Stereotactic radiotherapy vs whole brain radiation therapy in EGFR mutated NSCLC: Results & reflections from the prematurely closed phase III HYBRID trial.

BACKGROUND: All known randomized trials of stereotactic radiotherapy (SRT) versus whole brain radiotherapy (WBRT) for brain metastases (BMs) comprise mixed histologies. The phase III HYBRID trial (NCT02882984) attempted to evaluate the non-inferiority of SRT vs. WBRT specifically for EGFR-mutated non-small cell lung cancer (EGFRm NSCLC) BMs. METHODS: Inclusion criteria were ≤ 5 BMs (any size) from treatment-naïve EGFRm NSCLC. All patients started a first-generation tyrosine kinase inhibitor on the first day of WBRT (37.5 Gy/15 fractions) or SRT (25-40 Gy/5 fractions per tumor volume). The primary endpoint was 18-month intracranial progression-free survival (iPFS; intention-to-treat). RESULTS: The trial commenced in June 2015 and was closed in April 2021 after screening 208 patients but enrolling 85 (n = 41 WBRT, n = 44 SRT; median follow-up 31 and 36 months, respectively). Respectively, 9.5 % vs. 10.2 % of patients experienced intracranial progression at 18 months, and the median iPFS was 21.4 vs. 22.3 months (p > 0.05 for all). The SRT arm experienced higher overall survival and cognitive preservation (p < 0.05 for all). The most notable reason for low enrollment was patients not wishing to risk neurocognitive decline from WBRT. CONCLUSIONS: Although this phase III trial was underpowered, there was no evidence that SRT yielded outcome detriments compared to WBRT for EGFRm NSCLC BMs. Lessons from prematurely closed trials are valuable, as they often provide important experiential perspectives for investigators designing/executing future trials. In the current era, randomized trials involving WBRT without cognitive sparing measures may be at high risk of underaccrual; trial investigators are encouraged to carefully consider our experience when attempting to design such trials. However, trials of molecular-/biologically-stratified patients are highly recommended as the notion of "individualized medicine/oncology" continues to expand.

One-Pot Synthesis of Ce-SSZ-39 Zeolite with Performance in the NH3-SCR Reaction.

Cu-SSZ-39 zeolite with 8-membered rings is regarded as a very promising catalyst in the NH3-SCR reaction, but its hydrothermal stability still remains to be improved. One of the solutions to promote hydrothermal stability is the insertion of rare earth elements in the product. Nevertheless, normal ion exchange of rare earth elements limits their contents in the zeolite product due to their large hydrated ionic radius and alkaline environment under hydrothermal conditions. Herein, we for the first time present a new method for the one-pot synthesis of Ce-SSZ-39 zeolite under solvent-free conditions. The key to success is the use of Ce-FAU zeolite as a precursor. The obtained product shows good crystallinity, sheet-like morphology, large BET surface area, and 4-coordinated Al species. Detailed investigations illustrate that Ce species in the Cu/Ce-SSZ-39 zeolite micropore can prevent the dealumination and thus formation of CuAlOx species during hydrothermal aging at 850 °C for 16 h, giving the excellent hydrothermal stability and thus showing the excellent catalytic performance in the NH3-SCR reaction. One-pot synthesis of Ce-SSZ-39 zeolite with excellent catalytic performance might open a new door for developing very efficient selective catalytic reduction (SCR) catalysts in near future.

Optimal Time-to-Surgery Recommendations Based on Primary Tumor Volume Regression for Patients with Resectable Esophageal Cancer after Neoadjuvant Chemoradiotherapy: A Retrospective Study.

BACKGROUND: Neoadjuvant chemoradiotherapy (NCRT) has shown promise in improving the prognosis of individuals with locally advanced esophageal squamous cell carcinoma (LA-ESCC). However, the factors influencing tumor response and long-term survival in these patients remain unknown. The optimal timing for surgery after the completion of radiotherapy in LA-ESCC remains controversial. Therefore, this study was designed to identify biomarkers and to determine the optimal post-NCRT time-to-surgery (TTS) for patients with LA-ESCC. METHODS: This retrospective study included patients with resectable LA-ESCC who underwent NCRT between May 2017 and June 2021. The tumor shrinkage rate was calculated as the difference between the pre- and post-primary gross tumor volume (GTVp) divided by the pre-GTVp. Univariate and multivariate Cox regression analyses and Kaplan-Meier curves were used to calculate overall survival (OS) and progression-free survival (PFS). RESULTS: We collected data from 248 patients with resectable LA-ESCC who underwent computed tomography (CT) scans before the initiation of treatment. The median follow-up time was 37.7 months. The optimal cutoff of tumor shrinkage was 45%. In the univariate and multivariate analyses, we found a significant association between the tumor shrinkage rate and PFS (p = 0.001). Among the subgroup of patients who responded to treatment, extending the TTS was associated with improved OS (p = 0.037) and PFS (p = 0.028). CONCLUSIONS: For patients with resectable LA-ESCC, the tumor shrinkage rate is an independent prognostic factor for PFS. Thus, for responders, prolonging TTS is recommended to obtain a better OS.

Single versus multiple renal arteries in living donor kidney transplantation: A systematic review and patient-level meta-analysis.

INTRODUCTION: Grafts with multiple renal arteries (MRAs) were historically considered a relative contraindication to transplantation due to the higher risk of vascular and urologic complications. This study aimed to evaluate graft and patient survival between single renal artery (SRA) and MRA living-donor kidney transplants. METHODS: An electronic literature search was conducted on PubMed, EMBASE, and Scopus for prospective or retrospective studies comparing SRA versus MRA in living donor renal transplantation, with the provision of Kaplan-Meier curves for recipient overall survival (OS) or graft survival (GS). A graphical reconstructive algorithm was used to obtain OS and GS of individual patients, which was then pooled under random-effects individual patient data (IPD) meta-analysis using Cox-models to determine hazard ratios (HRs) and 95% confidence intervals (CIs). Meta-regression of baseline covariates versus HRs of OS and GS was performed for variables reported in 10 or more studies. RESULTS: Fourteen studies were retrieved, of which 13 (8400 patients) reported OS and 9 (6912 patients) reported GS. There were no significant differences in OS (shared-frailty HR = .94, 95%CI = .85-1.03, p = .172) or GS (shared-frailty HR = .95, 95%CI = .83-1.08, p = .419) between SRA and MRA. This comparison remained non-significant even when restricted to open- or laparoscopic-only studies. Meta-regression yielded no significant associations of GS with donor age, recipient age, and percentage of double renal arteries within the MRA arm. CONCLUSIONS: The similar rates of GS and OS between MRA and SRA grafts suggest that there is no need for discrimination between the two when evaluating donors for nephrectomy.

Safety and effectiveness of magnetic ureteric stent removal under ultrasound control: a randomized single center trial.

PURPOSE: To assess the safety and effectiveness of magnetic ureteric stent removal with a special magnet retriever under ultrasound guidance. METHODS: A total of 60 male patients, who underwent ureteroscopy from October 2020 to March 2022, were prospectively enrolled and randomized into two groups. Group A patients underwent conventional double-J (DJ) stent insertion and subsequent stent removal via flexible cystoscopy. Group B patients underwent stent insertion using magnetic ureteric stent [Blackstar, Urotech (Achenmühle, Germany)] and stents were removed using a special magnet retriever under ultrasound guidance. Stents were left in situ for 30 days in both groups. All patients had follow-ups with a ureter stent symptoms questionnaire at 3- and 30-days post stent insertion. Visual analog scale (VAS) was assessed immediately after stent removal. RESULTS: Stent removal time (142.5 s vs 142.5 s, group A vs group B, p < 0.0001) and VAS scores (4 vs 1, group A vs group B, p = 0.0008) were significantly lower in Group B. There were no statistically significant differences between both groups in the "urinary symptoms" (p = 0.3471) and "sexual matters" (p = 0.6126) in the USSQ domains. There was marginal statistical significance favoring Group A in the "body pain" (p = 0.0303), "general health score" (p = 0.0072), "additional problems" (p = 0.0142), and "work performance" (p < 0.0001) domains. CONCLUSIONS: Magnetic ureteric stent can be considered as a safe and efficient alternative to conventional DJ stent. This approach avoids the need for cystoscopy, saving resources while minimizing patient discomfort.

A Blue/NIR ratiometric fluorescent probe for intracellular detection of Tyrosinase and the inhibitor screening.

A novel ratiometric fluorescent tyrosinase assay is developed based on hybrid nano-assembly of gold nanocluster and tyrosine-containing peptides. The AuNCs@YCY nano-probe (AYNP) is fabricated through the hydrophobic interactions and π-π stacking between the tyrosine residues of the Tyr-Cys-Tyr tripeptide (YCY) and the ligands on the surfaces of AuNCs under the near-isoelectric pH value. The resulted AYNP shows distinct fluorescence responses, spontaneous turn-on of the blue emission and turn-off of the near-infrared emission, with a single wavelength excitation. It is demonstrated that the enhancement and quenching are due to the production of pheomelanin and dopaquinone structures, respectively, induced by tyrosinase oxidation. The internal referencing system provides the tyrosinase assay with superior sensitivity and a detection limit as low as 6.3 U L-1 could be achieved. The experimental results also demonstrate the excellent selectivity, good photo-stability, and both in vitro and cellular applications of AYNP. This assay technique is low-cost, easy to prepare, and shows excellent potential as a novel melanoma clinical diagnostic platform and a tyrosinase inhibitor screening tool.

Tailoring the morphology and electrochemical properties of Co-ZIF-L derived CoNi layered double hydroxides via Ni2+ etching towards high-performance supercapacitors.

The metal ion etching induced transformation of zeolitic imidazolate frameworks (ZIFs) to layered double hydroxides (LDHs) is closely related to the etching conditions. Here, by tuning the Ni2+ etching conditions (e.g., initial Ni2+ concentration and etching time), Co-ZIF-L templated CoNi-LDH with diverse morphologies and tailorable compositions are obtained and their resultant electrochemical properties are optimized. Mechanism study reveals that the etching conditions significantly affect the disassembling rate of Co-ZIF-L as well as the formation rate of CoNi-LDH, leading to the morphological and compositional variance of etched samples, which further results in their distinct electrochemical activities. The resultant asymmetric supercapacitor assembled with Co-ZIF-L derived CoNi-LDH and activated carbon can achieve a maximum energy density of 77.3 Wh/kg at a power density of 700 W/kg with the capacity retention of 85.7 % after 2000 cycles, superior or comparable to other advanced CoNi-LDH based supercapacitors.

Self-templated transformation of Co-ZIF-L into hierarchical porous CoS2/Co-Ni LDHs with improved electrochemical activities.

CoS2/Co-Ni layered double hydroxides (LDHs) with a rational tailored pore structure are developed by partial sulfurization of Co-ZIF-L and subsequent Ni2+ etching for the transformation of zeolitic imidazolate frameworks (ZIFs) to layered double hydroxides. The as-synthesized CoS2/Co-Ni LDHs maintain the leaf-like structure and have rich hierarchical pores. More importantly, CoS2 nanoparticles are uniformly embedded among Co-Ni LDH layers, facilitating mass diffusion and favorably exposing more active sites. Benefiting from these desirable compositional and structural features, a remarkable specific capacitance (capacity) of 1784 F/g (223 mAh/g) at 1 A/g is delivered by CoS2/Co-Ni LDHs. Furthermore, the as-assembled CoS2/Co-Ni LDH//activated carbon as the asymmetric supercapacitor device also exhibits a high energy density of 125 Wh/kg at a power density of 800 W/kg and a superb capacitance retention of 98 % after 5000 cycles, outperforming many Co-Ni LDH based electrode materials reported in the literature.

Lignocellulose hydrogels fabricated from corncob residues through a green solvent system.

It is still a challenge to find an effective solvent system that can simultaneously dissolve the cellulose and lignin in biomass residues to fabricate lignocellulose hydrogels (LHs). Herein, corncob residues from furfural production were pretreated with alkaline peroxide to regulate the lignin content. The lignin/cellulose composites with various lignin content were then dissolved and regenerated by a green and facile ZnCl2/CaCl2 solvent system. The inorganic salt solvents were served as linkers and flexible LHs were obtained. Substrate material containing 10.75% lignin shows the best compressive stress (76.71 kPa). Inspired by its superior ionic conductivity, the hydrogels were assembled into a solid-state electrolyte for a zinc-ion hybrid supercapacitor. This research develops a feasible, simple, and low-cost route for lignin-containing hydrogel preparation and offers insights into the high-value application of agro-industrial lignocellulosic wastes.

Clinicopathological features of non-conventional renal cell carcinoma histological subtypes: Learning points from a large contemporary series spanning over three decades.

PURPOSE: To perform a retrospective review of the clinicopathological features of patients with conventional and non-conventional renal cell carcinoma (cRCC and ncRCC). MATERIALS AND METHODS: A large prospectively maintained uro-oncological registry was accessed to extract clinicopathological data of patients diagnosed with renal tumors who subsequently underwent nephrectomy from 1990-2019. Demographics and operative parameters were extracted. Analyses of overall survival (OS) and cancer-specific survival (CSS) were performed using the Kaplan-Meier method. Cox proportional-hazards analysis was used to identify risk factors which influenced survival. RESULTS: There were a total of 1,686 consecutive nephrectomies which was retrieved, with 1,286 cRCC and 400 ncRCC. The commonest ncRCC subtypes were papillary (n=198, 11.7%), clear cell papillary (n=50, 3.0%) and chromophobe (n=49, 2.9%) RCC. Kaplan-Meier estimates of OS were higher in cRCC (0.74; 95% confidence interval [CI], 0.71-0.78) than ncRCC (hazard ratio, 1.47; 95% CI, 1.16-1.87). Among individual subtypes, chromophobe RCC had the highest 5-year OS (0.90; 95% CI, 0.79-1.0). Among ncRCC subtypes, acquired cystic RCC demonstrated the highest association with end-stage renal failure and hypertension, with the highest CSS. MiT family translocation RCC had the youngest mean age at presentation (45.6±12.8 y) and excellent CSS. Factors associated with increased OS in the entire cohort included shorter operative time, partial nephrectomy and lower tumor stages. CONCLUSIONS: This study provides a comprehensive contemporary overview of ncRCCs which are yet poorly characterized, in comparison to cRCCs. Data from this study would contribute towards tailored patient counseling and healthcare resource planning.

Metal ion-assisted conversion of Co-ZIF-L to CoNi-layered double hydroxides with high electrochemical properties for supercapacitors.

Metal ion-induced etching can effectively convert zeolitic imidazolate frameworks (ZIFs) to CoNi-layered double hydroxides (LDH). Here, different metal-ion-assisted etching methods are utilized to convert Co-ZIF-L to CoNi-LDH with various morphologies and electrochemical properties. The resultant CoNi-LDH (CoNi-1) with a composition of Co0.7Ni0.3(OH)2 displayed a high electrochemical performance when Co-ZIF-L was treated in N, N-dimethylformamide-ethanol solution containing Co2+ ions followed by Ni2+ ion-induced etching under hydrothermal condition. The improved electrochemical performance of CoNi-1 can be attributed to structural advantages, where the well-dispersed ultrathin CoNi-LDH layers favor the exposure of surface active sites and promote ion diffusion to maximize electrochemical properties.

Development of a 48-Well Dynamic Suspension Culture System for Pancreatic Differentiation from Human Embryonic Stem Cells.

BACKGROUND: Human pluripotent stem cells (hPSCs) have started to emerge as a potential tool with application in fields of drug discovery, disease modelling and cell therapy. A variety of protocols for culturing and differentiating pluripotent stem cells into pancreatic ß like cells have been published. However, small-scale dynamic suspension culture systems, which could be applied toward systematically optimizing production strategies for cell replacement therapies to accelerate the pace of their discovery and development toward the clinic, are overlooked. METHODS: Human embryonic stem cell (hESC) line H9 was used to establish the novel 48-well dynamic suspension culture system. The effects of various rotational speeds and culture medium volumes on cell morphology, cell proliferation, cell viability and cell phenotype were evaluated. Effect of cell density on the pancreatic differentiation efficiency from H9 cells in 48-well plates was further investigated. In vitro the function of pancreatic ß like cells was assessed by measuring glucose-stimulated insulin secretion. MAIN RESULTS: A 48-well dynamic suspension culture system for hESC expansion as cell aggregates was developed. With optimized rotational speed and culture medium volume, hESCs maintained normal karyotype, viability and pluripotency. Furthermore, the system can also support the hESC aggregates subsequent differentiation into functional pancreatic ß like cells after optimizing initial cell seeding density. CONCLUSION: A controllable 48-well suspension culture system in microplates for hESCs maintenance, expansion and pancreatic differentiation was developed, which may provide an efficient platform for high-throughput drug screening.

Generation and characterization of a human iPSC line HECi001-A from a healthy adult donor pancreata.

Human induced pluripotent stem cells (hiPSC) are considered promising sources of pancreatic islet organoids to treat diabetes. Due to that epigenetic memory predisposes iPSCs to enhanced differentiation into the parental cell type, we sought to generate iPSC lines from islet cells isolated from healthy adult pancreata. Islet cells were reprogrammed with CytoTune-iPS 2.0 Sendai Reprogramming Kit, where the generated iPSCs showed normal karyotype, expression of pluripotency associated markers and in vivoteratoma formation. This cell line will be a valuable resource for drug screening, and potential source for high-efficient generation of insulin-producing islets for treating diabetes.

Artificial Atomic Vacancies Tailor Near-Infrared II Excited Multiplexing Upconversion in Core-Shell Lanthanide Nanoparticles.

Epitaxial growth of an inert shell around the optical active lanthanide upconversion nanoparticles (UCNPs) is a general strategy to enhance their brightness. Yet, its potential as a tool in multiplexing emission tailoring has rarely been reported. Here, by developing the atomic vacancies into color selectivity actuators, we present an efficient strategy to achieve inert-shell-modulated multiplexing upconversion in 1540 nm activated UCNPs. Artificially generated fluoride atomic vacancies, owing to the decreased NaOH/NH4F dosage during shell growth, reduce the coordination number of Y-F and lattice densities in the inert shell, leading to the core-engineered shell nanoparticles with distinctive emission profiles. The multicolor tailoring is independent of shell thickness and can be readily applied to Lu3+/Gd3+-based shells. The upconversion emission can be exploited to visualize in security decoding and in vivo multiplexing bioimaging. This method of regulating atomic vacancies based on the inert-shell engineering opens new insights of upconversion modulation in core-shell lanthanide nanostructures.

Holmium:Yttrium-Aluminum-Garnet Laser Pulse Type Affects Irrigation Temperatures in a Benchtop Ureteral Model.

Introduction: MOSES™ technology is a holmium:yttrium-aluminum-garnet laser pulse mode shown to minimize stone retropulsion. This may facilitate lithotripsy at higher power settings. However, power and heat production are proportional, and temperatures capable of tissue injury may occur during ureteroscopic lithotripsy. Although previous in vitro studies demonstrate the importance of irrigation and activation time on heat production, the impact of pulse type has not been evaluated. Methods: A flexible ureteroscope with a 365 µm laser fiber was placed in an 11/13 F access sheath inserted into a 50 mL saline bag to simulate a ureter, renal pelvis, and antegrade irrigant flow. A thermocouple was placed adjacent to the laser tip, and the laser fired for 30 seconds at 0.6 J/6 Hz, 0.8 J/8 Hz, 1 J/10 Hz, 1 J/20 Hz, and 0.2 J/70 Hz at irrigation pressure of 100 mmHg. Four runs were tested per setting using short pulse, long pulse (LP), MOSES-contact (MC), and MOSES-distance (MD) modes. The mean temperature changes (dT) were compared and thermal dose was calculated in cumulative equivalent minutes at 43°C (CEM43) using an adjusted baseline of 37°C. CEM43 ≥ 120 minutes was considered the tissue injury threshold. Results: At 0.8 J/8 Hz, LP produced the greatest dT, significantly higher than MC (p = 0.041). CEM43 did not exceed the injury threshold. At 1 J/10 Hz, dT was significantly higher for LP versus MC and MD (p = 0.024 and 0.045, respectively). Thermal dose remained below the injury threshold. No differences in dT were seen between pulse types at 0.6 J/6 Hz, 0.2 J/70 Hz, or 1 J/20 Hz. At 1 J/20 Hz, thermal dose exceeded the injury threshold for all pulse types within 3 seconds. Conclusions: Laser pulse type and length seemed to impact heat production in our ureteral model. LP produced significantly greater temperatures at 0.8 J/8 Hz and 1 J/10 Hz relative to MOSES settings. Fortunately, thermal dose remained safe at these settings. Both LP and MOSES technology have been shown to reduce stone retropulsion. At power ≤10 W, the latter may confer this advantage with decreased heat production.

The Rise and Fall of High Temperatures During Ureteroscopic Holmium Laser Lithotripsy.

Introduction: Temperatures over 43°C-the threshold for cellular injury-may be achieved during ureteroscopic holmium laser lithotripsy. The time to reach and subsequently clear high temperatures at variable laser power settings and irrigation pressures has not been studied. Methods: A flexible or semirigid ureteroscope was placed within an 11/13 F ureteral access sheath inserted into a 250-mL saline bag simulating a normal-caliber ureter, renal pelvis reservoir, and antegrade irrigation flow. A thermocouple was placed adjacent to a 365 µm fiber fired for 45 seconds at 0.6 J/6 Hz, 0.8 J/8 Hz, 1 J/10 Hz, 1 J/20 Hz, and 0.2 J/80 Hz. Irrigation pressures of 200, 100, and 0 mm Hg were tested. Mean temperature changes were recorded with 6°C increase as a threshold for injury (as body temperature is 6°C below 43°C). Results: Semirigid scope: At 200 mm Hg no temperature changes >6°C were observed. At 100 mm Hg, changes >6°C occurred with 1 J/20 Hz within 1 second of activation and returned to ≤6°C within 1 second of cessation. At 0 mm Hg, changes >6°C occurred with all settings; within 1 second at power ≥10 W. Temperatures returned to ≤6°C within 5-10 seconds. Flexible scope: At 200 mm Hg, changes >6°C occurred at 1 J/10 Hz (15 seconds), 0.2 J/80 Hz (3 seconds), and 1 J/20 Hz (2 seconds). Temperatures returned within 6°C of baseline within 2 seconds. At 100 mm Hg, changes >6°C occurred in all but 0.6 J/6 Hz. Temperatures returned to ≤6°C in 5-10 seconds. At 0 mm Hg, all settings produced changes >6°C within 3 seconds, except 0.6 J/6 Hz (35 seconds). Temperatures returned to ≤6°C in under 10 seconds. Conclusions: High temperatures were achieved in our in vitro model in as little as 1 second at common irrigation pressures and laser settings, particularly with a flexible ureteroscope and power ≥10 W. However, with laser cessation, temperatures quickly returned to a safe level at each irrigation pressure.

Avoiding a Lemon: Performance Consistency of Single-Use Ureteroscopes.

INTRODUCTION AND OBJECTIVES: Single-use flexible ureteroscopes are increasingly popular because of high repair costs of reusable ureteroscopes. As new single-use ureteroscopes enter the market, the consistency of performance of these devices has been questioned. Our objective was to compare two single-use ureteroscopes: the Pusen PU3022a (Zhuhai Pusen) and the LithoVue (Boston Scientific) with emphasis on physical and optical performance consistency. METHODS: Ten LithoVue and 10 Pusen ureteroscopes were evaluated in never-used condition. The following parameters were recorded: maximal tip deflection with an empty working channel, 200 µm laser fiber, and 1.9F basket; image resolution at 10, 20, and 50 mm; and irrigation flow rate; all ureteroscopes were then fully deflected for 200 cycles. Maximum deflection was remeasured. Mean values for each parameter were compared. To examine within-manufacturer consistency, the variance was calculated and an F-test performed to evaluate for equivalence. RESULTS: Both ureteroscopes provided max deflection over 270°. The Pusen flexed to a greater degree than LithoVue. The Pusen lost more deflection with a laser fiber in the working channel. LithoVue had higher resolution at 10 mm, but the ureteroscopes were similar at 20 and 50 mm. Although the working channel diameter is identical, irrigation flow was higher with the Pusen. However, its working channel was 7 cm shorter than LithoVue. After 200 cycles of deflections, LithoVue had less deflection loss, although one ureteroscope was excluded from analysis because of mechanical failure. Variability was minimal and not significant between manufacturers at all measured parameters. CONCLUSIONS: LithoVue and the newer PU3022a have similar "out-of-the-box" performance characteristics and seem durable. These two single-use flexible ureteroscopes performed consistently regardless of the manufacturer.