De novo design of peptides that bind specific conformers of α-synuclein.

Insoluble amyloids rich in cross-ß fibrils are observed in a number of neurodegenerative diseases. Depending on the clinicopathology, the amyloids can adopt distinct supramolecular assemblies, termed conformational strains. However, rapid methods to study amyloids in a conformationally specific manner are lacking. We introduce a novel computational method for de novo design of peptides that tile the surface of α-synuclein fibrils in a conformationally specific manner. Our method begins by identifying surfaces that are unique to the conformational strain of interest, which becomes a "target backbone" for the design of a peptide binder. Next, we interrogate structures in the PDB with high geometric complementarity to the target. Then, we identify secondary structural motifs that interact with this target backbone in a favorable, highly occurring geometry. This method produces monomeric helical motifs with a favorable geometry for interaction with the strands of the underlying amyloid. Each motif is then symmetrically replicated to form a monolayer that tiles the amyloid surface. Finally, amino acid sequences of the peptide binders are computed to provide a sequence with high geometric and physicochemical complementarity to the target amyloid. This method was applied to a conformational strain of α-synuclein fibrils, resulting in a peptide with high specificity for the target relative to other amyloids formed by α-synuclein, tau, or Aß40. This designed peptide also markedly slowed the formation of α-synuclein amyloids. Overall, this method offers a new tool for examining conformational strains of amyloid proteins.

The Interplay Between Human Leukocyte Antigen Antibody Profile and COVID-19 Vaccination in Waitlisted Renal Transplant Patients.

CONTEXT.­: Mass COVID-19 vaccination is mandated in vulnerable populations in our renal transplant waitlist cohort. However, the anti-human leukocyte antigen (anti-HLA) profile after COVID-19 vaccination is controversial, and the side effects are yet to be discerned. OBJECTIVE.­: To evaluate the status of HLA antibodies in waitlist renal transplant patients before and 3 weeks after each vaccination and if comorbidities are associated with the HLA antibody profile. DESIGN.­: A total of 59 waitlisted kidney transplant patients were included in this study. The anti-HLA antibodies were analyzed before and 6 months after their last COVID-19 vaccination. The mean fluorescence intensity change in the anti-HLA antibody levels was used to classify patients into 3 groups: high inducers, low inducers, and noninducers. RESULTS.­: There were significant HLA antibody profile changes after COVID-19 vaccination, showing 21 antibodies generated against HLA class I antigens and 7 against HLA class II antigens to their baseline. Compared with the noninducers, the high and low inducers showed a higher prevalence of COVID-19 infection, COVID-19 vaccine type, and background hypertension history. CONCLUSIONS.­: Our data suggest that COVID-19 vaccination propagates anti-HLA class I and II antibodies for waitlisted renal transplant patients. The clinical significance of these antibodies needs further study. Furthermore, comorbidities, such as history of COVID-19 infection and hypertension, supplemented this effect. Anti-HLA antibody monitoring may be warranted in vaccinated, waitlisted renal transplant patients with COVID-19 vaccinations, and a history of COVID-19 infection or hypertension.

Corrigendum to "RPN (Radius, Position of tumour, iNvasion of renal sinus) Classification and Nephrometry Scoring System: An Internationally Developed Clinical Classification To Describe the Surgical Difficulty for Renal Masses for Which Robotic Partial Nephrectomy Is Planned" [Eur. Urol. Open Sci. 54 (2023) 33-42].

[This corrects the article DOI: 10.1016/j.euros.2023.05.007.].

Validation of next-generation sequencing-based chimerism testing for accurate detection and monitoring of engraftment in hematopoietic stem cell transplantation.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a life-saving treatment for various hematological disorders. The success of allo-HSCT depends on the engraftment of donor cells and the elimination of recipient cells monitored through chimerism testing. We aimed to validate a next-generation sequencing (NGS)-based chimerism assay for engraftment monitoring and to emphasize the importance of including the most prevalent cell subsets in proficiency testing (PT) programs. We evaluated the analytical performance of NGS-based chimerism testing (AlloSeq-HCT and CareDx) with a panel of targeted 202 informative single-nucleotide polymorphisms (SNPs) (i.e., linearity and precision, analytical sensitivity and specificity, system accuracy, and reproducibility). We further compared the performance of our NGS panel with conventional short tandem repeat (STR) analysis in unfractionated whole blood and cell-subset-enriched CD3 and CD66. Our NGS-based chimerism monitoring assay has an impressive detection limit (0.3% host DNA) for minor alleles and analytical specificity (99.9%). Pearson's correlation between NGS- and STR-based chimerism monitoring showed a linear relationship with a slope of 0.8 and r = 0.973. The concordance of allo-HSCT patients using unfractionated whole blood, CD3, and CD66 was 0.95, 0.96, and 0.54, respectively. Utilization of CD3+ cell subsets for mixed chimerism detection yielded an average of 7.3 ± 7-fold higher donor percentage detection compared to their corresponding unfractionated whole blood samples. The accuracy of the NGS assay achieved a concordance of 98.6% on blinded external quality control STR samples. The reproducibility series showed near 100% concordance with respect to inter-assay, inter-tech, inter-instrument, cell flow kits, and AlloSeq-HCT software versions. Our study provided robust validation of NGS-based chimerism testing for accurate detection and monitoring of engraftment in allo-HSCT patients. By incorporating the cell subsets (CD3 and CD66), the sensitivity and accuracy of engraftment monitoring are significantly improved, making them an essential component of any PT program. Furthermore, the implementation of NGS-based chimerism testing shows potential to streamline high-volume transplant services and improve clinical outcomes by enabling early relapse detection and guiding timely interventions.

De novo Design of Peptides that Bind Specific Conformers of α-Synuclein.

Insoluble amyloids rich in cross-ß fibrils are observed in a number of neurodegenerative diseases. Depending on the clinicopathology, the amyloids can adopt distinct supramolecular assemblies, termed conformational strains. However, rapid methods to study amyloid in a conformationally specific manner are lacking. We introduce a novel computational method for de novo design of peptides that tile the surface of α-synuclein fibrils in a conformationally specific manner. Our method begins by identifying surfaces that are unique to the conformational strain of interest, which becomes a "target backbone" for the design of a peptide binder. Next, we interrogate structures in the PDB database with high geometric complementarity to the target. Then, we identify secondary structural motifs that interact with this target backbone in a favorable, highly occurring geometry. This method produces monomeric helical motifs with a favorable geometry for interaction with the strands of the underlying amyloid. Each motif is then symmetrically replicated to form a monolayer that tiles the amyloid surface. Finally, amino acid sequences of the peptide binders are computed to provide a sequence with high geometric and physicochemical complementarity to the target amyloid. This method was applied to a conformational strain of α-synuclein fibrils, resulting in a peptide with high specificity for the target relative to other amyloids formed by α-synuclein, tau, or Aß40. This designed peptide also markedly slowed the formation of α-synuclein amyloids. Overall, this method offers a new tool for examining conformational strains of amyloid proteins.

RPN (Radius, Position of tumour, iNvasion of renal sinus) Classification and Nephrometry Scoring System: An Internationally Developed Clinical Classification To Describe the Surgical Difficulty for Renal Masses for Which Robotic Partial Nephrectomy Is Planned.

Background: The surgical difficulty of partial nephrectomy (PN) varies depending on the operative approach. Existing nephrometry classifications for assessment of surgical difficulty are not specific to the robotic approach. Objective: To develop an international robotic-specific classification of renal masses for preoperative assessment of surgical difficulty of robotic PN. Design setting and participants: The RPN classification (Radius, Position of tumour, iNvasion of renal sinus) considers three parameters: tumour size, tumour position, and invasion of the renal sinus. In an international survey, 45 experienced robotic surgeons independently reviewed de-identified computed tomography images of 144 patients with renal tumours to assess surgical difficulty of robot-assisted PN using a 10-point Likert scale. A separate data set of 248 patients was used for external validation. Outcome measurements and statistical analysis: Multiple linear regression was conducted and a risk score was developed after rounding the regression coefficients. The RPN classification was correlated with the surgical difficulty score derived from the international survey. External validation was performed using a retrospective cohort of 248 patients. RPN classification was also compared with the RENAL (Radius; Exophytic/endophytic; Nearness; Anterior/posterior; Location), PADUA (Preoperative Aspects and Dimensions Used for Anatomic), and SPARE (Simplified PADUA REnal) scoring systems. Results and limitation: The median tumour size was 38 mm (interquartile range 27-49). The majority (81%) of renal tumours were peripheral, followed by hilar (12%) and central (7.6%) locations. Noninvasive and semi-invasive tumours accounted for 37% each, and 26% of the tumours were invasive. The mean surgical difficulty score was 5.2 (standard deviation 1.9). Linear regression analysis indicated that the RPN classification correlated very well with the surgical difficulty score (R2 = 0.80). The R2 values for the other scoring systems were: 0.66 for RENAL, 0.75 for PADUA, and 0.70 for SPARE. In an external validation cohort, the performance of all four classification systems in predicting perioperative outcomes was similar, with low R2 values. Conclusions: The proposed RPN classification is the first nephrometry system to assess the surgical difficulty of renal masses for which robot-assisted PN is planned, and is a useful tool to assist in surgical planning, training and data reporting. Patient summary: We describe a simple classification system to help urologists in preoperative assessment of the difficulty of robotic surgery for partial kidney removal for kidney tumours.

Pediatric intracranial tuberculoma: illustrative case.

BACKGROUND: Tuberculosis is an airborne disease caused by Mycobacterium tuberculosis. Intracranial tuberculoma is a rare complication of extrapulmonary tuberculosis due to hematogenous spread to subpial and subependymal regions. Intracranial tuberculoma can occur with or without meningitis. OBSERVATIONS: A 3-year-old male who had recently emigrated from Sudan presented to the emergency department with right-sided seizures lasting 30 minutes, which were aborted with levetiracetam and midazolam. Head computed tomography revealed a multilobulated left supratentorial mass with solid and cystic components and measuring 8.0 × 4.8 × 6.5 cm. The patient had successful resection of the mass, which was positive for M. tuberculosis. He was started on rifampin, isoniazid, pyrazinamide, ethambutol, and fluoroquinolone and was discharged home in stable condition. LESSONS: A literature review on pediatric intracranial tuberculoma was performed, which included 48 studies (n = 49). The mean age was 8.8 ± 5.4 years with a slight female predilection (59%). Predominant solitary tuberculomas (63%) were preferentially managed with both resection and antituberculosis therapy (ATT), whereas multifocal tuberculomas were preferentially managed with ATT. Intracranial tuberculoma is a rare but treatable cause of space-occupying lesions in children. Clinicians should maintain a high level of suspicion in patients from endemic regions and involve the infectious disease service early.

Emergence of triplet therapy for metastatic castration-sensitive prostate cancer: An updated systematic review and network meta-analysis.

INTRODUCTION: There have been a growing number of treatment options available for men with metastatic castration-sensitive prostate cancer. Not only have newer agents entered the clinical landscape, there is a trend toward treatment intensification by combining multiple agents simultaneously. We aim to assess the best contemporary treatment option for men with mCSPC. MATERIALS AND METHODS: We perform an updated systematic review and network meta-analysis of randomized control trials that evaluated systemic therapies in men with castration-sensitive prostate cancer. We searched multiple databases up to April 2022. We included all randomized trials assessing the effect of systemic agents. We performed subgroup analyses based on disease volume and timing of presentation. Statistical analysis was performed with Bayesian methods. RESULTS: We found 10 eligible trials with 10,065 patients who were included in this analysis. Triplet therapy with darolutamide or abiraterone with docetaxel and ADT improved overall survival. In the sensitivity analysis, the respective hazard ratios for triplet therapy was HR 0.70 (95%CI 0.61-0.80) compared to docetaxel+ADT and 0.77 (95%CI 0.65-0.91) compared to androgen receptor pathway inhibitors+ADT combinations. It was estimated that there was 96% chance that one of the triplet therapy combinations were the best treatment option from an OS perspective. Triplet therapy also improved progression-free survival. These benefits were pronounced in men with high-volume disease burden and those with de novo metastatic disease. CONCLUSION: The finding suggest that triplet therapy is likely the most efficacious available option in men with metastatic, castration-sensitive prostate cancer, especially in those with high-volume disease burden.

Salmonella Mississippi: An unusual cause of renal abscess in an immunocompetent patient.

Renal abscess is a rare manifestation of Salmonella infection. This usually occurs in the presence of risk factors that include immunosuppression, renal stones and urinary structural abnormality. We describe a 19-year-old male with no risk factors who developed a left renal abscess and gram-negative sepsis caused by Salmonella Mississippi. This was managed successfully with percutaneous drainage of the abscess and a prolonged course of antibiotics. To our knowledge, this is the first reported case of Salmonella Mississippi as a cause for renal abscess in an individual with no identifiable risk factors.

Defining Prostatic Vascular Pedicle Recurrence and the Anatomy of Local Recurrence of Prostate Cancer on Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography.

Background: The term local recurrence in prostate cancer is considered to mean persistent local disease in the prostatic bed, most commonly at the site of the vesicourethral anastomosis (VUA). Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging for assessment of early biochemical recurrence (BCR), we have found histologically confirmed prostate cancer in the prostatic vascular pedicle (PVP). If a significant proportion of local recurrences are distant to the VUA, it may be possible to alter adjuvant and salvage radiation fields in order to reduce the potential morbidity of radiation in selected patients. Objective: To describe PVP local recurrence and to map the anatomic pattern of prostate bed recurrence on PSMA PET/CT. Design setting and participants: This was a retrospective multicentre study of 185 patients imaged with PSMA PET/CT following radical prostatectomy (RP) between January 2016 and November 2018. All patient data and clinical outcomes were prospectively collected. Recurrences were documented according to anatomic location. For patients presenting with local recurrence, the precise location of the recurrence within the prostate bed was documented. Intervention: PSMA PET/CT for BCR following RP. Results and limitations: A total of 43 local recurrences in 41/185 patients (22%) were identified. Tumour recurrence at the PVP was found in 26 (63%), VUA in 15 (37%), and within a retained seminal vesicle and along the anterior rectal wall in the region of the neurovascular bundle in one (2.4%) each. Histological and surgical evidence of PVP recurrence was acquired in two patients. The study is limited by its retrospective nature with inherent selection bias. This is an observational study reporting on the anatomy of local recurrence and does not include follow-up for patient outcomes. Conclusions: Our study showed that prostate cancer can recur in the PVP and is distant to the VUA more commonly than previously thought. This may have implications for RP technique and for the treatment of selected patients in the local recurrence setting. Patient summary: We investigated more precise identification of the location of tumour recurrence after removal of the prostate for prostate cancer. We describe a new definition of local recurrence in an area called the prostatic vascular pedicle. This new concept may alter the treatment recommended for recurrent disease.

Effect of local steroids on urethral strictures: A systematic review and meta-analysis.

PURPOSE: Urethral stricture disease is common and has high associated morbidity and impact on quality-of-life. This systematic review and meta-analysis aims to summarise current evidence on the efficacy of local urethral steroids post-direct vision internal urethrotomy (DVIU) for the treatment of urethral strictures in males. MATERIALS AND METHODS: A comprehensive search was performed using reputable databases and registries, up to 22 February 2022. Only randomised control trials in which participants were randomised to DVIU plus local urethral steroids versus DVIU only were included. Statistical analyses were performed using a random-effects model. Quality of evidence was rated according to the GRADE approach. RESULTS: The search identified seven studies in which 365 participants were randomised to DVIU plus local urethral steroids versus DVIU only. The application of local steroids appeared to reduce recurrence rates (risk ratio, 0.67; 95% confidence interval [CI], 0.49-0.90) and time-to-recurrence (hazard ratio, 0.58; 95% CI, 0.39-0.85). Qmax also improved following steroid application (mean difference, 0.82; 95% CI, -1.02-2.66); however, this was not statistically significant. No heterogeneity was identified between included studies for all outcomes. The certainty of evidence was downgraded due to study limitations with a small sample size and unclear risk-of-bias related to insufficient trial information. CONCLUSIONS: Compared to DVIU alone, adjuvant steroids applied to the urethra may reduce risk of recurrence and time-to-recurrence. These findings were statistically significant and likely also clinically significant given low associated costs and risk. However, more robust randomised trials are necessary to enhance the validity of these outcomes.

Cross-Seeding Controls Aß Fibril Populations and Resulting Functions.

Amyloid peptides nucleate from monomers to aggregate into fibrils through primary nucleation. Pre-existing fibrils can then act as seeds for additional monomers to fibrillize through secondary nucleation. Both nucleation processes occur simultaneously, yielding a distribution of fibril polymorphs that can generate a spectrum of neurodegenerative effects. Understanding the mechanisms driving polymorph structural distribution during both nucleation processes is important for uncovering fibril structure-function relationships, as well as for creating polymorph distributions in vitro that better match fibril structures found in vivo. Here, we explore how cross-seeding wild-type (WT) Aß1-40 with Aß1-40 mutants E22G (Arctic) and E22Δ (Osaka), as well as with WT Aß1-42, affects the distribution of fibril structural polymorphs and how changes in structural distribution impact toxicity. Transmission electron microscopy analysis revealed that fibril seeds derived from mutants of Aß1-40 imparted their structure to WT Aß1-40 monomers during secondary nucleation, but WT Aß1-40 fibril seeds do not affect the structure of fibrils assembled from mutant Aß1-40 monomers, despite the kinetic data indicating accelerated aggregation when cross-seeding of any combination of mutants. Additionally, WT Aß1-40 fibrils seeded with mutant fibrils produced similar structural distributions to the mutant seeds with similar cytotoxicity profiles. This indicates that mutant fibril seeds not only impart their structure to growing WT Aß1-40 aggregates but also impart cytotoxic properties. Our findings establish a relationship between the fibril structure and the phenotype on a polymorph population level and that these properties can be passed on through secondary nucleation to the succeeding generations of fibrils.

Protocol for CAMUS Delphi Study: A Consensus on Comprehensive Reporting and Grading of Complications After Urological Surgery.

BACKGROUND: Reproducible assessment of postoperative complications is essential for reliable evaluation of quality of care to enable comparison between healthcare centres and ensure transparent patient counselling. Currently, significant discrepancies exist in complication reporting and grading due to heterogeneous definitions and methodologies. OBJECTIVE: To develop a standardised and reproducible assessment of perioperative complications and overall associated morbidity, to allow for the construction of a uniform language for complication reporting and grading. DESIGN, SETTING, AND PARTICIPANTS: The 12-part REDCap-based Delphi survey was developed in conjunction with methodologist review and experienced urologist opinion. International urologists, anaesthetists, and intensive care unit specialists will be included. A minimum sample size of 750 participants (500 urologists and 250 critical care specialities) is targeted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The survey assesses participant demographics, opinion on complication reporting and the proposed Complications After Major & Minor Urological Surgery (CAMUS) reporting recommendations, grading of intervention events using the existing Clavien-Dindo classification and the proposed CAMUS classification, and rating of various clinical scenarios. Consensus will be defined as ≥75% majority agreement. If consensus is not reached, then subsequent Delphi rounds will be performed under steering committee guidance. RESULTS AND LIMITATIONS: Twenty-one participants completed the draft survey. The median survey completion time was 128 min (interquartile range 88-135). The survey revealed that 90% of participants believe that the current complication classification systems are useful but inaccurate, while 100% of participants believe that there is a universal demand for reporting consensus. Several amendments were made following feedback. Limitations include complexity of the proposed supplemental grades and time to completion of the survey. CONCLUSIONS: To ensure comprehensive and comparable complication reporting and grading across centres worldwide, a conclusive uniform language for complication reporting must be created. We intend to address shortcomings of the current complication reporting and classification systems with a new CAMUS classification system developed through multidisciplinary expert consensus obtained through a Delphi survey. Ultimately, standardisation of urological complication reporting and grading may improve patient counselling and quality of care. PATIENT SUMMARY: The reporting and grading of operative complications that occur during or after an operation and associated costs provide a means to stratify quality of patient care. Current complication reporting and classification systems are not standardised and somewhat inaccurate, and thus significantly underestimate patient morbidity and surgical risk. This Delphi survey will provide the basis for the creation of a uniform complication reporting and grading system. Our new system may allow improved reporting and grading between centres, and ultimately improve patient counselling and care.

There is a Need for a Universal Language in the Reporting and Grading of Complication and Intervention Events to Ensure Comparability and Improvement of Surgical Care.

To enhance the clarity and quality of complication reporting and grading for clinicians and patients, the CAMUS-Collaboration aims to develop the following: (1) a data dictionary; (2) parameters required for reporting; (3) risk-based reporting; (4) nursing and patient opinions; and (5) prospective reporting and grading of short- and long-term complications.

Xylan Is Critical for Proper Bundling and Alignment of Cellulose Microfibrils in Plant Secondary Cell Walls.

Plant biomass represents an abundant and increasingly important natural resource and it mainly consists of a number of cell types that have undergone extensive secondary cell wall (SCW) formation. These cell types are abundant in the stems of Arabidopsis, a well-studied model system for hardwood, the wood of eudicot plants. The main constituents of hardwood include cellulose, lignin, and xylan, the latter in the form of glucuronoxylan (GX). The binding of GX to cellulose in the eudicot SCW represents one of the best-understood molecular interactions within plant cell walls. The evenly spaced acetylation and 4-O-methyl glucuronic acid (MeGlcA) substitutions of the xylan polymer backbone facilitates binding in a linear two-fold screw conformation to the hydrophilic side of cellulose and signifies a high level of molecular specificity. However, the wider implications of GX-cellulose interactions for cellulose network formation and SCW architecture have remained less explored. In this study, we seek to expand our knowledge on this by characterizing the cellulose microfibril organization in three well-characterized GX mutants. The selected mutants display a range of GX deficiency from mild to severe, with findings indicating even the weakest mutant having significant perturbations of the cellulose network, as visualized by both scanning electron microscopy (SEM) and atomic force microscopy (AFM). We show by image analysis that microfibril width is increased by as much as three times in the severe mutants compared to the wild type and that the degree of directional dispersion of the fibrils is approximately doubled in all the three mutants. Further, we find that these changes correlate with both altered nanomechanical properties of the SCW, as observed by AFM, and with increases in enzymatic hydrolysis. Results from this study indicate the critical role that normal GX composition has on cellulose bundle formation and cellulose organization as a whole within the SCWs.

Monitoring damage of self-assembled monolayers using metastable excited helium atoms.

The breaking of molecular bonds during exposure to ionizing radiation and electron beams creates irreversible damage in the molecular structure. In some cases, such as lithography, controlled damage of a molecular resist is a desirable process and is the basis for the entire semiconductor industry. In other cases, such as environmental exposure or probing of the molecular structure, the induced damage is a major problem that has limited advances in science and technology. We report here the use of an in situ probe that is minimally invasive to detect real-time damage induced in organic materials. Specifically, we use metastable excited helium atoms in the 3S1 state to characterize the damage caused by a low-energy electron beam ∼30 eV on an organic self-assembled monolayer of 11-bromo-1-undecanethiol on a gold substrate. We were able to monitor the damage caused by the electron beam without introducing any additional observed damage by the probing metastable atoms.

Functionalized Mesoporous Silicas Direct Structural Polymorphism of Amyloid-ß Fibrils.

The aggregation of amyloid-ß (Aß) is associated with the onset of Alzheimer's disease (AD) and involves a complex kinetic pathway as monomers self-assemble into fibrils. A central feature of amyloid fibrils is the existence of multiple structural polymorphs, which complicates the development of disease-relevant structure-function relationships. Developing these relationships requires new methods to control fibril structure. In this work, we evaluated the effect that mesoporous silicas (SBA-15) functionalized with hydrophobic (SBA-PFDTS) and hydrophilic groups (SBA-PEG) have on the aggregation kinetics and resulting structure of Aß1-40 fibrils. The hydrophilic SBA-PEG had little effect on amyloid kinetics, while as-synthesized and hydrophobic SBA-PFDTS accelerated aggregation kinetics. Subsequently, we quantified the relative population of fibril structures formed in the presence of each material using electron microscopy. Fibrils formed from Aß1-40 exposed to SBA-PEG were structurally similar to control fibrils. In contrast, Aß1-40 incubated with SBA-15 or SBA-PFDTS formed fibrils with shorter crossover distances that were more structurally representative of fibrils found in AD patient derived samples. Overall, our results suggest that mesoporous silicas and other exogenous materials are promising scaffolds for the de novo production of specific fibril polymorphs of Aß1-40 and other amyloidogenic proteins.

Detection and localisation of primary prostate cancer using 68 gallium prostate-specific membrane antigen positron emission tomography/computed tomography compared with multiparametric magnetic resonance imaging and radical prostatectomy specimen pathology.

OBJECTIVE: To compare the accuracy of 68 gallium prostate-specific membrane antigen positron emission tomography/computed tomography (68 Ga-PSMA PET/CT) with multiparametric MRI (mpMRI) in detecting and localising primary prostate cancer when compared with radical prostatectomy (RP) specimen pathology. PATIENTS AND METHODS: Retrospective review of men who underwent 68 Ga-PSMA PET/CT and mpMRI for primary prostate cancer before RP across four centres between 2015 and 2018. Patients undergoing imaging for recurrent disease or before non-surgical treatment were excluded. We defined pathological index tumour as the lesion with highest International Society of Urological Pathology Grade Group (GG) on RP specimen pathology. Our primary outcomes were rates of accurate detection and localisation of RP specimen pathology index tumour using 68 Ga-PSMA PET/CT or mpMRI. We defined tumour detection as imaging lesion corresponding with RP specimen tumour on any imaging plane, and localisation as imaging lesion matching RP specimen index tumour in all sagittal, axial, and coronal planes. Secondary outcomes included localisation of clinically significant and transition zone (TZ) index tumours. We defined clinically significant disease as GG 3-5. We used descriptive statistics and the Mann-Whitney U-test to define and compare demographic and pathological characteristics between detected, missed and localised tumours using either imaging modality. We used the McNemar test to compare detection and localisation rates using 68 Ga-PSMA PET/CT and mpMRI. RESULTS: In all, 205 men were included in our analysis, including 133 with clinically significant disease. There was no significant difference between 68 Ga-PSMA PET/CT and mpMRI in the detection of any tumour (94% vs 95%, P > 0.9). There was also no significant difference between localisation of all index tumours (91% vs 89%, P = 0.47), clinically significant index tumours (96% vs 91%, P = 0.15) or TZ tumours (85% vs 80%, P > 0.9) using 68 Ga-PSMA PET/CT and mpMRI. Limitations include retrospective study design and non-central review of imaging and pathology. CONCLUSION: We found no significant difference in the detection or localisation of primary prostate cancer between 68 Ga-PSMA PET/CT and mpMRI. Further prospective studies are required to evaluate a combined PET/MRI model in minimising tumours missed by either modality.

Suppression of serum luteinizing hormone in postmenopausal women by an orally administered nonpeptide antagonist of the gonadotropin-releasing hormone receptor (NBI-42902).

CONTEXT: Parenteral administration of peptide GnRH analogs is widely used in clinical practice for the suppression of pituitary gonadotropins. NBI-42902 is an orally available, high-affinity nonpeptide antagonist of the human GnRH receptor. OBJECTIVE: The objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropin secretion of NBI-42902 in postmenopausal women. DESIGN: This was a phase I, double-blind, placebo-controlled, single-dose study with sequential dose escalation. PARTICIPANTS: Fifty-six healthy, postmenopausal women were included. FSH levels were greater than 40 IU/liter, and body mass index was within 20% of ideal values for all subjects. INTERVENTIONS: Subjects were administered 5, 10, 25, 50, 75, 100, 150, or 200 mg NBI-42902 as an oral solution. MAIN OUTCOME MEASURES: Safety, tolerability, and serum LH and FSH concentrations were evaluated. RESULTS: NBI-42902 was well tolerated. Serum LH concentrations rapidly declined, and dose-dependent suppression was observed. Maximal change from baseline LH concentrations ranged from -19 +/- 5% in the 5-mg group to -55 +/- 2% in the 150-mg group. Suppression of FSH was less pronounced (-15 to -22% of baseline). NBI-42902 was rapidly absorbed after oral administration with a terminal elimination half-life ranging from 2.7 +/- 0.3 to 4.8 +/- 0.8 h. A clear relationship between plasma NBI-42902 concentrations and LH suppression was evident. CONCLUSIONS: Dose-dependent LH suppression was achieved by oral administration of a nonpeptide GnRH antagonist suggesting that compounds such as NBI-42902 may enable adjustable gonadotropin suppression as part of novel treatment strategies for benign gynecological conditions.

Phase I trial of intravenous IL-4 pseudomonas exotoxin protein (NBI-3001) in patients with advanced solid tumors that express the IL-4 receptor.

NBI-3001 is a novel immunotoxin of attenuated Pseudomonas exotoxin fused to circularly permutated IL-4, which has shown some antitumor effects in glioblastoma multiforme with intratumoral administration. The authors evaluated the safety and tolerability of NBI-3001 administered intravenously in a dose-escalation design to patients with renal cell and non-small cell lung carcinoma whose tumors showed at least 10% IL-4 receptor expression. Cohorts of three to six patients were treated at dose levels of 0.008, 0.016, and 0.027 mg/m2 daily x 5 days every 28 days. Neutralizing antibody (NAB) titers, plasma levels of NBI-3001, and patient tolerability were monitored sequentially. 14 patients received a total of 36 cycles of NBI-3001 (range 1-6). No dose-limiting toxicities were noted at dose levels 0.008 and 0.016 mg/m2. At 0.027 mg/m2, two patients developed self-limiting, grade 3 or 4 transaminase elevation during cycle 1. NAB titers of more than 1:100 were detected in five of the seven patients treated with at least two cycles; the median titer after cycle 1 and the median maximum titer in subsequent cycles were 1:50 and approximately 1:1,710, respectively. No objective tumor responses were noted. Eight of 12 evaluable patients with renal cell carcinoma had stable disease; four patients had disease progression. High NAB titers resulted in four patients being withdrawn from the study. The dose-limiting toxicity for intravenous NBI-3001 was transaminase elevation at 0.027 mg/m2. NBI-3001 at 0.016 mg/m2 was well tolerated. Low circulating levels of NBI-3001, coupled with rising NAB titers, may have contributed to the lack of response in tumors that express IL-4R.