Dr. Amy Krambeck discusses 90-day trial of disposable ureteroscope.

Speaking of Urology Podcast

offers perspective on noteworthy research in the peer-reviewed literature. Dr. Mian is professor of surgery in the division of urology at Albany Medical College, New York.

Active surveillance (AS) strategies for prostate cancer with low-risk features, such Grade Group 1 (GG1), are increasingly being utilized to avoid treatment-related complications. Due to the long natural history of prostate cancer and low risk of progression, long-term risk of metastasis or death is not well defined, resulting in some uncertainty about patient selection for AS. A recent study by Maggi et al noted that although reclassification of the initial biopsy Grade Group or switch from surveillance to active treatment occurred frequently, less than 1% of men died of prostate cancer.

 They analyzed the data from a large, prospectively maintained AS cohort to identify the variables associated with disease progression and metastases while on AS.

The investigators identified 1450 men on AS between 1990 and 2018 who met the inclusion criteria of low- or intermediate-risk prostate cancer. AS eligibility criteria included organ-confined disease with biopsy GG1, 33% or less positive biopsy cores, and PSA density (PSAD) lower than 0.15 ng/mL/cm3. However, few selected patients with GG2 and/or higher PSAD were also enrolled into the AS program. 1303 patients (90%) were diagnosed with initial biopsy GG1 and 147 (10%) with GG2. Median PSA at initial biopsy was 5.4 ng/mL, with median PSAD of 0.13 ng/mL/cm3. Median age was 62 years and median follow-up was 77 months. Additional testing such as Genomic Prostate Score (GPS) was performed in 34% of men (mean GPS 25), whereas multiparametric magnetic resonance imaging (mpMRI) was performed in 46% of men, of whom 24% had lesions classified as Prostate Imaging Reporting and Data System (PI-RADS) 4-5.

The primary outcome of interest was emergence of metastatic prostate cancer noted on imaging or pathology of delayed prostatectomy. Secondary outcomes included upgrading on surveillance biopsy to GG2 or greater, receipt of active treatment, and prostate cancer-specific and overall survival. For this analysis, patients were divided into 3 subgroups based on the initial biopsy GG and PSA. Of these, GG1 with PSAD lower than 0.15 was noted in 57%, GG1 with PSAD of 0.15 or higher in 32%, and GG2 in 10%.

At 7 years, biopsy GG upgrade-free survival was 40%, and median time to biopsy GG upgrade was 25 months. The 7-year upgrade-free survival was higher in patients with initial GG1 with PSAD lower than 0.15 (47%) compared with those with GG1 with PSAD of 0.15 or higher (28%) or initial GG2 (44%) (log rank 

 < .01). The 7-year treatment-free survival was 59%, with a median time to receiving active treatment of 32 months. The 7-year treatment-free survival was higher in patients with initial GG1 with PSAD lower than 0.15 (69%) compared with those with GG1 with PSAD of 0.15 or higher (46%) or initial GG2 (42%) (log rank 

At 7 years, metastasis-free survival was 99%, and median time to metastases was 62 months. Of the 15 patients who developed metastases, 2 were lost to follow-up, 9 had lymph node metastasis, 2 had lymph node and bone metastasis, 1 had bone metastasis, and 1 had bone and visceral organ metastasis. Initial biopsy GG2 disease was associated with lower 7-year metastasis-free survival (96%) than those with GG1 with PSAD lower than 0.15 (99 %) and with GG1 with PSAD of 0.15 or higher (100%) (log rank 

 < .01). On multivariable analysis, risk factors for increased risk of metastases included initial GG2, PSA velocity, and PI-RADS 4-5 lesion. However, age, PSAD, and GPS did not increase the risk of metastases. Of note, in those who did not develop metastases, the median follow-up was quite sufficient at 77 months.

Overall, 64 of 1450 patients died at a median of 84 months. The 7-year overall survival was 97% for the entire cohort. Overall survival rates differed by sub-groups: GG1 with PSAD lower than 0.15 (98%) compared to those with GG1 with PSAD of 0.15 or higher (96%) or initial GG2 (87%). Only 4 of 64 patients in this AS program died of advanced prostate cancer. The 7-year prostate cancer-specific survival was greater than 99%.

This report is based on one of the few large AS cohorts with long-term follow-up. Although 60% of patients experienced upgrading on subsequent biopsies, only 41% underwent deferred treatment, suggesting that upgrading alone may not necessitate immediate treatment. The goal of AS protocols is to avoid or delay treatment for those who may not benefit from it, and still maintain the curative intent through early capture of any disease progression. The success of AS protocol is evident from the data showing that 1% of men with low-risk prostate cancer developed metastases, and only 0.27% died of prostate cancer.

Further details about other prognostic variables in patients with initial GG2, such as age, focality, or percentage of Gleason pattern 4, would have been instructive in identifying the optimal candidates for AS. Additionally, this AS protocol included variable diagnostic testing and surveillance protocol during the study period. Should patients with GG2 on AS be managed with a more strict or intensive surveillance program than those with GG1? Although most of the patients in this study were Caucasian (92%) and the general applicability may be questioned, recent studies have highlighted the safety of AS in African American men with low-risk prostate cancer.

The boundaries of AS inclusion criteria are being expanded to include selected men with GG2 prostate cancer. Incorporating mpMRI, and perhaps genomic tests, will further facilitate the selection of appropriate candidates for AS, thus increasing its acceptability by urologists and patients. Despite some heterogeneity in the type and frequency of testing during the surveillance period, these results provide reassurance and increased confidence in the safe utilization of AS protocols for men with low-risk GG1, and selected GG2, prostate cancer.

1. Maggi M, Cowan JE, Fasulo V, et al. The long-term risks of metastases in men on active surveillance for early stage prostate cancer. 

. 2020;204(6):1222-1228. doi:10.1097/JU.0000000000001313

Articles

"Despite some heterogeneity in the type and frequency of testing during the surveillance period, these results provide reassurance and increased confidence in the safe utilization of AS protocols for men with low-risk GG1, and selected GG2, prostate cancer," Mian writes.

Active surveillance data in prostate cancer show frequent upgrading, rare mortality

In this interview, Stephanie J. Kielb, MD, discusses the recent 

study, The impact of stricter guidelines on post-interview contact, restricted interview topics and differences by gender in the urology match, for which she served as senior author. Kielb is chief of reconstruction and neurourology and professor of urology, medical education, and obstetrics and gynecology at Northwestern University Feinberg School of Medicine, Chicago.

Urology trainees carry high levels of debt

Investigators evaluate Peyronie disease patient education videos

Group-based pelvic floor muscle training is noninferior to individual PFMT

Videos

Urology residency program applicants continue to face interview questions on restricted topics such as plans for having children.

Restricted interview questions persist in urology match process

What are the best options to save for my child’s future?

Whether it’s for a college education, a down payment on a house, a future wedding, or just giving them a little leg up once they reach adulthood, saving for a child’s future is an important goal for many physicians. With costs rising across the board, many physicians wonder what is the best way to save. The answer, as with many things, depends. Parents should ask themselves: Do I want this money to go toward a specific goal? Do I want my children to have access to the funds all at once? Will my child manage this money responsibly? The answers to these questions can determine what type of account is best.

A common goal for many parents is to start saving early for their children’s college educations. With the rising cost of college, this can seem like a daunting task. The Internal Revenue Service allows those who wish to save, the ability to contribute to a 529 plan. A 529 account is an investment account that provides favorable tax treatments if the money is used for qualified education expenses such as tuition, room and board, equipment, student loan payments, and apprenticeships.

Money contributed to a 529 plan can be invested in various mutual funds. These investments will (hopefully) grow as the child does. If withdrawals are taken to pay for a qualified education expense, the balance including the investment gain comes out of the account tax free. In addition, some states give a state income tax deduction for contributing to a 529 account, so there may be additional tax incentives for contributing.

However, if money is withdrawn from the account for a nonqualified reason, the account owner will need to include the investment gain in their income and pay ordinary income tax. In addition, nonqualified distributions are subject to a 10% penalty. Withdrawing money from a 529 for a nonqualified purpose can be very costly, but if used for to pay for education expenses, it can be a very useful savings tool.

What if your goal is to save for a down payment on a home, pay for a wedding, or simply give your child a financial head start?

First determine the level of control you want to retain over the account and its ultimate use. Parents who have a specific purpose in mind or are unsure their child will be responsible enough to manage the money in a sensible way, will want to make sure they or someone else controls how the money can be distributed.

There are 2 primary ways to accomplish this. The first is to keep the money yourself. You control the assets and their distribution. However, depending on your estate planning goals, this may not distribute the assets as intended in the event of your death.

The other option is to create a trust. Establishing a trust fund creates a vehicle that sets terms for the way assets are to be held, gathered, or distributed in the future. Common reasons for distribution often include health, education, maintenance, and support (HEMS), but can expand beyond these. The definitions of HEMS or other allowed distributions can be as strict or relaxed as you choose.

Most trusts also create a timeline for when the beneficiary can access a greater portion or the full balance of the assets. Creating a trust ensures the assets are controlled until the recipient is deemed old enough or responsible enough to take over the money themselves.

If control is not a primary motivation, then custodial accounts can be opened. Commonly referred to as UTMA (Uniform Transfers to Minors Act) accounts, custodial accounts have lots of flexibility in terms of the assets that can be held. However, once the minor reaches the legal age of adulthood in their state of residence, control of the account officially transfers to the named beneficiary, and they claim full use of the funds.

There are many ways to save for your child’s future, but the intent and the level of control you want to maintain will determine which account type is best.

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529 plans and trusts help save and manage money destined for your children.

Saving for your child’s future: What should you consider?

Long-term oncologic outcomes were superior with adjuvant androgen-deprivation therapy (ADT) over neoadjuvant ADT when combining hormone therapy with radiation therapy (RT) in localized prostate cancer, according to findings from a pooled analysis of 2 randomized phase 3 trials.

At a median follow-up of 15 years, the pooled analysis showed statistically significant improvements with adjuvant ADT over neoadjuvant ADT in biochemical failure, distant metastasis, and progression-free survival rates.

“We demonstrate for the first time that sequencing of ADT with RT significantly impacts long-term oncologic outcomes in localized prostate cancer, favoring an adjuvant- rather than neoadjuvant-based approach, without increasing late toxicity. This data has important implications to ongoing and future clinical trial design,” first study author Daniel E. Spratt, MD, professor of radiation oncology at the University of Michigan, Ann Arbor, and coinvestigators wrote in their study conclusion.

The first trial used for the pooled analysis was a phase 3 trial by Malone et al

 which randomized patients with localized prostate cancer to neoadjuvant/concurrent or concurrent/adjuvant ADT for 6 months with prostate only radiotherapy. These data were combined with the prostate only radiotherapy arms of the phase 3 RTOG 9413 trial,

 in which patients were randomized to 4 months of either adjuvant ADT or neoadjuvant/concurrent ADT.

In the pooled analysis, the “neoadjuvant” group included patients in the neoadjuvant/concurrent arms of both prior studies, and the “adjuvant” group included patients from the adjuvant arm of RTOG 9413 and the concurrent/adjuvant arm of Malone et al’s study.

Overall, there were 1065 patients included in the pooled analysis, comprising 531 patients who received neoadjuvant ADT and 534 patients who received adjuvant ADT. Baseline patient and tumor characteristics were well balanced between the 2 arms.

The biochemical failure rate at 15 years was 33% with adjuvant ADT versus 43% with neoadjuvant ADT (HR, 1.37; 

 = .002). At 15 years, 12% of patients receiving adjuvant ADT had distant metastasis compared with 18% of patients who received neoadjuvant ADT (HR, 1.40; 

 = .04). The 15-year PFS rates were 36% versus 29%, respectively (HR, 1.25; 

Prostate cancer–specific mortality (PCSM) rates were also lower with adjuvant ADT at 15% versus 20% with neoadjuvant ADT; however, the difference was not statistically significant (HR, 1.29; 

 = 0.10). Of note, the difference in PCSM rate favoring adjuvant ADT did approach statistical significance in patients with high-risk disease (HR, 1.39; 

Although the 15-year overall survival rate was higher with adjuvant ADT, the difference was not statistically significant: 39% versus 34% (HR, 1.11; 

Regarding toxicity, late grade ≥3 gastrointestinal (

 = .98) adverse events were not significantly higher with adjuvant ADT.

1. Spratt DE, Malone S, Roy S, et al. Short-Term adjuvant versus neoadjuvant hormone therapy in localized prostate cancer: a pooled individual patient analysis of two randomized phase 3 trials. 

. 2020;108(3):S17. doi.org/10.1016/j.ijrobp.2020.07.2099

2. Malone S, Roy S, Eapen L, et al. Sequencing of androgen-deprivation therapy with external-beam radiotherapy in localized prostate cancer: A phase III randomized controlled trial. 

. 2020;38(6):593-601. doi: 10.1200/JCO.19.01904

3. Roach M, Moughan J, Lawton CAF, et al. Sequence of hormonal therapy and radiotherapy field size in unfavourable, localised prostate cancer (NRG/RTOG 9413): long-term results of a randomised, phase 3 trial. 

. 2018;19(11):1504-1515. doi: 10.1016/S1470-2045(18)30528-X

Analysis supports using adjuvant over neoadjuvant ADT with RT for localized prostate cancer

Mark Painter is CEO of PRS Urology SC in Denver.

As 2020 winds down, typically everyone from newscasters to sports reporters to anyone with a Twitter handle will write a “Year in Review” article, adding their predictions for the upcoming year. So we thought we would do the same—take a look back and also a look ahead.

2020 has been a fascinating year. The public health emergency (PHE) due to coronavirus disease 2019 (COVID-19) threw a huge curveball to the planet, including the delivery of medical care. All medical practices were affected. There was an explosion of telemedicine. We saw restrictions in elective surgeries, the barring of loved ones from visiting patients in hospitals, and numerous protections put in place.

® end-of-year article would have provided updates on the final rule for the 2021 Medicare Physician Fee Schedule, as we would have had time to review the document and alert providers of changes they would need to make in their practices. But due to the PHE, the final rule will not be released until after this article has been written. The Centers for Medicare & Medicaid Services (CMS) is running behind on several fronts. As we look forward, we are not going to stick with predictions but instead provide a series of goals and actions to reach those goals.

Relative value unit and conversion factor changes

As evaluation and management (E/M) code changes are due to take place on January 1, 2021, which will represent the first major change since 1997, there is a projected 8% increase in payments to urology, based on the increase in valuation of E/M codes. In addition, there is a new add-on Healthcare Common Procedure Coding System code (GPC1X) for patients with diseases that require an ongoing relationship with a urologist that will be able to be used with patients on Medicare. Finally, there is an increase in many practice expense values for services performed in the office.

The increase, however, comes with a price; specifically, a decrease in the Medicare Conversion Factor by 10.6%, due to budget neutrality. This will result in lower payments in 2021 for most medical services outside of E/M codes. The decreased conversion factor also will result in payment decreases for many other specialties, including anesthesiology, radiology, pathology, therapists, and most of the surgical specialties. There are a few proposals to stop this dramatic shift in payments, including a proposal to suspend budget neutrality for next year.

Our hope is that CMS and the US Congress will act to suspend budget neutrality for this year at least, with legislation that does not kick funding down the road, sending us down a path of eternal conversion factor reduction threat similar to the years prior to the Medicare Access and CHIP Reauthorization Act of 2015. As this will require an act of Congress, we encourage you to contact your senators and representatives and encourage them to suspend budget neutrality for 2021 to help health care providers recover from the PHE.

The majority of medical providers and a significant number of patients became fans of telemedicine in 2020, citing its convenience and practicality. Luckily for many of us, Medicare appears to also be a fan of telemedicine. Patients have enjoyed the experience. Many physicians have found a place for telehealth during the PHE with equal pay for services rendered. During the PHE, Medicare has covered telephone-only services at reasonable rates to allow for services to patients without technology services or ability. Medicare also has expanded remote patient monitoring services.

Although we can appreciate the changes that Medicare is proposing in an effort to add telehealth as a treatment path for many patients, we note that they have not been able to go far enough. When the PHE ends, many of these services will not be supported in way that will make telehealth a truly viable treatment option for many patients and circumstances.

Our desire is to see fair reimbursement, continued expansion of these services, and the ability to treat patients while they are at home, regardless of where they live.

In the proposed rule, Medicare has indicated a desire to keep or even expand some of these services but not others. For services such as telephone-only support that Medicare does intend to cover after the PHE ends, we encourage you to continue to support the American Urological Association, American Medical Association, and other groups lobbying for these services to be extended permanently.

If Medicare is going to truly make telehealth a viable service option, we need new legislation. We would encourage you to also mention expansion of telehealth services for patients in their home at rates comparable to in-office services when you contact your senators and representatives about the conversion factor.

As we have written about and provided instructions to urologists around the country, we have become even bigger fans of the updated E/M outpatient codes. Although change is never as easy as we would like it to be, we are confident that those who embrace the changes and break through the initial learning curve also will realize the benefits to patients, providers, and practices.

Our hope is that providers embrace these changes. Anyone involved in patient care should get appropriate training, study a little bit, and become a student of the practice. Jump in with both feet early and keep an open mind.

The changes to the E/M codes are going to allow providers to stop all the unnecessary clicking and “note bloat” seen when trying to meet the coding guideline rules, and instead allow providers to get back to their expertise: patient care. Practices should change their patient intake forms to focus on the medically necessary data needed without having to collect information no longer needed or relevant. Shortening these forms will not only make patients happy but also will allow practices to have a more efficient workflow, taking pressure off of front desk and other support staff struggling to set up or update the medical records. If done correctly, staff can be freed to focus on the patient experience, tracking services can be provided, and the stress in the office will decrease.

Physicians then will be more able to focus on clinical services, reduce time spent with the electronic health record, and develop notes that can be understood by patients and other medical professionals. In addition, the services will be more able to be accurately reported to better reflect the appropriate level of service chosen.

For a minimal investment of time, we hope providers enjoy these changes.

Although our hopes are not all guaranteed to pan out, we again encourage everyone to take action where they can. Learn the new E/M system. Get involved with advocacy. Even a small investment in time may indeed bring about changes to make 2021 and beyond a more pleasant experience for all.

The information in this column is designed to be authoritative, and every effort has been made to ensure its accuracy at the time it was written. However, readers are encouraged to check with their individual carrier or private payers for updates and to confirm that this information conforms to their specific rules.

Evaluation/management changes should benefit providers and patients.

How urology coding changed in 2020—and what to watch for in 2021

The FDA has granted Fast Track Designation to RV001, an investigational synthetic long peptide vaccine that targets RhoC, for the treatment to patients with prostate cancer.

RhoC is a small GTPase that is overexpressed in advanced solid tumors. Results from a phase 1/2 first-in-human study published in the 

showed that 18 of 21 evaluable patients had an immunological response to RV001.

 Safety data showed that the vaccine was tolerable with no grade ≥3 treatment-related adverse events reported. 

"We are extremely pleased and proud that our drug candidate, RV001, has earned Fast Track Designation by the FDA. We obviously appreciate the benefits that this might entail in terms of access to FDA advice and an accelerated approval process. But also the fact that the FDA has reviewed our data, and found our drug candidate worthy of this level of priority, obviously sends a clear signal of recognition of the drug's potential to all our would-be partners, which is something of great importance to us," Anders Månsson, CEO of RhoVac, the manufacturer of RV001, stated in a press release.

The phase 1/2 study (NCT03199872) included 22 patients aged ≥18 years who had previously received radical prostatectomy. Patients had histologically confirmed adenocarcinoma of the prostate gland and were not receiving anticancer therapy at the time of enrollment. Prior androgen-deprivation therapy was not allowed. Patients had an ECOG performance status of 0 or 1.

RV001 was administered subcutaneously every 2 weeks for 6 injections, then 5 times every 4 weeks for a total treatment regimen duration of 30 weeks. Safety was the primary outcome measure with immunological response as a secondary outcome measure.

Overall, 18 of 21 evaluable patients developed a strong CD4 T cell response against the vaccine. The response durations all lasted at least 10 months after the patient received the last injection of RV001. The investigators identified 3 promiscuously presented HLA-class II epitopes. “Vaccine-specific CD4 T cells were polyfunctional and effector memory T cells that stably expressed PD-1 (CD279) and OX-40 (CD134), but not LAG-3 (CD223),” the study authors explained.

 Additionally, there was 1 detected CD8 T cell response.

“Targeting of RhoC induced a potent and long-lasting T cell immunity in the majority of the patients. The study demonstrates an excellent safety and tolerability profile,” the authors wrote in their study conclusion.

RV001 is currently being evaluated in the double-blind phase 2 BRaVac trial in men with biochemical failure following curatively intended therapy for localized prostate cancer. Patients enrolled on the trial will be randomized to RV001 or placebo. The primary outcome measure is time to PSA progression and the estimated primary completion date is September 2021.

1. RhoVac's Prostate Cancer Drug Candidate, RV001, is granted Fast Track Designation by the FDA. Posted online November 25, 2020. https://prn.to/3m86J9X. Accessed November 25, 2020.

2. Schuhmacher J, Heidu S, Balchen T, et al. Vaccination against RhoC induces long-lasting immune responses in patients with prostate cancer: results from a phase I/II clinical trial. 

. 2020;8(2):e001157. doi: 10.1136/jitc-2020-001157

The vaccine RV001 targets RhoC, a small GTPase that is overexpressed in advanced solid tumors.

FDA grants Fast Track Designation to novel peptide-based vaccine in prostate cancer

Based on a partnership with Urology Times, articles from the American Association of Clinical Urologists (AACU) provide updates on legislative processes and issues affecting urologists. We welcome your comments and suggestions. Contact the AACU government affairs office at 847-517-1050 or info@aacuweb.org

With the exception of a few uncalled House races and 2 Senate runoff races scheduled for January 5 in Georgia, the outcomes of the 2020 election are largely now determined: A new Democratic president, a slightly narrower majority for Democrats in the House of Representatives, and pending the outcome of the Georgia runoffs, a likely Republican-controlled Senate.

Such a scenario would mean the continuation of divided government in Washington for at least the next 2 years, likely halting, or at least scaling back, an ambitious health policy agenda envisioned by Democrats under a Biden administration. Creating a public option government health plan is probably off the table, as is lowering the eligibility age for Medicare to 60, which could expand the population of beneficiaries by more than 20 million Americans.

With a GOP-controlled Senate and Democrat-controlled House, the most plausible path for President-elect Biden to advance his health care agenda will be via administrative action, such as executive orders and regulatory rulemaking. For example, he is likely to roll back Medicaid work requirements sought by the Trump administration and bolster the Affordable Care Act in several areas. Some of these actions, however, are required to undergo the full regulation-writing process and comment period, which can take many months, occasionally years.

There are also some limited areas, including surprise medical billing, prescription drug pricing, and a shift to value-based care, where policymakers may be willing to work together to advance policies broadly supported by the electorate. Whether their popularity with voters will be enough to break the partisan gridlock on Capitol Hill, however, remains to be seen.

Lawmakers have gotten close to reaching a deal on surprise billing a couple of times over the last 12 months, but ultimately failed to agree on how exactly to protect patients from bills incurred when they receive care from a doctor or hospital not in their insurer’s network. More than 2 dozen states have enacted protections to address surprise medical billing, but Congress has not passed such a measure. At issue is how to resolve payment disputes that arise between providers and insurers.

One possible solution would require insurers to pay for out-of-network care at a benchmark rate, such as the average Medicare price for the service in a specific geographic area. Providers oppose this proposal as it would drastically lower reimbursement. Instead, they back arbitration under which an independent third party determines the amount insurers must pay out-of-network providers.

There are a lot of factors that favor action on this issue. Voters 

 legislation that would limit patients’ exposure to charges from non-network providers. At a time when millions of people have lost their employer-sponsored insurance due to the pandemic’s financial effects and thousands are admitted to hospitals every day due to COVID-19, there is increased pressure on Congress to address the issue. President-elect Biden has talked about the need to protect patients from hospital bills incurred when the patient doesn’t have control over which provider he or she sees (ie, emergency transport and surgery), but has not addressed the issue of payment disputes.

 health costs over the past decade has been the rising cost of prescription drugs. There is bipartisan support in Congress for measures aimed at lowering drug prices, but so far efforts have stalled amid opposition from the pharmaceutical and insurance industries. There are numerous approaches to addressing the issue and dozens of lawmakers on both sides of the aisle who view it as a top priority.

Notably, Medicare is still barred from negotiating prescription drug prices directly with drug companies even though the drugs account for nearly 20% of Medicare’s overall spending each year. Instead, pharmacy benefit managers are in charge of acquiring drugs for the Part D prescription drug benefit. The President-elect has promised to work with Congress to eliminate the exception so that Medicare can negotiate drug prices directly with pharmaceutical companies the same way private insurers do—a reform that could save Medicare, according to some estimates, 

President-elect Biden supports limiting launch prices for drugs that don’t face competition by establishing an independent review board to assess a drug’s value based on the average price in other countries, also called “external reference pricing.” He also supports limiting drug price increases to inflation, capping out-of-pocket drug costs for Medicare Part D, allowing drug importation from other countries, and eliminating drug companies’ advertising tax breaks, which equaled $6 billion in 2016.

The transition from Medicare fee-for-service to value-based care has received strong bipartisan support. Payment models under which physicians are reimbursed based on the value, rather than the volume, of their services allow providers to deliver better-quality, lower-cost care. Although COVID-19 has slowed the progress that has been made toward implementing alternative reimbursement models, it has also exposed some of the 

Over the coming years, the federal government will need to find methods for cutting costs after spending trillions on the COVID-19 response. The continued adoption of value-based care will help achieve that goal as providers agree to take on more financial risk in order to preserve resources and avoid payment cuts.

Although the President-elect has not commented directly on value-based care, his health plan includes several proposals aimed at closing gaps in health care among racial groups. Alternative payment models could help close racial disparities and gaps in health care by paying providers for taking an active role in addressing disparities that exist between patients based on their race, ethnicity, gender, or sexual orientation. The individuals tapped to fill top posts at HHS and CMS may provide a clue as to how aggressive the incoming administration will be in advancing new payment models.

In the immediate term, the Biden administration will take executive action to roll back some of the more controversial health care regulations implemented under President Trump. Assuming Congress does not come to an agreement during the current lame-duck session, 1 of the first orders of business is likely to be enacting a new COVID-19 relief package, which will include a variety of provisions that impact providers and patients.

There is also strong support in Congress for addressing health care price transparency and further expanding access to telehealth, items President-Elect Biden would certainly support. As for the portions of Biden’s health care agenda that are more controversial, such as increasing ACA premium subsidies for the middle-class and lowering the age for Medicare eligibility, legislative success may hinge on the long-shot possibilities of Democrats winning both Georgia runoff elections or a newfound willingness on the part of Democratic and Republican leadership to find compromise, perhaps by trading increased health care spending for cuts in other areas.

"Although the President-elect has not commented directly on value-based care, his health plan includes several proposals aimed at closing gaps in health care among racial groups," writes Yehuda A. Sugarman of the American Association of Clinical Urologists.

Biden signals focus on common-ground health policies

Cheryl Guttman Krader is a contributor to Dermatology Times, Ophthalmology Times, and Urology Times.

Urine culture remains the standard of care for the diagnostic evaluation of patients with complicated and recurrent urinary tract infections (UTIs), but next-generation DNA sequencing (NGS) is its future, according to J. Curtis Nickel, MD.

“The development of molecular technology for diagnosing infections of the urinary tract has outstripped our knowledge of how to use it, but understanding of its clinical application is catching up, thanks to ongoing research,” said Nickel, who is a professor of urology at Queen’s University School of Medicine in Kingston, Ontario.   

“When the studies are completed, I strongly believe that NGS will be ready for prime time, and the use of urine cultures will be relegated to the wastebasket of medical history,” Nickel said.

®, Jonathan Rubenstein, MD, and Jennifer Anger, MD, MPH, agreed that NGS holds great promise as a diagnostic test for patients with lower urinary tract symptoms, but they felt more work is needed before it is adopted into clinical care. In contrast, based on extensive experience using the technology, Timothy Hlavinka, MD, considers NGS a revolutionary development and invaluable for evaluating challenging patients with lower urinary tract symptoms.

Urine culture, which detects uropathogens based on visible inspection, is recognized to have limitations as a method for UTI diagnosis, including lack of clarity on the threshold for growth to define clinically significant bacteriuria and the difficulty of culturing most bacteria, including those living in biofilms.

Molecular diagnostic techniques for uropathogen detection, including NGS and polymerase chain reaction (PCR) methodology, are based on DNA detection. PCR assays the sample for unique gene sequences that are present in a defined and limited panel of bacteria representing the most common uropathogens. It is a rapid, semiquantitative test that reports bacteria load as low, medium, or high. It also can test for genes that mediate resistance to main antibiotic families.

In contrast, NGS can identify more than 50,000 microorganisms, including most fungi, and it provides a ranking of the quantity of the detected organisms based on their percentage of the total load.

“PCR may be good if you are looking for particular organisms. However, because we now understand that cystitis-like symptoms may be caused by an abnormal microbiome [called dysbiosis], not just a single pathogen, I prefer NGS, particularly as a research tool, since it shows whatever organisms are present,” Nickel said.

The 2019 American Urological Association (AUA)/Canadian Urological Association/Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction guideline on recurrent uncomplicated UTIs in women discussed sensitive molecular diagnostic techniques for UTIs, but cautioned against relying on their use, said Anger, lead author of the published guideline and associate professor of urology at Cedars-Sinai Medical Center in Los Angeles, California.

“We know now that the lower urinary tract in healthy individuals is not sterile, but we still have a lot to learn about the urinary tract microbiome in health and disease,” Anger said. “We do not yet know if the DNA of bacteria and fungi identified by NGS represent DNA only, dead organisms, live commensal organisms, or organisms causing infection. The guideline committee concluded that the clinical utility of sensitive molecular diagnostic techniques for UTI remains unproven and may lead to overdiagnosis and associated overtreatment.”

Rubenstein said that he has used NGS in the work-up of patients who present with urinary symptoms that are worrisome for infection and that have not been diagnosed by routine culture. Whereas he has found the test useful if it is negative because it allows him to rule out infection, he remains uncertain about the value of a positive test.

“Although I have treated some patients based on the findings of the NGS test, I do not have enough outcome data to comment about its benefit,” said Rubenstein, clinical associate professor of surgery at the University of Maryland School of Medicine in Baltimore.

Nickel said that results from NGS were a source of confusion in some patients and likely led to overtreatment of others. However, he also had patients who were symptomatic and culture-negative respond to treatment based on NGS findings.

“Once we have more information on the urinary microbiome in health and disease, I believe we will be able to use NGS to consistently get more predictable responses,” he said.

Hlavinka, who has reviewed data from more than 800 assays that he ordered plus several hundred more from his practice partners, is convinced that NGS has enabled better patient 

outcomes. He said he routinely sent specimens for parallel culture in the first 6 months after he began using NGS until he was confident there was no advantage to cross-checking the results.

“Repeating a negative or errant test for patients who have had multiple negative cultures or infections that are refractory to culture and sensitivity report-directed treatment only adds to cost,” said Hlavinka, who is in private practice in San Antonio, Texas.

“Cultures often detect an organism that is not clinically significant or fail to detect a significant organism. Even if it is just 2% of the bacterial load, a significant pathogen in a symptomatic patient with a refractory UTI must be covered by the antibiotic I prescribe. That may not happen with treatment decisions driven by culture and sensitivity testing, especially if the minor pathogen has significant resistance,” Hlavinka said.

Led by Nickel and Anger, an evaluation of urine specimens obtained from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network will help describe the normal urinary microbiome and determine if Hunner’s lesions in interstitial cystitis/bladder pain syndrome may be caused by dysbiosis of the microbiome. Nickel also is studying the normal healthy microbiome in a study funded by MicroGenDx using the company’s NGS assay.

In addition, he is analyzing information contained in the more than 50,000 reports from symptomatic patients in the MicroGenDx database, aiming to define “community states” or urotypes of microorganism and then see whether patients with diagnoses of interstitial cystitis/bladder pain syndrome or chronic prostatitis fit into specific urotypes.

“The information from this study will help us figure out the relevance of NGS in the real world,” Nickel said.

Nickel also has obtained additional support from MicroGenDx for a study to examine the potential benefit of NGS-guided treatment for patients with cystitis and/or bladder pain who are culture-negative or refractory to culture-directed antibiotic treatment.

Hlavinka said that reimbursement for the NGS test is available through Medicare and most commercial insurance plans. Nevertheless, he cautions patients upfront about the potential for an out-of-pocket cost.

“In my experience, patients needing a work-up for perplexing urinary symptoms accept the cost of the test when it is discussed in terms of the alternative scenario that can involve multiple repeat cultures, copays for additional visits and antibiotic courses, and the potential for antibiotic-related side effects,” he said.

Rubenstein, who is chair of the AUA Coding and Reimbursement Committee, said that if he contemplates ordering an NGS test, he first explains to the patient how NGS differs from standard culture and that the test may not be covered by insurance.

Rubinstein emphasized that medical necessity is the overarching criterion for payment. He also stressed the importance of following local coverage determinations for appropriate ICD-10 codes and making sure that the ICD-10 code aligns with the laboratory billing code, which can be organism-specific.

Disclosures: Nickel has received research grants from MicroGenDx; Hlavinka is a consultant to MicroGenDx.

1. Anger J, Lee U, Ackerman AL, et al. Recurrent uncomplicated urinary tract infections in women: AUA/CUA/SUFU guideline. 

 2019;202(2):282-289. doi:10.1097/JU.0000000000000296

Next-generation DNA sequencing can identify more than 50,000 microorganisms.

NGS brings power and potential to molecular analysis of urine specimens

Nadofaragene firadenovec induced complete responses (CRs) in over half of patients with high-grade

 BCG-unresponsive non-muscle invasive bladder cancer (NMIBC), according to phase 3 data now published in the 

In patients with carcinoma in situ with or without concomitant high-grade Ta or T1 disease (CIS ± Ta/T1), the CR rate with nadofaragene firadenovecwas 53.4% at 3 months. The 12-month CR rate was 24.3% and the median duration of CR was 9.69 months.

“Once patients with high-grade, non-muscle invasive bladder cancer no longer benefit from their initial BCG treatments, patients often make an informed decision to decline cystectomy—a highly complex and life-altering bladder removal surgery—or are often medically ineligible for this complex operation, leaving them with limited options,” Colin P. N. Dinney, MD, chairman, Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, and senior author of the publication, stated in a press release.

 show that nadofaragene firadenovec, a first-of-its-kind therapy, may be an effective treatment option for BCG-unresponsive non-muscle invasive bladder cancer patients,” added Dinney.

The multicenter, open-label, repeat-dose phase 3 study (NCT02773849) accrued patients with BCG-unresponsive NMIBC at 33 clinical sites in the United States. Among 157 treated patients, there were 107 patients with CIS ± Ta/T1 tumors. The median patient age in this group was 72 years (range, 66-77), 89% were male, 93% were white, and the median time from initial bladder cancer diagnosis was 20 months (range, 13-35).

Overall, 90.7% of patients had an ECOG performance score of 0, and 3.7% had prior radiotherapy. The number of prior BCG courses included 1 (0.9%), 2 (42.1%), 3-8 (53.3%), and ≥9 (3.7%).

The novel intravesical gene-mediated therapy nadofaragene firadenovec was administered by catheter as a single dose into the bladder. Those patients without recurrence received repeat doses at 3, 6, and 9 months. The primary end point was the CR rate in patients with CIS± Ta/T1 tumors.

Of the 107 patients with CIS± Ta/T1 disease, 103 were included in the efficacy analysis (4 patients were excluded because they did not meet the study definition of BCG-unresponsive NMIBC). Among these 103 patients, 55 (53.4%) had a CR at month 3, and 25 (24.3%) were in CR at 12 months.

“As a practicing urologist, I’m encouraged by these efficacy and safety data which demonstrate the potential for a novel treatment option that fits within the urology practice and gives patients the choice of receiving treatment once every 3 months—which may be a particularly important consideration in this evolving healthcare environment,” Gennady Bratslavsky, MD, president of the Society of Urologic Oncology Clinical Trials Consortium (SUO-CTC), and professor and chair of Urology at SUNY Upstate Medical University, stated in the press release. “Our organization is proud to have played a key role in the mid- and late-stage clinical studies for nadofaragene firadenovec.”

The safety analysis included all 157 patients enrolled on the trial who received at least 1 dose of nadofaragene firadenovec. The most common grade 3 treatment-related adverse event (TRAE) was micturition urgency, which occurred in 2 patients. There were four other grade 3 TRAEs occurring in 1 patient each: bladder spasm, syncope, hypertension, and urinary incontinence.No grade 4 TRAEs were reported and there were no treatment-related deaths.

The trial remains ongoing with the study design set up for a 4-year treatment and monitoring phase.

In their study summary, the authors wrote, “Future research [of nadofaragene firadenovec] should include analyses to help to identify early treatment responders and provide insights into the potential mechanisms of treatment non-response.

1. FerGene announces Landmark Phase 3 study published in Lancet Oncology. Published online November 30, 2020. https://bit.ly/3mnNzx1. Accessed November 30, 2020.

2. Boorjian SA, Alemozaffar M, Bad Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial [published online November 27, 2020]. 

“These data published in the Lancet Oncology show that nadofaragene firadenovec, a first-of-its-kind therapy, may be an effective treatment option for BCG-unresponsive non-muscle invasive bladder cancer patients,” Colin P. N. Dinney, MD.

Nadofaragene firadenovec published data show strong efficacy in BCG-unresponsive NMIBC

β3 agonist treatment of overactive bladder (OAB) may also improve erectile dysfunction (ED) in men who have symptoms of both disorders, according to study results reported at the 2020 Sexual Medicine Society of North America (SMSNA) 21st Annual Fall Scientific Meeting.

Five of 13 men with OAB and mild to moderate ED experienced clinically relevant increases in erectile function after 12 weeks of treatment with mirabegron (Myrbetriq), a β3-adrenoceptor agonist approved by the FDA for treatment of OAB. As expected, symptoms of OAB also improved, with no serious adverse events noted over 12 weeks, said Serkan Karakus, MD, a clinical fellow with the James Buchanan Brady Urological Institute at Johns Hopkins School of Medicine in Baltimore, Maryland.

“This is a single-arm, observational study and small study group, but we found some promising results,” Karakus said in an interview. “So I think we could move forward to larger, randomized studies.”

These preliminary findings at least suggest that mirabegron could be an alternative for ED treatment when phosphodiesterase type 5 (PDE5) inhibitor treatment fails or is contraindicated, according to coinvestigator Arthur L. Burnett II, MD, MBA, a professor of urology at Johns Hopkins School of Medicine.

“The question is whether have we solved ED treatment entirely with PDE5 inhibitors, and the answer is no,” Burnett said in an interview. “So why not explore alternative mechanisms with a thought that this new therapy, which may not necessarily be addressing a predominant mechanism of penile erection, could still be a complementary or additive therapy to consider.”

In his SMSNA presentation, Karakus described OAB and ED as disorders of the lower genitourinary tract that share several pathophysiologic mechanisms, including dysregulation of the nitric oxide-cyclic guanosine monophosphate pathway, increased sympathetic tone, upregulation of Rho kinase expression, and chronic hypoxia.

The β3 adrenoceptor has been found in human corpus cavernosum, he added, noting that mirabegron could act simultaneously in the bladder and corpus cavernosum via β3-adrenoceptor activation.

The nonrandomized, single-arm study by Karakus and colleagues included 20 men with OAB and mild to moderate ED as defined by International Index of Erectile Function (IIEF) Erectile Function domain scores between 11 and 25 or Sexual Health Inventory for Men (SHIM) scores between 8 and 21. Patients received mirabegron 25 mg daily for 2 weeks and then 50 mg daily for the next 10 weeks.

Seven patients were lost to follow-up, and 13 remained in the study for the full 12 weeks, according to investigators. Treatment with mirabegron was associated with significant improvements in mean SHIM scores through week 4 and week 8 (

=.0003). The SHIM score decreased slightly by week 12, so no significant improvement was noted at that time, according to Karakus.

However, looking at individual SHIM scores, 5 of 13 patients experienced a 4-point increase at 12 weeks, and there were no clinically relevant decreases in SHIM or IIEF scores for any patient.

IIEF scores trended toward significant improvement at week 4 and week 8 evaluations (

=0.08), and no changes were seen in orgasmic function or sexual desire.

As anticipated, treatment with mirabegron significantly improved symptoms of OAB and OAB-related quality of life, according to the investigators. In addition, no serious adverse events were observed; transient nonserious adverse events included headache, constipation, back or leg pain, flu-like symptoms, rash, and elevated blood pressure, Karakus said.

According to Burnett, senior author of the study, these findings support continued investigation of the safety and efficacy of mirabegron in men with OAB and concurrent ED.

“This is not a definitive study, it’s not a randomized controlled trial, and the numbers aren’t there that need to be done,” Burnett said. “But I think it does provide some interesting initial observations to test the hypothesis and possibly will be a foundation to move forward with something more rigorous to come.”

Disclosure: Astellas Pharma US, Inc provided funding for the study.

1. Karakus S, Musicki B, Burnett AL. Mirabegron for erectile dysfunction. Abstract presented at: 2020 Sexual Medicine Society of North America 21st Annual Fall Scientific Meeting; November 9-15, 2020; virtual.

The findings support continued investigation of the safety and efficacy of mirabegron in men with OAB and concurrent ED, says study author Arthur L. Burnett, II, MD, MBA.

NGS brings power and potential to molecular analysis of urine specimens

Nadofaragene firadenovec published data show strong efficacy in BCG-unresponsive NMIBC

Mirabegron may improve erectile dysfunction in men with overactive bladder symptoms