Structures of TGF-ß with betaglycan and the signaling receptors reveal the mechanism whereby betaglycan potentiates receptor complex assembly and signaling.

Betaglycan (BG) is a transmembrane co-receptor of the transforming growth factor-ß (TGF-ß) family of signaling ligands. It is essential for embryonic development and tissue homeostasis and fertility in adults. It functions by enabling binding of the three TGF-ß isoforms to their signaling receptors and is additionally required for inhibin A (InhA) activity. Despite its requirement for the functions of TGF-ßs and InhA in vivo, structural information explaining BG ligand selectivity and its mechanism of action is lacking. Here, we determine the structure of TGF-ß bound both to BG and the signaling receptors, TGFBR1 and TGFBR2. We identify key regions responsible for ligand engagement, which has revealed novel binding interfaces that differ from those described for the closely related co-receptor of the TGF-ß family, endoglin, thus demonstrating remarkable evolutionary adaptation to enable ligand selectivity. Finally, we provide a structural explanation for the hand-off mechanism underlying TGF-ß signal potentiation.

Mismatch repair deficiency and microsatellite instability in urothelial carcinoma: a systematic review and meta-analysis.

Background: Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) occur in a subset of cancers and have been shown to confer sensitivity to immune checkpoint inhibition (ICI); however, there is a lack of prospective data in urothelial carcinoma (UC). Methods and analysis: We performed a systematic review to estimate the prevalence of dMMR and MSI-H in UC, including survival and clinical outcomes. We searched for studies published up to 26 October 2022 in major scientific databases. We screened 1745 studies and included 110. Meta-analyses were performed if the extracted data were suitable. Results: The pooled weighted prevalences of dMMR in bladder cancer (BC) and upper tract UC (UTUC) were 2.30% (95% CI 1.12% to 4.65%) and 8.95% (95% CI 6.81% to 11.67%), respectively. The pooled weighted prevalences of MSI-H in BC and UTUC were 2.11% (95% CI 0.82% to 5.31%) and 8.36% (95% CI 5.50% to 12.53%), respectively. Comparing localised versus metastatic disease, the pooled weighted prevalences for MSI-H in BC were 5.26% (95% CI 0.86% to 26.12%) and 0.86% (95% CI 0.59% to 1.25%), respectively; and in UTUC, they were 18.04% (95% CI 13.36% to 23.91%) and 4.96% (95% CI 2.72% to 8.86%), respectively. Cumulatively, the response rate in dMMR/MSI-H metastatic UC treated with an ICI was 22/34 (64.7%) compared with 1/9 (11.1%) with chemotherapy. Conclusion: Both dMMR and MSI-H occur more frequently in UTUC than in BC. In UC, MSI-H occurs more frequently in localised disease than in metastatic disease. These biomarkers may predict sensitivity to ICI in metastatic UC and resistance to cisplatin-based chemotherapy.

Comparative study of immune response to local tumor destruction modalities in a murine breast cancer model.

Introduction: Immunotherapy is revolutionizing the management of multiple cancer types. However, only a subset of patients responds to immunotherapy. One mechanism of resistance is the absence of immune infiltrates within the tumor. In situ vaccine with local means of tumor destruction that can induce immunogenic cell death have been shown to enhance tumor T cell infiltration and increase efficacy of immune checkpoint blockade. Methods: Here, we compare three different forms of localize tumor destruction therapies: radiation therapy (RT), vascular targeted photodynamic therapy (VTP) and cryoablation (Cryo), which are known to induce immunogenic cell death, with their ability to induce local and systemic immune responses in a mouse 4T1 breast cancer model. The effects of combining RT, VTP, Cryo with anti-PD1 was also assessed. Results: We observed that RT, VTP and Cryo significantly delayed tumor growth and extended overall survival. In addition, they also induced regression of non-treated distant tumors in a bilateral model suggesting a systemic immune response. Flow cytometry showed that VTP and Cryo are associated with a reduction in CD11b+ myeloid cells (granulocytes, monocytes, and macrophages) in tumor and periphery. An increase in CD8+ T cell infiltration into tumors was observed only in the RT group. VTP and Cryo were associated with an increase in CD4+ and CD8+ cells in the periphery. Conclusion: These data suggest that cell death induced by VTP and Cryo elicit similar immune responses that differ from local RT.

Structures of synaptic vesicle protein 2A and 2B bound to anticonvulsants.

Epilepsy is a common neurological disorder characterized by abnormal activity of neuronal networks, leading to seizures. The racetam class of anti-seizure medications bind specifically to a membrane protein found in the synaptic vesicles of neurons called synaptic vesicle protein 2 (SV2) A (SV2A). SV2A belongs to an orphan subfamily of the solute carrier 22 organic ion transporter family that also includes SV2B and SV2C. The molecular basis for how anti-seizure medications act on SV2s remains unknown. Here we report cryo-electron microscopy structures of SV2A and SV2B captured in a luminal-occluded conformation complexed with anticonvulsant ligands. The conformation bound by anticonvulsants resembles an inhibited transporter with closed luminal and intracellular gates. Anticonvulsants bind to a highly conserved central site in SV2s. These structures provide blueprints for future drug design and will facilitate future investigations into the biological function of SV2s.

A Description and Safety Overview of Irreversible Electroporation for Prostate Tissue Ablation in Intermediate-Risk Prostate Cancer Patients: Preliminary Results from the PRESERVE Trial.

The PRESERVE study (NCT04972097) aims to evaluate the safety and effectiveness of the NanoKnife System to ablate prostate tissue in patients with intermediate-risk prostate cancer (PCa). The NanoKnife uses irreversible electroporation (IRE) to deliver high-voltage electrical pulses to change the permeability of cell membranes, leading to cell death. A total of 121 subjects with organ-confined PCa ≤ T2c, prostate-specific antigens (PSAs) ≤ 15 ng/mL, and a Gleason score of 3 + 4 or 4 + 3 underwent focal ablation of the index lesion. The primary endpoints included negative in-field biopsy and adverse event incidence, type, and severity through 12 months. At the time of analysis, the trial had completed accrual with preliminary follow-up available. Demographics, disease characteristics, procedural details, PSA responses, and adverse events (AEs) are presented. The median (IQR) age at screening was 67.0 (61.0-72.0) years and Gleason distribution 3 + 4 (80.2%) and 4 + 3 (19.8%). At 6 months, all patients with available data (n = 74) experienced a median (IQR) percent reduction in PSA of 67.6% (52.3-82.2%). Only ten subjects (8.3%) experienced a Grade 3 adverse event; five were procedure-related. No Grade ≥ 4 AEs were reported. This study supports prior findings that IRE prostate ablation with the NanoKnife System can be performed safely. Final results are required to fully assess oncological, functional, and safety outcomes.

Surgical Outcomes and Genomic Insights of Nonclear Cell Renal Cell Carcinoma With Synchronous and Metachronous Nodal Disease.

INTRODUCTION: Oncological outcomes in patients with nonclear cell renal cell carcinoma (non-ccRCC) treated with surgery for locoregional nodal disease (ND) remain incompletely characterized. The objective was to investigate the characteristics and outcomes of non-ccRCC patients treated with lymph node dissection (LND) and salvage-LND (S-LND). METHODS: A total of 1627 patients underwent nephrectomy for nonmetastatic non-ccRCC at Memorial Sloan Kettering Cancer Center between 2007 and 2023. Histology was grouped as papillary, chromophobe, unclassified, and rare subtypes. Retrospective evaluation identified 2.5% (n = 40) of patients with nodal disease at time of nephrectomy (synchronous-ND) and 1.1% (n = 18) with metachronous nodal disease limited to the retroperitoneum (metachronous-ND). Patients' demographics and tumor characteristics were recorded and evaluated by univariate and multivariate cox regression models. Recurrence-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Patients who underwent tumor DNA sequencing during their clinical course were considered for genomic analysis. RESULTS: OS trended toward longer in metachronous-ND (51 vs 105 months; P = .2), though 23% of patients with synchronous-ND were recurrence-free at 45 months median follow-up. In multivariate analysis, rare histologies were associated with decreased OS (P = .030) and metachronous-ND with improved OS (P = .036). RFS and OS after S-LND was 15 and 96 months, respectively. Late onset of metachronous-ND/recurrence was associated with improved OS (P = .008). Genetic alterations in SETD2, TP53, B2M, and FGFR3 were exclusively seen in synchronous-ND, and tumor mutation burden (TMB) was also higher in patients with synchronous-ND (P = .016). CONCLUSIONS: Patients with metachronous-ND tend to have prolonged OS compared to synchronous-ND, but a substantial portion of patients with synchronous-ND still enter a durable disease-free state following LND. S-LND can likewise provide long-term survival, particularly in patients with longer time to metachronous nodal recurrence. Synchronous-ND was associated with SETD2, TP53, and NF2 alteration as well as higher TMB.

Implementation and Validation of an Automated, Longitudinal Robotic Surgical Evaluation and Feedback Program at a High-volume Center and Impact on Training.

Background: Surgical education lacks a standardized, proficiency-based approach to evaluation and feedback. Objective: To assess the implementation and reception (ie, feasibility) of an automated, standardized, longitudinal surgical skill assessment and feedback system, and identify baseline trainee (resident and fellow) characteristics associated with achieving proficiency in robotic surgery while learning robotic-assisted laparoscopic prostatectomy. Design setting and participants: A quality improvement study assessing a pilot of a surgical experience tracking program was conducted over 1 yr. Participants were six fellows, eight residents, and nine attending surgeons at a tertiary cancer center. Intervention: Trainees underwent baseline self-assessment. After each surgery, an evaluation was completed independently by the trainee and attending surgeons. Performance was rated on a five-point anchored Likert scale (trainees were considered "proficient" when attending surgeons' rating was ≥4). Technical skills were assessed using the Global Evaluative Assessment of Robotic Skills (GEARS) and Prostatectomy Assessment and Competency Evaluation (PACE). Outcome measurements and statistical analysis: Program success and utility were assessed by evaluating completion rates, evaluation completion times, and concordance rates between attending and trainee surgeons, and exit surveys. Baseline characteristics were assessed to determine associations with achieving proficiency. Results and limitations: Completion rates for trainees and attending surgeons were 72% and 77%, respectively. Fellows performed more steps/cases than residents (median [interquartile range]: 5 [3-7] and 3 [2-4], respectively; p < 0.01). Prior completion of robotics or laparoscopic skill courses and surgical experience measures were associated with achieving proficiency in multiple surgical steps and GEARS domains. Interclass correlation coefficients on individual components were 0.27-0.47 on GEARS domains. Conclusions: An automated surgical experience tracker with structured, longitudinal evaluation and feedback can be implemented with good participation and minimal participant time commitment, and can guide curricular development in a proficiency-based education program by identifying modifiable factors associated with proficiency, individualizing education, and identifying improvement areas within the education program. Patient summary: An automated, standardized, longitudinal surgical skill assessment and feedback system can be implemented successfully in surgical education settings and used to inform education plans and predict trainee proficiency.

Structural mechanisms for VMAT2 inhibition by tetrabenazine.

The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson's disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2's importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here, we report a 3.1 Å resolution cryo-electron microscopy (cryo-EM) structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington's chorea. We find TBZ interacts with residues in a central binding site, locking VMAT2 in an occluded conformation and providing a mechanistic basis for non-competitive inhibition. We further identify residues critical for cytosolic and lumenal gating, including a cluster of hydrophobic residues which are involved in a lumenal gating strategy. Our structure also highlights three distinct polar networks that may determine VMAT2 conformational dynamics and play a role in proton transduction. The structure elucidates mechanisms of VMAT2 inhibition and transport, providing insights into VMAT2 architecture, function, and the design of small-molecule therapeutics.

Changes in the Perioperative Management and Outcomes of Patients With Upper Tract Urothelial Carcinoma Undergoing Radical Nephroureterectomy at Memorial Sloan Kettering Cancer Center: Over 20 Years of Experience.

INTRODUCTION: We evaluated surgical trends, perioperative management evolution, and oncologic outcomes in patients who underwent radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) at a tertiary cancer center over a 24-year period. METHODS: Between 1995 and 2018, we evaluated 743 consecutive patients with UTUC who underwent RNU. Generalized additive models were used to estimate the associations between date of surgery and continuous outcomes using a linear model, dichotomous outcomes using a logit link, categorical outcomes using multinomial models, and 2- and 5-year survival outcomes using Cox proportional hazards models. RESULTS: Over the study period, preoperative diagnostic endoscopic biopsies increased from 10% to 66%, along with the proportion of patients who underwent RNU for high-grade disease from 55% to 91%. The rate of open RNU declined from 100% to 56% with a rise in minimally invasive approaches. Median lymph node yield increased with more retroperitoneal lymph node dissections performed. Neoadjuvant chemotherapy utilization increased with a contemporary utilization rate of 32%, coinciding with an increase in pT0 rate from 2% to 8%. Cancer-specific survival probabilities improved over the study period, while metastasis-free and overall survival remained stable. CONCLUSIONS: We found several changes in treatment patterns and outcomes for patients with UTUC over the past 2 decades. How individual alterations in management factors, such as patient selection, perioperative chemotherapy, lymphadenectomy, and salvage therapies, impact patient outcomes is challenging in the setting of multiple overlapping practice changes for this rare disease and warrants further investigation.

Localised non-metastatic sarcomatoid renal cell carcinoma: a 31-year externally verified study.

OBJECTIVE: To evaluate post-nephrectomy outcomes and predictors of cancer-specific survival (CSS) between patients with localised sarcomatoid renal cell carcinoma (sRCC) and those with Grade 4 RCC (non-sRCC), as most sRCC research focuses on advanced or metastatic disease with limited studies analysing outcomes of patients with localised non-metastatic sRCC. PATIENTS AND METHODS: A total of 564 patients with localised RCC underwent partial or radical nephrectomy between June 1988 to March 2019 for sRCC (n = 204) or World Health Organization/International Society of Urological Pathology Grade 4 non-sRCC (n = 360). The CSS at every stage between groups was assessed. Phase III ASSURE clinical trial data were used to externally validate the CSS findings. The Mann-Whitney U-test and chi-squared test compared outcomes and the Kaplan-Meier method evaluated CSS, overall survival (OS) and recurrence-free survival. Clinicopathological features associated with RCC death were evaluated using Cox proportional hazards regression. RESULTS: The median follow-up was 31.5 months. The median OS and CSS between the sRCC and Grade 4 non-sRCC groups was 45 vs 102 months and 49 vs 152 months, respectively (P < 0.001). At every stage, sRCC had worse CSS compared to Grade 4 non-sRCC. Notably, pT1 sRCC had worse CSS than pT3 Grade 4 non-sRCC. Negative predictors of CSS were sarcomatoid features, non-clear cell histology, positive margins, higher stage (pT3/pT4), and use of minimally invasive surgery (MIS). ASSURE external verification showed worse CSS in patients with sRCC (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.12-2.36; P = 0.01), but not worse outcomes in MIS surgery (HR 1.39, 95% CI 0.75-2.56; P = 0.30). CONCLUSIONS: Localised sRCC had worse CSS compared to Grade 4 non-sRCC at every stage. Negative survival predictors included positive margins, higher pathological stage, use of MIS, and non-clear cell histology. sRCC is an aggressive variant even at low stages requiring vigilant surveillance and possible inclusion in adjuvant therapy trials.

Structural mechanisms for VMAT2 inhibition by tetrabenazine.

The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson's disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2's importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here we report a 3.1 Å resolution cryo-EM structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington's chorea. We find TBZ interacts with residues in a central binding site, locking VMAT2 in an occluded conformation and providing a mechanistic basis for non-competitive inhibition. We further identify residues critical for cytosolic and lumenal gating, including a cluster of hydrophobic residues which are involved in a lumenal gating strategy. Our structure also highlights three distinct polar networks that may determine VMAT2 conformational dynamics and play a role in proton transduction. The structure elucidates mechanisms of VMAT2 inhibition and transport, providing insights into VMAT2 architecture, function, and the design of small-molecule therapeutics.

Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration.

Parkinson's disease (PD) targets some dopamine (DA) neurons more than others. Sex differences offer insights, with females more protected from DA neurodegeneration. The mammalian vesicular glutamate transporter VGLUT2 and Drosophila ortholog dVGLUT have been implicated as modulators of DA neuron resilience. However, the mechanisms by which VGLUT2/dVGLUT protects DA neurons remain unknown. We discovered DA neuron dVGLUT knockdown increased mitochondrial reactive oxygen species in a sexually dimorphic manner in response to depolarization or paraquat-induced stress, males being especially affected. DA neuron dVGLUT also reduced ATP biosynthetic burden during depolarization. RNA sequencing of VGLUT+ DA neurons in mice and flies identified candidate genes that we functionally screened to further dissect VGLUT-mediated DA neuron resilience across PD models. We discovered transcription factors modulating dVGLUT-dependent DA neuroprotection and identified dj-1ß as a regulator of sex-specific DA neuron dVGLUT expression. Overall, VGLUT protects DA neurons from PD-associated degeneration by maintaining mitochondrial health.

Consultation on UTUC II Stockholm 2022: diagnostic and prognostic methods-what's around the corner?

PURPOSE: To map current literature and provide an overview of upcoming future diagnostic and prognostic methods for upper tract urothelial carcinoma (UTUC), including translational medical science. METHODS: A scoping review approach was applied to search the literature. Based on the published literature, and the experts own experience and opinions consensus was reached through discussions at the meeting Consultation on UTUC II in Stockholm, September 2022. RESULTS: The gene mutational profile of UTUC correlates with stage, grade, prognosis, and response to different therapeutic strategies. Analysis of pathway proteins downstream of known pathogenic mutations might be an alternative approach. Liquid biopsies of cell-free DNA may detect UTUC with a higher sensitivity and specificity than urinary cytology. Extracellular vesicles from tumour cells can be detected in urine and may be used to identify the location of the urothelial carcinoma in the urinary tract. 3D microscopy of UTUC samples may add information in the analysis of tumour stage. Chemokines and chemokine receptors were linked to overall survival and responsiveness to neoadjuvant chemotherapy in muscle-invasive bladder cancer, which is potentially also of interest in UTUC. CONCLUSION: Current diagnostic methods for UTUC have shortcomings, especially concerning prognostication, which is important for personalized treatment decisions. There are several upcoming methods that may be of interest for UTUC. Most have been studied for urothelial carcinoma of the bladder, and it is important to keep in mind that UTUC is a different entity and not all methods are adaptable or applicable to UTUC.

Feasibility and tissue concordance of genomic sequencing of urinary cytology in upper tract urothelial carcinoma.

BACKGROUND: There is limited ability to accurately diagnose and clinically stage patients with upper tract urothelial carcinoma (UTUC). The most easily available and widely used urinary biomarker is urine cytology, which evaluates cellular material yet lacks sensitivity. We sought to assess the feasibility of performing next-generation sequencing (NGS) on urine cytology specimens from patients with UTUC and evaluate the genomic concordance with tissue from primary tumor. METHODS: In this retrospective study, we identified 48 patients with a diagnosis of UTUC treated at Memorial Sloan Kettering Cancer Center (MSK) between 2019 and 2022 who had banked or fresh urine samples. A convenience cohort of matching, previously sequenced tumor tissue was used when available. Urine specimens were processed and the residual material, including precipitated cell-free DNA, was sequenced using our tumor-naïve, targeted exome sequencing platform that evaluates 505 cancer-related genes (MSK-IMPACT). The primary outcome was at least 1 detectable mutation in urinary cytology specimens. The secondary outcome was concordance to matched tissue (using ANOVA or Chi-Square, as indicated). RESULTS: Genomic sequencing was successful for 45 (94%) of the 48 urinary cytology patient samples. The most common mutations identified were TERT (62.2%), KMT2D (46.7%), and FGFR3 (35.6%). All patients with negative urine cytology and low-grade tissue had successful cytology sequencing. Thirty-six of the 45 patients had matching tumor tissue available; concordance to matched tissue was 55% overall (131 of the total 238 oncogenic or likely oncogenic somatic mutations identified). However, in 94.4% (n = 34/36) of patients, the cytology had at least 1 shared mutation with tissue. Eleven (30.6%) patients had 100% concordance between cytology and tissue. CONCLUSIONS: Sequencing urinary specimens from selective UTUC cytology is feasible in nearly all patients with UTUC. Prospective studies are underway to investigate a clinical role for this promising technology.

Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline.

PURPOSE: The purpose of this guideline is to provide a useful reference on the effective evidence-based diagnoses and management of non-metastatic upper tract urothelial carcinoma (UTUC). MATERIALS/METHODS: The Pacific Northwest Evidence-based Practice Center of Oregon Health & Science University (OHSU) team conducted searches in Ovid MEDLINE (1946 to March 3rd, 2022), Cochrane Central Register of Controlled Trials (through January 2022), and Cochrane Database of Systematic Reviews (through January 2022). The searches were updated August 2022. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions (Table 1).[Table: see text]Results:This Guideline provides updated, evidence-based recommendations regarding diagnosis and management of non-metastatic UTUC including risk stratification, surveillance and survivorship. Treatments discussed include kidney sparing management, surgical management, lymph node dissection (LND), neoadjuvant/adjuvant chemotherapy and immunotherapy. CONCLUSION: This standardized guideline seeks to improve clinicians' ability to evaluate and treat patients with UTUC based on available evidence. Future studies will be essential to further support these statements for improving patient care. Updates will occur as the knowledge regarding disease biology, clinical behavior and new therapeutic options develop.

Health-related Quality of Life After Robotic-assisted vs Open Radical Cystectomy: Analysis of a Randomized Trial.

PURPOSE: We compare health-related quality of life using a broad range of validated measures in patients randomized to robotic-assisted radical cystectomy vs open radical cystectomy. METHODS: We retrospectively analyzed patients that had enrolled in both a randomized controlled trial comparing robotic-assisted laparoscopic radical cystectomy vs open radical cystectomy and a separate prospective study of health-related quality of life. The prospective health-related quality of life study collected 14 patient-reported outcomes measures preoperatively and at 3, 6, 12, 18, and 24 months postoperatively. Linear mixed-effects models with an interaction term (study arm×time) were used to test for differences in mean domain scores and differing effects of approach over time, adjusting for baseline scores. RESULTS: A total of 72 patients were analyzed (n=32 robotic-assisted radical cystectomy, n=40 open radical cystectomy). From 3-24 months post-radical cystectomy, no significant differences in mean scores were detected. Mean differences were small in the following European Organization for Research and Treatment of Cancer QLQ-C30 (Core Quality of Life Questionnaire) domains: Global Quality of Life (-1.1; 95% CI -8.4, 6.2), Physical Functioning (-0.4; 95% CI -5.8, 5.0), Role Functioning (0.7; 95% CI -8.6, 10.0). Mean differences were also small in bladder cancer-specific domains (European Organization for Research and Treatment of Cancer QLQ-BLM30 [Muscle Invasive Bladder Cancer Quality of Life Questionnaire]): Body Image (2.9; 95% CI -7.2, 13.1), Urinary Symptoms (8.0; 95% CI -3.0, 19.0). In Urostomy Symptoms, there was a significant interaction term (P < .001) due to lower open radical cystectomy scores at 3 and 24 months. Other domains evaluating urinary, bowel, sexual, and psychosocial health-related quality of life were similar. CONCLUSIONS: Over a broad range of health-related quality of life domains comparing robotic-assisted radical cystectomy and open radical cystectomy, there are unlikely to be clinically relevant differences in the medium to long term, and therefore health-related quality of life over this time period should not be a consideration in choosing between approaches.

Final Results of a Phase I Trial of WST-11 (TOOKAD Soluble) Vascular-targeted Photodynamic Therapy for Upper Tract Urothelial Carcinoma.

PURPOSE: Vascular-targeted photodynamic therapy with the intravascular photosensitizing agent padeliporfin (WST-11/TOOKAD-Soluble) has demonstrated therapeutic efficacy as an ablative treatment for localized cancer with potential adaptation for endoscopic management of upper tract urothelial carcinoma. This Phase I trial (NCT03617003) evaluated the safety of vascular-targeted photodynamic therapy with WST-11 in upper tract urothelial carcinoma. MATERIALS AND METHODS: Nineteen patients underwent up to 2 endoscopic vascular-targeted photodynamic therapy treatments, with follow-up for up to 6 months. Patients who had residual or recurrent upper tract urothelial carcinoma (any grade/size) failing prior endoscopic treatment or unable or unwilling to undergo surgical resection were eligible for inclusion. The primary endpoint was to identify the maximally tolerated dose of laser light fluence. A dose escalation model was employed, with increasing light fluence (100-200 mW/cm) using a modified continual reassessment method. The secondary endpoint was treatment efficacy, defined by absence of visible tumor and negative urine cytology 30 days posttreatment. RESULTS: Fourteen (74%) patients received the maximally tolerated dose of 200 mW/cm, 2 (11%) of whom experienced a dose-limiting toxicity. The initial 30-day treatment response rate was 94% (50% complete, 44% partial). Eight patients underwent a second treatment, with a final observed 68% complete response rate. Leading toxicities were flank pain (79%) and hematuria (84%), which were transient. No ureteral strictures associated with treatment were identified during follow-up. CONCLUSIONS: Vascular-targeted photodynamic therapy with WST-11 has an acceptable safety profile with strong potential as an effective, kidney-sparing endoscopic management option for upper tract urothelial carcinoma. The recently initiated multicenter Phase 3 ENLIGHTED trial (NCT04620239) is expected to provide further evidence on this therapy.

Macrophage activity at the site of tumor ablation can promote murine urothelial cancer via transforming growth factor-ß1.

Cell death and injury at the site of tumor ablation attracts macrophages. We sought to understand the status and activity of these cells while focusing on transforming growth factor-ß1 (TGF-ß1), a potent immunosuppressive and tumorigenic cytokine. Patients with urothelial cancer who underwent ablation using electrocautery or laser demonstrated increased infiltration and numbers of CD8+ T cells, along with FoxP3+ regulatory T cells, CD68+ macrophages and elevated levels of TGF-ß1 in recurrent tumors. Similar findings were reproduced in a mouse model of urothelial cancer (MB49) by partial tumor ablation with irreversible electroporation (IRE). Stimulation of bone marrow derived macrophages with MB49 cell debris produced using IRE elicited strong M2 polarization, with exuberant secretion of TGF-ß1. The motility, phenotypic markers and cytokine secretion by macrophages could be muted by treatment with Pirfenidone (PFD), a clinically approved drug targeting TGF-ß1 signaling. MB49 cancer cells exposed to TGF-ß1 exhibited increased migration, invasiveness and upregulation of epithelial-mesenchymal transition markers α-Smooth Muscle Actin and Vimentin. Such changes in MB49 cells were reduced by treatment with PFD even during stimulation with TGF-ß1. IRE alone yielded better local tumor control when compared with control or PFD alone, while also reducing the overall number of lung metastases. Adjuvant PFD treatment did not provide additional benefit under in vivo conditions.