The accuracy of cystoscopy in predicting muscle invasion in newly diagnosed bladder cancer patients.

PURPOSE: The prognosis of muscle-invasive bladder cancer (MIBC) has not improved for three decades. Transurethral resection of the bladder tumor (TURBT) is the standard procedure for local tumor staging. TURBT has several limitations, including the spread of tumor cells. Therefore, an alternative is needed in patients with suspected MIBC. Recent studies have shown that mpMRI is very accurate in staging bladder tumors. Because the diagnostic efficacy of urethrocystoscopy (UCS) has been reported as good as the efficacy of mpMRI to predict muscle invasion we performed this prospective multicenter study in which we compare UCS with pathology. METHODS: From July 2020 until March 2022, 321 patients with suspected primary BC in seven participating Dutch hospitals were included in this study. A flexible UCS was performed by urologists, physician assistants, or residents. Predictions of muscle invasion using a 5-point Likert scale alongside the histopathology data were recorded. The sensitivity, specificity, predictive values, and 95% confidence intervals were determined using a standard contingency table. RESULTS: Of the 321 included patients, 232 (72.3%) received a histopathological diagnosis of non-muscle-invasive bladder cancer (NMIBC) and 71 (22.1%) were histopathologically diagnosed as MIBC. In 2 patients (0.6%), classification was not possible (Tx). Cystoscopy predicted muscle invasion with a sensitivity of 71.8% (95% CI 59.9-81.9), and a specificity of 89.9% (95% CI 85.4-93.3). This corresponds to a positive predictive value (PPV) of 67.1% and a negative predictive value (NPV) of 91.7%. CONCLUSION: Our study shows a moderate accuracy of cystoscopy to predict muscle invasion. This result does not support the use of cystoscopy only instead of TURBT for local staging.

Selecting interventions for a psychosocial support program for prostate cancer patients undergoing active surveillance: A modified Delphi study.

OBJECTIVE: Curative treatment of low-risk prostate cancer (LR-PCa) does not improve cancer specific survival and active surveillance (AS) is recommended. Although AS is cost-effective and reduces treatment-related complications, it requires psychosocial support. Research on psychosocial interventions specifically focused on men undergoing AS is limited. Aim of this study is to reach consensus amongst relevant stakeholders on selecting interventions offering psychosocial support to PCa patients during AS. METHODS: In accordance with the RAND/UCLA method, a modified Delphi approach was used to establish consensus on selecting interventions. During phase one, interventions were identified through a literature review and open survey among all participants. During phase two, three consensus rounds were conducted to rate potential interventions and obtain statistical consensus. The IQ healthcare consensus tool was used to calculate statistical consensus. RESULTS: After the first consensus round, 31 participants scored individual interventions on relevance using a 9-point Likert scale resulting in the selection of six interventions. During the second consensus round 13 discussion items were reviewed during a focus group. After the third consensus round, seven additional interventions were selected by 23 participants. CONCLUSIONS: In total, 13 interventions were selected for inclusion in a support program. This included four interventions within the domain information and education, three within coping and support, one intervention within physical wellbeing and four within the domain lifestyle.

What interventions affect the psychosocial burden experienced by prostate cancer patients undergoing active surveillance? A scoping review.

PURPOSE: Living with untreated prostate cancer (PCa) may cause anxiety and uncertainty in men undergoing active surveillance (AS). Developing a psychosocial support program for such patients might promote psychosocial well-being and patient engagement. This review aims to identify interventions with the potential to influence the psychosocial burden of prostate cancer patients undergoing AS. METHODS: A scoping review was conducted in accordance with the PRISMA Extension for Scoping Reviews Checklist. A systematic search was conducted in six databases and included publications dating from 2009. All available and eligible evidence was included in this review. RESULTS: After screening 2824 articles, 12 studies were included in the review: nine quantitative, one qualitative, and two mixed method papers. The relative strength of these studies was limited and the quality of most was moderate. CONCLUSIONS: The described interventions can be categorized into three major themes: information and education, coping and (psycho)social support, and lifestyle. Psychosocial support for men undergoing AS should entail involvement of family and spouse during the decision-making process, tailored information about PCa treatments, risks, benefits, protocols, lifestyle adjustments, and complementary and alternative medicine. Assessment and promotion of effective coping and self-management strategies are recommended. Healthcare providers should actively promote physical activity and nutritional improvements. Physical activity programs may also be helpful in facilitating peer support, which is especially important for men with limited social support. Future research should investigate combining interventions to increase efficacy and optimize supportive care during AS.

Bone-Targeting Polymer Vesicles for Effective Therapy of Osteoporosis.

With the aging of the population, postmenopausal osteoporosis becomes increasingly widespread and severe as fractures caused by osteoporosis may lead to permanent disabilities and even death. Inspired by extracellular vesicles that participate in bone remodeling, we present a biomimicking polymer vesicle for bone-targeted ß-estradiol (E2) delivery. This vesicle is self-assembled from a poly(ε-caprolactone)28-block-poly[(l-glutamic acid)7-stat-(l-glutamic acid-alendronic acid)4] (PCL28-b-P[Glu7-stat-(Glu-ADA)4]) diblock copolymer. The alendronic acid (ADA) on the coronas endows the polymer vesicles with a high bone affinity and acts synergistically with E2 to achieve an enhanced therapeutic effect. As confirmed with ovariectomized osteoporosis rat models, bone loss was significantly reversed as the recovery rates of total BMD (bone mineral density) and trabecular BMD were 70.4% and 99.3%, respectively. Overall, this work provides fresh insight into the treatment of osteoporosis.

Argus-T adjustable male sling: A follow-up study on urinary incontinence and patient's satisfaction.

AIMS: The use of Argus-T adjustable sling may be a promising alternative option for the treatment of urinary incontinence after radical prostatectomy, however long-term data is lacking. The aim of this study is to evaluate the long-term results of the Argus-T sling on incontinence rates, patient's quality of life and tape-related complications. METHODS: Patients were eligible if persistent stress incontinence was present ≥12 months after radical prostatectomy. Measurements included 24 h frequency volume micturition list, 24 h pad test, 24 h pad count and quality of life questionnaires. Argus-T adjustable sling was placed with a single perineal route incision approach. RESULTS: Seventy-eight patients were included, 69 ± 6 years, pre-intervention 24 h urinary loss 212 (75-385) g. Directly after surgery, 63.6% of the patients was completely dry, 79.2% of the patients reported greater than 90% improvement of their urinary loss and 92.2% > 50% improvement. Median follow-up time was 3.2 (2.5-6.1) years. After 5 years of follow-up, 53.3% of the patients were completely dry, 71.5% reported an improvement greater than 90% and 79.6% reported an improvement of greater than 50%. Patients with preoperative urinary loss less than 250 g reported significantly higher improvement of their urinary loss compared to patients with urinary loss ≥250 g (p = .02). Patients satisfaction was still increased after 5 years follow-up (70 ± 21 vs.16 ± 9, p < .001) and patients quality of life remained high (85 ± 20 vs. 88 ± 13, p = .1). Complications were mainly observed directly after surgery. Two patients (2.6%) needed reimplantation of the sling. CONCLUSION: These data indicate that Argus-T sling is an effective treatment option in obtaining substantial long-term incontinence relief in patients with invalidating moderate stress urinary incontinence after radical prostatectomy.

Effect of Salt on the Formation and Stability of Water-in-Oil Pickering Nanoemulsions Stabilized by Diblock Copolymer Nanoparticles.

Sterically stabilized diblock copolymer nanoparticles are prepared in n-dodecane using polymerization-induced self-assembly. Precursor Pickering macroemulsions are then prepared by the addition of water followed by high-shear homogenization. In the absence of any salt, high-pressure microfluidization of such precursor emulsions leads to the formation of relatively large aqueous droplets with DLS measurements indicating a mean diameter of more than 600 nm. However, systemically increasing the salt concentration produces significantly finer droplets after microfluidization, until a limiting diameter of around 250 nm is obtained at 0.11 M NaCl. The mean size of these aqueous droplets can also be tuned by systematically varying the nanoparticle concentration, applied pressure, and the number of passes through the microfluidizer. The mean number of nanoparticles adsorbed onto each aqueous droplet and their packing efficiency are calculated. SAXS studies conducted on a Pickering nanoemulsion prepared using 0.11 M NaCl confirms that the aqueous droplets are coated with a loosely packed monolayer of nanoparticles. The effect of varying the NaCl concentration within the droplets on their initial rate of Ostwald ripening is investigated using DLS. Finally, the long-term stability of these water-in-oil Pickering nanoemulsions is assessed using analytical centrifugation. The rate of droplet ripening can be substantially reduced by using 0.11 M NaCl instead of pure water. However, increasing the salt concentration up to 0.43 M provided no further improvement in the long-term stability of such nanoemulsions.

Time-resolved small-angle neutron scattering studies of the thermally-induced exchange of copolymer chains between spherical diblock copolymer nanoparticles prepared via polymerization-induced self-assembly.

Sterically-stabilized diblock copolymer nanoparticles (a.k.a. micelles) are prepared directly in non-polar media via polymerization-induced self-assembly (PISA). More specifically, a poly(lauryl methacrylate) chain transfer agent is chain-extended via reversible addition-fragmentation chain transfer (RAFT) dispersion polymerization of methyl methacrylate (MMA) to form sterically-stabilized spheres at 20% w/w solids in n-dodecane at 90 °C. Both fully hydrogenous (PLMA39-PMMA55 and PLMA39-PMMA94) and core-deuterated (PLMA39-d8PMMA57 and PLMA39-d8PMMA96) spherical nanoparticles with mean core diameters of approximately 20 nm were prepared using this protocol. After diluting each dispersion in turn to 1.0% w/w with n-dodecane, small-angle X-ray scattering studies confirmed essentially no change in spherical nanoparticle diameter after thermal annealing at 150 °C. Time-resolved small angle neutron scattering was used to examine whether copolymer chain exchange occurs between such nanoparticles at elevated temperatures. Copolymer chain exchange for a binary mixture of PLMA39-PMMA55 and PLMA39-d8PMMA57 nanoparticles produced hybrid (mixed) cores containing both PMMA55 and d8PMMA57 blocks within 3 min at 150 °C. In contrast, a binary mixture of PLMA39-PMMA94 and PLMA39-d8PMMA96 nanoparticles required 8 min at this temperature before no further reduction in neutron scattering intensity could be observed. These observations suggest that the rate of copolymer chain exchange depends on the degree of polymerization of the core-forming block. Relatively slow copolymer chain exchange was also observed at 80 °C, which is below the Tg of the core-forming PMMA block as determined by DSC studies. These observations confirm rapid exchange of individual copolymer chains between sterically-stabilized nanoparticles at elevated temperature. The implications of these findings are briefly discussed in the context of PISA, which is a powerful technique for the synthesis of sterically-stabilized nanoparticles.

Focal Salvage MR Imaging-Guided Cryoablation for Localized Prostate Cancer Recurrence after Radiotherapy: 12-Month Follow-up.

PURPOSE: To evaluate safety, quality of life (QoL), and local cancer control after focal salvage MR imaging-guided cryoablation in patients with local recurrence of prostate cancer (PCa) after radiotherapy. MATERIALS AND METHODS: A retrospective, single-center study was performed in 62 patients with radiorecurrent PCa who underwent MR imaging-guided cryoablation since May 2011 with a follow-up ≥12 months in December 2017. Rates and descriptions of adverse events were reported. Ablation complications were classified according to the Clavien and SIR systems. Validated questionnaires were used to observe functional outcomes and QoL before therapy and 6 and 12 months after therapy. Cancer control was defined as no biochemical failure according to Phoenix criteria and no other clinical evidence for local or metastatic disease. RESULTS: All procedures were technically feasible. The number of complications requiring major therapy (Clavien grade 3b/4 or SIR grade D/E/F) was low (2 [3.2%] and 1 [1.6%], respectively). After 12 months, the International Consultation of Incontinence Questionnaire-Short Form (P < .001) and 5-item International Index of Erectile Function (P = .001) scores became significantly worse, indicating increased symptoms of incontinence and diminished erectile function, without compromising QoL. Six patients developed metastases within 6 months. After 12 months, 36 patients (63%) were disease-free. CONCLUSIONS: Focal salvage MR imaging-guided cryoablation is safe and is associated with a high technical success rate, preservation of QoL, and local PCa control. This treatment can be a reasonable alternative to salvage radical prostatectomy in properly selected patients with low morbidity and preservation of QoL; however, longer follow-up is needed.

Synthesis of High χ-Low N Diblock Copolymers by Polymerization-Induced Self-Assembly.

Polymerization-induced self-assembly (PISA) enables the scalable synthesis of functional block copolymer nanoparticles with various morphologies. Herein we exploit this versatile technique to produce so-called "high χ-low N" diblock copolymers that undergo nanoscale phase separation in the solid state to produce sub-10 nm surface features. By varying the degree of polymerization of the stabilizer and core-forming blocks, PISA provides rapid access to a wide range of diblock copolymers, and enables fundamental thermodynamic parameters to be determined. In addition, the pre-organization of copolymer chains within sterically-stabilized nanoparticles that occurs during PISA leads to enhanced phase separation relative to that achieved using solution-cast molecularly-dissolved copolymer chains.

In Situ Small-Angle X-ray Scattering Studies During Reversible Addition-Fragmentation Chain Transfer Aqueous Emulsion Polymerization.

Polymerization-induced self-assembly (PISA) is a powerful platform technology for the rational and efficient synthesis of a wide range of block copolymer nano-objects (e.g., spheres, worms or vesicles) in various media. In situ small-angle X-ray scattering (SAXS) studies of reversible addition-fragmentation chain transfer (RAFT) dispersion polymerization have previously provided detailed structural information during self-assembly (see M. J. Derry et al., Chem. Sci. 2016 , 7 , 5078 - 5090 ). However, conducting the analogous in situ SAXS studies during RAFT aqueous emulsion polymerizations poses a formidable technical challenge because the inherently heterogeneous nature of such PISA formulations requires efficient stirring to generate sufficiently small monomer droplets. In the present study, the RAFT aqueous emulsion polymerization of 2-methoxyethyl methacrylate (MOEMA) has been explored for the first time. Chain extension of a relatively short non-ionic poly(glycerol monomethacrylate) (PGMA) precursor block leads to the formation of sterically-stabilized PGMA-PMOEMA spheres, worms or vesicles, depending on the precise reaction conditions. Construction of a suitable phase diagram enables each of these three morphologies to be reproducibly targeted at copolymer concentrations ranging from 10 to 30% w/w solids. High MOEMA conversions are achieved within 2 h at 70 °C, which makes this new PISA formulation well-suited for in situ SAXS studies using a new reaction cell. This bespoke cell enables efficient stirring and hence allows in situ monitoring during RAFT emulsion polymerization for the first time. For example, the onset of micellization and subsequent evolution in particle size can be studied when preparing PGMA29-PMOEMA30 spheres at 10% w/w solids. When targeting PGMA29-PMOEMA70 vesicles under the same conditions, both the micellar nucleation event and the subsequent evolution in the diblock copolymer morphology from spheres to worms to vesicles are observed. These new insights significantly enhance our understanding of the PISA mechanism during RAFT aqueous emulsion polymerization.

In Situ Spectroscopic Studies of Highly Transparent Nanoparticle Dispersions Enable Assessment of Trithiocarbonate Chain-End Fidelity during RAFT Dispersion Polymerization in Nonpolar Media.

We report the synthesis of highly transparent poly(stearyl methacrylate)-poly(2,2,2-trifluoroethyl methacrylate) (PSMA-PTFEMA) diblock copolymer nanoparticles via polymerization-induced self-assembly (PISA) in nonpolar media at 70 °C. This was achieved by chain-extending a PSMA precursor block via reversible addition-fragmentation chain transfer (RAFT) dispersion polymerization of TFEMA in n-tetradecane. This n-alkane has the same refractive index as the PTFEMA core-forming block at 70 °C, which ensures high light transmittance when targeting 33 nm spherical nanoparticles. Such isorefractivity enables visible absorption spectra to be recorded with minimal light scattering even at 30% w/w solids. However, in situ monitoring of the trithiocarbonate RAFT end-groups during PISA requires selection of a weak n → π* band at 446 nm. Conversion of TFEMA into PTFEMA causes a contraction in the reaction solution volume, leading to an initial increase in absorbance that enables the kinetics of polymerization to be monitored via dilatometry. At ∼98% TFEMA conversion, this 446 nm band remains constant for 2 h at 70 °C, indicating surprisingly high RAFT chain-end fidelity (and hence pseudoliving character) under monomer-starved conditions. In situ 19F NMR spectroscopy studies provide evidence for (i) the onset of micellar nucleation, (ii) solvation of the nanoparticle cores by TFEMA monomer, and (iii) surface plasticization of the nanoparticle cores by n-tetradecane at 70 °C. Finally, the kinetics of RAFT chain-end removal can be conveniently monitored by in situ visible absorption spectroscopy: addition of excess initiator at 70 °C causes complete discoloration of the dispersion, with small-angle X-ray scattering studies confirming no change in nanoparticle morphology under these conditions.

The impact of prostate cancer diagnosis and treatment decision-making on health-related quality of life before treatment onset.

OBJECTIVE: The objective of this study is to test if patients' health-related quality of life (HRQoL) declines after prostate biopsy to detect Pca, and after subsequent treatment decision-making in case Pca is confirmed, and to test whether personality state and traits are associated with these potential changes in HRQoL. METHODS: Patients who were scheduled for prostate biopsy to detect Pca (N = 377) filled out a baseline questionnaire about HRQoL (EORTC QLQ-C30 and PR25), "big five" personality traits (BFI-10), optimism (LOT-r), and self-efficacy (Decision Self-efficacy Scale) (t0). Patients with confirmed Pca (N = 126) filled out a follow-up questionnaire on HRQoL within 2 weeks after treatment was chosen but had not yet started (t1). RESULTS: HRQoL declined between t0 and t1, reflected in impaired role and cognitive functioning, and elevated fatigue, constipation, and prostate-specific symptoms. Sexual activity and functioning improved. Baseline HRQoL scores were unrelated to the selection of a particular treatment, but for patients who chose a curative treatment, post-decision HRQoL showed a greater decline compared to patients who chose active surveillance. Optimism was associated with HRQoL at baseline; decisional self-efficacy was positively associated with HRQoL at follow-up. No associations between HRQoL and the "big five" personality traits were found. CONCLUSION: Patients who have undergone prostate biopsy and treatment decision-making for Pca experience a decline in HRQoL. Choosing treatment with a curative intent was associated with greater decline in HRQoL. Interventions aimed at optimism and decision self-efficacy could be helpful to reduce HRQoL impairment around the time of prostate biopsy and treatment decision-making.

Clinical Outcomes and Testosterone Levels Following Continuous Androgen Deprivation in Patients with Relapsing or Locally Advanced Prostate Cancer: A Post Hoc Analysis of the ICELAND Study.

PURPOSE: Lower serum testosterone levels correlate with improved cause specific survival and longer time to progression in year 1 of continuous androgen deprivation in men with prostate cancer. ICELAND was a large European study demonstrating the efficacy of leuprorelin (Eligard®) during continuous androgen deprivation. In this post hoc analysis we investigated serum testosterone levels within year 1 of continuous androgen deprivation to determine survival and time to progression. MATERIALS AND METHODS: In ICELAND (ClinicalTrials.gov NCT00378690) patients with locally advanced or relapsing nonmetastatic prostate cancer and with prostate specific antigen 1 ng/ml or less following 6-month induction with leuprorelin 3-month depot 22.5 mg (plus bicalutamide 50 mg per day for 1 month) were randomized 1:1 to continuous androgen deprivation (361) or intermittent androgen deprivation (340) with leuprorelin for 36 months. Patients receiving continuous androgen deprivation were stratified by minimum, median and maximum testosterone levels during year 1 of therapy into 20 or less, greater than 20 to 50 and greater than 50 ng/dl subgroups. Cause specific survival and time to prostate specific antigen (castrate resistant prostate cancer) progression were analyzed. RESULTS: A total of 90.1%, 83.5% and 74.5% of patients receiving continuous androgen deprivation achieved minimum, median and maximum serum testosterone levels of 20 ng/dl or less, respectively. Cause specific survival rates and time to prostate specific antigen progression did not differ among the testosterone subgroups. CONCLUSIONS: In patients receiving continuous androgen deprivation cause specific survival and time to prostate specific antigen progression did not differ according to testosterone levels in year 1 of therapy. This finding may in part be due to the induction period and the effectiveness of leuprorelin in lowering testosterone.

MRI-guided focal laser ablation for prostate cancer followed by radical prostatectomy: correlation of treatment effects with imaging.

PURPOSE: To correlate treatment effects of MRI-guided focal laser ablation in patients with prostate cancer with imaging using prostatectomy as standard of reference. METHODS: This phase I study was approved by the Institutional Review Board. Three weeks prior to prostatectomy, five patients with histopathologically proven, low/intermediate grade prostate cancer underwent transrectal MRI-guided focal laser ablation. Per patient, only one ablation was performed to investigate the effect of ablation on the tissue rather than the effectiveness of ablation. Ablation was continuously monitored with real-time MR temperature mapping, and damage-estimation maps were computed. A post-ablation high-resolution T1-weighted contrast-enhanced sequence was acquired. Ablation volumes were contoured and measured on histopathology specimens (with a shrinkage factor of 1.15), T1-weighted contrast-enhanced images, and damage-estimation maps, and were compared. RESULTS: A significant volume correlation was seen between the ablation zone on T1-weighted contrast-enhanced images and the whole-mount histopathology section (r = 0.94, p = 0.018). The damage-estimation maps and histopathology specimen showed a correlation of r = 0.33 (p = 0.583). On histopathology, the homogeneous necrotic area was surrounded by a reactive transition zone (1-5 mm) zone, showing neovascularisation, and an increased mitotic index, indicating increased tumor activity. CONCLUSIONS: The actual ablation zone was better indicated by T1-weighted contrast-enhanced than by damage-estimation maps. Histopathology results highlight the importance of complete tumor ablation with a safety margin.

Argus-T Adjustable Male Sling: The Influence of Surgical Technique on Complications and Short-Term Efficacy.

OBJECTIVES: The study aims to investigate and evaluate the influence of 2 different methods of implantation of the Argus transobturator (Argus-T) adjustable male sling on complication rate and short-term efficacy. METHODS: A prospective mono-center evaluation was conducted on consecutive patients treated for persistent post-radical prostatectomy incontinence. Thirty-six patients were implanted with the Argus-T adjustable male sling--18 by inguinal-perineal incision (IPI) and 18 by single-perineal incision (SPI). Measurements included 24-hour frequency volume micturition list, 24-hour pad test, 24-hour pad count, Visual Analogue Scale for continence and satisfaction, flowmetry and residual voided urine. RESULTS: Cure rate for IPI and SPI at 1, 6 and 12 months was 67, 75, 62% and 59, 63, 63%, respectively (no statistically significant difference). Although more clinically significant complications were seen in the IPI group, a statistical significant difference was observed only for wound infection between the IPI and the SPI groups (33 vs. 0%, p = 0.019). CONCLUSIONS: The Argus-T male sling SPI suspension operation is a minimally invasive and safe procedure for the management of male postoperative stress incontinence which is highly appreciated by the patients.

Investigation of alkyne regioselectivity in the ni-catalyzed benzannulation of cyclobutenones.

A Ni-catalyzed benzannulation reaction of cyclobutenones and alkynes provides a rapid synthesis of heavily substituted phenols. The regioselectivity of this reaction can be modulated by variation of substituents on the alkyne. Though the incorporation of Lewis basic donors provides modest selectivities, the use of aryl substituents can provide high levels of regiocontrol. Finally, alkynylboronates derived from alkyl-substituted acetylenes provide both high yields and regioselectivities. This study suggests that alkynes bearing one sp(2) - and one sp(3) -based substituent can undergo benzannulation with high levels of regiocontrol whereby the sp(3) -based group is incorporated ortho-to the phenolic OH.

Short-term Changes in Health-related Quality of Life of Patients Undergoing Radical Surgery for Upper Urinary Tract Urothelial Carcinoma: Results from a Prospective Phase 2 Clinical Trial.

Background and objective: The possible negative impact of radical surgery on patients' health-related quality of life (HRQoL) plays an important role in preoperative counseling. Here, we analyzed the HRQoL of patients treated for upper urinary tract urothelial carcinoma (UTUC) in the context of a single-arm phase 2 multicenter study, in which the safety and efficacy of a single preoperative intravesical instillation with mitomycin C were investigated. Our objective was to investigate early changes in HRQoL in patients undergoing radical surgery for UTUC and identify factors associated with these outcomes. Methods: Patients with pTanyN0-1M0 UTUC were prospectively included. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) questionnaire at baseline, and at 1 and 3 mo after surgery. A linear mixed model was used to evaluate the changes in HRQoL over time and identify the variables associated with these outcomes. The clinical effect size was used to assess the clinical impact and level of perceptibility of HRQoL changes for clinicians and/or patients based on given thresholds. Key findings and limitations: Between 2017 and 2020, 186 patients were included. At baseline, 1 mo after surgery, and 3 mo after surgery, response rates were 91%, 84%, and 78%, respectively. One month after surgery, a statistically significant and clinically relevant deterioration was observed in physical, role, and social functioning, and for the included symptom scales: constipation, fatigue, and pain. An improvement in emotional functioning was observed. At 3 mo, HRQoL returned to baseline levels, except emotional functioning, which improved at 1 mo and persisted to be better than that before surgery. Age >70 yr was associated with worse physical functioning, but better social and emotional functioning. Male patients reported better emotional functioning than females. Postoperative complications were negatively associated with social functioning. Conclusions and clinical implications: UTUC patients treated with radical surgery experienced a significant, albeit temporary, decline in HRQoL. Three months following surgery, HRQoL outcomes returned to baseline levels. This information can be used to counsel UTUC patients before undergoing radical surgery and contextualize recovery after surgery. Patient summary: We investigated the changes in quality of life as reported by patients who underwent surgery for upper tract urothelial carcinoma (UTUC). We found that patients experienced a decline in quality of life 1 mo after surgery, but this was temporary, with full recovery of quality of life 3 mo after surgery. These findings can help doctors and other medical staff in counseling UTUC patients before undergoing radical surgery.

Results of a phase 1 dose escalation study of intravesical TMX-101 in patients with nonmuscle invasive bladder cancer.

PURPOSE: Imiquimod, a toll like receptor 7 (TLR-7) agonist, is effective as a topical treatment for skin malignancies. TMX-101 is a liquid formulation of imiquimod. In this study we establish a safety profile of TMX-101 in patients with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: We conducted a multicenter phase 1 dose escalation study in patients with nonmuscle invasive bladder cancer. Patients were included in 1 of 4 dose groups (0.05%, 0.1%, 0.2% or 0.4%) and treated with 6 weekly instillations of TMX-101, starting 2 weeks after transurethral resection of bladder tumor. Patients were evaluated weekly, and pharmacokinetic and pharmacodynamic parameters were measured. RESULTS: A total of 16 patients were included in the study with 4 per dose group. Two patients dropped out after instillation 2 in dose groups 1 and 2. Overall, 88 instillations were administered without serious adverse events. There were 118 adverse events, of which 84 were related to the study drug. All adverse events were mild or moderate and number or severity was not correlated with dose group. Of the related adverse events 70% were confined to the genitourinary tract and resolved without intervention. There was a dose dependent systemic uptake with low plasma levels up to dose group 3 (0.2%, 100 mg). Maximum plasma concentration in dose group 4 (0.4%, 200 mg) was 71.7 ng/ml. This is below plasma concentrations of 123 and 128 ng/ml without significant side effects measured in healthy volunteers after subcutaneous (30 mg) or oral intake (100 mg) of imiquimod, respectively. CONCLUSIONS: Intravesical treatment with TMX-101 is safe. The side effects are common but mild and mostly limited to the genitourinary tract. There is a low systemic uptake.

Drug delivery approaches for enhanced antibiofilm therapy.

Biofilms have attracted increasing attention in recent years. Many bacterial infections are associated with biofilm formation. A bacterial biofilm is an aggregated membrane-like substance that is composed of a large number of bacteria and their secreted extracellular polymeric substances. The traditional antibiofilm approaches, such as chemotherapy based on antibiotics, are often ineffective in eradicating biofilms owing to the limited diffusion ability of antibiotics within biofilms and inactivation of antibiotics by biofilms. Moreover, a larger dosage of antibiotics could be effective, but leads to an increased tolerance. Smart drug delivery systems that deliver antibiotics into the biofilm interior is a promising strategy to meet this challenge. In this review, we focus on the methods to improve drug delivery efficiency for enhanced chemotherapy of biofilms. Furthermore, we have summarized chemical approaches for enhanced drug delivery, such as chemical shields, charge reversal, and dual corona enhanced delivery strategies; these methods focus on physicochemical biofilm properties and specific biofilm features. Afterwards, physical approaches are discussed, such as magnetism-mediated drug delivery, electricity-mediated drug delivery, ultrasound-mediated drug delivery, and shock wave-mediated drug delivery. Finally, a perspective on the development of next-generation antibiofilm drug delivery systems is given.