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Abstract Background A vaccine against Trypanosoma cruzi, the agent of Chagas disease, would be an excellent additional tool for disease control. A recombinant vaccine based on Tc24 and TSA1 parasite antigens was found to be safe and immunogenic in naïve macaques. Methods We used RNA-sequencing and performed a transcriptomic analysis of PBMC responses to vaccination of naïve macaques after each vaccine dose, to shed light on the immunogenicity of this vaccine and guide the optimization of doses and formulation. We identified differentially expressed genes and pathways and characterized immunoglobulin and T cell receptor repertoires. Results RNA-sequencing analysis indicated a clear transcriptomic response of PBMCs after three vaccine doses, with the up-regulation of several immune cell activation pathways and a broad non-polarized immune profile. Analysis of the IgG repertoire showed that it had a rapid turnover with novel IgGs produced following each vaccine dose, while the TCR repertoire presented several persisting clones that were expanded after each vaccine dose. Conclusions These data suggest that three vaccine doses may be needed for optimum immunogenicity and support the further evaluation of the protective efficacy of this vaccine.

Objective REFLECT is the first randomised, double-masked, placebo-controlled multicentre phase 3 clinical trial that evaluated the efficacy and safety of bilateral intravitreal (IVT) injection of lenadogene nolparvovec in subjects with Leber hereditary optic neuropathy carrying the m.11778G>A mutation.Methods and analysis A total of 98 subjects were enrolled with vision loss of ≤12 months. The subjects were randomised to one of two treatment arms with all subjects receiving an intravitreal (IVT) injection of lenadogene nolparvovec in their first affected eye and the second-affected eye randomised to receive IVT of either lenadogene nolparvovec or placebo.Results The majority of subjects were male with a mean duration of vision loss of 8.3 months. All but one subject experienced bilateral loss of vision at the time of injection. The mean best-corrected visual acuity of first-affected eyes was worse compared with second/not-yet-affected eyes. Analysis of retinal anatomical parameters showed increased thinning in the first-affected eyes when compared with the second/not-yet-affected eyes with both treatment arms showing significant changes compared with unaffected individuals.Conclusion The REFLECT trial is the third and the largest phase 3 clinical study evaluating lenadogene nolparvovec in m.11778G>A Leber hereditary optic neuropathy (LHON) subjects. The observed demographics in REFLECT are consistent with previous reports in LHON subjects in the acute and dynamic phases of LHON disease. Combined with the visual function and anatomical parameters obtained in the previous RESCUE and REVERSE trials, REFLECT has provided a uniformly collected data set that should help direct future LHON clinical trials.

Frieze patterns appear frequently in architectural designs and ornamental patterning but their aesthetic qualities have never been studied experimentally. In the first experiment, 39 undergraduates used a seven-point rating scale to assess the perceived beauty of the seven basic frieze types presented at a horizontal orientation. The friezes consisted of individual curved and linear motifs as well as random textures. Friezes that filled the entire pattern region and which contained emergent global features were preferred the most. In a second experiment, we utilized horizontal texture friezes that were completely filled and which varied in size and number of elements. Participants preferred patterns with larger features, probably because they make detection of the symmetric transformations more visible. The frieze with the greatest number of symmetries was preferred most but symmetric complexity by itself could not completely account for the predicted preference ordering. In both studies, friezes containing horizontal mirrors (translation, 180° rotation, horizontal mirror, vertical mirror, and glide reflection and translation, horizontal mirror, and glide reflection) were preferred far more than any other condition. Horizontal symmetry may enhance perceived beauty in these cases because it runs parallel to and so emphasizes the overall frieze orientation.

Abstract Secondary brain injury impacts patient prognosis and can lead to long-term morbidity and mortality in cases of trauma. Continuous monitoring of secondary injury in acute clinical settings is primarily limited to intracranial pressure (ICP); however, ICP is unable to identify essential underlying etiologies of injury needed to guide treatment (e.g. immediate surgical intervention vs medical management). Here we show that a novel intracranial bioimpedance monitor (BIM) can detect onset of secondary injury, differentiate focal (e.g. hemorrhage) from global (e.g. edema) events, identify underlying etiology and provide localization of an intracranial mass effect. We found in an in vivo porcine model that the BIM detected changes in intracranial volume down to 0.38 mL, differentiated high impedance (e.g. ischemic) from low impedance (e.g. hemorrhagic) injuries (p

Abstract Background Chagas disease is a zoonotic disease caused by the protozoan parasite Trypanosoma cruzi. The role of dogs as sentinels has been proposed in multiple regions, as they are a domestic reservoir for T. cruzi. Our objective was to determine the prevalence of T. cruzi infection in shelter dogs from southern Louisiana, and assess its magnitude and distribution. Results A total of 540 dogs were enrolled, from 20 animal shelters, and tested for T. cruzi infection by serological tests (rapid test, ELISA and western blot) and PCR. We documented a high prevalence of T. cruzi infection with at least 6.9% (95% CI: 5.0–9.3%) seropositive and 15.7% (95% CI: 12.9–19.1%) PCR-positive dogs. Serological tests showed limited agreement, and concordance between serology and PCR was higher when considering reactivity to single serological tests. Trypanosoma cruzi infection was distributed evenly among shelters. Infection was significantly correlated with age (R 2 = 0.99), indicating an incidence of new cases of 2.27 ± 0.25% per year. Conclusion Trypanosoma cruzi infection is a significant and widespread veterinary problem in shelter dogs in the region, although it is mostly unnoticed by health professionals. This highlights the need for greater awareness of T. cruzi infection among the veterinary community and dog owners.

Despite substantial federal, state, and local investments in improving early care and education (ECE), we know little about whether ECE program quality has improved over time. The lack of data tracking the quality of publicly funded ECE programs at scale creates a substantial evidence gap for policymakers attempting to weigh the returns on, and future of, quality improvement policies. Data from Quality Rating and Improvement Systems (QRIS) provide a promising opportunity to address this problem. Using 4 years of data from a mandatory, statewide QRIS covering subsidized child care, Head Start, and state prekindergarten, we document systemwide quality and improvement trends over a period of targeted investment in quality improvement statewide. We find improvements in quality overall, across sectors and communities over this period. Results also reveal differential growth across sectors such that quality gaps diminished. This study highlights the potential of statewide ECE data for informing quality improvement efforts.

BackgroundChagas disease is a neglected zoonosis of growing concern in the southern US, caused by the parasite Trypanosoma cruzi. We genotyped parasites in a large cohort of PCR positive dogs to shed light on parasite transmission cycles and assess potential relationships between parasite diversity and serological test performance.Methodology/principal findingsWe used a metabarcoding approach based on deep sequencing of T. cruzi mini-exon marker to assess parasite diversity. Phylogenetic analysis of 178 sequences from 40 dogs confirmed the presence of T. cruzi discrete typing unit (DTU) TcI and TcIV, as well as TcII, TcV and TcVI for the first time in US dogs. Infections with multiple DTUs occurred in 38% of the dogs. These data indicate a greater genetic diversity of T. cruzi than previously detected in the US. Comparison of T. cruzi sequence diversity indicated that highly similar T. cruzi strains from these DTUs circulate in hosts and vectors in Louisiana, indicating that they are involved in a shared T. cruzi parasite transmission cycle. However, TcIV and TcV were sampled more frequently in vectors, while TcII and TcVI were sampled more frequently in dogs.Conclusions/significanceThese observations point to ecological host-fitting being a dominant mechanism involved in the diversification of T. cruzi-host associations. Dogs with negative, discordant or confirmed positive T. cruzi serology harbored TcI parasites with different mini-exon sequences, which strongly supports the hypothesis that parasite genetic diversity is a key factor affecting serological test performance. Thus, the identification of conserved parasite antigens should be a high priority for the improvement of current serological tests.

The genetic evolution of HIV-1 from its progenitor virus SIV following cross-species transmission is not well understood. Here we simulated the SIVcpz initial transmission to humans using humanized mice and followed the viral evolution during serial passages lasting more than a year. All three SIVcpz progenitor viruses used, namely LB715 and MB897 (group M) as well as EK505 (group N) readily infected hu-mice resulting in chronic viremia. Viral loads increased progressively to higher set-points and the CD4+ T cell decline became more pronounced by the end of the second serial passage indicating viral adaptation and increased pathogenicity. Viral genomes sequenced at different time points revealed many non-synonymous variants not previously reported that occurred throughout the viral genome, including the gag, pol, env, and nef genes. These results shed light on the potential changes that the SIVcpz genome had undergone during the initial stages of human infection and subsequent spread.

Competitive figure skaters often suffer from overuse injuries, which may be due to the high impact forces endured during jump repetitions performed in practice and competition. However, to date, forces during on-ice figure skating have not been quantified due to technological limitations. The purpose of this study was to determine the optimal calibration procedure for a previously developed instrumented figure skating blade (IceSense). Initial calibration was performed by collecting data from the blade while 11 skaters performed off-ice jumps, landing on a force plate in the lab. However, mean peak force measurements from the blade were greater than the desired error threshold of ±10%. Therefore, we designed a series of controlled experiments which included measuring forces from a load cell rigidly attached to the top of the blade concurrently with strain data from the strain gauges on the blade. Forces were applied to the blade by adding weight to a drop tower or by manually applying force in a quasi-static manner. Both methods showed similar accuracy, though using the drop tower allowed precise standardization. Therefore, calibration was performed using the weighted drop method. This calibration was applied to strain gauge data from out-of-sample drop trials, resulting in acceptable estimates of peak force (less than 10% error). Using this calibration, we collected data on one figure skater and present results from an exemplar on-ice double flip jump. Using the IceSense device to quantify on-ice forces in a research setting may help inform training, technique, and equipment design.

Farmers' markets are an innovative strategy to potentially increase healthy nutrition environments. Kaiser Permanente (KP), the largest private, nonprofit healthcare system in the country, has been hosting farmers' markets on its medical campuses since 2003 and now has markets in nearly 40 KP locations in four states: California, Hawaii, Oregon, and Maryland. This paper describes the KP farmers' market program and summarizes the results of a patron survey conducted in 2010 among 2,435 market patrons. The majority of patrons are KP physicians and staff, and a quarter of patrons are KP members and community residents. The markets appear to have an impact on what people are eating: 74% of all patrons reported eating more fruits and vegetables as a result of coming to the market. The KP experience may be generalizable to other healthcare organizations and to other large employers.

Canada lags behind many of its First World counterparts when it comes to business innovation, and urgently needs to improve its performance if it is to remain competitive and attractive to investment. The Expert Panel Report on Federal Support to Research and Development has recommended several policy initiatives that governments need to enact to close the gap. This paper reviews all six major recommendations made by the Expert Panel and provides thorough assessments of each, with ample consideration given to their implications for the private sector. The two most promising are: (1) the consolidation of research and development spending programs at the federal level and (2) the adoption of smart procurement as a means of spurring innovation in the non-government sector. While some of the other recommendations need refinement and raise concerns about their impact on the economy, the message for government and business is clear: the former can and should facilitate Canadian business innovation by removing tax and regulatory burdens and facilitating better public-private cooperation, while the latter must make innovation a major part of corporate culture. This paper explains the consequences of the Panel’s recommendations for both sectors, identifies the deficiencies, and offers clear-eyed guidance for ameliorating them.

Many rationales for wildlife conservation have been suggested. One rationale not often mentioned is the impact of extinctions on the traditions of local people, and conservationists′ subsequent need to strongly consider culturally based reasons for conservation. As a first step in strengthening the case for this rationale, we quantitatively examined the presence and representation of eight potentially extinct mammals in folklore of 48 Native American tribes that live/lived near to 11 national parks in the United States. We aimed to confirm if these extinct animals were traditionally important species for Native Americans. At least one-third of the tribes included the extinct mammals in their folklore (N=45 of 124) and about half of these accounts featured the extinct species with positive and respectful attitudes, especially the carnivores. This research has shown that mammals that might have gone locally extinct have been prevalent and important in Native American traditions. Research is now needed to investigate if there indeed has been or might be any effects on traditions due to these extinctions. Regardless, due to even the possibility that the traditions of local people might be adversely affected by the loss of species, conservationists might need to consider not only all the biological reasons to conserve, but also cultural ones.

Fusion inhibitors are a class of antiretroviral drugs used to prevent entry of HIV into host cells. Many of the fusion inhibitors being developed, including the drug enfuvirtide, are peptides designed to competitively inhibit the viral fusion protein gp41. With the emergence of drug resistance, there is an increased need for effective and unique alternatives within this class of antivirals. One such alternative is a class of cyclic, cationic, antimicrobial peptides known as θ-defensins, which are produced by many non-human primates and exhibit broad-spectrum antiviral and antibacterial activity. Currently, the θ-defensin analog RC-101 is being developed as a microbicide due to its specific antiviral activity, lack of toxicity to cells and tissues, and safety in animals. Understanding potential RC-101 resistance, and how resistance to other fusion inhibitors affects RC-101 susceptibility, is critical for future development. In previous studies, we identified a mutant, R5-tropic virus that had evolved partial resistance to RC-101 during in vitro selection. Here, we report that a secondary mutation in gp41 was found to restore replicative fitness, membrane fusion, and the rate of viral entry, which were compromised by an initial mutation providing partial RC-101 resistance. Interestingly, we show that RC-101 is effective against two enfuvirtide-resistant mutants, demonstrating the clinical importance of RC-101 as a unique fusion inhibitor. These findings both expand our understanding of HIV drug-resistance to diverse peptide fusion inhibitors and emphasize the significance of compensatory gp41 mutations.

Variation in genes underlying host immunity can lead to marked differences in susceptibility to HIV infection among humans. Despite heavy reliance on non-human primates as models for HIV/AIDS, little is known about which host factors are shared and which are unique to a given primate lineage. Here, we investigate whether copy number variation (CNV) at CCL3-like genes (CCL3L), a key genetic host factor for HIV/AIDS susceptibility and cell-mediated immune response in humans, is also a determinant of time until onset of simian-AIDS in rhesus macaques. Using a retrospective study of 57 rhesus macaques experimentally infected with SIVmac, we find that CCL3L CNV explains approximately 18% of the variance in time to simian-AIDS (p

Abstract Background CNS myelination disturbances commonly occur in chronic white matter lesions in neurodevelopmental and adult neurological disorders. Recent studies support that myelination failure can involve a disrupted cellular repair mechanism where oligodendrocyte (OL) progenitor cells (OPCs) proliferate in lesions with diffuse astrogliosis, but fail to fully differentiate to mature myelinating OLs. There are no in vitro models that reproduce these features of myelination failure. Results Forebrain coronal slices from postnatal day (P) 0.5/1 rat pups were cultured for 1, 5, or 9 days in vitro (DIV). Slices rapidly exhibited diffuse astrogliosis and accumulation of the extracellular matrix glycosaminoglycan hyaluronan (HA), an inhibitor of OPC differentiation and re-myelination. At 1 DIV ~1.5% of Olig2+ OLs displayed caspase-3 activation, which increased to ~11.5% by 9 DIV. At 1 DIV the density of PDGFRα+ and PDGFRα+/Ki67+ OPCs were significantly elevated compared to 0 DIV (P < 0.01). Despite this proliferative response, at 9 DIV ~60% of white matter OLs were late progenitors (preOLs), compared to ~7% in the postnatal day 10 rat (P < 0.0001), consistent with preOL maturation arrest. Addition of HA to slices significantly decreased the density of MBP+ OLs at 9 DIV compared to controls (217 ± 16 vs. 328 ± 17 cells/mm2, respectively; P = 0.0003), supporting an inhibitory role of HA in OL lineage progression in chronic lesions. Conclusions Diffuse white matter astrogliosis and early OPC proliferation with impaired OL maturation were reproduced in this model of myelination failure. This system may be used to define mechanisms of OPC maturation arrest and myelination failure related to astrogliosis and HA accumulation.

Background/objectives: Effective communication between patients and healthcare providers is essential for informed decision making in cancer care. Communication aids that can help prostate cancer patients optimize their involvement in treatment care planning are not widely used in the U.S. This research details the adaptation and validation process of a patient prompt list for localized prostate cancer patients undergoing treatment decisions., Methods: This process occurred in three steps: Step 1 involved gathering usable questions from the literature; in Step 2, we evaluated the tool's content via expert (N = 6) feedback; and in Step 3, we assessed the usefulness of the prompt list with patients (N = 30)., Results: Sixty percent of candidate questions (20/33) were retained for inclusion after achieving acceptable item-level content validity index (range: 0.83-1.00) and scale-level content validity index (S-CVI = 0.96) scores. The final 20 questions were classified into 5 domains (1: Treatment Options and Information, 2: Side Effects, Risks, and Recovery, 3: Emotional and Social Support, 4: Logistical and Practical Concerns, and 5: Future Health Considerations) through a card sorting exercise with a subset of patients (N = 3) and providers (N = 2). Most patients rated the prompt list as "useful or very useful" both to themselves (80%, N = 24) and to other men presenting with prostate cancer (83%, N = 25)., Conclusions: The participatory process used to develop and validate the prompt list offers insights for the development of similar tools.

Introduction: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. We examined the association of RAS inhibitors (RASi)-namely angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB)-with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) preceding radical cystectomy (RC)., Patients and Methods: We retrospectively investigated concurrent RASi use with NAC prior to RC in 302 patients with MIBC from 3 academic institutions. Outcomes included pathologic complete response (pCR) and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected., Results: Overall pCR rate was 26.2% and 5-year OS was 62%. Concurrent ACEi intake with NAC approached significance for association with pCR (odds ratio [OR] = 1.71; 95% CI, 0.94-3.11; P = .077). Patients with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% vs. 17.7%, P = .056) than those not on ACEi. Female sex had a statistically significant favorable interaction for pCR with ACEi intake (P = .044). ACEi intake was not associated with OS, while pCR, PS and lower clinical stage were significantly associated with improved OS., Conclusion: ACEi intake is potentially associated with increased pCR in patients with MIBC receiving NAC prior to RC, and this association is more pronounced in patients with higher clinical stage of disease at the initiation of therapy and female sex. Our data suggest the potential relevance of the RAS as a therapeutic target in aggressive MIBC., Competing Interests: Disclosure Parvaneh Fallah Scientific advisor/consultant: BMS, Seagen, Pfizer, Astrazeneca, EMD Sereno Canada Honoraria: Astrazeneca, EMD Sereno Canada, Gilead, Merck, Janssen Rohit K Jain Receiving honoraria from FLASCO, Curio Science, DAVA Oncology, NCCN/Pfizer, and OncLive/MJH Life Sciences Consulting for AVEO, Bristol Myers Squibb, Sanofi, EMD Serono, Gilead Sciences, IDEOlogy Pfizer, and Seattle Genetics/Astellas In the speakers’ bureau of Gilead Sciences, Seagen, and Seattle Genetics/Astellas Receiving research funding from Bristol Myers Squibb, Gilead Sciences, and NCI. Praful Ravi Research funding to institution: Lilly, Bayer, Telix Speaker's fees: OncLive Charlene Mantia Consulting/advisory role: Aadi Bioscience, Synthekine, Nextech Institutional research funding: Bristol Myers Squibb Bradley Alexander McGregor Received funds for consulting: Arcus, BMS, Eisai, Exelixis, Gliead, Pfizer, SeaGen Funding to institution - BMS, Exelixis, Gilead, Pfizer, SeaGen Roger Li Research support: Predicine; Veracyte; CG Oncology; Valar labs; Merck. Clinical trial protocol committee: CG Oncology; Merck; Janssen. Scientific advisor/consultant: BMS, Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, CG Oncology, Janssen, Thericon. Honoraria: SAI MedPartners, Solstice Health Communications, Putnam Associates, UroToday. Wassim Kassouf Consultant or advisory roles: Sesen Bio, Ferring, Roche, BMS, Merck, Janssen, Bayer, Astellas, Seagen, Pfizer/EMD Serono, Photocure Clinical trials: BMS, Roche, Janssen, Theralase, Pfizer, CG Oncology Gregory Russell Pond Received honorariums from Astra-Zeneca and Takeda Received consulting fees from Merck and Profound Medical. Close family member who is employed by Roche Canada, and who owns stock in Roche Ltd. Raskesh K. Jain Received consultant fees from Cur, DynamiCure, Elpis, Merck, SPARC, SynDevRx Owns equity in Accurius, Enlight, SynDevRx Served on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund Received grants from Boehringer Ingelheim and Sanofi. Research is supported by NIH R01CA259253, R01CA269672, R01-NS118929, U01CA261842, and grants from the National Foundation for Cancer Research, Jane's Trust Foundation, Niles Albright Research Foundation, and Harvard Ludwig Cancer Center. Guru Sonpavde Advisory Board: EMD Serono, BMS, Merck, Seattle Genetics/Astellas, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, Eli Lilly/Loxo Oncology, Vial, PrecisCa, Atkis, Kura Oncology, Daiichi-Sankyo Consultant/Scientific Advisory Board (SAB): Syapse, Merck, Servier, Syncorp Research Support to institution: EMD Serono, Jazz Therapeutics, BMS Speaker: Seagen, Gilead, Natera, Exelixis, Janssen, Astellas, Bayer, Aveo, Merck, Pfizer Data safety monitoring committee (honorarium): Mereo Employment: Spouse employed by Myriad Travel: BMS, Astellas, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To quantify the oncological risks of bladder-sparing therapy (BST) in patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) compared to upfront radical cystectomy (RC)., Patients and Methods: Pre-specified data elements were collected from retrospective cohorts of patients with BCG-unresponsive NMIBC from 10 international sites. After Institutional Review Board approval, patients were included if they had BCG-unresponsive NMIBC meeting United States Food and Drug Administration criteria. Oncological outcomes were collected following upfront RC or BST. BST regimens included re-resection or surveillance only, repeat BCG, intravesical chemotherapy, systemic immunotherapy, and clinical trials., Results: Among 578 patients, 28% underwent upfront RC and 72% received BST. The median (interquartile range) follow-up was 50 (20-69) months. There were no statistically significant differences in metastasis-free survival, cancer-specific survival, or overall survival between treatment groups. In the BST group, high-grade recurrence rates were 37% and 52% at 12 and 24 months and progression to MIBC was observed in 7% and 13% at 12 and 24 months, respectively. RC was performed in 31.7% in the BST group and nodal disease was found in 13% compared with 4% in upfront RC (P = 0.030)., Conclusion: In a selected cohort of patients, initial BST offers comparable survival outcomes to upfront RC in the intermediate term. Rates of recurrence and progression increase over time especially in patients treated with additional lines of BST., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: Intermittent androgen deprivation therapy (iADT) alleviates some side effects of continuous (c) ADT in patients with prostate cancer (PC), but its relative impact on ADT-associated comorbidities is uncertain. We assessed real-world use of iADT and cADT and associated risk of cardiovascular and endocrine/metabolic events in patients with nonmetastatic (nm) PC., Methods: This retrospective longitudinal cohort study included patients with nmPC initiating systemic ADT with gonadotropin-releasing hormone agonists (goserelin, histrelin, leuprolide, and triptorelin) or antagonists (degarelix) in the US Surveillance, Epidemiology and End Results-Medicare database (2010-2017), who had ≥ 36 months of continuous insurance coverage, unless death occurred, and did not receive chemotherapy or next-generation hormonal therapies during follow-up (through 2019). Risk of major adverse cardiovascular events (MACE [myocardial infarction, stroke, cardiomyopathy/heart failure, pulmonary embolism, ischemic heart disease, all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, and osteoporosis) were examined between cohorts. Inverse probability of treatment-weighted Cox regression models estimated adjusted hazard ratios (HRs) of the outcomes., Results: Of 10,655 eligible patients, 2,095 (19.7%) received iADT and 8,560 (80.3%) cADT. Median follow-up was 43.9 and 48.4 months and median ADT duration (excluding iADT gaps) was 22.0 and 13.5 months for the iADT and cADT cohorts, respectively. Patients receiving cADT had a lower risk of MACE vs. iADT (HR 0.90; 95% confidence interval [CI] 0.83-0.96). No difference in risk of endocrine/metabolic events was observed (HR 0.97; 95% CI 0.92-1.03). Subgroup analysis found that the difference in MACE was maintained in patients with a history of cardiovascular disease (HR 0.90; 95% CI 0.83-0.98) and eliminated in patients without (HR 0.94; 95% CI 0.82-1.08)., Conclusions: Patients with nmPC who received cADT had a lower risk of MACE and similar risk of endocrine/metabolic events vs. those who received iADT. Further research assessing both regimens is needed to inform treatment decisions., Competing Interests: Declaration of competing interest MAP reports a consultancy role for Bayer and Pfizer Inc.; research funding from Merck and Progenics Pharmaceuticals Inc. RE reports honoraria from Chiesi, Sumitomo Pharma America, Inc. (formerly Myovant Sciences, Inc.), and Novo Nordisk; consultancy role for Novo Nordisk; speaker's bureau for Chiesi and Novo Nordisk; research funding from Boehringer Ingelheim. PB, RD, and MSD report being employees of Analysis Group Inc. which received funding from Pfizer Inc. to conduct and report on the study. RG and RD report being employees of Myovant Sciences, Inc., with stock ownership in Myovant Sciences, Inc., at the time of the study. SH and AH report being employees of Pfizer Inc., with stock ownership in Pfizer Inc. AKM reports speaker's bureau for Advanced Accelerator Applications, Astellas Scientific and Medical Affairs, Inc., Astellas Pharma Inc., AstraZeneca, Bayer, Clovis Oncology, Exelixis, Genentech, Janssen, Janssen Oncology, Merck, Sumitomo Pharma America, Inc. (formerly Myovant Sciences, Inc.), Sanofi, and Pfizer Inc.; consultancy role or advisory role for  Advanced Accelerator Applications, Astellas Pharma Inc., AstraZeneca, Bayer, Bayer, Blue Earth Diagnostics Ltd, Exelixis, Janssen, Lantheus Medical Imaging, Inc., Sumitomo Pharma America, Inc. (formerly Myovant Sciences, Inc.), Myriad Genetics, Merck, Novartis, and Sanofi; research funding from AstraZeneca, Astellas Scientific and Medical Affairs, Inc., Bayer, Dendreon Pharmaceuticals LLC, Genentech, Inc., Sumitomo Pharma America, Inc. (formerly Myovant Sciences, Inc.), Sanofi, and Seattle Genetics, Inc./Astellas Pharma Inc.; and travel, accommodations, and expenses from Sanofi., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Family history and germline genetic risk single nucleotide polymorphisms (SNPs) have been separately shown to stratify lifetime risk of prostate cancer. Here, we evaluate the combined prognostic value of family history of prostate and other related cancers and germline risk SNPs among patients with favorable-risk prostate cancer., Materials and Methods: A total of 1367 participants from the prospective Health Professionals Follow-up Study diagnosed with low- or favorable intermediate-risk prostate cancer from 1986 to 2017 underwent genome-wide SNP genotyping. Multivariable Cox regression was used to estimate the association between family history, specific germline risk variants, and a 269 SNP polygenic risk score with prostate cancer‒specific death., Results: Family history of prostate, breast, and/or pancreatic cancer was observed in 489 (36%) participants. With median follow-up from diagnosis of 14.9 years, participants with favorable-risk prostate cancer with a positive family history had a significantly higher risk of prostate cancer‒specific death (HR 1.95, 95% CI 1.15-3.32, P = .014) compared to those without any family history. The rs2735839 (19q13) risk allele was associated with prostate cancer‒specific death (HR 1.81 per risk allele, 95% CI 1.04-3.17, P = .037), whereas the polygenic risk score was not. Combined family history and rs2735839 risk allele were each associated with an additive risk of prostate cancer‒specific death (HR 1.78 per risk factor, 95% CI 1.25-2.53, P = .001)., Conclusions: Family history of prostate, breast, or pancreatic cancer and/or a 19q13 germline risk allele are associated with an elevated risk of prostate cancer‒specific death among favorable-risk patients. These findings have implications for how family history and germline genetic risk SNPs should be factored into clinical decision-making around favorable-risk prostate cancer.

Background: Patients with localized, unfavorable intermediate-risk and high-risk prostate cancer have an increased risk of relapse after radical prostatectomy (RP). The authors previously reported on part 1 of this phase 2 trial testing neoadjuvant apalutamide, abiraterone, prednisone, plus leuprolide (AAPL) or abiraterone, prednisone, and leuprolide (APL) for 6 months followed by RP. The results demonstrated favorable pathologic responses (tumor <5 mm) in 20.3% of patients (n = 24 of 118). Herein, the authors report the results of part 2., Methods: For part 2, patients were randomized 1:1 to receive either AAPL for 12 months (arm 2A) or observation (arm 2B), stratified by neoadjuvant therapy and pathologic tumor classification. The primary end point was 3-year biochemical progression-free survival. Secondary end points included safety and testosterone recovery (>200 ng/dL)., Results: Overall, 82 of 118 patients (69%) enrolled in part 1 were randomized to part 2. A higher proportion of patients who were not randomized to adjuvant therapy had a favorable prostatectomy pathologic response (32.3% in nonrandomized patients compared with 17.1% in randomized patients). In the intent-to-treat analysis, the 3-year biochemical progression-free survival rate was 81% for arm 2A and 72% for arm 2B (hazard ratio, 0.81; 90% confidence interval, 0.43-1.49). Of the randomized patients, 81% had testosterone recovery in the AAPL group compared with 95% in the observation group, with a median time to recovery of <12 months in both arms., Conclusions: In this study, because 30% of patients declined adjuvant treatment, part B was underpowered to detect differences between arms. Future perioperative studies should be biomarker-directed and include strategies for investigator and patient engagement to ensure compliance with protocol procedures., (© 2024 American Cancer Society.)

Bladder cancer, the sixth most common cancer in the United States, is most commonly of the urothelial carcinoma histologic subtype. The clinical spectrum of bladder cancer is divided into 3 categories that differ in prognosis, management, and therapeutic aims: (1) non-muscle-invasive bladder cancer (NMIBC); (2) muscle invasive, nonmetastatic disease; and (3) metastatic bladder cancer. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Bladder Cancer, including changes in the fifth edition of the WHO Classification of Tumours: Urinary and Male Genital Tumours and how the NCCN Guidelines aligned with these updates; new and emerging treatment options for bacillus Calmette-Guérin (BCG)-unresponsive NMIBC; and updates to systemic therapy recommendations for advanced or metastatic disease.

Background: Colorectal cancer screening rates remain suboptimal, particularly among low-income populations. Our objective was to evaluate the long-term effects of Medicaid expansion on colorectal cancer screening., Design, Setting, and Participants: This cross-sectional study analyzed data from 354,384 individuals aged 50-64 with an income below 400% of the federal poverty level (FPL), who participated in the Behavioral Risk Factors Surveillance System from 2010 to 2018. A difference-in-difference analysis was employed to estimate the effect of Medicaid expansion on colorectal cancer screening. Subgroup analyses were conducted for individuals with income up to 138% of the FPL and those with income between 139% and 400% of the FPL. The effect of Medicaid expansion on colorectal cancer screening was examined during the early, mid, and late expansion periods., Main Outcomes and Measures: The primary outcome was the likelihood of receiving colorectal cancer screening for low-income adults aged 50-64., Results: Medicaid expansion was associated with a significant 1.7 percentage point increase in colorectal cancer screening rates among adults aged 50-64 with income below 400% of the FPL (p < 0.05). A significant 2.9 percentage point increase in colorectal cancer screening was observed for those with income up to 138% the FPL (p < 0.05), while a 1.5 percentage point increase occurred for individuals with income between 139% and 400% of the FPL. The impact of Medicaid expansion on colorectal cancer screening varied based on income levels and displayed a time lag for newly eligible beneficiaries., Conclusions: Medicaid expansion was found to be associated with increased colorectal cancer screening rates among low-income individuals aged 50-64. The observed variations in impact based on income levels and the time lag for newly eligible beneficiaries receiving colorectal cancer screening highlight the need for further research and precision public health strategies to maximize the benefits of Medicaid expansion on colorectal cancer screening rates., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives:  Our objective was to pilot test an electronic health record-embedded decision support tool to facilitate prostate-specific antigen (PSA) screening discussions in the primary care setting., Methods:  We pilot-tested a novel decision support tool that was used by 10 primary care physicians (PCPs) for 6 months, followed by a survey. The tool comprised (1) a risk-stratified algorithm, (2) a tool for facilitating shared decision-making (Simple Schema), (3) three best practice advisories (BPAs: <45, 45-75, and >75 years), and (4) a health maintenance module for scheduling automated reminders about PSA rescreening., Results:  All PCPs found the tool feasible, acceptable, and clear to use. Eight out of ten PCPs reported that the tool made PSA screening conversations somewhat or much easier. Before using the tool, 70% of PCPs felt confident in their ability to discuss PSA screening with their patient, and this improved to 100% after the tool was used by PCPs for 6 months. PCPs found the BPAs for eligible (45-75 years) and older men (>75 years) more useful than the BPA for younger men (<45 years). Among the 10 PCPs, 60% found the Simple Schema to be very useful, and 50% found the health maintenance module to be extremely or very useful. Most PCPs reported the components of the tool to be at least somewhat useful, with 10% finding them to be very burdensome., Conclusion:  We demonstrated the feasibility and acceptability of the tool, which is notable given the marked low acceptance of existing tools. All PCPs reported that they would consider continuing to use the tool in their clinic and were likely or very likely to recommend the tool to a colleague., Competing Interests: S.V.C. has received travel reimbursement and speaker honorarium from Ipsen and has served on an advisory board, unrelated to the present study. The authors have no other potential conflicts of interest to disclose., (Thieme. All rights reserved.)

Information seeking anxiety is a multidimensional construct that is operationalized as having elements of worry, confusion, and disorganization. Much remains unknown about the ways information seeking anxiety operates among cancer patients in the United States. This study investigated the application of the information seeking anxiety concept among prostate cancer patients by documenting their assessment experiences and examining relationships between information seeking anxiety and treatment information search behaviors. A purposive sample of African American and Caucasian men ( N = 63) within 5 years of being diagnosed with localized disease (stage T1 or T2) were recruited to participate through cancer registries, advertisements, and word-of-mouth. Participants completed a self-administered survey with items that collected demographic information, treatment information-seeking behaviors, and information seeking anxiety evaluations. All surveys were completed in one sitting and a majority of men (82.5%, N = 52) completed the information seeking anxiety assessment with no assistance. During their first interactions with available sources of information (e.g., doctors, internet, peers), most survivors (95.2%, N = 60) reported some level of information seeking anxiety. Specifically, 55.5% ( N = 35) were confused about what to look for, 60.3% ( N = 38) were worried they would not find the right information, 55.5% ( N = 35) were uncomfortable with the search process, and 49.2% ( N = 31) reported being disorganized. The composite information seeking anxiety measure was moderately correlated with men's self-reported time to start searching for treatment information ( p = .02; r = .306). Information seeking anxiety appears to delay the treatment information gathering activities of prostate cancer survivors with localized disease. This previously undocumented barrier to the delivery of prostate cancer care services should be investigated in other studies with larger and more diverse samples., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

To assess the clinical impact of delayed testosterone recovery (TR) following the discontinuation of medical androgen deprivation therapy (ADT), a retrospective, longitudinal analysis was conducted in adult males with prostate cancer using the Optum® de-identified Electronic Health Record data set and Optum® Enriched Oncology Data (2010-2021). Of 3875 patients who initiated and discontinued ADT, 1553 received one or more testosterone-level tests within the 12 mo following discontinuation and were included in this study. These 1553 patients were categorized into two cohorts: 25% as TR (testosterone levels >280 ng/dl at any test within 12 mo following ADT discontinuation) and 75% as non-TR. At baseline, non-TR patients were older, had lower testosterone levels, and were more likely to have diabetes, hyperlipidemia, and hypertension, but less likely to have sexual dysfunction. After adjustment for baseline characteristics, the TR cohort had a lower risk of new-onset diabetes (hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.27-0.79), trended toward a lower risk of new-onset depression (HR 0.58; 95% CI 0.33-1.02), and had a higher likelihood of seeking treatment for sexual dysfunction (HR 1.33; 95% CI 0.99-1.78) versus the non-TR cohort. These findings support monitoring testosterone levels after ADT discontinuation to manage potential long-term comorbidities in patients with prostate cancer., Patient Summary: This real-world analysis of males with prostate cancer who were treated with medical androgen deprivation therapy (ADT) found that most patients did not have their testosterone level checked in the 12 mo after stopping ADT. Of those who did, 75% did not achieve normal testosterone levels (>280 ng/dl), and these patients were more likely to experience new-onset diabetes than those who achieved normal testosterone levels. These results suggest that to ensure effective clinical decision-making, physicians should check patients' testosterone levels after stopping ADT., (© 2023 Published by Elsevier B.V. on behalf of European Association of Urology.)

Background: Prostate cancer is the most diagnosed cancer in African American men, yet prostate cancer screening regimens in this group are poorly guided by existing evidence, given underrepresentation of African American men in prostate cancer screening trials. It is critical to optimize prostate cancer screening and early detection in this high-risk group because underdiagnosis may lead to later-stage cancers at diagnosis and higher mortality while overdiagnosis may lead to unnecessary treatment., Methods: We performed a review of the literature related to prostate cancer screening and early detection specific to African American men to summarize the existing evidence available to guide health-care practice., Results: Limited evidence from observational and modeling studies suggests that African American men should be screened for prostate cancer. Consideration should be given to initiating screening of African American men at younger ages (eg, 45-50 years) and at more frequent intervals relative to other racial groups in the United States. Screening intervals can be optimized by using a baseline prostate-specific antigen measurement in midlife. Finally, no evidence has indicated that African American men would benefit from screening beyond 75 years of age; in fact, this group may experience higher rates of overdiagnosis at older ages., Conclusions: The evidence base for prostate cancer screening in African American men is limited by the lack of large, randomized studies. Our literature search supported the need for African American men to be screened for prostate cancer, for initiating screening at younger ages (45-50 years), and perhaps screening at more frequent intervals relative to men of other racial groups in the United States., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Human papillomavirus (HPV) is the most common sexually transmitted infection (STI). To address STIs, one rural county public school district developed a series of Family Life Programs to educate pre-teens about pertinent health information. The Schooling Cancer Program (SCP) was developed in partnership with the local Cancer Research and Resource Center to raise awareness about cancer risk factors including HPV-related cancers and HPV prevention methods., Methods: We collected a post-evaluation survey from students who attended a SCP session at one of the targeted middle schools. The SCP educated students about topics focusing on healthy lifestyles. The survey asked students' knowledge on the SCP topics, HPV knowledge, tobacco usage, and factors that reduced cancer development., Results: 87% agreed that tobacco products are associated with cancer, and 81% did not agree that E-cigarettes are scientifically proven to be safer than cigarettes. Although we do not have pre-evaluation data about these students' HPV knowledge, our evaluation survey shows that 80% of students correctly identified HPV as the most common STI, and 84% of students correctly identified the factors that decrease their risk of developing cancer., Conclusion: Through this initiative, students learned essential health concepts and HPV-related risk factors., Competing Interests: Conflict of interest The authors declare no potential conflicts of interest.

Introduction: Robot-assisted laparoscopic prostatectomy (RALP) and transurethral resection of bladder tumor (TURBT) are two common surgeries for prostate and bladder cancer. We aim to assess the trends in the site of care for RALP and TURBT before and after the COVID outbreak., Materials and Methods: We identified adults who underwent RALP and TURBT within the California Healthcare Cost and Utilization Project State Inpatient Database and the State Ambulatory Surgery Database between 2018 and 2020. Multivariable analysis and spline analysis with a knot at COVID outbreak were performed to investigate the time trend and factors associated with ambulatory RALP and TURBT., Results: Among 17,386 RALPs, 6,774 (39.0%) were ambulatory. Among 25,070 TURBTs, 21,573 (86.0%) were ambulatory. Pre-COVID, 33.5% of RALP and 85.3% and TURBT were ambulatory, which increased to 53.8% and 88.0% post-COVID (both p < 0.001). In multivariable model, RALP and TURBT performed after outbreak in March 2020 were more likely ambulatory (OR 2.31, p < 0.0001; OR 1.25, p < 0.0001). There was an overall increasing trend in use of ambulatory RALP both pre- and post-COVID, with no significant change of trend at the time of outbreak (p = 0.642). TURBT exhibited an increased shift towards ambulatory sites post-COVID (p < 0.0001)., Conclusions: We found a shift towards ambulatory RALP and TURBT following COVID outbreak. There was a large increase in ambulatory RALP post-COVID, but the trend of change was not significantly different pre- and post-COVID - possibly due to a pre-existing trend towards ambulatory RALP which predated the pandemic.

Importance: The effect of testosterone replacement therapy (TRT) on the risk of prostate cancer and other adverse prostate events is unknown., Objective: To compare the effect of TRT vs placebo on the incidences of high-grade prostate cancers (Gleason score ≥4 + 3), any prostate cancer, acute urinary retention, invasive prostate procedures, and pharmacologic treatment for lower urinary tract symptoms in men with hypogonadism., Design, Setting, and Participants: This placebo-controlled, double-blind randomized clinical trial enrolled 5246 men (aged 45-80 years) from 316 US trial sites who had 2 testosterone concentrations less than 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. Men with prostate-specific antigen (PSA) concentrations greater than 3.0 ng/mL and International Prostate Symptom Score (IPSS) greater than 19 were excluded. Enrollment took place between May 23, 2018, and February 1, 2022, and end-of-study visits were conducted between May 31, 2022, and January 19, 2023., Intervention: Participants were randomized, with stratification for prior CVD, to topical 1.62% testosterone gel or placebo., Main Outcomes and Measures: The primary prostate safety end point was the incidence of adjudicated high-grade prostate cancer. Secondary end points included incidence of any adjudicated prostate cancer, acute urinary retention, invasive prostate surgical procedure, prostate biopsy, and new pharmacologic treatment. Intervention effect was analyzed using a discrete-time proportional hazards model., Results: A total of 5204 men (mean [SD] age, 63.3 [7.9] years) were analyzed. At baseline, the mean (SD) PSA concentration was 0.92 (0.67) ng/mL, and the mean (SD) IPSS was 7.1 (5.6). The mean (SD) treatment duration as 21.8 (14.2) months in the TRT group and 21.6 (14.0) months in the placebo group. During 14 304 person-years of follow-up, the incidence of high-grade prostate cancer (5 of 2596 [0.19%] in the TRT group vs 3 of 2602 [0.12%] in the placebo group; hazard ratio, 1.62; 95% CI, 0.39-6.77; P = .51) did not differ significantly between groups; the incidences of any prostate cancer, acute urinary retention, invasive surgical procedures, prostate biopsy, and new pharmacologic treatment also did not differ significantly. Change in IPSS did not differ between groups. The PSA concentrations increased more in testosterone-treated than placebo-treated men., Conclusions and Relevance: In a population of middle-aged and older men with hypogonadism, carefully evaluated to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer and other prostate events were low and did not differ significantly between testosterone- and placebo-treated men. The study's findings may facilitate a more informed appraisal of the potential risks of TRT., Trial Registration: ClinicalTrials.gov Identifier: NCT03518034.

Purpose: Bacillus Calmette-Guerin (BCG) is the standard of care for high-risk nonmuscle invasive bladder cancer (NMIBC), but half of patients develop disease recurrence. Intravesical regimens for BCG unresponsive NMIBC are limited. We report the safety, efficacy, and differential response of sequential gemcitabine/docetaxel (gem/doce) depending on BCG failure classification., Methods: Multi-institutional retrospective analysis of patients treated with induction intravesical gem/doce (≥5/6 instillations) for recurrent high-risk NMIBC after BCG therapy from May 2018 to December 2021. Maintenance therapy was provided to those without high-grade (HG) recurrence on surveillance cystoscopy. Kaplan-Meier curves and Cox regression analyses were utilized to assess survival and risk factors for disease recurrence., Results: Our cohort included 102 patients with BCG-unresponsive NMIBC. Median age was 72 years and median follow-up was 18 months. Six-, 12-, and 24-month high-grade recurrence-free survival was 78%, 65%, and 49%, respectively. Twenty patients underwent radical cystectomy (median 15.5 months from induction). Six patients progressed to muscle invasive disease. Fifty-seven percent of patients experienced mild/moderate adverse effects (AE), but only 6.9% experienced a delay in treatment schedule. Most common AE were urinary frequency/urgency (41%) and dysuria (21%). Patients with BCG refractory disease were more likely to develop HG recurrence when compared to patients with BCG relapsing disease (HR 2.14; 95% CI 1.02-4.49)., Conclusions: In patients with recurrence after BCG therapy, sequential intravesical gem/doce is an effective and well-tolerated alternative to early cystectomy. Patients with BCG relapsing disease are more likely to respond to additional intravesical gem/doce. Further investigation with a prospective trial is imperative., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Radical cystectomy (RC) is an integral part of the management of patients with advanced-stage bladder cancer. This major oncologic operation is prone to complications resulting in morbidity and mortality. We analyzed the critical steps of open RC, performed an evidence-based review of these steps, and discussed our experience and approach. We conducted a literature review of the open RC technique, identified the critical steps that consistently appeared across different sources, and organized these steps into a framework. PubMed was queried with the critical steps as keywords for relevant articles published from 1 January 2013 to 1 August 2023. We utilized this query to conduct a systematic review of the literature using the outcomes of overall survival and 90-day complication rate. We developed the "Summary for the 10 Critical Operative Steps of Radical Cystectomy", a concise guide to the approach to open RC. When available, an evidence-based analysis of each critical step was performed. We also included additional components of cystectomy optimization such as pre-habilitation in the preoperative phase, standard versus extended lymphadenectomy, the vaginal-sparing approach to female radical cystectomy, patient-reported outcomes following urinary diversion, the use of a mesh for stoma formation, and the use of the ERAS protocol for postoperative care. An evidence-based assessment of RC may help provide valuable information to optimize surgical techniques and patient outcomes.

Background: Radiohybrid (rh) 18 F-rhPSMA-7.3 is a novel high-affinity prostate-specific membrane antigen (PSMA)-targeting radiopharmaceutical for prostate cancer (PCa) imaging., Objective: To evaluate the diagnostic performance and safety of 18 F-rhPSMA-7.3 in newly diagnosed PCa patients planned for prostatectomy., Design, Setting, and Participants: Data on 18 F-rhPSMA-7.3 were reported from the phase 3 prospective, multicentre LIGHTHOUSE study (NCT04186819)., Outcome Measurements and Statistical Analysis: Patients underwent positron emission tomography/computed tomography (PET/CT) 50-70 min after an injection of 296 MBq 18 F-rhPSMA-7.3. Images were interpreted locally and by three blinded independent readers. The coprimary endpoints were patient-level sensitivity and specificity for the detection of pelvic lymph node (PLN) metastases, validated using histopathology at PLN dissection. Prespecified statistical thresholds (lower bounds of 95% confidence interval [CI]) were set at 22.5% for sensitivity and 82.5% for specificity., Results and Limitations: Of 372 patients screened, 352 had evaluable 18 F-rhPSMA-7.3-PET/CT and 296 (99 [33%] with unfavourable intermediate-risk [UIR] and 197 [67%] with high-/very-high-risk [VHR] PCa) subsequently underwent surgery. As per the independent reads, 23-37 (7.8-13%) patients had 18 F-rhPSMA-7.3-positive PLN. Seventy (24%) patients had one or more positive PLNs on histopathology. The sensitivity for PLN detection was 30% (95% CI, 19.6-42.1%) for reader 1, 27% (95% CI, 17.2-39.1%) for reader 2, and 23% (95% CI, 13.7-34.4%) for reader 3, not meeting the prespecified threshold. Specificity was 93% (95% CI, 88.8-95.9%), 94% (95% CI, 89.8-96.6%), and 97% (95% CI, 93.7-98.7%), respectively, exceeding the threshold for all readers. Specificity was high (≥92%) across both risk stratifications. Sensitivity was higher among high-risk/VHR (24-33%) than among UIR (16-21%) patients. Extrapelvic (M1) lesions were reported for 56-98/352 (16-28%) patients who underwent 18 F-rhPSMA-7.3-PET/CT irrespective of surgery. Verification of these (predominantly by conventional imaging) gave a verified detection rate of 9.9-14% (positive predictive value, 51-63%). No serious adverse events were observed., Conclusions: Across all risk stratifications, 18 F-rhPSMA-7.3-PET/CT had high specificity, meeting the specificity endpoint. The sensitivity endpoint was not met, although higher sensitivity was noted among high-risk/VHR than among UIR patients. Overall, 18 F-rhPSMA-7.3-PET/CT was well tolerated, and identified N1 and M1 disease prior to surgery in newly diagnosed PCa patients., Patient Summary: In order to select the most appropriate treatment for patients with prostate cancer, it is critical to diagnose the disease burden accurately at initial diagnosis. In this study, we investigated a new diagnostic imaging agent in a large population of men with primary prostate cancer. We found it to have an excellent safety profile and to provide clinically useful information regarding the presence of disease beyond the prostate., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: We studied whether adding percent free PSA to total PSA improves prediction of clinically significant prostate cancer and fatal prostate cancer., Materials and Methods: A total of 6,727 men within the intervention arm of PLCO (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial) had baseline percent free PSA. Of this cohort, 475 had clinically significant prostate cancer and 98 had fatal prostate cancer. Cumulative incidence and Cox analyses were conducted to evaluate the association between percent free PSA/PSA and clinically significant prostate cancer/fatal prostate cancer. Harrell's C index evaluated predictive ability. Kaplan-Meier analysis assessed survival., Results: Median follow-up was 19.7 years, median baseline PSA was 1.19 ng/mL, median percent free PSA was 18%. Cumulative incidence of fatal prostate cancer for men with baseline PSA ≥2 ng/mL and percent free PSA ≤10 was 3.2% and 6.1% at 15 and 25 years, respectively, compared to 0.03% and 1.1% for men with percent free PSA >25%. In younger men (55-64 years) with baseline PSA 2-10 ng/mL, C index improved from 0.56 to 0.60 for clinically significant prostate cancer and from 0.53 to 0.64 for fatal prostate cancer with addition of percent free PSA. In older men (65-74 years), C index improved for clinically significant prostate cancer from 0.60 to 0.66, with no improvement in fatal prostate cancer. Adjusting for age, digital rectal exam, family history of prostate cancer, and total PSA, percent free PSA was associated with clinically significant prostate cancer (HR 1.05, P < .001) per 1% decrease. Percent free PSA improved prediction of clinically significant prostate cancer and fatal prostate cancer for all race groups., Conclusions: In a large U.S. screening trial, the addition of percent free PSA to total PSA in men with baseline PSA ≥2 ng/mL improved prediction of clinically significant prostate cancer and fatal prostate cancer. Free PSA should be used to risk-stratify screening and decrease unnecessary prostate biopsies.

Background: The association between statin use and risk of renal cell carcinoma (RCC) has been debated. We aimed to evaluate whether statin use is associated with RCC risk. Material and methods: We studied 100,195 women in the Nurses' Health Study (NHS) from 1994 to 2016; 91,427 women in the Nurses' Health Study II (NHS II) from 1999 to 2015; and 45,433 men in the Health Professionals Follow-up Study (HPFS) from 1990 to 2016. Statins and covariate data were collected at baseline and then biennially. Outcome was measured as incidence of total RCC and clinically relevant disease subgroups. Cox proportional hazards models estimated covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During follow-up, 661 participants developed RCC. There was no significant association between the use of statins and the risk of overall RCC, fatal RCC, or advanced or localized disease. Across cohorts, the adjusted HR for ever vs. never users was 0.97 (95% CI 0.81-1.16). Female ever users of statins were at increased risk of high-grade disease in the NHS only (HR 1.75, 95% CI 1.07-2.85). Among men only, ≥4 years of statin use was associated with an increased risk of clear cell RCC (HR 1.65, 95% CI 1.10-2.47). Conclusions: Statin use was not associated with the overall risk of RCC. However, it was associated with an increased risk of high-grade disease among women in the NHS cohort and an increased risk of clear cell RCC among men. The reasons for these inconsistent results by sex are unclear.

Purpose: To report the trends, predictors, and patient outcomes of same-day discharge (SDD) versus non-SDD for robot-assisted laparoscopic radical prostatectomy (RALP)., Materials and Methods: We queried our centralized data warehouse to identify men with prostate cancer who underwent RALP between January 2020 and May 2022. Patient demographics and clinical characteristics were compared between SDD and non-SDD. Then, we examined the utilization of SDD in a univariable logistic regression. Then, we fitted a logistic regression model to identify the predictors of SDD. To examine the safety profile of SDD, an inverse probability of treatment weighting (IPTW) adjusted logistic regression was fitted to examine the effect of SDD on 30-day postoperative complications and readmissions., Results: Overall, 1,153 patients underwent RALP, of which 224 (19.4%) were SDD. The proportion of SDD increased from 4.4% in the fourth quarter of 2020 to 45% in the second quarter of 2022 (p < 0.01). The predictors of SDD were the facility where the surgery was performed (OR: 1.57; 95%CI [1.08-2.28]; p = 0.02) and whether a high-volume surgeon performed it (OR: 1.96; 95%CI [1.09-3.54]; p = 0.03). After IPTW, SDD compared to non-SDD was not associated with a difference in complications (OR: 1.07; 95%CI [0.38-2.95]; p = 0.90) or readmissions (OR: 1.22; 95%CI [0.40-3.74]; p = 0.72)., Conclusion: In our health system, the use of SDD is safe and currently composes of half of our RALP volume. With the advent of the hospital-at-home services, we anticipate that almost all our RALP cases will be SDD., Competing Interests: Declaration of Competing Interest APC reports research funding from the American Cancer Society and Pfizer Global Medical Grants. ASK reports consulting fees from Profound, Janssen, Merck, Bayer, Cellvax, Candel, Bristle-Meyer Squibb QDT reports personal fees from Astellas, Bayer, and Janssen outside the submitted work and research funding from the American Cancer Society and Pfizer Global Medical Grants., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Context: Patients undergoing radical cystectomy frequently suffer from infectious complications, including urinary tract infections (UTIs) and surgical site infections (SSIs) leading to emergency department visits, hospital readmission, and added cost., Objective: To summarize the literature regarding perioperative antibiotic prophylaxis, ureteric stent usage, and prevalence of infectious complications after cystectomy., Evidence Acquisition: A systematic review of PubMed/Medline, EMBASE, Cochrane Library, and reference lists was conducted., Evidence Synthesis: We identified 20 reports including a total of 55 306 patients. The median rates of any infection, UTIs, SSIs, and bacteremia were 40%, 20%, 11%, and 6%, respectively. Perioperative antibiotic prophylaxis differed substantially between reports. Perioperative antibiotics were used only during surgery in one study but were continued over several days after surgery in all other studies. Empirical use of antibiotics for 1-3 d after surgery was described in 12 studies, 3-10 d in two studies, and >10 d in four studies. Time to stent removal ranged from 4 to 25 d after cystectomy. Prophylactic antibiotics were used before stent removal in nine of 20 studies; two of these studies used targeted antibiotics based on urine cultures from the ureteric stents, and the other seven studies used a single shot or 2 d of empirical antibiotics. Studies with any prophylactic antibiotic before stent removal found a lower median percentage of positive blood cultures after stent removal than studies without prophylactic antibiotics before stent removal (2% vs 9%)., Conclusions: We confirmed a high proportion of infectious complications after cystectomy, and a heterogeneous pattern of choice and duration of antibiotics during and after surgery or stent removal. These findings highlight a need for further studies and support quality prospective trials., Patient Summary: In this review, we observed wide variability in the use of antibiotics before or after surgical removal of the bladder., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Men with a low prostate-specific antigen (PSA) level (<1 ng/ml) in midlife may extend the rescreening interval (if aged 40-59 yr) or forgo future PSA screening (if aged >60 yr) owing to their low risk of aggressive prostate cancer (PCa). However, there is a subset of men who develop lethal PCa despite low baseline PSA. We investigated how a PCa polygenic risk score (PRS) in addition to baseline PSA impacts the prediction of lethal PCa among 483 men aged 40-70 yr from the Physicians' Health Study followed over a median of 33 yr. We examined the association of the PRS with the risk of lethal PCa (lethal cases vs controls) using logistic regression adjusted for baseline PSA. The PCa PRS was associated with risk of lethal PCa (odds ratio per 1 standard deviation in PRS [OR] 1.79, 95% confidence interval [CI] 1.28-2.49). The association between the PRS and lethal PCa was stronger for those with PSA <1 ng/ml (OR 2.23, 95% CI 1.19-4.21) than for men with PSA ≥1 ng/ml (OR 1.61, 95% CI 1.07-2.42). Our PCa PRS improved the identification of men with PSA <1 ng/ml at greater risk of future lethal PCa who should consider ongoing PSA testing., Patient Summary: A subset of men develop fatal prostate cancer despite having low prostate-specific antigen (PSA) levels in middle age. A risk score based on multiple genes can help in predicting men who may be at risk of developing lethal prostate cancer and who should be advised to have regular PSA measurements., (© 2023 The Authors.)

Background: Since tobacco smoking represents the most established risk factor for bladder cancer, we sought to assess the ecological association between tobacco smoking prevalence and bladder cancer incidence and to contrast it with lung cancer., Methods: The annual overall tobacco smoking prevalence rates were extracted from the Report of the Surgeon General and the Center for Disease Control between 1953 and 1983. The overall age-adjusted incidence rates for bladder and lung cancers were derived from the Surveillance, Epidemiology, and End Results database between 1983 and 2013 (30-year latency period). Weighted least square regression models were used to assess bladder and lung cancer incidence rate differences (IRD) related to trends in tobacco smoking prevalence. A Wald test was used to compare whether the prevalence of tobacco smoking, as an explanatory variable, differentially predicts bladder versus lung cancer incidence rates., Results: The associations between tobacco smoking prevalence and bladder cancer incidence were not significant in the overall (IRD = +0.04; 95%CI (-0.14; +0.22); p = 0.63), male (IRD = +0.07; 95%CI (-0.09; +0.23); p = 0.37), or female (IRD = +0.12; 95%CI (-0.01; +0.25); p = 0.06) populations. There was an association between tobacco smoking prevalence and lung cancer incidence in the overall (IRD: +3.55; 95%CI ( +3.09; +4.00); p < 0.001), male (IRD: +4.82; 95%CI (+4.44; +5.20); p < 0.001), and female (IRD: +3.55; 95%CI (+3.12; +3.99); p < 0.001) populations. The difference between the observed associations of tobacco smoking prevalence with bladder versus lung cancer incidence was also significant in all examined populations ( p < 0.001)., Conclusions: Variations in tobacco smoking prevalence only partially explained the trends in the incidence of bladder cancer, indicating that its etiology is complex.

Disparities in colorectal cancer (CRC) incidence and mortality persist in rural and underserved communities. Our Community Outreach and Engagement (COE) activities are grounded in a bi-directional Community-to-Bench model in which the National Outreach Network Community Health Educator (NON CHE) Screen to Save (S2S) initiative was implemented. In this study, we assessed the impact of the NON CHE S2S in rural and underserved communities. Descriptive and comparative analyses were used to examine the role of the NON CHE S2S on CRC knowledge and CRC screening intent. Data included demographics, current CRC knowledge, awareness, and future CRC health plans. A multivariate linear regression was fit to survey scores for CRC knowledge. The NON CHE S2S engaged 441 participants with 170 surveys completed. The difference in participants' CRC knowledge before and after the NON CHE S2S intervention had an overall mean of 0.92 with a standard deviation of 2.56. At baseline, White participants had significantly higher CRC knowledge scores, correctly answering 1.94 (p = 0.007) more questions on average than Black participants. After the NON CHE S2S intervention, this difference was not statistically significant. Greater than 95% of participants agreed that the NON CHE S2S sessions impacted their intent to get screened for CRC. Equity of access to health information and the health care system can be achieved with precision public health strategies. The COE bi-directional Community-to-Bench model facilitated community connections through the NON CHE and increased awareness of CRC risk reduction, screening, treatment, and research. The NON CHE combined with S2S is a powerful tool to engage communities with the greatest health care needs and positively impact an individual's intent to "get screened" for CRC., (© 2021. American Association for Cancer Education.)

Introduction: There is a scarcity of data on the impact of behavioral habits, such as exercise, on physical health in patients with bladder cancer. We investigated the association of exercise on self-reported physical health status and examined the prevalence of bladder cancer patients with sedentary lifestyle., Methods: We examined cross-sectional data of participants diagnosed with bladder cancer within the Behavioral Risk Factor Surveillance System (BRFSS) from 2016-2020. Patient health status was surveyed using self-reported measures, such as the total days per month when their "physical health is not good." The primary outcome was patient-reported poor physical health for more than 14 days within a one-month period., Results: Out of 2 193 981 survey participants, we identified 936 with a history of bladder cancer. Nearly one in three bladder cancer patients reported being sedentary within the last month, as a total of 307 (32.8%) patients reported no exercise within the last 30 days. The remaining 628 (67.2%) reported exercising for at least one day within the last month. In multivariable logistic regression model analysis, we found that exercise is protective for self-reported poor physical health status (odds ratio 0.37, 95% confidence interval 0.25-0.56, p<0.001). Patients that exercised were less likely to report bad physical health., Conclusions: Approximately one in three bladder cancer patients report no exercise within 30 days, suggesting a sedentary lifestyle. Patients that are active are less likely to self-report poor physical health status. Implementation of exercise programs for bladder cancer patients could be promising in improving health status.

Introduction: The aim of this study was to examine the relationship between duration of surgical intervention and postoperative complications in radical cystectomy (RC). We hypothesized that the complication rate increases with longer operative time., Methods: We analyzed the National Surgical Quality Improvement Program database 2011-2017 to identify all patients who underwent RC. Clinicodemographic characteristics, operative time, and perioperative complications using the Clavien-Dindo Classification (CDC) were abstracted. We fit a generalized linear model with linear splines for operative time to analyze if the relationship between operative time and probability of complication changed over time., Results: A total of 10,520 RC patients were identified with a mean operative time of 5.5 h (standard deviation 2.03). In 55% and 18.2%, any complication and major complications (CDC ≥3) occurred within 30 days postoperatively, respectively. The spline regression model for any complication showed an almost linear relationship between the complication rate and operative time, ranging from 55% at 2.5 h to 82% at 10 h. For major complications, the model revealed the inflection point (knot) at 4.5 h, which corresponds to the lowest complication rate with 15%. Operative times at the extremes of the distribution had higher complication rates: 17.5% if <2.5 h and 28% if >10 h., Discussion/conclusion: Operative time of RC is associated with postoperative complications. Though many factors impact the duration of surgery, surgeries that lasted between 4 and 5 h had trend toward the lowest complication rates. Attention to factors impacting operative time may allow surgeons to identify strategies for optimizing surgical care and reducing complications after RC., (© 2022 S. Karger AG, Basel.)

To disentangle the "obesity paradox" in renal cell carcinoma (RCC), we examined associations of body mass index (BMI) and weight change with RCC risk and survival in the Health Professionals Follow-up Study (HPFS) and Nurses' Health Study (NHS) 1 and 2. We estimated cohort-specific and summary covariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for RCC incidence, as well as RCC-specific survival among cases in the pooled HPFS and NHS data. Cumulative average BMI was associated with a higher risk of total RCC (summary HR 2.16, 95% CI 1.77-2.63 for BMI ≥30 vs 18-<25 kg/m 2 ; p trend <0.001) and fatal RCC (HR 2.03, 95% CI 1.37-3.01; p trend <0.001). Prediagnosis BMI was not associated with RCC death. However, first postdiagnosis BMI (HR 0.51, 95% CI 0.29-0.89; p trend 0.006) and prediagnosis to postdiagnosis weight change (HR 0.52, 95% CI 0.29-0.91; p trend 0.001) were significantly inversely associated with RCC death. These results support obesity as a risk factor for total and fatal RCC. They undermine the obesity paradox by suggesting that weight loss around diagnosis, and not low BMI itself, is associated with worse prognosis. PATIENT SUMMARY: We studied obesity in kidney cancer and found that obesity is associated with getting and dying from the disease. Body mass index at diagnosis is not an ideal factor for predicting prognosis, as patients who have lost weight are likely to have more aggressive cancer., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: The impact of anemia in postoperative complications following radical cystectomy (RC) is not completely elucidated and its association with direct hospital costs has not been characterized in depth. Our goal is to determine the association between anemia, 90-day surgical complications and the expenditure attributed to preoperative anemia in patients undergoing RC., Materials and Methods: We captured all patients who underwent RC between 2003 and 2017 using the Premier Hospital Database (Premier Inc, Charlotte, NC). Patient, hospital and surgical characteristics were evaluated. Anemia was defined by a corresponding diagnostic code that was present on admission prior to RC. Unadjusted patients' demographic characteristics with and without anemia, hospital and surgeon characteristics were compared, and multivariable regression models were developed to evaluate 90-day complications and total direct hospital costs., Results: The cohort included 83,470 patients that underwent RC between 2003 and 2017 and 11% were found to be anemic. On multivariable analysis, preoperative anemia more than doubled the odds of having a complication (odds ratio 2.19 (1.89-2.53)) and significantly increased the risk of major complications (odds ratio 1.51 (1.31-1.75)) at 90-days after RC. Anemic patients had significantly higher 90-days total direct costs due to higher laboratory, pharmacologic, radiology and operating room costs., Conclusions: Anemic cystectomy patients face a 50% increase in the risk of major complications within the first 90-days after surgery. This increased risk persisted after adjusting for patient, hospital and surgical factors. Our study suggests hematocrit level prior to RC may be used as a pre-exisitng condition for increased risk of surgical complications., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The NCCN Guidelines for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines regarding the treatment of non-muscle-invasive bladder cancer, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors in non-muscle invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody-drug conjugates for metastatic bladder cancer.

Background: How 5-alpha reductase inhibitor (5-ARI) use influences prostate cancer mortality is unclear. The objective of this study was to determine whether men taking 5-ARIs with regular health care access have increased prostate cancer mortality., Methods: We undertook two analyses in the Health Professionals Follow-up Study examining 5-ARI use, determined by biennial questionnaires, and prostate cancer. A cohort analysis followed 38,037 cancer-free men for prostate cancer incidence from 1996 through January 2017 and mortality through January 2019. A case-only analysis followed 4,383 men with localized/locally advanced prostate cancer for mortality over a similar period. HRs and 95% confidence intervals (CI) were calculated for prostate cancer incidence and mortality., Results: Men using 5-ARIs underwent more PSA testing, prostate exams and biopsies. Over 20 years of follow-up, 509 men developed lethal disease (metastases or prostate cancer death). Among men initially free from prostate cancer, 5-ARI use was not associated with developing lethal disease [HR, 1.02; 95% confidence interval (CI), 0.71-1.46], but was associated with reduced rates of overall and localized disease (HR, 0.71; 0.60-0.83). Among men diagnosed with prostate cancer, there was no association between 5-ARI use and cancer-specific (HR, 0.78; 95% CI, 0.48-1.27) or overall survival (HR, 0.88; 95% CI, 0.72-1.07)., Conclusions: Men using 5-ARIs were less likely to be diagnosed with low-risk prostate cancer, without increasing long-term risk of lethal prostate cancer or cancer-specific death after diagnosis., Impact: Our results provide evidence that 5-ARI use is safe with respect to prostate cancer mortality in the context of regular health care access. See related commentary by Hamilton, p. 1259., (©2022 American Association for Cancer Research.)