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This article presents an overview of the pathophysiology of varicoceles and discusses indications for treatment, two primary repair techniques, and treatment outcomes.

Varicocele: Treatment indications and repair techniques

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

A 35-year-old male from Sudan was hospitalized with a right obstructing 1-cm ureteral stone seen on KUB. The KUB also revealed curvilinear calcification in the bladder wall. The patient was taken to the operating room for ureteroscopy and laser lithotripsy.

During cystoscopy, a rim of calcification was seen along the right ureteric ridge (figure 1a). A biopsy of this area was taken with the pathology shown in figure 1b.

B. Squamous cell carcinoma of the bladder

A 35-year-old male from Sudan presented with a 1-cm obstructing ureteral stone and curvilinear calcification in the bladder wall, as seen on KUB imaging. The patient underwent ureteroscopy and laser lithotripsy. During cystoscopy, calcification was observed along the right ureteric ridge. A biopsy was performed on this area to further investigate the pathology. The findings from the biopsy are crucial for understanding the underlying condition contributing to the calcification and obstruction, which may have implications for the patient's treatment and management.

A 35-year-old male from Sudan was hospitalized with a right obstructing 1-cm ureteral stone seen on KUB. The KUB also revealed curvilinear calcification in the bladder wall. The patient was taken to the operating room for ureteroscopy and laser lithotripsy. During cystoscopy, a rim of calcification was seen along the right ureteric ridge. What is the diagnosis?

Residents Corner

Quiz: Sandy patch on cystoscopy

Managing Overactive Bladder: From Dual Diagnoses to Geriatric Challenges

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Panelists discuss how managing overactive bladder in older adults requires a holistic approach that integrates treatment of comorbidities, emerging therapeutic options, and quality-of-life considerations to optimize patient outcomes.

Video Series

Episode 2 Video: Managing Overactive Bladder: From Dual Diagnoses to Geriatric Challenges

Experts discuss overactive bladder and the impacts on quality of life, distinguishing OAB from BPH, and how a delayed diagnosis can worsen symptoms.  

Episode 1 Video: Understanding Overactive Bladder (OAB): Pathophysiology, Diagnosis, and Management In Older Adults

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. 

Thomas A. Masterson, MD

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