Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer.

Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.

Diverse values of nature for sustainability.

Twenty-five years since foundational publications on valuing ecosystem services for human well-being1,2, addressing the global biodiversity crisis3 still implies confronting barriers to incorporating nature's diverse values into decision-making. These barriers include powerful interests supported by current norms and legal rules such as property rights, which determine whose values and which values of nature are acted on. A better understanding of how and why nature is (under)valued is more urgent than ever4. Notwithstanding agreements to incorporate nature's values into actions, including the Kunming-Montreal Global Biodiversity Framework (GBF)5 and the UN Sustainable Development Goals6, predominant environmental and development policies still prioritize a subset of values, particularly those linked to markets, and ignore other ways people relate to and benefit from nature7. Arguably, a 'values crisis' underpins the intertwined crises of biodiversity loss and climate change8, pandemic emergence9 and socio-environmental injustices10. On the basis of more than 50,000 scientific publications, policy documents and Indigenous and local knowledge sources, the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) assessed knowledge on nature's diverse values and valuation methods to gain insights into their role in policymaking and fuller integration into decisions7,11. Applying this evidence, combinations of values-centred approaches are proposed to improve valuation and address barriers to uptake, ultimately leveraging transformative changes towards more just (that is, fair treatment of people and nature, including inter- and intragenerational equity) and sustainable futures.

Publisher Correction: Intensive farming drives long-term shifts in avian community composition.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Intensive farming drives long-term shifts in avian community composition.

Agricultural practices constitute both the greatest cause of biodiversity loss and the greatest opportunity for conservation1,2, given the shrinking scope of protected areas in many regions. Recent studies have documented the high levels of biodiversity-across many taxa and biomes-that agricultural landscapes can support over the short term1,3,4. However, little is known about the long-term effects of alternative agricultural practices on ecological communities4,5 Here we document changes in bird communities in intensive-agriculture, diversified-agriculture and natural-forest habitats in 4 regions of Costa Rica over a period of 18 years. Long-term directional shifts in bird communities were evident in intensive- and diversified-agricultural habitats, but were strongest in intensive-agricultural habitats, where the number of endemic and International Union for Conservation of Nature (IUCN) Red List species fell over time. All major guilds, including those involved in pest control, pollination and seed dispersal, were affected. Bird communities in intensive-agricultural habitats proved more susceptible to changes in climate, with hotter and drier periods associated with greater changes in community composition in these settings. These findings demonstrate that diversified agriculture can help to alleviate the long-term loss of biodiversity outside natural protected areas1.

Biodiversity and infrastructure interact to drive tourism to and within Costa Rica.

SignificanceTourism accounts for roughly 10% of global gross domestic product, with nature-based tourism its fastest-growing sector in the past 10 years. Nature-based tourism can theoretically contribute to local and sustainable development by creating attractive livelihoods that support biodiversity conservation, but whether tourists prefer to visit more biodiverse destinations is poorly understood. We examine this question in Costa Rica and find that more biodiverse places tend indeed to attract more tourists, especially where there is infrastructure that makes these places more accessible. Safeguarding terrestrial biodiversity is critical to preserving the substantial economic benefits that countries derive from tourism. Investments in both biodiversity conservation and infrastructure are needed to allow biodiverse countries to rely on tourism for their sustainable development.

Why nature matters: A systematic review of intrinsic, instrumental, and relational values.

In this article, we present results from a literature review of intrinsic, instrumental, and relational values of nature conducted for the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services, as part of the Methodological Assessment of the Diverse Values and Valuations of Nature. We identify the most frequently recurring meanings in the heterogeneous use of different value types and their association with worldviews and other key concepts. From frequent uses, we determine a core meaning for each value type, which is sufficiently inclusive to serve as an umbrella over different understandings in the literature and specific enough to help highlight its difference from the other types of values. Finally, we discuss convergences, overlapping areas, and fuzzy boundaries between different value types to facilitate dialogue, reduce misunderstandings, and improve the methods for valuation of nature's contributions to people, including ecosystem services, to inform policy and direct future research.

Induction and maintenance of sequential intravesical gemcitabine/docetaxel for intermediate and high-risk non-muscle invasive bladder cancer with different dosage protocols.

INTRODUCTION: The combination of sequential intravesical gemcitabine and docetaxel (Gem/Doce) chemotherapy has been considered a feasible option for BCG (Bacillus Calmette-Guérin) treatment in non-muscle invasive bladder cancer (NMIBC), gaining popularity during BCG shortage period. We seek to determine the efficacy of the treatment by comparing Gem/Doce induction alone vs induction with maintenance, and to evaluate the treatment outcomes of two different dosage protocols. METHODS: A bi-center retrospective analysis of consecutive patients treated with Gem/Doce for NMIBC between 2018 and 2023 was performed. Baseline characteristics, risk group stratification (AUA 2020 guidelines), pathological, and surveillance reports were collected. Kaplan-Meier survival analysis was performed to detect Recurrence-free survival (RFS). RESULTS: Overall, 83 patients (68 males, 15 females) with a median age of 73 (IQR 66-79), and a median follow-up time of 18 months (IQR 9-25), were included. Forty-one had an intermediate-risk disease (49%) and 42 had a high-risk disease (51%). Thirty-seven patients (45%) had a recurrence; 19 (23%) had a high-grade recurrence. RFS of Gem/Doce induction-only vs induction + maintenance was at 6 months 88% vs 100%, at 12 months 71% vs 97%, at 18 months 57% vs 91%, and at 24 months 31% vs 87%, respectively (log-rank, p < 0.0001). Patients who received 2 g Gemcitabine with Docetaxel had better RFS for all-grade recurrences (log-rank, p = 0.017). However, no difference was found for high-grade recurrences. CONCLUSION: Gem/Doce induction with maintenance resulted in significantly better RFS than induction-only. Combining 2 g gemcitabine with docetaxel resulted in better RFS for all-grade but not for high-grade recurrences. Further prospective trials are necessary to validate our results.

The State of Urotrauma Education Among Residency Programs in the United States: A Systematic Review and Meta-Analysis.

PURPOSE OF REVIEW: Management of urotrauma is a crucial part of a urologist's knowledge and training. We therefore sought to understand the state of urotrauma education in the United States. RECENT FINDINGS: Using themes of "Urotrauma" and "Education," we performed a systematic review and meta-analysis by searching for studies in MEDLINE, all Cochrane libraries, EMBASE, BIOSIS, Scopus, and Web of Science through May 2023. The primary outcome was the pooled rate of urology trainee and program director attitudes toward urotrauma education. Secondary outcomes involved a descriptive summary of existing urotrauma curricula and an assessment of factors affecting urotrauma exposure. Of 12,230 unique records, 11 studies met the final eligibility criteria, and we included 2 in the meta-analysis. The majority of trainees and program directors reported having level 1 trauma center rotations (range 88-89%) and considered urotrauma exposure as an important aspect of residency education (83%, 95% CI 76-88%). Despite possible increases in trainee exposure to Society of Genitourinary Reconstructive Surgeons (GURS) faculty over the preceding decade, nearly a third of trainees and program directors currently felt there remained inadequate exposure to urotrauma during training (32%, 95% CI 19-46%). Factors affecting urotrauma education include the limited exposure to GURS-trained faculty and clinical factors such as case infrequency and non-operative trauma management. Urology resident exposure to urotrauma is inadequate in many training programs, underscoring the potential value of developing a standardized curriculum to improve urotrauma education for trainees. Further investigation is needed to characterize this issue and to understand how it impacts trainee practice readiness.

Cytogenetic analysis of 130 renal oncocytomas identify three distinct and mutually exclusive diagnostic classes of chromosome aberrations.

The cytogenetic alterations in renal oncocytoma (RO) are poorly understood. We analyzed 130 consecutive RO for karyotypic alterations. Clonal chromosome abnormalities were identified in 63 (49%) cases, which could be categorized into three classes of mutually exclusive cytogenetic categories. Class 1 (N = 20) RO had diploid karyotypes with characteristic 11q13 rearrangement in balanced translocations with 10 or more different chromosome partners in all cases. We identified recurrent translocation partners at 5q35, 6p21, 9p24, 11p13-14, and 11q23, and confirmed that CCND1 gene rearrangement at 11q13 utilizing fluorescence in situ hybridization (FISH). Class 2 RO (N = 25) exhibited hypodiploid karyotypes with loss of chromosome 1 and/or losses of Y in males and X in females in all cases. The class 3 tumors comprising of 18 cases showed diverse types of abnormalities with the involvement of two or more chromosomes exclusive of abnormalities seen in classes 1 and 2 tumors. Furthermore, karyotypically uninformative cases were subjected to FISH analysis to identify classes 1 and 2 abnormalities. In this group, we found similar frequencies of CCND1 rearrangement, loss of chromosome 1 or Y as with karyotypically abnormal cases. We validated our results against 91 tumors from the Mitelman database. Correlation of clinical data with all the three classes of ROs showed no clear evidence of overall patient survival. Our findings support the hypothesis that RO exhibit three principal cytogenetic categories, which may have different roles in initiation and/or progression. These cytogenetic markers provide a key tool in the diagnostic evaluation of RO.

A Phase I Trial of Intravesical Cabazitaxel, Gemcitabine and Cisplatin for the Treatment of Nonmuscle Invasive bacillus Calmette-Guérin Unresponsive or Recurrent/Relapsing Urothelial Carcinoma of the Bladder.

PURPOSE: For patients with bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer, multi-agent intravesical trials have been limited. In this study we investigate the safety of intravesical cabazitaxel, gemcitabine and cisplatin in the salvage setting. MATERIALS AND METHODS: This was a dose escalation, drug escalation trial for patients with bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer who declined or were ineligible for radical cystectomy. All patients underwent a 6-week induction regimen of sequentially administered cabazitaxel, gemcitabine and cisplatin. Complete response was defined as no cancer on post-induction transurethral bladder tumor resection and negative urine cytology, while partial response allowed for positive cytology. Responders continued with maintenance cabazitaxel and gemcitabine monthly for the first year and bimonthly for the second year. RESULTS: A total of 18 patients were enrolled. Mean age was 71 years, median followup was 27.8 months (range 16.3 to 46.9) and mean number of previous rounds of intravesical therapies before trial enrollment was 3.7. Nine patients (50%) had received intravesical chemotherapy after bacillus Calmette-Guérin and 7 (39%) were previously treated in a phase I clinical trial setting. At enrollment 6 (33%) subjects had T1 disease and 13 (72%) had carcinoma in situ. There were no dose limiting toxicities. Initial partial and complete response rates were 94% and 89%, respectively. At 1 year recurrence-free survival was 0.83 (range 0.57 to 0.94) and at 2 years estimated recurrence-free survival was 0.64 (0.32 to 0.84). CONCLUSIONS: In this high risk and highly pretreated cohort of bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer cases combination intravesical cabazitaxel, gemcitabine and cisplatin was a well tolerated and potentially effective regimen.

ICUD-SIU International Consultation on Bladder Cancer 2017: management of non-muscle invasive bladder cancer.

PURPOSE: To provide a summary of the Third International Consultation on Bladder Cancer recommendations for the management of non-muscle invasive bladder cancer (NMIBC). METHODS: A detailed review of the literature was performed focusing on original articles for the management of NMIBC. An international committee assessed and graded the articles based on the Oxford Centre for Evidence-based Medicine system. The entire spectrum of NMIBC was covered such as prognostic factors of recurrence and progression, risk stratification, staging, management of positive urine cytology with negative white light cystoscopy, indications of bladder and prostatic urethral biopsies, management of Ta low grade (LG) and high risk tumors (Ta high grade [HG], T1, carcinoma in situ [CIS]), impact of BCG strain and host on outcomes, management of complications of intravesical therapy, role of alternative therapies, indications for early cystectomy, surveillance strategies, and new treatments. The working group provides several recommendations on the management of NMIBC. RESULTS: Recommendations were summarized with regard to staging; management of primary and recurrent LG Ta and high risk disease, positive urine cytology with negative white light cystoscopy and prostatic urethral involvement; indications for timely cystectomy; and surveillance strategies. CONCLUSION: NMIBC remains a common and challenging malignancy to manage. Accurate staging, grading, and risk stratification are critical determinants of the management and outcomes of these patients. Current tools for risk stratification are limited but informative, and should be used in clinical practice when determining diagnosis, surveillance, and treatment of NMIBC.

Large-scale climatic and geophysical controls on the leaf economics spectrum.

Leaf economics spectrum (LES) theory suggests a universal trade-off between resource acquisition and storage strategies in plants, expressed in relationships between foliar nitrogen (N) and phosphorus (P), leaf mass per area (LMA), and photosynthesis. However, how environmental conditions mediate LES trait interrelationships, particularly at large biospheric scales, remains unknown because of a lack of spatially explicit data, which ultimately limits our understanding of ecosystem processes, such as primary productivity and biogeochemical cycles. We used airborne imaging spectroscopy and geospatial modeling to generate, to our knowledge, the first biospheric maps of LES traits, here centered on 76 million ha of Andean and Amazonian forest, to assess climatic and geophysical determinants of LES traits and their interrelationships. Elevation and substrate were codominant drivers of leaf trait distributions. Multiple additional climatic and geophysical factors were secondary determinants of plant traits. Anticorrelations between N and LMA followed general LES theory, but topo-edaphic conditions strongly mediated and, at times, eliminated this classic relationship. We found no evidence for simple P-LMA or N-P trade-offs in forest canopies; rather, we mapped a continuum of N-P-LMA interactions that are sensitive to elevation and temperature. Our results reveal nested climatic and geophysical filtering of LES traits and their interrelationships, with important implications for predictions of forest productivity and acclimation to rapid climate change.

Progressive forest canopy water loss during the 2012-2015 California drought.

The 2012-2015 drought has left California with severely reduced snowpack, soil moisture, ground water, and reservoir stocks, but the impact of this estimated millennial-scale event on forest health is unknown. We used airborne laser-guided spectroscopy and satellite-based models to assess losses in canopy water content of California's forests between 2011 and 2015. Approximately 10.6 million ha of forest containing up to 888 million large trees experienced measurable loss in canopy water content during this drought period. Severe canopy water losses of greater than 30% occurred over 1 million ha, affecting up to 58 million large trees. Our measurements exclude forests affected by fire between 2011 and 2015. If drought conditions continue or reoccur, even with temporary reprieves such as El Niño, we predict substantial future forest change.

Biodiversity monitoring, earth observations and the ecology of scale.

Human activity and land-use change are dramatically altering the sizes, geographical distributions and functioning of biological populations worldwide, with tremendous consequences for human well-being. Yet our ability to measure, monitor and forecast biodiversity change - crucial to addressing it - remains limited. Biodiversity monitoring systems are being developed to improve this capacity by deriving metrics of change from an array of in situ data (e.g. field plots or species occurrence records) and Earth observations (EO; e.g. satellite or airborne imagery). However, there are few ecologically based frameworks for integrating these data into meaningful metrics of biodiversity change. Here, I describe how concepts of pattern and scale in ecology could be used to design such a framework. I review three core topics: the role of scale in measuring and modelling biodiversity patterns with EO, scale-dependent challenges linking in situ and EO data and opportunities to apply concepts of pattern and scale to EO to improve biodiversity mapping. From this analysis emerges an actionable approach for measuring, monitoring and forecasting biodiversity change, highlighting key opportunities to establish EO as the backbone of global-scale, science-driven conservation.

Conservative Management Following Complete Clinical Response to Neoadjuvant Chemotherapy of Muscle Invasive Bladder Cancer: Contemporary Outcomes of a Multi-Institutional Cohort Study.

PURPOSE: We report the outcomes in patients with muscle invasive bladder cancer from 2 institutions who experienced a clinically complete response to neoadjuvant platinum based chemotherapy and elected active surveillance. It was unknown whether conservative treatment could be safely implemented in these patients. MATERIALS AND METHODS: We retrospectively reviewed the records of patients with muscle invasive bladder cancer at our institutions who elected surveillance following a clinically complete response to transurethral resection of bladder tumors and neoadjuvant chemotherapy from 2001 to 2017. A clinically complete response was defined as absent tumor on post-chemotherapy transurethral resection of bladder tumor, negative cytology and normal cross-sectional imaging. RESULTS: In the 148 patients followed a median of 55 months (range 5 to 145) the 5-year disease specific, overall, cystectomy-free and recurrence-free survival rates were 90%, 86%, 76% and 64%, respectively. Of the patients 71 (48%) experienced recurrence in the bladder, including 16 (11%) with muscle invasive disease and 55 (37%) with noninvasive disease. Salvage radical cystectomy prevented cancer specific death in 9 of 12 patients (75%) who underwent cystectomy after muscle invasive relapse and in 13 of 14 (93%) after noninvasive relapse. CONCLUSIONS: We observed high rates of overall and disease specific survival with bladder preservation in patients who achieved a clinically complete response to neoadjuvant chemotherapy. These outcomes support the safety of active surveillance in carefully selected, closely monitored patients with muscle invasive bladder cancer. Future studies should aim to improve patient selection by identifying biomarkers predicting invasive relapse and developing novel imaging methods of early detection.

Discordance between Ureteroscopic Biopsy and Final Pathology for Upper Tract Urothelial Carcinoma.

PURPOSE: We evaluated the discordance between ureteroscopic biopsy and surgical pathology findings for grading and staging upper tract urothelial carcinoma. We also sought to establish preoperative predictors of aggressive tumors. MATERIALS AND METHODS: We retrospectively reviewed the records of 314 patients who underwent ureteroscopic biopsy followed by surgical management of upper tract urothelial carcinoma from 2000 to 2016 at a total of 3 institutions. Our primary outcomes were muscle invasive (pT2 or greater) disease at surgical pathology and upgrading of clinical low grade tumors to pathological high grade. RESULTS: At biopsy 61% of the patients had clinical high grade tumors and 21% had subepithelial connective tissue invasion (cT1+). On final pathology 79% of the patients had pathological high grade tumors and 45% had stage pT2 or greater. On multivariate analysis advanced patient age, clinical high grade and cT1+ were independently associated with pT2 or greater. The combined presence of clinical high grade and cT1+ had 86% positive predictive value for muscle invasion while the combined absence of clinical high grade and cT1+ had 80% negative predictive value. The likelihood of missing invasion on biopsy in patients with muscle invasive disease was increased when biopsy fragments were limited to 1 mm or less. Of clinical low grade cases on biopsy 51% were upgraded at surgery. The presence of positive urine cytology was associated with an increased risk of upgrading but this was not statistically significant. CONCLUSIONS: Clinical high grade, cT1+ on biopsy and advanced patient age are independent risk factors for muscle invasive upper tract urothelial carcinoma. There is a significant risk of upgrading in patients with clinical low grade tumors on biopsy, especially when urine cytology is positive. The predictive value of biopsy can likely be improved by more extensive ureteroscopic sampling.

Impact of Surgeon Case Volume on Reoperation Rates after Inflatable Penile Prosthesis Surgery.

PURPOSE: We investigated the impact of surgeon annual case volume on reoperation rates after inflatable penile prosthesis surgery. MATERIALS AND METHODS: The New York Statewide Planning and Research Cooperative System database was queried for inflatable penile prosthesis cases from 1995 to 2014. Multivariate proportional hazards regression was performed to estimate the impact of surgeon annual case volume on inflatable penile prosthesis reoperation rates. We stratified our analysis by indication for reoperation to determine if surgeon volume had a similar effect on infectious and noninfectious complications. RESULTS: A total of 14,969 men underwent inflatable penile prosthesis insertion. Median followup was 95.1 months (range 0.5 to 226.7) from the time of implant. The rates of overall reoperation, reoperation for infection and reoperation for noninfectious complications were 6.4%, 2.5% and 3.9%, respectively. Implants placed by lower volume implanters were more likely to require reoperation for infection but not for noninfectious complications. Multivariable analysis demonstrated that compared with patients treated by surgeons in the highest quartile of annual case volume (more than 31 cases per year), patients treated by surgeons in the lowest (0 to 2 cases per year), second (3 to 7 cases per year) and third (8 to 31 cases per year) annual case volume quartiles were 2.5 (p <0.001), 2.4 (p <0.001) and 2.1 (p=0.01) times more likely to require reoperation for inflatable penile prosthesis infection, respectively. CONCLUSIONS: Patients treated by higher volume implanters are less likely to require reoperation after inflatable penile prosthesis insertion than those treated by lower volume surgeons. This trend appears to be driven by associations between surgeon volume and the risk of prosthesis infection.

Scale dependence of canopy trait distributions along a tropical forest elevation gradient.

Average responses of forest foliar traits to elevation are well understood, but far less is known about trait distributional responses to elevation at multiple ecological scales. This limits our understanding of the ecological scales at which trait variation occurs in response to environmental drivers and change. We analyzed and compared multiple canopy foliar trait distributions using field sampling and airborne imaging spectroscopy along an Andes-to-Amazon elevation gradient. Field-estimated traits were generated from three community-weighting methods, and remotely sensed estimates of traits were made at three scales defined by sampling grain size and ecological extent. Field and remote sensing approaches revealed increases in average leaf mass per unit area (LMA), water, nonstructural carbohydrates (NSCs) and polyphenols with increasing elevation. Foliar nutrients and photosynthetic pigments displayed little to no elevation trend. Sample weighting approaches had little impact on field-estimated trait responses to elevation. Plot representativeness of trait distributions at landscape scales decreased with increasing elevation. Remote sensing indicated elevation-dependent increases in trait variance and distributional skew. Multiscale invariance of LMA, leaf water and NSC mark these traits as candidates for tracking forest responses to changing climate. Trait-based ecological studies can be greatly enhanced with multiscale studies made possible by imaging spectroscopy.