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  • Transrectal Ultrasound Is Getting an Upgrade

  • From the Director

  • Men's Health

    Erectile Dysfunction and Low Testosterone Offer Gateway to Men's Health
  • Prostate Cancer

    Study Shows African-American Men Are at Greater Risk for Aggressive Prostate Cancer
  • Bladder Cancer

    Urine Test Detects New, Recurrent Bladder Cancer
  • Pediatrics

    A Novel Approach to Bladder Exstrophy Closure Yields Insights

Transrectal Ultrasound Is Getting an Upgrade

Prostate cancer
Christian Pavlovich

"Compared with LoTRUS, HiTRUS was both more sensitive and specific. It also was better at showing high-grade lesions."
–Christian Pavlovich

It's new, it's first-generation and nobody's suggesting that it is ready to replace prostate biopsies, but high-resolution ultrasound (HiTRUS) has shown great potential in its first-ever pilot study. Now it's being investigated in a multi-institutional, randomized trial of prostate biopsy involving five centers in the U.S. and Canada.

"Prostate imaging by HiTRUS (16-21 MHz) had never been done before," says Christian Pavlovich, director of urologic oncology at Johns Hopkins Bayview Medical Center and the pilot study's principal investigator who's spearheading the new trial. "What we were trying to do initially was see how well it performed against conventional transrectal ultrasound (LoTRUS at 7-12 MHz) in identifying clinically localized prostate cancer." 

In the first trial, a blinded study, 25 men who were scheduled for radical prostatectomy were imaged before surgery with both LoTRUS and HiTRUS; those images were correlated with the areas where the cancers were found by pathologists after surgery, and the accuracy of each imaging modality was compared. In that study, reported in Urologic Oncology, HiTRUS clearly outperformed LoTRUS: "Out of 69 sextant areas with prostate cancer, HiTRUS found 45 and missed 24, while LoTRUS visualized 26 and missed 43," says Pavlovich. "Compared with LoTRUS, HiTRUS was both more sensitive and specific. It also was better at showing high-grade lesions."

Pavlovich believes a few upgrades to the technology, such as image-enhancing Doppler flow and more experience with HiTRUS images of the prostate, will make the technology and outcomes even better. "The potential is exciting," he says. He also likes the fact that this is not a completely new and complicated imaging system; it's just a better version of a tool that's "already a standard part of the clinical practice of every urologist who performs prostate biopsy in the U.S." Indeed, "there is a great need for urologist-performed, office-based prostate imaging to better identify men with an elevated PSA or abnormal DRE who should undergo a prostate biopsy, and to perhaps target this biopsy more accurately in real time." 

Ultimately, he adds, the combination of HiTRUS and MRI may prove good enough to reduce the number of biopsies that need to be performed. 

From the Director

Alan Partin

Alan W. Partin, M.D., Ph.D.
David Hall McConnell Professor and Director
Johns Hopkins Brady Urological Institute

In this issue of Johns Hopkins Urology, our cover story features a multicenter trial, led by Christian Pavlovich, of high-resolution ultrasound, which has outperformed conventional transrectal ultrasound in detecting prostate cancer. In a related story is cutting-edge research by Ted Schaeffer showing that African-American men have a one-third chance of having more aggressive cancer than the biopsy suggests. 

Johns Hopkins has been a world referral center for bladder exstrophy for nearly four decades. Now Heather Di Carlo is pioneering a new way to approach exstrophy closure using MRI-guided navigation of the pelvic floor.

Our multidisciplinary Men's Health and Vitality Program, led by Kevin Billups, doesn't just treat erectile dysfunction and low testosterone, but allows us to address the underlying causes and help the whole patient. 

And finally, a new urine test developed at Johns Hopkins may soon help detect bladder cancer, pick up recurrent cancer and separate aggressive tumors from indolent cancers. This is part of the momentum generated by our new Greenberg Bladder Cancer Institute and part of our overall multifaceted, multidisciplinary approach to all of urology.


Men's Health

Erectile Dysfunction and Low Testosterone Offer Gateway to Men's Health

Stephen Schatz

"Men often think it's just a sex drive thing," says Kevin Billups, "but a lot of what we see is related to other common conditions."

Erectile dysfunction (ED) and low testosterone might be the symptoms that get men through the door to see urologist Kevin Billups, director of the Men's Health and Vitality Program. But they're generally not the only things he ends up treating. "The first thing I do," he says, "is point out that these problems don't occur in a vacuum. What else is going on?"

For example, if a man between 40 and 50 has ED, growing evidence suggests that he could have a nearly fifty-fold increased risk of developing heart disease over the next 10 years. Billups refers many of his patients to general urologists, primary care physicians, sleep specialists or preventive cardiologists for further testing when needed. "We're offering very integrated, multidisciplinary care."

Low testosterone is another cause of concern for many men. It doesn't help that many have seen advertisements for testosterone-boosting supplements promising to cure all—except, Billups notes, the underlying cause. "Men think it's just a sex drive thing, but a lot of what we see is related to other common chronic conditions. Treating that one symptom without finding out the whole story would not be a good idea." Diabetes or even prediabetes can lower testosterone; so can a big gut, he adds. "Having a waist circumference greater than 40 inches lowers testosterone. Fat, especially belly fat, makes the enzyme aromatase, which converts testosterone to estrogen.  

The most common symptoms of low testosterone are ED, fatigue, feeling sluggish, loss of strength or endurance, daytime sleepiness, even cognition issues. "We can document with a blood test that your testosterone is low, but what's going on with your cardiovascular status, your thyroid? Is there any depression going on?  If a man has obstructive sleep apnea and low testosterone, he really needs to get the apnea addressed first, because that can make the testosterone worse." 


Study Shows African-American Men Are at Greater Risk for Aggressive Prostate Cancer

Ted Schaeffer

Ted Schaeffer, director of Johns Hopkins' prostate cancer program.

Ted Schaeffer

Stained sections of African-American (bottom) and Caucasian prostates. The circled areas are cancer, demonstrating that African-American men are more likely to develop cancers in the anterior region, making it more difficult to find on regular biopsy.

Why should men of African ancestry take prostate cancer very seriously? Ted Schaeffer, director of Johns Hopkins' prostate cancer program, who has made key discoveries that have important clinical implications for these men, is glad you asked. 

African-American men often present with more aggressive cancers than other men. For example, says Schaeffer, "if you're seeing an African-American man who's been diagnosed with Gleason 6 disease, you can definitely advise him that he has a one-third higher chance of having more aggressive cancer than the biopsy suggests." Also, "we found that when these men have surgery, they have a higher likelihood of needing additional adjuvant treatment." These findings, published in Urology, were based on the outcomes of more than 17,000 men who underwent radical prostatectomy at Johns Hopkins; 1,650 of them were of African ancestry and were not only more likely to have higher-grade cancer and larger tumors, but to experience recurrence of cancer compared with Caucasian men. 

Schaeffer initially observed that African-American men who could be candidates for active surveillance turned out to have a much higher chance of having aggressive disease if they later needed surgery. "We validated in our surveillance cohort that the chance of failing surveillance or being reclassified is 30 percent higher for black men compared to white men. We also found that even after surgery, if you control for the grade and stage of the cancer, men of African ancestry are more likely to have their cancers come back."

The findings suggest that African-American men with prostate cancer make less PSA per gram of cancer tissue than other men. "There are fewer early warning signs," says Schaeffer. Another key difference, he discovered, is location: African-American men tend to develop anterior tumors, at the top of the prostate, an area that's harder to sample for a standard biopsy. All high-risk and African-American patients at Johns Hopkins get an MRI-guided biopsy. 

Schaeffer also directs Johns Hopkins' prostate cancer multidisciplinary clinic. "We have world expertise in treating high-grade, high-risk prostate cancer, and also very rare forms of prostate cancer, like prostate sarcomas." The bottom line, he says, is "if a man has aggressive, high-risk cancer, if we really go after it with multimodal treatment, we can still get a cure."


Urine Test Detects New, Recurrent Bladder Cancer

Trinity Bivalacqua

Trinity Bivalacqua: "This test has great potential to be lifesaving."

It's not a substitute for surveillance cystoscopy and transurethral bladder biopsy, but a new urine test developed at Johns Hopkins may soon become part of the arsenal for detecting bladder cancer, picking up recurrent cancer and predicting aggressive tumors, says Trinity Bivalacqua, director of urologic oncology.

The test looks for mutations in the promoter of the telomerase reverse transcriptase (TERT) gene. A multidisciplinary team led by genitourinary pathologist George Netto, along with scientists from the Ludwig Cancer Research team, and Bivalacqua and Mark Schoenberg,  found a very high prevalence of TERT promoter mutations in a wide range of precursor bladder tumors. 

"We knew it had the potential to be useful in early diagnosis," says Bivalacqua. "Then we wondered if this biomarker could also pick up the return of bladder cancer after treatment." The scientists looked for TERT mutations in early tumors, follow-up urine samples from patients who developed recurrent bladder cancer and patients who did not have recurrent cancer. Among patients whose tumors harbored TERT promoter mutations, the same mutations were present in follow-up urine samples in those who developed a recurrence—but not in the urine of patients whose cancer did not recur. 

 "The real value of this test," Bivalacqua notes, "is to be able to predict aggressive cancers from the more indolent cancers that don't need invasive treatments." This work was published in Cancer Research.

Momentum in bladder cancer: "There's a new wave of bladder cancer research at Johns Hopkins," says Bivalacqua. The institution recently opened the Greenberg Bladder Cancer Institute, funded with the help of philanthropists Erwin L. and Stephanie Cooper Greenberg. Netto received a Greenberg grant to support his urinary biomarker research, and Bivalacqua has received funding for research on genetically engineered mouse models of bladder cancer and to investigate new forms of nanoparticle delivery of chemotherapeutic agents and novel immunotherapies to treat noninvasive bladder cancer. "This has really allowed us to grow our research and treatment programs," says Bivalacqua. "Bladder cancer has not received the attention it deserves. We are changing that now." 


A Novel Approach to Bladder Exstrophy Closure Yields Insights

ohn Gearhart and Heather Di Carlo

John Gearhart and Heather Di Carlo, who recently presented this work at the meeting of the Society of Pediatric Urologists in Miami.

Johns Hopkins has been a world referral center for bladder exstrophy repair for nearly four decades, building on the pioneering work of pediatric urologists Robert Jeffs and John Gearhart. Now Heather Di Carlo is adding to that legacy with a new way to approach exstrophy closure: using MRI-guided navigation of the pelvic floor. 

Di Carlo and colleagues have received approval from the Food and Drug Administration and Johns Hopkins' Internal Review Board to adapt a navigation system—one neurosurgeons and orthopaedists have been using for years—for urologic and reconstructive surgery.

Here's how it works: The day before surgery, the patient gets an MRI. Di Carlo and pediatric radiologist Aylin Tekes identify important anatomic features like the anterior superior iliac spines and the pubic tubercles, the umbilicus, and anus. Just before surgery, Di Carlo secures a strap on the patient's chest; the strap has three tiny microarrays that signal fixed spots. Then, using a registering pointer connected to the system, Di Carlo correlates the patient's anatomy with the MRI. Next, pediatric orthopaedic surgeon Paul Sponseller corrects the pelvic bones and stabilizes them with an external fixator, "which changes the pelvic floor anatomy," Di Carlo says, "but that doesn't make any difference because we already registered the key landmarks." A major reason why Johns Hopkins is a referral center, she notes, is that the dissection of the pelvic floor is so crucial to getting a secure closure to the bladder and pelvis. That is a crucial part of the operation. "When we're operating," she says, "we're able to see those muscles, and we know  we're getting those fibers completely dissected."

The team has used the MRI-guided system on 10 patients, boys and girls, for primary closures and reclosures; all had osteotomies. "There have been no adverse events," Di Carlo says.

Di Carlo hopes to expand the MRI-guided navigation to include other procedures such as cloacal exstrophy and epispadias repair.

the team has used the MRI-guided system on 10 patients. "There have been no adverse events."
—Heather Di Carlo

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