Dividing cells face daunting challenges when replicating the billions of letters of DNA in their genomes. For instance, DNA letters in new cells can get mixed up, and then the affected genes don’t function correctly. To fix that problem, healthy cells can deploy so-called mismatch repair (MMR) genes that put scrambled DNA letters back in the correct order. But when those genes are themselves defective, then this repair system breaks down. And as a result, cells develop a progressive condition called microsatellite instability that leaves them vulnerable to cancer.
Those sorts of defects are shared by many different tumor types. The good news is that they are susceptible to the killing effects of an immunotherapy drug called pembrolizumab. The FDA approved that drug last year for all MMR/MSI-positive metastatic cancers, regardless of where they originate in the body. Pembrolizumab works by prompting the immune system’s T cells to recognize and destroy cancer cells bearing this genetic biomarker.
Earlier this year, scientists reported new findings with pembrolizumab in men with prostate cancer. Of the 839 men they evaluated, 2.5% had MMR defects and high levels of microsatellite instability. In about a quarter of the men, those defects were somatic, meaning they had been acquired after conception and were localized to the cancer. In the rest of the men, the defects were inherited and expressed by all the cells in their bodies.
This was the first study to investigate how the drug performs in men with MMR/MSI-positive prostate cancer, and the results were encouraging: Among half the treated men, PSA levels dropped by 60% to 80%. Since prostate cancer cells release PSA, a decline in the level of that hormone shows the drug is working. Moreover, tumors also shrank in as many as 40% of the men whose PSA levels were responding to treatment.
The authors of this study recommended that all metastatic prostate cancer patients be tested for these defects, since pembrolizumab might also work for them. Dr. Marc Garnick, the Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, and editor in chief of HarvardProstateKnowledge.org, agrees. “This is an exciting development as it opens up therapeutic possibilities that would have never been considered previously,” he said. “Moreover, our own personal experiences in testing for MMR mutations and treatment with pembrolizumab have been remarkable. Testing will likely become mandatory as more experience is gathered.” You may have heard melasma referred to as “the mask of pregnancy,” because it is sometimes triggered by an increase in hormones in pregnant women. But while the condition may be common among pregnant women, you don’t have to be pregnant to experience melasma.
“It’s not only associated with pregnancy, but can affect women at all stages of life,” says Dr. Shadi Kourosh, director of the Pigmentary Disorder and Multi-Ethnic Skin Clinic at Harvard-affiliated Massachusetts General Hospital. And it may last for many years. “Women who develop melasma in their teens or 20s or 30s may see it stay around for decades,” says Dr. Barbara Gilchrest, senior lecturer on dermatology at Harvard Medical School.
Melasma can be hard to treat
While melasma isn’t painful and doesn’t present any health risks, it can cause significant emotional distress. The condition can be difficult to treat, and there’s a lot of misinformation out there about what causes it, says Dr. Kourosh.
You’re more likely to get melasma if you have a darker skin type, probably because your skin naturally has more active pigment-producing cells, according to the American Academy of Dermatology. Melasma appears when these cells become hyperactive and produce too much pigment in certain areas of the skin. Melasma is more common in women, but it can also affect men. It may have a genetic component, as it often runs in families.
Causes of melasma
Melasma has a lot of different causes, says Dr. Kourosh. Two in particular stand out:
Hormones (including hormonal medications). Fluctuations in certain hormones can cause melasma, which is why it commonly occurs during pregnancy. Melasma may also occur when you either start or stop hormonal contraception, including birth control pills, or when you take hormone replacement therapy, says Dr. Gilchrest.
Sun exposure. The sun is the big culprit in triggering melasma. “Underlying factors such as hormonal changes may not manifest until a person goes on vacation to a southern location like Florida, or during the summertime when she spends more time in the sun,” says Dr. Kourosh. “The sun is the major exacerbating factor, whatever the underlying cause.” Melasma can be caused or worsened by not only the sun’s rays, but also heat and visible light. This means that even sunscreens that protect against skin cancer aren’t enough to ward off melasma, says Dr. Kourosh. This makes treating melasma a challenge, particularly in the summer months.
Finding the cause of melasma
The first step is to confirm that the darkened skin patches are indeed melasma and try to identify the cause. Treating melasma is unlikely to be effective if the underlying cause isn’t addressed, says Dr. Kourosh. “Even the oral treatments that now exist for severe cases of melasma are really pointless to do if there are still triggers in place,” she says. “We take a thorough medical history to find out what’s causing the melasma,” says Dr. Kourosh. Then adjustments are made. If a hormonal contraceptive is causing the problem, a woman might consider switching to a nonhormonal option, such as a copper intrauterine device.
Medications and topical treatments
Some commonly used options are topical retinols and retinoid treatments, which are applied to the skin to help speed your body’s natural cell turnover process. This may help dark patches clear more quickly than they would on their own. In addition, some doctors may prescribe bleaching agents, such as hydroquinone, which works by blocking melanin production. But while products with hydroquinone can be purchased over the counter, they should only be used under a doctor’s care — and only on the darkened areas of the skin. “Higher concentrations of hydroquinone can cause white spots to develop on the skin,” says Dr. Gilchrest. The medication may even cause a darkening of the skin in some cases. Other topical lightening agents (like kojic acid or azelaic acid) may be recommended. Other treatment options may include chemical peels, laser treatments, and skin microneedling. But at this point they’re not reliably effective, says Dr. Gilchrest.
A critical part of treatment: protect skin from the sun
It is critical to prevent the sun from aggravating the condition. This may require extreme diligence. “The sun is stronger than any medicine I can give you,” says Dr. Kourosh. The most important way to clear up melasma is by using a strict sunscreen regimen. But keep in mind that not all sunscreens are created equal. To prevent against melasma, you need a sunscreen that blocks not only the sun’s rays, but also its light and heat, such as one that includes zinc or titanium dioxide. Chemical sunscreens don’t offer the same protection for melasma, and in some instances, they may even trigger allergic reactions that can make melasma worse, she says. As men get older, their prostates often get bigger and block the flow of urine out of the bladder. This condition, which is called benign prostatic hyperplasia, causes bothersome symptoms. Since men can’t fully empty their bladders, they experience sudden and frequent urges to urinate. Treatments can relieve these symptoms, but not without troubling side effects: pharmaceutical BPH treatments cause dizziness, fatigue, and retrograde ejaculation, meaning that semen gets diverted to the bladder during orgasm instead of being ejected from the body. Surgical treatments such as transurethral resection of the prostate, or TURP, can relieve symptoms for many years. But they also take weeks or months to recover from, and men can experience permanent retrograde ejaculation, and in some instances, long-term impotence.
Still, it’s important to treat BPH to avoid even worse problems later. Left untreated, men can develop urinary retention, which is an acute inability to urinate without a catheter, and their bladder health can also deteriorate over time.
An alternative
Now a newer BPH procedure, called prostatic urethral lift, or UroLift, provides another option. And unlike drugs and older BPH surgeries, it spares sexual functioning.
During a UroLift procedure, doctors use tiny implants and sutures to pull the prostate away from the bladder so that urine flows more freely out of the body. The procedure can be performed in a doctor’s office, and most men go home the same day without a catheter. Clinical studies have shown that symptomatic improvements hold up for at least five years, which is comparable to study results with TURP.
The FDA approved UroLift for enlarged prostates in 2013, and the American Urological Association began recommending it as a standard of care option this year. Urologists around the country are getting up to speed on the procedure, which is now becoming increasingly available. Readers should be aware that the AUA gave UroLift a “C” grade, in part because the long-term data in support of the procedure aren’t as plentiful as they are for TURP and other more invasive surgeries, which received a grade of “B.”
For more information, we spoke to Daniel Rukstalis, M.D., a professor of urology at Wake Forest School of Medicine in Winston-Salem, North Carolina. Dr. Rukstalis led the clinical trials behind UroLift’s approval by the FDA, and he’s performed the UroLift procedure on over 350 BPH patients. (For full disclosure, Dr. Rukstalis is a clinical investigator for NeoTract, the company that developed UroLift).
Q: Dr. Rukstalis, thank you for joining us. Why would a man consider UroLift offer over other BPH treatments?
Rukstalis: Well, all the available therapies can lessen obstructive urinary symptoms and minimize long-term risks to the bladder. But UroLift is at this moment the only BPH treatment that completely spares erectile and ejaculatory functioning.
Q: How good is it at improving BPH symptoms overall?
Rukstalis: Our clinical trial led to a 12-point drop on average in International Prostate Symptom Scores (IPSS). [The IPSS is an eight-question screening tool that scores the severity of symptoms such as incomplete bladder emptying, urinary frequency, and weak streams. Men treated for BPH usually have IPSS scores of at least 20.] The trial had 206 participants. And at five years, their IPSS scores were still improved by about a third and their quality of life scores were also about 50% higher than when they had the procedure.
Q: Who is eligible for a UroLift?
Rukstalis: It’s FDA-approved for men 45 and older with prostates up to 80 grams in size (a normal prostate in a man ranges between 7 to 11 grams). But my view is that UroLift works best in prostates ranging from 25 to 60 grams. About a third of men with BPH also have what’s called a “median lobe,” or a bit of prostate tissue that protrudes up into the bladder. We just completed a clinical trial showing that UroLift works well for these men too. On the basis of that study, the FDA approved UroLift for men with median lobes in early 2018. We’ll typically evaluate potential candidates with a pelvic ultrasound, which provides a lot of information about the health of the bladder and the size and shape of the prostate.
Q: What can a man expect going into the procedure?
Rukstalis: We’ll put him to sleep with intravenous propofol, which is the same anesthetic used during a colonoscopy. The UroLift implants get delivered into the prostate with a rigid metal scope that goes directly through the penis. By pulling excess prostate tissue out of the way, the implants create a channel through which urine can flow. (This YouTube video provides a good overview.) We do this as an outpatient procedure.
Q: What will he experience after the procedure is done?
Rukstalis: He can expect some transient blood in the urine and a burning sensation when he pees, but this all clears up within about three days. About 2% to 4% of the men I treat spend a few days using a catheter.
Q: Why doesn’t UroLift work for larger prostates over 60 grams?
Rukstalis: Because beyond a certain size threshold, the implants don’t open the channel well enough. Also you wind up needing too many implants, and they’re very expensive — anywhere from $700 to $1,000 each. The procedure is optimized for four to six implants and you really don’t want to use more than seven of them.
Q: This is a new procedure. How important is the doctor’s experience?
Rukstalis: UroLift is a judgment-based procedure in terms of the number of implants used and where in the prostate a doctor puts them. What I would say is that you’re looking for a doctor who’s comfortable with a cystoscope [which is a hollow metal rod with a lens used for prostate examinations]. If a doctor is comfortable with cystoscopy equipment, then he or she can adopt quite readily to the technology. And there are excellent UroLift training programs around the country for any urologist who wants to do it.
Q: What about long-term prospects? Do men need repeat treatments?
Rukstalis: We know that most men still benefit from treatment at five years. But we can’t say whether those results predict benefits at 10 years or longer. We haven’t done those studies yet, but they haven’t been for TURP and the other surgical procedures either. My view is that it depends on prostate size. Men with smaller prostates will benefit for longer durations.
Q: Does having had a UroLift complicate things for a man who might need a TURP later?
Rukstalis: Not in my experience. I’ve performed TURPs, prostatectomies, and laser prostate surgeries in people who had a UroLift with no trouble.
Q: Do you have any criticisms of the procedure?
Rukstalis: It’s too expensive. We need to find ways of doing UroLift at lesser cost. And some men find it doesn’t work as well as they had hoped, even though in these men, the procedure goes a long way toward protecting bladder functioning.
Q: Thanks very much! I’m sure our readers will appreciate your insights.
Dr. Marc Garnick, the Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, and editor in chief of HarvardProstateKnowledge.org also commented on the UroLift: “This is one of many emerging options for non-pharmacologic BPH treatment that can now be offered to the proper patient matched to the appropriately trained urologist. As with many procedures, longer-term outcomes are needed to determine its proper role in treating this very common problem.”
Those sorts of defects are shared by many different tumor types. The good news is that they are susceptible to the killing effects of an immunotherapy drug called pembrolizumab. The FDA approved that drug last year for all MMR/MSI-positive metastatic cancers, regardless of where they originate in the body. Pembrolizumab works by prompting the immune system’s T cells to recognize and destroy cancer cells bearing this genetic biomarker.
Earlier this year, scientists reported new findings with pembrolizumab in men with prostate cancer. Of the 839 men they evaluated, 2.5% had MMR defects and high levels of microsatellite instability. In about a quarter of the men, those defects were somatic, meaning they had been acquired after conception and were localized to the cancer. In the rest of the men, the defects were inherited and expressed by all the cells in their bodies.
This was the first study to investigate how the drug performs in men with MMR/MSI-positive prostate cancer, and the results were encouraging: Among half the treated men, PSA levels dropped by 60% to 80%. Since prostate cancer cells release PSA, a decline in the level of that hormone shows the drug is working. Moreover, tumors also shrank in as many as 40% of the men whose PSA levels were responding to treatment.
The authors of this study recommended that all metastatic prostate cancer patients be tested for these defects, since pembrolizumab might also work for them. Dr. Marc Garnick, the Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, and editor in chief of HarvardProstateKnowledge.org, agrees. “This is an exciting development as it opens up therapeutic possibilities that would have never been considered previously,” he said. “Moreover, our own personal experiences in testing for MMR mutations and treatment with pembrolizumab have been remarkable. Testing will likely become mandatory as more experience is gathered.” You may have heard melasma referred to as “the mask of pregnancy,” because it is sometimes triggered by an increase in hormones in pregnant women. But while the condition may be common among pregnant women, you don’t have to be pregnant to experience melasma.
“It’s not only associated with pregnancy, but can affect women at all stages of life,” says Dr. Shadi Kourosh, director of the Pigmentary Disorder and Multi-Ethnic Skin Clinic at Harvard-affiliated Massachusetts General Hospital. And it may last for many years. “Women who develop melasma in their teens or 20s or 30s may see it stay around for decades,” says Dr. Barbara Gilchrest, senior lecturer on dermatology at Harvard Medical School.
Melasma can be hard to treat
While melasma isn’t painful and doesn’t present any health risks, it can cause significant emotional distress. The condition can be difficult to treat, and there’s a lot of misinformation out there about what causes it, says Dr. Kourosh.
You’re more likely to get melasma if you have a darker skin type, probably because your skin naturally has more active pigment-producing cells, according to the American Academy of Dermatology. Melasma appears when these cells become hyperactive and produce too much pigment in certain areas of the skin. Melasma is more common in women, but it can also affect men. It may have a genetic component, as it often runs in families.
Causes of melasma
Melasma has a lot of different causes, says Dr. Kourosh. Two in particular stand out:
Hormones (including hormonal medications). Fluctuations in certain hormones can cause melasma, which is why it commonly occurs during pregnancy. Melasma may also occur when you either start or stop hormonal contraception, including birth control pills, or when you take hormone replacement therapy, says Dr. Gilchrest.
Sun exposure. The sun is the big culprit in triggering melasma. “Underlying factors such as hormonal changes may not manifest until a person goes on vacation to a southern location like Florida, or during the summertime when she spends more time in the sun,” says Dr. Kourosh. “The sun is the major exacerbating factor, whatever the underlying cause.” Melasma can be caused or worsened by not only the sun’s rays, but also heat and visible light. This means that even sunscreens that protect against skin cancer aren’t enough to ward off melasma, says Dr. Kourosh. This makes treating melasma a challenge, particularly in the summer months.
Finding the cause of melasma
The first step is to confirm that the darkened skin patches are indeed melasma and try to identify the cause. Treating melasma is unlikely to be effective if the underlying cause isn’t addressed, says Dr. Kourosh. “Even the oral treatments that now exist for severe cases of melasma are really pointless to do if there are still triggers in place,” she says. “We take a thorough medical history to find out what’s causing the melasma,” says Dr. Kourosh. Then adjustments are made. If a hormonal contraceptive is causing the problem, a woman might consider switching to a nonhormonal option, such as a copper intrauterine device.
Medications and topical treatments
Some commonly used options are topical retinols and retinoid treatments, which are applied to the skin to help speed your body’s natural cell turnover process. This may help dark patches clear more quickly than they would on their own. In addition, some doctors may prescribe bleaching agents, such as hydroquinone, which works by blocking melanin production. But while products with hydroquinone can be purchased over the counter, they should only be used under a doctor’s care — and only on the darkened areas of the skin. “Higher concentrations of hydroquinone can cause white spots to develop on the skin,” says Dr. Gilchrest. The medication may even cause a darkening of the skin in some cases. Other topical lightening agents (like kojic acid or azelaic acid) may be recommended. Other treatment options may include chemical peels, laser treatments, and skin microneedling. But at this point they’re not reliably effective, says Dr. Gilchrest.
A critical part of treatment: protect skin from the sun
It is critical to prevent the sun from aggravating the condition. This may require extreme diligence. “The sun is stronger than any medicine I can give you,” says Dr. Kourosh. The most important way to clear up melasma is by using a strict sunscreen regimen. But keep in mind that not all sunscreens are created equal. To prevent against melasma, you need a sunscreen that blocks not only the sun’s rays, but also its light and heat, such as one that includes zinc or titanium dioxide. Chemical sunscreens don’t offer the same protection for melasma, and in some instances, they may even trigger allergic reactions that can make melasma worse, she says. As men get older, their prostates often get bigger and block the flow of urine out of the bladder. This condition, which is called benign prostatic hyperplasia, causes bothersome symptoms. Since men can’t fully empty their bladders, they experience sudden and frequent urges to urinate. Treatments can relieve these symptoms, but not without troubling side effects: pharmaceutical BPH treatments cause dizziness, fatigue, and retrograde ejaculation, meaning that semen gets diverted to the bladder during orgasm instead of being ejected from the body. Surgical treatments such as transurethral resection of the prostate, or TURP, can relieve symptoms for many years. But they also take weeks or months to recover from, and men can experience permanent retrograde ejaculation, and in some instances, long-term impotence.
Still, it’s important to treat BPH to avoid even worse problems later. Left untreated, men can develop urinary retention, which is an acute inability to urinate without a catheter, and their bladder health can also deteriorate over time.
An alternative
Now a newer BPH procedure, called prostatic urethral lift, or UroLift, provides another option. And unlike drugs and older BPH surgeries, it spares sexual functioning.
During a UroLift procedure, doctors use tiny implants and sutures to pull the prostate away from the bladder so that urine flows more freely out of the body. The procedure can be performed in a doctor’s office, and most men go home the same day without a catheter. Clinical studies have shown that symptomatic improvements hold up for at least five years, which is comparable to study results with TURP.
The FDA approved UroLift for enlarged prostates in 2013, and the American Urological Association began recommending it as a standard of care option this year. Urologists around the country are getting up to speed on the procedure, which is now becoming increasingly available. Readers should be aware that the AUA gave UroLift a “C” grade, in part because the long-term data in support of the procedure aren’t as plentiful as they are for TURP and other more invasive surgeries, which received a grade of “B.”
For more information, we spoke to Daniel Rukstalis, M.D., a professor of urology at Wake Forest School of Medicine in Winston-Salem, North Carolina. Dr. Rukstalis led the clinical trials behind UroLift’s approval by the FDA, and he’s performed the UroLift procedure on over 350 BPH patients. (For full disclosure, Dr. Rukstalis is a clinical investigator for NeoTract, the company that developed UroLift).
Q: Dr. Rukstalis, thank you for joining us. Why would a man consider UroLift offer over other BPH treatments?
Rukstalis: Well, all the available therapies can lessen obstructive urinary symptoms and minimize long-term risks to the bladder. But UroLift is at this moment the only BPH treatment that completely spares erectile and ejaculatory functioning.
Q: How good is it at improving BPH symptoms overall?
Rukstalis: Our clinical trial led to a 12-point drop on average in International Prostate Symptom Scores (IPSS). [The IPSS is an eight-question screening tool that scores the severity of symptoms such as incomplete bladder emptying, urinary frequency, and weak streams. Men treated for BPH usually have IPSS scores of at least 20.] The trial had 206 participants. And at five years, their IPSS scores were still improved by about a third and their quality of life scores were also about 50% higher than when they had the procedure.
Q: Who is eligible for a UroLift?
Rukstalis: It’s FDA-approved for men 45 and older with prostates up to 80 grams in size (a normal prostate in a man ranges between 7 to 11 grams). But my view is that UroLift works best in prostates ranging from 25 to 60 grams. About a third of men with BPH also have what’s called a “median lobe,” or a bit of prostate tissue that protrudes up into the bladder. We just completed a clinical trial showing that UroLift works well for these men too. On the basis of that study, the FDA approved UroLift for men with median lobes in early 2018. We’ll typically evaluate potential candidates with a pelvic ultrasound, which provides a lot of information about the health of the bladder and the size and shape of the prostate.
Q: What can a man expect going into the procedure?
Rukstalis: We’ll put him to sleep with intravenous propofol, which is the same anesthetic used during a colonoscopy. The UroLift implants get delivered into the prostate with a rigid metal scope that goes directly through the penis. By pulling excess prostate tissue out of the way, the implants create a channel through which urine can flow. (This YouTube video provides a good overview.) We do this as an outpatient procedure.
Q: What will he experience after the procedure is done?
Rukstalis: He can expect some transient blood in the urine and a burning sensation when he pees, but this all clears up within about three days. About 2% to 4% of the men I treat spend a few days using a catheter.
Q: Why doesn’t UroLift work for larger prostates over 60 grams?
Rukstalis: Because beyond a certain size threshold, the implants don’t open the channel well enough. Also you wind up needing too many implants, and they’re very expensive — anywhere from $700 to $1,000 each. The procedure is optimized for four to six implants and you really don’t want to use more than seven of them.
Q: This is a new procedure. How important is the doctor’s experience?
Rukstalis: UroLift is a judgment-based procedure in terms of the number of implants used and where in the prostate a doctor puts them. What I would say is that you’re looking for a doctor who’s comfortable with a cystoscope [which is a hollow metal rod with a lens used for prostate examinations]. If a doctor is comfortable with cystoscopy equipment, then he or she can adopt quite readily to the technology. And there are excellent UroLift training programs around the country for any urologist who wants to do it.
Q: What about long-term prospects? Do men need repeat treatments?
Rukstalis: We know that most men still benefit from treatment at five years. But we can’t say whether those results predict benefits at 10 years or longer. We haven’t done those studies yet, but they haven’t been for TURP and the other surgical procedures either. My view is that it depends on prostate size. Men with smaller prostates will benefit for longer durations.
Q: Does having had a UroLift complicate things for a man who might need a TURP later?
Rukstalis: Not in my experience. I’ve performed TURPs, prostatectomies, and laser prostate surgeries in people who had a UroLift with no trouble.
Q: Do you have any criticisms of the procedure?
Rukstalis: It’s too expensive. We need to find ways of doing UroLift at lesser cost. And some men find it doesn’t work as well as they had hoped, even though in these men, the procedure goes a long way toward protecting bladder functioning.
Q: Thanks very much! I’m sure our readers will appreciate your insights.
Dr. Marc Garnick, the Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, and editor in chief of HarvardProstateKnowledge.org also commented on the UroLift: “This is one of many emerging options for non-pharmacologic BPH treatment that can now be offered to the proper patient matched to the appropriately trained urologist. As with many procedures, longer-term outcomes are needed to determine its proper role in treating this very common problem.”
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