A novel biopsy scheme for prostate cancer: targeted and regional systematic biopsy.

PURPOSE: To explore a novel biopsy scheme for prostate cancer (PCa), and test the detection rate and pathological agreement of standard systematic (SB) + targeted (TB) biopsy and novel biopsy scheme. METHODS: Positive needles were collected from 194 patients who underwent SB + TB (STB) followed by radical prostatectomy (RP). Our novel biopsy scheme, targeted and regional systematic biopsy (TrSB) was defined as TB + regional SB (4 SB-needles closest to the TB-needles). The McNemar test was utilized to compare the detection rate performance for clinical significant PCa (csPCa) and clinical insignificant PCa (ciPCa). Moreover, the accuracy, positive predictive value (PPV) and negative predictive value (NPV) were investigated. The agreement between the different biopsy schemes grade group (GG) and RP GG were assessed. The concordance between the biopsy and the RP GG was evaluated using weighted κ coefficient analyses. RESULTS: In this study, the overall detection rate for csPCa was 83.5% (162 of 194) when SB and TB were combined. TrSB showed better NPV than TB (97.0% vs. 74.4%). Comparing to STB, the TB-detection rate of csPCa had a significant difference (p < 0.01), while TrSB showed no significant difference (p > 0.999). For ciPCa, the overall detection rate was 16.5% (32 of 194). TrSB showed better PPV (96.6% vs. 83.3%) and NPV (97.6% vs. 92.9%) than TB. Comparing to STB, the detection rate of both schemes showed no significant difference (p = 0.077 and p = 0.375). All three schemes GG showed poor agreement with RP GG (TB: 43.3%, TrSB: 46.4%, STB: 45.9%). Using weighted κ, all three schemes showed no difference (TB: 0.48, TrSB: 0.51, STB: 0.51). In our subgroup analysis (PI-RADS = 4/5, n = 154), all three schemes almost showed no difference (Weighted κ: TB-0.50, TrSB-0.51, STB-0.50). CONCLUSION: Our novel biopsy scheme TrSB (TB + 4 closest SB needles) may reduce 8 cores of biopsy compared with STB (standard SB + TB), which also showed better csPCa detection rate than TB only, but the same as STB. The pathological agreement between three different biopsy schemes (TB/TrSB/STB) GG and RP GG showed no difference.

Minimally invasive ureteroplasty with lingual mucosal graft for complex ureteral stricture: analysis of surgical and patient-reported outcomes.

OBJECTIVE: To evaluate objective treatment efficacy and safety, and subjective patient-reported outcomes in patients with complex ureteral strictures (US) undergoing minimally invasive lingual mucosal graft ureteroplasty (LMGU). MATERIALS AND METHODS: We prospectively enrolled patients underwent robotic or laparoscopic LMGU between May 2020 and July 2022. Clinical success was defined as symptom-free and no radiographic evidence of re-obstruction. Patient-reported outcomes, including health-related quality of life (HRQoL), mental health status and oral health-related quality of life (OHRQoL), were longitudinally evaluated before surgery, 6 and 12 months postoperatively. RESULTS: Overall, 41 consecutive patients were included. All procedures were performed successfully with 32 patients in robotic approach and 9 in laparoscopic. Forty (97.56%) patients achieved clinical success during the median follow-up of 29 (range 15-41) months. Although patients with complex US experienced poor baseline HRQoL, there was a remarkable improvement following LMGU. Specifically, the 6-month and 12-month postoperative scores were significantly improved compared to the baseline (p < 0.05) in most domains. Twenty-eight (68.3%) and 31 (75.6%) patients had anxiety and depression symptoms before surgery, respectively. However, no significant decrease in the incidence of these symptoms was observed postoperatively. Moreover, there was no significant deterioration of OHRQoL at 6 months and 12 months postoperatively when compared to the baseline. CONCLUSIONS: LMGU is a safe and efficient procedure for complex ureteral reconstruction that significantly improves patient-reported HRQoL without compromising OHRQoL. Assessing patients' quality of life enables us to monitor postoperative recovery and progress, which should be considered as one of the criteria for surgical success.

Recent Progress in the Application of Ion Beam Technology in the Modification and Fabrication of Nanostructured Energy Materials.

The development of green, renewable energy conversion and storage systems is an urgent task to address the energy crisis and environmental issues in the future. To achieve high performance, stable, and safe operation of energy conversion and storage systems, energy materials need to be modified and fabricated through rationalization. Among various modification and fabrication strategies, ion beam technology has been widely used to introduce various defects/dopants into energy materials and fabricate various nanostructures, where the structure, composition, and property of prefabricated materials can be further accurately tailored to achieve better performance. In this paper, we review the recent progress in the application of ion beam technology in material modification and fabrication, focusing on nanostructured energy materials for energy conversion and storage including photo- (electro-) water splitting, batteries (solar cells, fuel cells, and metal-ion batteries), supercapacitors, thermoelectrics, and hydrogen storage. This review first provides a brief basic overview of ion beam technology and describes the classification and technological advantages of ion beam technology in the modification and fabrication of materials. Then, modification of energy materials by ion beams is reviewed mainly concerning doping and defect introduction. Fabrication of energy materials is also discussed mainly in terms of heterojunctions, nanoparticles, nanocavities, and other nanostructures. In particular, we emphasize the advantages of ion beam technology in improving the performance of energy materials. Finally, we point out our understanding of challenges and future perspectives in applying ion beam technology for the modification and fabrication of energy materials.

Comparison of Targeted Biopsy and Combined Biopsy to Avoid Unnecessary Systematic Biopsy in Patients with PI-RADS 5 Lesions.

PURPOSE: To evaluate the detection rates of prostate cancer (PCa) and clinically significant prostate cancer (CSPCa) detection via target biopsy (TB), systematic biopsy (SB), and combined biopsy (CB) in patients with PI-RADS 5 lesions. METHODS: Patients with at least one PI-RADS 5 lesion were retrospectively enrolled in a prospectively collected database. The patients underwent multiparametric magnetic resonance imaging (mpMRI) followed by transrectal TB of PI-RADS 5 lesions and SB. The PCa and CSPCa detection rates and cores of TB and SB were compared with those of CB. RESULTS: In 585 patients, prostate biopsy revealed PCa in 560 cases (95.73%) and CSPCa in 549 cases (93.85%). PCa was detected in T2 patients (93.13%, 217/233) and in T3/4 patients (97.44%, 343/352). CSPCa was detected in T2 patients (89.27%, 208/233) and in T3/4 patients (96.87%, 341/352). The positive rates of TB for T2/3/4, T3/4, and T2 were 94.02%, 96.21%, and 90.56%, respectively. SB added 1.71% (10/585) PCa and 1.37% (8/585) CSPCa detection to TB. There was no difference between TB and SB in detecting different stages of cancer (p > 0.05). In the biopsy core analysis, TB had fewer biopsy cores and a higher detection rate than SB (all p < 0.05). CONCLUSIONS: In patients with PI-RADS score 5 lesions, TB can achieve the same detection rate as, with fewer biopsy cores than, CB. SB adds minimal clinical value and can be omitted for these patients.

Broadband spectral combining of three pulse-shaped fiber amplifiers with 42fs compressed pulse duration.

We demonstrate ultra-broadband spectral combining of ultrashort pulses from Yb-doped fiber amplifiers, with coherently spectrally synthesized pulse shaping, to achieve tens-of-fs pulses. This method can fully compensate for gain narrowing and high order dispersion over broad bandwidth. We produce 42fs pulses by spectrally synthesizing three chirped-pulse fiber amplifiers and two programmable pulse shapers across an 80nm overall bandwidth. To the best of our knowledge, this is the shortest pulse duration achieved from a spectrally combined fiber system at one-micron wavelength. This work provides a path toward high-energy, tens-of-fs fiber chirped-pulse amplification systems.

Facile method to activate substrate for oxygen evolution by a galvanic-cell reaction.

NiFe layered double hydroxide (NiFe LDH) is a promising material with multiple functions. In this communication, a novel method is used to prepare NiFe LDH. This synthesis method is achieved via galvanic-cell corrosion between nickel and iron substrates in aqueous solutions containing a halogen group anion (e.g., Cl) at ambient temperature. The as-prepared NiFe LDH electrodes are developed as electrocatalysts for the oxygen evolution reaction (OER) and exhibit excellent catalytic activities and durability. This work provides an energy-efficient, cost-effective, and scaled-up corrosion engineering approach for manufacturing NiFe LDH materials.

Fully automated detection and localization of clinically significant prostate cancer on MR images using a cascaded convolutional neural network.

Purpose: To develop a cascaded deep learning model trained with apparent diffusion coefficient (ADC) and T2-weighted imaging (T2WI) for fully automated detection and localization of clinically significant prostate cancer (csPCa). Methods: This retrospective study included 347 consecutive patients (235 csPCa, 112 non-csPCa) with high-quality prostate MRI data, which were randomly selected for training, validation, and testing. The ground truth was obtained using manual csPCa lesion segmentation, according to pathological results. The proposed cascaded model based on Res-UNet takes prostate MR images (T2WI+ADC or only ADC) as inputs and automatically segments the whole prostate gland, the anatomic zones, and the csPCa region step by step. The performance of the models was evaluated and compared with PI-RADS (version 2.1) assessment using sensitivity, specificity, accuracy, and Dice similarity coefficient (DSC) in the held-out test set. Results: In the test set, the per-lesion sensitivity of the biparametric (ADC + T2WI) model, ADC model, and PI-RADS assessment were 95.5% (84/88), 94.3% (83/88), and 94.3% (83/88) respectively (all p > 0.05). Additionally, the mean DSC based on the csPCa lesions were 0.64 ± 0.24 and 0.66 ± 0.23 for the biparametric model and ADC model, respectively. The sensitivity, specificity, and accuracy of the biparametric model were 95.6% (108/113), 91.5% (665/727), and 92.0% (773/840) based on sextant, and were 98.6% (68/69), 64.8% (46/71), and 81.4% (114/140) based on patients. The biparametric model had a similar performance to PI-RADS assessment (p > 0.05) and had higher specificity than the ADC model (86.8% [631/727], p< 0.001) based on sextant. Conclusion: The cascaded deep learning model trained with ADC and T2WI achieves good performance for automated csPCa detection and localization.

Magnetic resonance imaging features of prostatic stromal tumour of uncertain malignant potential.

INTRODUCTION: Prostatic stromal tumours of uncertain malignant potential (STUMPs) are rare prostate tumours. The purpose of this study was to investigate the magnetic resonance imaging features of STUMPs. METHODS: A total of 12 patients with STUMP confirmed with pathology who underwent MRI from 2012 to 2020 were retrospectively reviewed. Pathological characteristics including histopathology and immunohistochemistry were also recorded. RESULTS: Among 12 STUMPs, the tumours were detected in the peripheral zone (41.7%[n = 5]) and transitional zone (58.3% [n = 7]) of the prostate. 8 cases (66.7%) were round shape. All lesions were well-defined and compressed the adjacent structures but without signs of an invasion. Homogeneous T1WI and heterogeneous T2WI signals were observed in the STUMPs. The tumours were mainly composed of solid components, while intratumoral cystic change (58.3%[n = 7]) and haemorrhage (8.3%[n = 1]) were seen. 10 cases(83.3%) were seen as relatively high DWI signal, while 2 cases(16.7%) with no increase in DWI. The mean ADC value was 1.084 ± 0.193 (range: 0.864-1.489 × 10-3 mm2 /s). STUMPs had heterogeneous enhancement, with persistent or gradual enhancement. In immunohistochemical staining, Vim, CD34, PR and SMA were positive in the majority of STUMPs. CONCLUSION: MRI features of STUMP are presented as regular, well-defined and isolated prostatic mass with intact pseudocapsule. The presence of heterogeneous T2WI signal, intratumoral cystic change, slightly low mean ADC value and persistent or gradual enhancement may help predict the STUMPs.

Experimental beam combining stabilization using machine learning trained while phases drift.

An 8-beam, diffractive coherent beam combiner is phase controlled by a learning algorithm trained while optical phases drift, using a differential mapping technique. Combined output power is stable to 0.4% with 95% of theoretical maximum efficiency, limited by the diffractive element.

Oxetane Promise Delivered: Discovery of Long-Acting IDO1 Inhibitors Suitable for Q3W Oral or Parenteral Dosing.

3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology.

Comprehensive Strategies to Bicyclic Prolines: Applications in the Synthesis of Potent Arginase Inhibitors.

Comprehensive synthetic strategies afforded a diverse set of structurally unique bicyclic proline-containing arginase inhibitors with a high degree of three-dimensionality. The analogs that favored the Cγ-exo conformation of the proline improved the arginase potency over the initial lead. The novel synthetic strategies reported here not only enable access to previously unknown stereochemically complex proline derivatives but also provide a foundation for the future synthesis of bicyclic proline analogs, which incorporate inherent three-dimensional character into building blocks, medicine, and catalysts and could have a profound impact on the conformation of proline-containing peptides and macrocycles.

Utilization of Metabolite Identification and Structural Data to Guide Design of Low-Dose IDO1 Inhibitors.

Herein the discovery of potent IDO1 inhibitors with low predicted human dose is discussed. Metabolite identification (MetID) and structural data were used to strategically incorporate cyclopropane rings into this tetrahydronaphthyridine series of IDO1 inhibitors to improve their metabolic stability and potency. Enabling synthetic chemistry was developed to construct these unique fused cyclopropyl compounds, leading to inhibitors with improved pharmacokinetics and human whole blood potency and a predicted human oral dose as low as 9 mg once daily (QD).

Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for Immuno-Oncology.

Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a, 18, and 27, demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model.

Discovery of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold.

A series of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold were identified with good cellular and human whole blood activity against IDO1. These inhibitors contain multiple chiral centers and all diastereomers were separated. The absolute stereochemistry of each isomers were not determined. Compounds 15 and 27 stood out as leads due to their good cellular as well as human whole blood IDO1 inhibition activity, low unbound clearance, and reasonable mean residence time in rat cassette PK studies.

SAR towards indoline and 3-azaindoline classes of IDO1 inhibitors.

A novel series of IDO1 inhibitors have been identified with good IDO1 Hela cell and human whole blood activity. These inhibitors contain an indoline or a 3-azaindoline scaffold. Their structure-activity-relationship studies have been explored. Compounds 37 and 41 stood out as leads due to their good potency in IDO1 Hela assay, good IDO1 unbound hWB IC50s, reasonable unbound clearance, and good MRT in rat and dog PK studies.

Carbamate and N-Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors.

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N-pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.

81-beam coherent combination using a programmable array generator.

We have generated 81 independently controllable beams using a spatial light modulator and combined them on a diffractive combiner, to characterize the combiner and develop a fast phase error detection scheme. A key parameter of the diffractive combiner is measured in a new way, enabling an efficient combination when programming calibrated phases of each beam. This testbed provides a platform for development of advanced feedback phase control of high channel-count beam combination.

Stabilization of the 81-channel coherent beam combination using machine learning.

We develop a rapidly converging algorithm for stabilizing a large channel-count diffractive optical coherent beam combination. An 81-beam combiner is controlled by a novel, machine-learning based, iterative method to correct the optical phases, operating on an experimentally calibrated numerical model. A neural-network is trained to detect phase errors based on interference pattern recognition of uncombined beams adjacent to the combined one. Due to the non-uniqueness of solutions in the full space of possible phases, the network is trained within a limited phase perturbation/error range. This also reduces the number of samples needed for training. Simulations have proven that the network can converge in one step for small phase perturbations. When the trained neural-network is applied to a realistic case of 360 degree full range, an iterative scheme exploits random walking at the beginning, with the accuracy of prediction on phase feedback direction, to allow the neural-network to step into the training range for fast convergence. This neural-network-based iterative method of phase detection works tens of times faster than the commonly used stochastic parallel gradient descent approach (SPGD) using a single-detector and random dither when both are tested with random phase perturbations.

Self-derivation-behaviour of substrates realizing enhanced oxygen evolution reaction.

Self-derivation-behaviour of substrates is utilized to fabricate monolithic electrodes for oxygen evolution, in which the selected substrate functions as both the precursor of the active catalyst and a conductive support. In particular, NiFe layered double hydroxide (LDH) can be directly derived from the surface metal of commercial NiFe foam (NFF). Moreover, the as-prepared monolithic electrode exhibits enhanced activity and durability, originating from the resultant defective nanosheet structure and autologous catalyst-support features.

Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy.

The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme-inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3, when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored.