the ocular muscle). Since clinical signs and symptoms can be subtle or absent, all patients with evidence of a pituitary lesion abutting or compressing the optic chiasm should have a formal visual field exam.2
Continue for surgical intervention >>
WHO REQUIRES SURGICAL INTERVENTION?
Patients with mass effect (headache, increased intracranial pressure, compromised optic chiasm) and those with hyperfunctioning nonprolactin adenomas, some (but not all) macroprolactinomas, or pituitary apoplexy should be referred for surgery.2 Almost all cases involve macroadenomas rather than microadenomas.
The preferred treatment for GH-secreting tumors and ACTH-secreting tumors is surgery. However, prolactinoma can be well controlled with pharmacologic agents (dopamine agonists) in most cases. For prolactinomas refractory to these medications, surgical resection is recommended. (Detailed treatment approaches are available elsewhere; those for hyperprolactinoma can be found on the Clinician Reviews website: http://bit.ly/1HOb9Jf.)
Pituitary apoplexy, a life-threatening emergency that requires prompt surgical decompression, is an infarction of the gland due to abrupt cessation of the blood supply, caused by either pituitary artery hemorrhage or sudden hypovolemia. Increased blood supply is needed due to the extra tissue and volume of the pituitary mass; this may stress the pituitary arteries, which are not equipped for this increased flow, causing them to rupture. Hemorrhage anywhere else in the body can lead to hypovolemia and decrease the blood supply to the pituitary gland. A classic example would be postpartum hemorrhage causing pituitary infarct, called Sheehan syndrome.
Due to increased estrogen levels, the pituitary gland doubles in size during pregnancy.4 A preexisting mass may further develop and compress the optic chiasm. Therefore, women of childbearing age should be engaged in discussion of the potential risks and benefits of decompression surgery before actively pursuing pregnancy—especially if the lesion is close to the optic chiasm.
Surgery can also be considered for patients with significant growth in adenoma size during monitoring, loss of endocrinologic function due to mass effect on other pituitary cells, or unremitting headache.2
Next: How should patients be monitored?
HOW SHOULD PATIENTS BE MONITORED?
Those who do not meet criteria for surgery can be closely monitored with periodic testing. Imaging can be repeated six months after the first scan for macroadenoma and in one year for microadenoma. If there is no change in the size of the mass, imaging can be done yearly for macroadenoma and for microadenoma, every one to two years for three years and then gradually less often thereafter.2
Unless the lesion is abutting the optic chiasm (seen via imaging) or the patient reports symptoms, visual field testing does not need to be repeated.
Lab testing should be repeated six months after initial testing for macroadenoma and yearly thereafter. No further testing is suggested for nonsecretory microadenoma, unless clinically indicated.2
If there are any changes in status—noted clinically or via imaging—more frequent testing is suggested.
Brian is reassured that pituitary adenoma is not an uncommon finding and that his adenoma is relatively small in size and nonsecretory. Repeat pituitary MRI in one year is recommended.
CONCLUSION
Most pituitary incidentalomas have no consequences to a patient’s health. However, patients often become highly anxious about the “brain tumor” they were told they have. Appropriate patient education and thorough evaluation can reassure patients and alleviate their concerns.
REFERENCES
1. Molitch ME. Nonfunctioning pituitary tumors and pituitary incidentalomas. Endocrinol Metab Clin North Am. 2008;37(1):151-171.
2. Freda PU, Beckers AM, Katznelson L, et al. Pituitary incidentaloma: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96(4):894-904.
3. Katznelson L, Atkinson JL, Cook DM, et al. American Association of Clinical Endocrinologists Medical Guidelines For Clinical Practice For The Diagnosis And Treatment Of Acromegaly–2011 Update. Endocr Pract. 2011;17(suppl 4).
4. Jameson JL. Harrison’s Endocrinology. 2nd ed. China: McGraw-Hill; 2010:16-49.