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"Overall, the take-home message is that [blue light cystoscopy], whether in the clinic or the OR, increases the detection of tumors," writes Jeffrey M. Holzbeierlein, MD.

In-office blue light: Solid data, and questions

The FDA has accepted a Biologics License Application (BLA) seeking approval of nivolumab (Opdivo) co-formulated with Halozyme’s proprietary recombinant human hyaluronidase (rHuPH20), or subcutaneous nivolumab, for the treatment of patients with all previously approved solid tumor indications for nivolumab as a monotherapy, monotherapy maintenance following completion of combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Nivolumab is currently approved under several indications, including in combination with ipilimumab for the first-line treatment of patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC), in combination with cabozantinib for the first-line treatment of patients with advanced RCC, for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy, and in combination with cisplatin and gemcitabine for the first-line treatment of patients with unresectable or metastatic urothelial carcinoma.

The FDA is set to have a decision regarding the subcutaneous nivolumab formulation on or by December 29, 2024.

 According to a news release from Bristol Myers Squibb,

 approval of the formulation would make it the first and only subcutaneously administered PD-1 inhibitor.

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” said Gina Fusaro, PhD, vice president, global program lead, Bristol Myers Squibb, in the news release.

 “Opdivo is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as IV Opdivo but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30-to-60-minute infusion.”

The BLA submission is supported by findings from the phase 3 CheckMate-67T trial (NCT04810078), in which subcutaneous nivolumab met the study’s co-primary end points by demonstrating noninferiority to intravenous (IV) nivolumab regarding time average nivolumab serum concentration over 28 days (C

; geometric mean ratio [GMR}, 2.098; 90% CI, 2.001-2.200) and minimum serum concentration at a steady state (C

Data from the study, which were presented at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California,

 also showed that subcutaneous nivolumab demonstrated noninferiority to IV nivolumab in the key powered secondary end point of objective response rate (ORR). Specifically, the subcutaneous arm demonstrated an ORR of 24.2% (95% CI, 19.0-30.0) per blinded independent central review (BICR), compared with 18.2% (95% CI, 13.6-23.6) in the IV arm.

The safety profile for subcutaneous nivolumab was consistent with that of the IV formulation. Among patients who received the subcutaneous formulation, 8.1% experienced injection-site reactions, with all being low-grade and transient. Deaths due to study drug toxicity occurred in 3 patients in the subcutaneous arm and 1 patient in the IV arm. Most deaths that occurred during the study were due to disease progression.

In total, the phase 3, open-label CheckMate-67T trial enrolled 495 patients with advanced or metastatic ccRCC who had received prior systemic therapy. Patients were randomly assigned 1:1 to receive 1200 mg subcutaneous nivolumab plus rHuPH20 every 4 weeks (n = 248) or to 3 mg/kg IV nivolumab every 2 weeks (n = 247) for up to 2 years of treatment or until disease progression, unacceptable toxicity, withdrawal, or death.

The co-primary pharmacokinetic end points for noninferiority testing were C

 of subcutaneous nivolumab vs IV nivolumab. The key secondary end point was ORR per BICR.

Final completion of the CheckMate-67T study is expected in January 2026.

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 7, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-Application-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx

2. Bristol Myers Squibb announces updated action date by the U.S. Food and Drug Administration for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Published online and accessed May 21, 2024. https://investors.bms.com/iframes/press-releases/press-release-details/2024/Bristol-Myers-Squibb-Announces-Updated-Action-Date-by-the-U.S.-Food-and-Drug-Administration-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx

3. George S, Bourlon TB, Chacon MR, et al. Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T. 

4. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Last updated March 1, 2024. Accessed May 7, 2024. https://clinicaltrials.gov/study/NCT04810078

The FDA is set to have a decision regarding the subcutaneous nivolumab formulation on or by December 29, 2024. 

News

FDA accepts BLA for subcutaneous nivolumab in solid tumors

Infections originating in a genitourinary source are among the most common hospital and outpatient clinical presentations in urology and non-urology settings. Antibiotic use and overtreatment are well known to cause multidrug-resistant organisms. The lack of new antibiotic therapies exacerbates this problem. Most antibiotics are decades old and were derived from bacterial sources—bacteria are in an arms race to occupy limited ecological niches. The selective pressure applied by this competitive landscape has resulted in bacteria evolving synthetic pathways that yield new antibiotics that kill competitors to make room for the index organism.

Scientists have capitalized on this evolutionary phenomenon to isolate antibiotics—this discovery pathway yielded the famous and serendipitous isolation of penicillin. However, this discovery pathway has been exhausted because most bacteria are not culturable with traditional methods. Once bacteria are removed from their niche, they cease to be able to be cultivated on/in media such as Luria-Bertani, sheep’s blood agar, chocolate agar, etc -the workhorses of modern microbiology labs.

This problem was creatively addressed by Ling et al, who described a simple, productive solution to the bacterial cultivation problem: Grow bacteria in incubators that recapitulate their natural niche. The authors developed a simple tool called iChip. This device is essentially a chamber with a semipermeable membrane on 2 sides and can be buried in dirt (or other natural ecological niches), recapitulating the native environment where bacteria would grow. To isolate individual species and strains, the soil samples are diluted exponentially such that 1 bacterial cell is inoculated into a single chamber. Nutrients, waste products, and other biologically active metabolites diffuse into/out of the chamber and can be isolated with chromatography. Isolated natural products can be screened for biological activity against pathological bacterial species.

This workflow was used to isolate teixobactin, a cell wall synthesis inhibitor that works via a novel mechanism. Teixobactin was isolated from a previously unidentified species of soil-dwelling bacteria named 

, confirming that iChips can be used to “culture the unculturable.” The authors sequenced the genome of 

. The organism’s genome contains an anabolic operon (string of genes that coordinate a physiological task) that synthesizes teixobactin, a peptide. The structure of teixobactin is 11 amino acids long, including 2 nonhuman amino acids. The last 4 amino acids form a ring structure that is generated by enzymes contained in the operon.

The drug was tested for antimicrobial activity and found to be highly potent against gram-positive organisms: 

; and the causative agents for anthrax and tuberculosis. The compound was nontoxic to cultured mammalian cells at 400 times the minimal inhibitory concentration (MIC) for MRSA (which had the highest MIC of the gram-positive organisms tested). Traditional experiments to identify resistance mechanisms did not generate resistance to teixobactin but did yield cultures resistant to oxacillin (a positive control for the experiment).

Ling et al then sought to identify the bacterial target of teixobactin. It was a potent inhibitor of cell wall biosynthesis and was bacteriolytic/bacteriocidal. To test which step of peptidoglycan biosynthesis was inhibited, they performed biochemical analysis of lysates generated by teixobactin-treated 

. They found that there was accumulation of the same peptidoglycan intermediate that accumulates upon treatment with vancomycin. They identified that the target for teixobactin was not an enzyme (as is the case for β-lactams) but a precursor molecule of peptidoglycan called lipid II. Teixobactin traps the lipid II molecule, sequestering it from further synthetic incorporation into the cell wall. This makes resistance highly unlikely, as the bacteria would have to completely reinvent a cell wall synthetic pathway to generate a teixobactin-resistant lipid component. They also found that teixobactin binds to lipid III, another peptidoglycan precursor. Lipid III is important because it sequesters enzymes called autolysins that hydrolyze peptidoglycan. Sequestration of lipid III results in the liberation of autolysins and unregulated hydrolysis of cell wall components and, therefore, bactericidal activity.

Finally, the authors determined whether teixobactin might be used as a drug. Teixobactin was stable in serum incubations, did not break down in microsomal assays, and had a viable circulating half-life in mice. To test its activity, MRSA was injected into the peritoneum of mice, followed by treatment with vancomycin or teixobactin at different doses. This resulted in a 100% survival rate for mice treated with teixobactin doses greater than 0.5 mg/kg but less than a 20% survival rate for mice treated with vancomycin at the same dose. Only single doses were used. Similar activity was seen when injecting MRSA into the thigh for an abscess model.

Where does this leave us? Teixobactin, and more broadly, the iChip approach to novel antibiotic discovery, is an exciting development in infection control. As of this writing, teixobactin is mentioned in 122 PubMed citations, but no publications are clinical trials, and teixobactin is not mentioned in trials listed in ClinicalTrials.gov. However, teixobactin research is being funded by the NIH in the form of a small business initiative research grant to perform key experiments that will validate teixobactin as a drug (toxicity, pharmacokinetic properties, manufacturing optimization), and this discovery platform is as well. It is promising that teixobactin can eventually become a clinically available and useful drug. Still, it also underscores the long path that it takes to translate a lab discovery into a clinical reality, even for urgent needs like infection/sepsis. In any case, iChip seems like a robust tool for developing new antibiotics/antifungals, and it seems likely that the tool could also be applied to the discovery of natural compounds that can be applied to other diseases.

Ling LL, Schneider T, Peoples AJ, et al. A new antibiotic kills pathogens without detectable resistance. 

2015;517(7535):455-459. doi:10.1038/nature14098

"Teixobactin, and more broadly, the iChip approach to novel antibiotic discovery, is an exciting development in infection control," write Philip Abbosh, MD, PhD, and Kate Gessner, MD, PhD.

Novel antibiotic discovery tool holds promise to uncover more natural compounds

For the second installment of Urology in the Lab, we focus on a study that uses a cross-species analysis of hibernating bears, patients with spinal cord injury (SCI), and mice to identify a conserved immobility-associated signature in platelets that protects against thrombosis.

 Urological care is an important consideration of patients with SCIs, so these patients are often under the care of urologic surgeons. This innovative work may change how we prevent development of venous thromboembolism (VTE) during periods of immobility, such as postoperative settings or intensive care unit admissions for septic stones.

The study published by Thienel et al takes a unique approach to identifying factors associated with protection against VTE formation by using the following premise: Brown bears, despite possessing key components of the coagulation cascade and the ability to form pulmonary embolism while active, are protected against immobility-associated VTE during their annual 4- to 7-month hibernation. By analyzing their blood for changes in coagulation-related proteins between hibernation and activity, the authors sought to identify VTE-protective factors that they could then relate to humans and other species.

The authors collected blood samples from 13 brown bears both during hibernation in winter and during activity the following spring and evaluated changes in blood components between the 2 time points. They tested the ability of the blood to form a clot using thromboelastographic analysis and demonstrated delayed clot formation during hibernation upon activation of the intrinsic coagulation pathway, which is causative of VTE related to vascular stasis. They then evaluated whether changes in coagulation factors themselves or platelets were responsible for this difference and identified that the seasonal differences in clot formation disappear when platelets are inhibited. Platelets isolated from blood in the winter also demonstrated delayed platelet aggregation when stimulated with collagen and low (but not high) doses of thrombin compared with platelets isolated in the summer. The authors characterized differences in the bear platelet proteome during hibernation and activity and identified heat shock protein 47 (HSP47) as the platelet protein with the largest seasonal change, with an impressive 55-fold downregulation in hibernating bears compared with active bears.

To further explore the functional role of HSP47 in VTE, the authors generated mice with loss of HSP47 function in platelets. In platelets with HSP47 loss, both the size and frequency of thromboses as well as other blood products associated with thrombosis decreased compared with those of control mice.

To investigate the relevance of HSP47 in human patients, the authors then tested HSP47 levels in patients with SCI, who display a similar VTE risk to the general population despite immobility. Remarkably, HSP47 levels on platelets were decreased compared with matched controls, whereas the expression of other platelet proteins did not change. The hibernating bear coagulation profile was recapitulated in patients with SCI, suggesting a conservation of HSP47 function across species.

To evaluate dynamic changes in HSP47 downregulation, the authors then analyzed samples from a cohort of 12 healthy individuals who underwent absolute and voluntary bed rest in the –6° Trendelenburg position for 30 days as part of a spaceflight simulation study. There was reduced HSP47 expression after 27 days of bed rest. By comparing this human data set with the hibernating bear data set, a cross-species comparison of proteomic changes induced by immobility identified not only HSP47 but also 3 other proteins (SYK, ASAP1, and ERP44) involved in platelet activation that are downregulated in immobile states.

These findings were further extrapolated to another mammalian model system, lactating pigs, which have limited mobility for 21 to 28 days following birth of their piglets. Indeed, HSP47 expression on platelets was decreased in lactating pigs compared with mobile, indoor pigs.

What does this all mean? This study identifies a new target for VTE prevention. Based on the described findings, the authors conclude that chronic immobilization triggers downregulation of HSP47, which protects against VTE. Further investigation into the timing of HSP47 decrease in different patient populations (besides healthy volunteers) may provide further insight into the possible impact of this pathway during shorter periods of immobility, such as those experienced by some patients postoperatively or during prolonged hospitalizations. This study also did not characterize bleeding risk during times of HSP47 downregulation. However, although acknowledging that further investigation is needed, this interesting study identifies a promising, natural thromboprotective pathway that could be harnessed to improve future VTE prophylaxis.

1. Thienel M, Müller-Reif JB, Zhang Z, et al. Immobility-associated thromboprotection is conserved across mammalian species from bear to human. 

. 2023;380(6641):178-187. doi:10.1126/science.abo5044

"This study identifies a new target for VTE prevention," writes Kate Gessner, MD, PhD, and Philip Abbosh, MD, PhD. 

Investigators identify new target for VTE prevention

 will be starting a new section that focuses more on basic science. This section, Urology in the Lab, will be written by us—Kate Gessner, MD, PhD, and Philip Abbosh, MD, PhD. We are 2 practicing urologists who have significant translational research efforts. Although we are both urologic oncologists, Urology in the Lab will not focus only on basic research in cancer. The goal of this section is to educate urologists on what we think are highly relevant studies whose findings have served or will serve as the basis for transformative urology. The papers on these findings will not necessarily have been published in the immediate past. More likely, we will focus on somewhat older papers (<10 years) that thoroughly tested a relevant hypothesis, changed or affirmed what we think about a certain condition or treatment, or are the basis (or could be the basis) for new treatments, preventive strategies, or diagnostics. Further,highlighted manuscripts may be somewhat peripheral to urology. (Note: We are open to suggestions for articles to highlight.)

Urology in the Lab starts off with data from a study that very strongly implicates Epstein-Barr virus (EBV) as the causative agent underlying multiple sclerosis (MS), a demyelinating disease that often finds its way into the urology clinic due to neurogenic bladder that can develop during the course of disease.

The study, published by Bjornevik et al, is based on a natural longitudinal experiment that occurred over 20 years in participants enlisted in the US military. The military, as part of standard testing, screens all enlistees for HIV using a blood test at the start of their career and every 2 years after that. Leftover serum from these tests is banked and includes more than 62,000,000 samples from more than 10,000,000 military personnel with diverse ethnic backgrounds. Through a collaboration with the military, Bjornevik et al used a serum test for anti-EBV antibodies to detect EBV in these longitudinally collected leftover samples. If MS is caused by EBV, then EBV infection should be detectable prior to symptom onset and diagnosis of MS. Although the EBV-positive rate for adults in the US is 95%, this large sample set provided hundreds of cases and controls to execute a proper study.

Programmed serial sampling permitted the authors to have 3 time points (earliest, last prior to MS diagnosis, and one in between) to test for anti-EBV antibodies. The authors identified 955 cases of MS that developed in the cohort, with 801 having all 3 available time points. Each case was matched to 2 controls with similar demographics who did not develop MS. Eight hundred of the 801 cases had positive EBV serum samples prior to the onset of MS. 35 participants with MS were EBV negative at the time of first serum sample, and 34 of 35 (97%) of these cases seroconverted during the study timeline. In contrast, only 57% of MS-negative cases seroconverted. Based on relative timing of EBV seroconversion and MS symptom onset, the authors estimate that the time from EBV infection to diagnosis of MS was 7.5 years in this cohort.

EBV is transmitted through saliva, similar to other herpes viruses, and therefore may simply be a confounder. To rule out confounding, the authors tested the rate of cytomegalovirus (CMV) seroconversion in case vs control and found similar rates of CMV seroconversion in both cohorts. CMV was an optimal choice for this control comparison because CMV has a similar transmission route (saliva) and infects humans with similar socioeconomic and demographic predilections as EBV. Additionally, CMV-positive cases had lower rates of MS, supporting the hypothesis that CMV infection prior to EBV decreases the negative inflammatory effects of EBV.

Finally, the authors also used an agnostic viral profiling tool in 30 MS cases and 30 non-MS cases and found no other virus whose presence was enriched in cases vs controls.

To further prove their hypothesis, the authors used the same serum samples to measure serum neurofilament light chain (sNFL) levels before and after seroconversion in cases and controls. sNFL is a sensitive marker for neurodegeneration that is known to increase in patients prior to MS clinical onset. sNFL levels were similar in MS and non-MS cases who later seroconverted in samples prior to seroconversion, but were elevated in MS cases after seroconversion but before the diagnosis of MS. Therefore, neural demyelination was occurring after EBV infection but before the formal diagnosis of MS.

The strength of the association between EBV infection and incident MS diagnosis is so strong that there are no other known risk factors that are plausible causes for MS.

What does this mean? The obvious implication (that we offer) is that an EBV vaccine could prevent MS. Because EBV is the causative agent for other diseases such as Burkitt lymphoma and nasopharyngeal carcinoma, the rationale for vaccine development is very strong. Furthermore, this work and previous work supports the idea that EBV not only causes MS, but also continues to affect disease progression. Therefore, in patients with MS, targeting EBV with antivirals could modify the progression of MS and, perhaps, reduce the development of neurogenic bladder.

1. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. 

2022;375(6578):296-301. doi:10.1126/science.abj8222

"This work and previous work supports the idea that EBV not only causes MS, but also continues to affect disease progression," write the authors.

Urology in the Lab: Researchers link EBV to multiple sclerosis

The urinary bladder is a dynamic organ that serves the complex functions of both storing urine and subsequently emptying it in response to neuromuscular signals. To fulfill these functions, the shape and pressure within the bladder change continuously in response to urine filling and emptying dynamics, and these movements affect bladder development and disease. However, many of the existing in vitro models of bladder disease do not mimic this physiologic movement or evaluate its impact on disease development. Additionally, the ability to study how molecular alterations, physiological stimuli, and medications affect bladder compliance is especially reliant on a 3D bladder model mimicking normal bladder movement.

Recognizing the importance of developing a model of the bladder that incorporates a 3D cellular scaffold and physiological movement of the urinary bladder, scientists have worked to develop in vitro models of the urinary bladder utilizing 3D bioprinting.

What is 3D bioprinting? It is an innovative technology that utilizes 3D printing to produce complex structures comprised of biomaterials, cells, and growth factors. Bioink, a hydrogel that can include living cells, is a material used in 3D bioprinting to create a suitable microenvironment for cellular growth. Bioink can consist of single-agent materials (which are components of extracellular matrix such as fibrin, alginate, and collagen) or decellularized extracellular matrix (dECM). The latter has the advantage of containing tissue-specific extracellular matrix components, recapitulating the structure, complexity, and function of that specific tissue or organ, and can be mixed with cells and printed onto a prepared platform to generate in vitro model systems.

Chae et al combined 3D bioprinting with mechanical movements to develop a biomimetic bladder model comprised of 3 essential components: the bladder tissue–derived dECM (bladder dECM) bioink, human bone marrow–derived mesenchymal stem cells, and a contract-release system for physiological stimulation. The bladder dECM is generated through delamination and decellularization of porcine bladder tissue, which is subsequently further processed into a pre-gel solution. The bladder dECM pre-gel solution is mixed with human bone marrow–derived mesenchymal stem cells and printed onto a sterilized polydimethylsiloxane (PDMS) membrane located within a custom integrated housing platform. This housing platform consists of a baseplate (bottom chamber) and a wall template. To mimic the physiologic movement of the bladder, Chae et al developed a contract-release system, which consists of a programmable syringe pump and syringe attached to the baseplate of the housing platform. When air is injected into the baseplate, the PDMS membrane and attached cells expand, while the removal of air returns the model to baseline position. For membranes testing physiological movement of the bladder, cyclical stretching was performed for 16 hours daily with 8 hours of daily rest.

Following generation of this in vitro bladder model, Chae et al evaluated its cellular ability to maintain viability, proliferate, and form organized muscle fibers. They first assessed cell viability and found that more than 90% of cells were viable over all time points across 10 days. Cell adhesion testing using F-actin staining demonstrated interconnected networks within the bladder dECM matrix. Finally, compared with a collagen-based, single-component bioink, the bladder dECM bioink showed increased cell proliferation (which was perceived to be a positive characteristic). These results overall demonstrate that the bladder dECM bioink provides a conducive environment in which mesenchymal stem cells can establish, proliferate, and form interconnected networks.

To test their hypothesis that mechanical stimulation improves stem cell differentiation into bladder smooth muscle lineage, Chae et al evaluated the impact of physiological stimuli on muscle formation in the in vitro model. Specifically, they measured cellular expression of markers for muscle tissue in tissue models that underwent cyclical stretching (mimicking regular bladder movement) compared with models that did not experience movement. Cells that experienced periodic movement expressed significantly higher levels of muscle lineage markers compared with those without movement and were longitudinally aligned along the axis of movement. This result highlights the role that external stimuli play on stem cell differentiation into the muscle lineage and reinforces the importance of incorporating physiological stimuli into models of the urinary bladder.

What does this all mean? The development of an in vitro bladder model incorporating mechanical stimuli provides a useful model for testing both bladder development and disease. For example, this model could be used to interrogate how altered physiologic bladder movements or specific gene alterations affect cellular organization or viability in the urinary bladder. There are some shortcomings to the model that could be addressed in future iterations. The lamina propria and urothelium are absent from this model and likely share bidirectional intercellular communication signals with the muscular layers of the bladder. Further, the tissue was expanded using compressed air rather than fluid and was stretched by 5% every 10 seconds. In organisms that use a bladder, it is expanded/contracted with liquid urine to a much higher volumetric fold change and occurs over a more protracted time course. However, this is only a very simplified, first-pass model and did recapitulate several key features of the bladder.

In addition to the advances in research studying bladder diseases, the use of 3D bioprinting will continue to revolutionize the scientific and medical fields. This exciting and innovative technology has a wide range of possible applications, including tissue engineering, drug development, and precision medicine.

Chae S, Kim J, Yi HG, Cho DW. 3D bioprinting of an in vitro model of a biomimetic urinary bladder with a contract-release system. 

"This exciting and innovative technology has a wide range of possible applications, including tissue engineering, drug development, and precision medicine," write Kate Gessner, MD, PhD, and Philip Abbosh, MD, PhD.

3D bioprinting technology facilitates development of an in vitro biomimetic bladder model

, highlights the importance of integrating mental health support into routine care for patients with bladder cancer. This was discussed during a session at the 2024 Bladder Cancer Advocacy Network (BCAN) Think Tank titled, “Navigating the Emotional Landscape: Addressing Mental Health Challenges in Bladder Cancer Survivorship.” Dunn is a urologic nurse practitioner at the University of North Carolina in Chapel Hill.

This transcription has been edited for clarity.

Could you highlight some of the key takeaways from your session at this year’s BCAN Think Tank?

I was joined by my co-chair, Krisztina Emodi, FNP, MPH, CNS, who is a nurse practitioner at the University of California, San Francisco, as well as by Dr. Nihal Mohamed and Dr. Deane Wolcott. We had this wonderful, robust discussion about the often overlooked mental health challenges in patients with bladder cancer. We found [that] some [of the] key takeaways actually came from different parts of the audience. For example, for patients and caregivers, some folks noted that they were never asked about their emotional or mental health needs. They had no idea how to bring it up with their cancer team, or they weren't sure of resources that were available for them to address it. They also expressed some fear about bringing up their fears due to perceived stigma around mental health.

From the health care provider side of the audience, some key takeaways were barriers. We're constantly talking about barriers to care in all aspects that we do, but in particular for mental health [these include] lack of time during visits to bring up this important topic and lack of training to address mental health needs, so not feeling well equipped or properly trained to even ask questions about mental health. Then on the back end of that, [there are some challenges with] asking questions and then not knowing what to do with the information that's given, not having access to resources at their own institutions, or, if there are resources at their institutions, not knowing the right pathway to get patients what they need and to the right people. So, those were the were some big takeaways from our session.

What are some of the common emotional and psychological challenges faced by bladder cancer survivors?

I think that you and I could probably talk about this for an hour. In fact, I had a meeting earlier that talked about this for an hour, but there are some common themes. [For starters], there are some physical aspects that play a role in the mental aspects. For example, include living with long-term side effects from treatment, such as intravesical therapy, surgery, chemotherapy, immunotherapy, and pain management, whether that's post-surgical or due to pain from their actual cancer. Changes in body image are also a physical change that can play a huge part in people's mental well-being. Sexual dysfunction [is another] as well.

There are also some emotional components, such as uncertainty and fear of recurrence. We've talked a lot about grief. Grief, in and of itself, is quite complicated. Folks talk about tangible things that they grieve, like the loss of their bladder or the loss of their hair or loss of urinary control after they get medicine into their bladder, for example. Then [there are] these intangible things that people grieve, like for a future that wasn't what they thought it was going to be. So, grief is a very complex one.

Then other [challenges include things] like changes in relationships, whether that's relationships with their partners, their family, or their co-workers. There can be trauma associated with all of this, which is another very complicated and complex topic and can encompass lots of feelings like sadness, depression, or anxiety. We know that everyone experiences cancer and cancer treatment in their own unique way. So, of course, not all of these things apply to any 1 person. We know that patients with bladder cancer at any stage have unique emotional and psychological needs due to the nature of their treatment, [such as] feeling isolated or not knowing anyone else who has bladder cancer, amongst others. So, it’s all pretty complicated.

How can urologists and APPs integrate mental health support into their routine care of bladder cancer survivors?

We know that addressing mental health concerns is an important but often overlooked part of cancer care, not just in bladder cancer, but in cancer care in general. There is no one to blame for this; no one's at fault. With all the complexities and barriers that are tied to cancer care, it really is nearly impossible to address every single need at every single visit. However, I think we're moving toward a shift in incorporating mental health assessment kind of as a vital sign, like we did with pain years ago. Just like how now we ask everyone about their pain number, I think we're seeing a shift in incorporating talking to folks about their emotional well-being into regular standard of care. That's because there's a lot more research in this arena, but also because patients have become more vocal about it too.

So, how can we as providers do a better job? I think how that looks will vary widely depending on each individual institution and practice. Do we use existing screening tools? There are several out there. If we're using those screening tools, when do those get done? Who gets the results? What do we do with the results? All of [those are] the major challenges to this part of patient care.

What I hear from patients of my own and also folks who are involved in a survivorship task force with me is that they want their cancer providers to ask them how they're doing emotionally, whether that's the urologist, the APP, the medical oncology team, whomever, even if that cancer provider isn't the one who's an expert in that domain. When we ask patients the question, it makes them feel heard, and it can lead down a path to getting them additional support from a multidisciplinary team such as social workers, therapists, psychiatrists, and psychologists. I do think it's important for all of us to have a basic understanding of how to help people manage mental health concerns, even if that's simply listening and being able to identify a pathway in our clinics to connecting people with mental health providers.

I also think there should be clear pathways in place if patients come in for a visit and are in significant distress, so that those of us who aren't psych experts can get patients acute help if needed. I don't think that that necessarily has to fall on the urologist or the APP. I think that aspect––creating that pathway––should be multidisciplinary, including clinic leadership and nursing leadership.

Also, I feel that it is important to recognize what we don't know. I tell my patients all the time, “I will be your expert in managing your cancer, but I'm not an expert in mental health.” But sometimes patients are reluctant to add someone else to their team; they're already seeing a lot of folks. But I find that they tend to be more accepting when I offer reassurance that while I am their cancer care expert, our partners in our psychiatry department are the experts in managing their mental health, and we'll work together to help coordinate all of this. It makes them feel like it's not just 1 more person they have to see, or that they're being abandoned by their cancer team just to have 1 other person help them. The words that we use as their cancer team matter. I think simply acknowledging what their concerns are, listening, and having pathways in place can make a huge difference. I know this all sounds like it could be very easily done overnight, but there are a lot of barriers. However, I really think we're getting where we need to be in making this more of a priority for folks.

In your BCAN session, you brought up this idea of "scanxiety," which is a term used to describe the anxiety related to diagnostic scans and screenings. How can urology professionals better support patients in managing this specific type of anxiety?

This is a very specific type of anxiety. I think that one of the main things that we can do is acknowledge it and warn people about it, for lack of a better way of putting it. It's normal for people to have some worry leading up to these things, specifically scans or cystoscopy or things like that. Patients have described that when there are gaps in between their visits and gaps in between scans, they have increased worry. We would want to know if people were worrying all the time, though. So, [if they're] thinking about that next scan 3 months from when that scan is coming up, or ruminating about it every single day, such that it's interfering with their ability to enjoy their day to day life, that [is what] we would absolutely want to know about.

A lot of times, what I hear about scanxiety is that they've been okay, and then a few days before their scan and their visit comes up, it starts in their head, [thinking] "oh, gosh, what if my scan is bad? What if I get bad news? What if my cancer is back?" So, as their urology providers, giving folks basic coping skills for how to plan ahead for those pre-scan days or pre-cystoscopy days can be a useful tool. We know that focusing on breathing and things like journaling and gratitude practice can help with mindfulness, which can, in turn, help with some of those anxious feelings that people experience.

Are there any recent innovations or emerging practices in survivorship care that show promise in enhancing mental health support for bladder cancer survivors?

I think the biggest promising thing is that we're having discussions about this. I know there's a lot of folks working behind the scenes on stuff that I am probably not aware of, but what I am intimately familiar with is the work that the Bladder Cancer Advocacy Network is doing to bring survivorship issues front and center. That includes mental health and emotional well-being. There is a survivorship task force that was formed a couple years ago after another breakout session at the 2022 Think Tank. I'm honored to be a part of that group, and we meet frequently to talk about specific survivorship needs. [We're] currently working on developing some resources for mental health and the emotional well-being aspect of cancer care for patients with a bladder cancer diagnosis. I think the fact that we're having these conversations, that they are being talked about at national meetings, and that we are bringing the patient voice into this is hugely important.

There are institutions who are leading the way for showing us how to effectively and efficiently integrate distress screening into clinic visits, so that we have the proper tools to use and understand who is going to assess that information and what to do with it. Having those pathways in place that we can adopt from other institutions will only benefit our patients. We're recognizing mental health is as equally as important as physical health. Providing documents to patients like survivorship care plans, which have a basic outline of what their treatment history was, their diagnosis, what their follow-up care plan should look like, and also resources for emotional and mental health [is helpful]. We're taking a lot of steps in the right direction so that we can continue to improve on this crucial aspect of patient care.

Is there anything else that you’d like to add?

There are 2 unique groups of people that sometimes get overlooked when we're thinking about the emotional and psychological aspect of patient care, and 1 group is caregivers. They have their own unique needs. I know sometimes it can be tricky from our side of the street as the professionals, since that person's not our patient, but they're such an integral part of our patients’ well-being. How do we make sure they're okay, too? I think having resources at institutions that are specifically tailored for the unique needs of caregivers is critical.

The other group of people who I think sometimes often get overlooked are patients who are living with advanced or metastatic disease. Historically, when we talk about cancer survivorship, we talk about patients who are being treated with the intent for cure, and not talking about people who are living with metastatic disease, which is oftentimes incurable in nature. These people are living longer because we have more medications to offer them for treatment, but we haven't often included their voice in what it means to be a survivor. It's important to point out that living with cancer is still surviving, and oftentimes thriving as well. Being mindful of the unique needs of caregivers and also patients living with advanced disease is something that we should we should focus on as well.

"I think the fact that we're having these conversations, that they are being talked about at national meetings, and that we are bringing the patient voice into this is hugely important," says Mary W. Dunn, MSN, NP-C, OCN, RN. 

Jeffrey M. Holzbeierlein, MD

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