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BACKGROUND: Cerebral vascular malformations (CCMs) are primarily found within the brain, where they result in increased risk for stroke, seizures, and focal neurological deficits. The unique feature of the brain vasculature is the blood-brain barrier formed by the brain neurovascular unit. Recent studies suggest that loss of CCM genes causes disruptions of blood-brain barrier integrity as the inciting events for CCM development. CCM lesions are proposed to be initially derived from a single clonal expansion of a subset of angiogenic venous capillary endothelial cells (ECs) and respective resident endothelial progenitor cells (EPCs). However, the critical signaling events in the subclass of brain ECs/EPCs for CCM lesion initiation and progression are unclear. METHODS: Brain EC-specific CCM3-deficient (Pdcd10BECKO) mice were generated by crossing Pdcd10fl/fl mice with Mfsd2a-CreERT2 mice. Single-cell RNA-sequencing analyses were performed by the chromium single-cell platform (10× genomics). Cell clusters were annotated into EC subtypes based on visual inspection and GO analyses. Cerebral vessels were visualized by 2-photon in vivo imaging and tissue immunofluorescence analyses. Regulation of mTOR (mechanistic target of rapamycin) signaling by CCM3 and Cav1 (caveolin-1) was performed by cell biology and biochemical approaches. RESULTS: Single-cell RNA-sequencing analyses from P10 Pdcd10BECKO mice harboring visible CCM lesions identified upregulated CCM lesion signature and mitotic EC clusters but decreased blood-brain barrier-associated EC clusters. However, a unique EPC cluster with high expression levels of stem cell markers enriched with mTOR signaling was identified from early stages of the P6 Pdcd10BECKO brain. Indeed, mTOR signaling was upregulated in both mouse and human CCM lesions. Genetic deficiency of Raptor (regulatory-associated protein of mTOR), but not of Rictor (rapamycin-insensitive companion of mTOR), prevented CCM lesion formation in the Pdcd10BECKO model. Importantly, the mTORC1 (mTOR complex 1) pharmacological inhibitor rapamycin suppressed EPC proliferation and ameliorated CCM pathogenesis in Pdcd10BECKO mice. Mechanistic studies suggested that Cav1/caveolae increased in CCM3-depleted EPC-mediated intracellular trafficking and complex formation of the mTORC1 signaling proteins. CONCLUSIONS: CCM3 is critical for maintaining blood-brain barrier integrity and CCM3 loss-induced mTORC1 signaling in brain EPCs initiates and facilitates CCM pathogenesis.

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Purpose: Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC. Materials and Methods: The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy. Results: The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC. Conclusions: CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.

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Background: Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature. Materials and Methods: The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators. Results: This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies. Conclusions: The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.

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PURPOSE OF REVIEW: The most common definitive treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy. However, removing the bladder and surrounding organs poses risks of morbidity that can reduce quality of life, and raises the risk of death. Treatment strategies that preserve the organs can manage the local tumor and mitigate the risk of distant metastasis. Recent data have demonstrated promising outcomes in several bladder-preservation strategies. RECENT FINDINGS: Bladder preservation with trimodality therapy (TMT), combining maximal transurethral resection of the bladder tumor, chemotherapy, and radiotherapy (RT), was often reserved for nonsurgical candidates for radical cystectomy. Recent meta-analyses show that outcomes of TMT and radical cystectomy are similar. More recent bladder-preservation approaches include combining targeted RT (MRI) and immune checkpoint inhibitors (ICIs), ICIs and chemotherapy, and selecting patients based on genomic biomarkers and clinical response to systemic therapies. These are all promising strategies that may circumvent the need for radical cystectomy. SUMMARY: MIBC is an aggressive disease with a high rate of systemic progression. Current management includes neoadjuvant cisplatin-based chemotherapy and radical cystectomy with lymph node dissection. Novel alternative strategies, including TMT approaches, combinations with RT, chemotherapy, and/or ICIs, and genomic biomarkers, are in development to further advance bladder-preservation options for patients with MIBC.

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OBJECTIVE: UGN-101 has been approved for the chemoablation of low-grade upper tract urothelial cancer (UTUC) involving the renal pelvis and calyces. Herein is the first reported cohort of patients with ureteral tumors treated with UGN-101. PATIENTS AND METHODS: We performed a retrospective review of patients treated with UGN-101 for UTUC at 15 high-volume academic and community centers focusing on outcomes of patients treated for ureteral disease. Patients received UGN-101 with either adjuvant or chemo-ablative intent. Response rates are reported for patients receiving chemo-ablative intent. Adverse outcomes were characterized with a focus on the rate of ureteral stenosis. RESULTS: In a cohort of 132 patients and 136 renal units, 47 cases had tumor involvement of the ureter, with 12 cases of ureteral tumor only (8.8%) and 35 cases of ureteral plus renal pelvic tumors (25.7%). Of the 23 patients with ureteral involvement who received UGN-101 induction with chemo-ablative intent, the complete response was 47.8%, which did not differ significantly from outcomes in patients without ureteral involvement. Fourteen patients (37.8%) with ureteral tumors had significant ureteral stenosis at first post-treatment evaluation, however, when excluding those with pre-existing hydronephrosis or ureteral stenosis, only 5.4% of patients developed new clinically significant stenosis. CONCLUSIONS: UGN-101 appears to be safe and may have similar efficacy in treating low-grade urothelial carcinoma of the ureter as compared to renal pelvic tumors.

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Localized upper tract urothelial carcinoma (UTUC) is a difficult disease for clinicians to treat, due to the multitude of oncological and patient factors to consider. Despite the challenges of diagnostic staging, endoscopic management, and disease recurrence, there is still a need for local therapeutic options that do not subject patients to the morbidities of radical nephroureterectomy (RNU). Intraluminal chemotherapies have allowed for improved oncological control in patients with low-grade disease receiving renal-sparing treatment approaches. This narrative review discusses the treatment modalities available for localized low-grade UTUC, with a focus on the current status of chemoablation. The OLYMPUS trial was a pivotal study that lead to the Food and Drug Administration (FDA) approval of UGN-101 (mitomycin-C) in April 2020 for the treatment of low-grade UTUC, and intraluminal chemotherapy is now a widely used modality for managing this disease. The trial reported a complete response (CR) rate of 59%, and an estimated treatment durability of 82% at 1 year. However, a concern was the reported 44% ureteral stricture rate using the retrograde approach. More research is currently underway to determine the ideal instillation method for intraluminal therapies (e.g., retrograde vs. antegrade). Lastly, we discuss upcoming treatment options. Newer novel agents like padeliporfin vascular targeted photodynamic (VTP) therapy (brand name TOOKAD) are currently being studied, which will in hope provide additional treatment options for UTUC patients.

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PURPOSE: Ureteroscopy is a commonly performed procedure, with postoperative pain that can lead to revisits and opioid prescribing. Perioperative gabapentinoids have shown promise in decreasing pain and opioid use. We hypothesized that single-dose perioperative pregabalin would be safe and efficacious for decreasing pain after ureteroscopy. MATERIALS AND METHODS: This was an Institutional Review Board-approved and registered blinded, placebo-controlled trial conducted at a single institution. Patients undergoing ureteroscopy without histories that would limit use of opioids, gabapentinoids, and nonsteroidal medications were enrolled. Either 300 mg pregabalin or placebo was administered 1 hour before ureteroscopy. Pain was assessed using a visual analogue scale before administration and 1 hour after surgery. Clinical factors, pain scores, a proxy for cognition, patient satisfaction, and opioid prescribing were assessed in the first 30 postoperative days. RESULTS: A total of 118 patients were enrolled over a 2-year period. Patients who received pregabalin were younger than those who received placebo (median of 44 years vs 57). Postoperative pain scores were higher in those who received pregabalin (3.7 vs 2.0, P = .004), a finding that remained statistically significant when accounting for patient age and preoperative pain scores. There was no difference in the measure of cognition or in reports of adverse events. CONCLUSIONS: In this trial evaluating the efficacy of single-dose perioperative pregabalin in ureteroscopy, pregabalin did not decrease postoperative pain when compared to placebo. Urologists should not routinely use this adjunctive medication in ureteroscopy, as it is unlikely to provide benefit.

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BACKGROUND: UGN-101 can be used for chemoablation of low-grade upper tract urothelial carcinoma (UTUC). The gel can be administered via a retrograde route through a ureteral catheter or an antegrade route via a nephrostomy tube. OBJECTIVE: To report outcomes of UGN-101 by route of administration. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective review of 132 patients from 15 institutions who were treated with UGN-101 for low-grade UTUC via retrograde versus antegrade administration. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Survival outcomes are reported per patient. Treatment, complications, and recurrence outcomes are reported per renal unit. Statistical analysis was performed for primary endpoints of oncological response and ureteral stricture occurrence. RESULTS AND LIMITATIONS: A total of 136 renal units were evaluated, comprising 78 retrograde and 58 antegrade instillations. Median follow-up was 7.4 mo. There were 120 cases (91%) of biopsy-proven low-grade UTUC. Tumors were in the renal pelvis alone in 89 cases (65%), in the ureter alone in 12 cases (9%), and in both in 35 cases (26%). Seventy-six patients (56%) had residual disease before UGN-101 treatment. Chemoablation with UGN-101 was used in 50/78 (64%) retrograde cases and 26/58 (45%) antegrade cases. A complete response according to inspection and cytology was achieved in 31 (48%) retrograde and 30 (60%) antegrade renal units (p = 0.1). Clavien grade 3 ureteral stricture occurred in 21 retrograde cases (32%) and only six (12%) antegrade cases (p < 0.01). Limitations include treatment bias, as patients in the antegrade group were more likely to undergo endoscopic mechanical ablation before UGN-101 instillation. CONCLUSIONS: These preliminary results show a significantly lower rate of stricture occurrence with antegrade administration of UGN-101, with no apparent impact on oncological efficacy. PATIENT SUMMARY: We compared results for two different delivery routes for the drug UGN-101 for treatment of cancer in the upper urinary tract. For the antegrade route, a tube is inserted through the skin into the kidney. For the retrograde route, a catheter is inserted past the bladder into the upper urinary tract. Our results show a lower rate of narrowing of the ureter (the tube draining urine from the kidney into the bladder) using the antegrade route, with no difference in cancer control.

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PURPOSE: Assess the real-world ablative effect of mitomycin reverse thermal gel for low-grade upper tract urothelial carcinoma (UTUC) in patients who undergo biopsy only or partial ablation and evaluate utility of complete ablation prior to UGN-101. MATERIAL AND METHODS: We retrospectively reviewed low-grade UTUC patients treated with UGN-101 from 15 high-volume centers. Patients were categorized based on initial endoscopic ablation (biopsy only, partial ablation, or complete ablation) and by size of remaining tumor (complete ablation, <1cm, 1-3cm, or >3cm) prior to UGN-101. The primary outcome was rendered disease free (RDF) rate at first post-UGN-101 ureteroscopy (URS), defined as complete response or partial response with minimal mechanical ablation to endoscopically clear the upper tract of visible disease. RESULTS: One hundred and sixteen patients were included for analysis after excluding those with high-grade disease. At first post-UGN-101 URS, there were no differences in RDF rates between those who at initial URS (pre-UGN-101) had complete ablation (RDF 77.0%), partial ablation (RDF 55.9%) or biopsy only (RDF 66.7%) (P = 0.14). Similarly, a complimentary analysis focusing on tumor size (completely ablated, <1cm, 1-3cm or >3cm) prior to UGN-101 induction did not demonstrate significant differences in RDF rates (P = 0.17). CONCLUSION: The results of the early real-world experience suggest that UGN-101 may play a role in initial chemo-ablative cytoreduction of larger volume low-grade tumors that may not initially appear to be amenable to renal preservation. Further studies will help to better quantify the chemo-ablative effect and to identify clinical factors for patient selection.

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BACKGROUND: Intracavitary UGN-101 is approved for the treatment of low-grade noninvasive upper tract urothelial carcinoma (UTUC). Post-commercialization studies underscore the benefit of UGN-101 administration for patients with imperative indications for whom radical nephroureterectomy (RNU) is not a viable option. OBJECTIVE: To describe the use, efficacy, and safety of UGN-101 in patients with UTUC with imperative indications for renal preservation, including high-grade disease. DESIGN, SETTING, AND PARTICIPANTS: Patients receiving UGN-101 with imperative indications were retrospectively analyzed using a multicenter centralized registry from 15 high-volume academic and community centers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We defined imperative indications as patients with a solitary kidney, the presence of chronic kidney disease (CKD) with a glomerular filtration rate <30 ml/min, bilateral UTUC, and patients unfit for or unwilling to undergo surgical extirpation. Tumor characteristics, disease progression/recurrence, and adverse events were recorded on a per-renal-unit basis. RESULTS AND LIMITATIONS: UGN-101 was instilled into 52 renal units (38%) in 48 patients for imperative indications, including 29 patients (56%) with a solitary kidney, 11 kidneys (21%) in the setting of bilateral UTUC, six patients (12%) with CKD, and six patients (12%) who were unfit for or unwilling to undergo RNU. Twelve renal units had biopsy-proven high-grade papillary disease. Tumors were completely ablated before induction therapy in 34% of cases, while 66% had tumor present. Following induction therapy, 17 patients (40%) had no evidence of disease (NED) on ureteroscopy, 88% of whom maintained this status at median follow-up of 10.8 mo. In the cohort with high-grade disease, five patients (45%) had NED at initial post-induction primary disease evaluation. Adverse events included pyelonephritis (8%), ureteral stenosis (8%), anemia (6%), and acute renal failure (4%). Limitations include the retrospective study design, the lack of long-term follow up, and patient selection bias. CONCLUSIONS: Intracavitary therapy with UGN-101 in patients with UTUC and imperative indications shows promise as a kidney-sparing treatment modality. While long-term follow-up is needed, this intracavitary treatment may help in prolonging time to RNU and delaying the morbidity of hemodialysis in this comorbid population. PATIENT SUMMARY: We reviewed results for patients with cancer in the upper urinary tract and an additional condition that would not allow kidney removal who received treatment with a gel called UGN-101. Our results suggest that UGN-101 shows promise as a kidney-sparing treatment. It may delay the time until kidney removal is needed in these patients and avoid the negative effects associated with dialysis.

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OBJECTIVE: To evaluate variability among hospitals in susceptibility of common uropathogens to antimicrobial agents frequently used in transurethral procedures in order to examine whether state-based guidelines might be more appropriate than national prophylactic guidelines. METHODS: Hospital-level antibiograms were requested from all hospitals throughout the state of Missouri. We studied Escherichia coli, Klebsiella, and Proteus sensitivities to evaluate common guideline recommended antimicrobials including trimethoprim sulfamethoxazole (TMP-SMX), third-generation cephalosporins, cefazolin, penicillin combinations, gentamicin, and fluoroquinolones. We evaluated variability and association between hospital characteristics and antimicrobial sensitivities. RESULTS: Data was requested from 81 hospitals across the state and 38 provided the requested data (47% response rate). Susceptibility was highest for third-generation cephalosporins for E. coli (mean of 94%), Proteus (96%), and Klebsiella (96%). Gentamicin also had high susceptibility for the bacteria studied; 94% for E. coli and 96% for Klebsiella. Current first line recommended agents showed more modest coverage for E. coli (cefazolin 84%, TMP-SMX 78%), Proteus (cefazolin 82%, TMP-SMX 71%), and Klebsiella (cefazolin 90%, TMP-SMX 89%). CONCLUSION: Post transurethral procedure infections are common. Rates can be limited with appropriate prophylaxis. Deciding on empirical coverage must take into account local resistance patterns. There is substantial variability among and within states in antimicrobial susceptibility for common uropathogens. When selecting antimicrobial prophylaxis, urologists should consider local- rather than state- or nation-level antibiograms, given the considerable variability. Future studies should consider the merits of very-broad spectrum prophylaxis and the potential role of molecular urinary pathogen (and pathogen-resistance) testing when selecting an optimal regimen.

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Trauma-informed care has become a pillar of competent psychological services. A foundation in understanding trauma and its treatment should be viewed as essential for clinical psychologists entering the field, as working with individuals that have experienced trauma is inevitable. OBJECTIVE: The objective of this study was to evaluate the number of accredited doctoral programs in clinical psychology that require a course in trauma-informed theory and intervention in their curriculum. METHOD: Clinical psychology programs accredited by the American Psychological Association were surveyed to determine their requirement for a course related to trauma-informed care. Program information was initially reviewed online and in the absence of clear indication within their program websites, survey questions were sent to the program Chair and/or Directors of Clinical Training. RESULTS: Data were obtained from 193 of the 254 APA-accredited programs included in this survey process. Only nine (5%) require a course related to trauma-informed care. Of these, five were PhD programs and four were PsyD programs. This equates to 202 (8%) of graduating doctoral students having been required to take a course related to trauma-informed care. CONCLUSIONS: Trauma exposure is common and a major factor to be considered in the development of psychological disorders and overall physical and emotional wellbeing. As a result, clinical psychologists should enter the field with a foundation in understanding the impact and treatment of trauma exposure. However, only a minority of graduating doctoral students have been required to take a course related to this topic in their graduate curriculum. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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OBJECTIVE: To determine if clustering methods can use a holistic assessment of health-related quality-of-life after bladder cancer diagnosis to predict survival outcomes independent of clinical characteristics. In the United States, an estimated 81,180 cases of bladder cancer will be diagnosed in 2022. We aim to help address the knowledge gap concerning the impact of patient functional status on outcomes. MATERIALS AND METHODS: This is a cross-sectional, retrospective cohort study of patients in the End Results-Medicare Health Outcomes Survey Registry. Age and 36-Item Short Form Survey (SF-36) responses were used as K-means inputs to identify homogenous clusters of older patients with bladder cancer. We analyzed the association between the identified clusters, patient and disease characteristics, and outcomes. We used Cox proportional hazard regression to compare overall survival. RESULTS: We identified 5 homogenous clusters that exhibited differences in patient characteristics and survival. There was no significant difference in cancer stage or surgery type among the clusters. The Cox proportional hazard regression demonstrated significant associations of cluster with gender, age, education, marital status, smoking status, type of surgery, and cancer stage on overall survival. Cluster independently predicted overall survival. CONCLUSION: Using unsupervised machine learning, we identified clusters of patients with bladder cancer who had similar mental and physical function scores. Cluster grouping suggests that patients' mental and physical function may not be based on disease or treatment. There are significant survival differences between all clusters, demonstrating that a holistic assessment of patient-reported health-related quality-of-life has the potential to predict survival and possible modifiable risk factors in older patients with bladder cancer.

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PURPOSE: We describe a novel application of the reverse thermal polymer gel of mitomycin C (UGN-101) as adjuvant therapy after complete endoscopic ablation of upper tract urothelial carcinoma. MATERIALS AND METHODS: We retrospectively reviewed patients treated with UGN-101 from 15 high-volume centers. Adjuvant therapy was defined as treatment administered following visually complete endoscopic ablation. Response at primary endoscopic evaluation was defined as no visual tumor or negative biopsy. Ipsilateral disease-free and progression-free survival were estimated by the Kaplan-Meier method. Ureteral stenosis and other adverse events were abstracted from the medical records. Ureteral stenosis was defined as a condition requiring ureteral stent or nephrostomy, or that would typically warrant stent or nephrostomy. RESULTS: Adjuvant UGN-101 after complete endoscopic ablation was used in 52 of 115 (45%) renal units in the oncologic analysis. At first endoscopic evaluation, 36/52 (69%) were without visible disease. At 6.8 months' median follow-up, the ipsilateral disease-free rate was 63%. Recurrence after adjuvant UGN-101 therapy was more likely in multifocal tumors compared to unifocal (HR 3.3, 95% CI 1.07-9.91). Compared with UGN-101 treatment for chemoablation of measurable disease, there were significantly fewer disease detections with adjuvant therapy (P < .001). Ureteral stenosis after UGN-101 was diagnosed in 10 patients (19%) undergoing adjuvant therapy compared to 17 (29%) undergoing chemoablative therapy (P = .28). CONCLUSIONS: In patients being considered for UGN-101, maximal endoscopic ablation prior to UGN-101 treatment may result in fewer patients with disease at first endoscopy and possibly fewer adverse events than primary chemoablative therapy. Longer follow-up is needed to determine if UGN-101 after complete endoscopic ablation will lead to durable disease-free interval.

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