Discovery and preclinical development of a therapeutically active nanobody-based chimeric antigen receptor targeting human CD22.

Chimeric antigen receptor (CAR) T cell therapies targeting B cell-restricted antigens CD19, CD20, or CD22 can produce potent clinical responses for some B cell malignancies, but relapse remains common. Camelid single-domain antibodies (sdAbs or nanobodies) are smaller, simpler, and easier to recombine than single-chain variable fragments (scFvs) used in most CARs, but fewer sdAb-CARs have been reported. Thus, we sought to identify a therapeutically active sdAb-CAR targeting human CD22. Immunization of an adult Llama glama with CD22 protein, sdAb-cDNA library construction, and phage panning yielded >20 sdAbs with diverse epitope and binding properties. Expressing CD22-sdAb-CAR in Jurkat cells drove varying CD22-specific reactivity not correlated with antibody affinity. Changing CD28- to CD8-transmembrane design increased CAR persistence and expression in vitro. CD22-sdAb-CAR candidates showed similar CD22-dependent CAR-T expansion in vitro, although only membrane-proximal epitope targeting CD22-sdAb-CARs activated direct cytolytic killing and extended survival in a lymphoma xenograft model. Based on enhanced survival in blinded xenograft studies, a lead CD22sdCAR-T was selected, achieving comparable complete responses to a benchmark short linker m971-scFv CAR-T in high-dose experiments. Finally, immunohistochemistry and flow cytometry confirm tissue and cellular-level specificity of the lead CD22-sdAb. This presents a complete report on preclinical development of a novel CD22sdCAR therapeutic.

The role of the Toll like receptor 4 signaling in sex-specific persistency of depression-like behavior in response to chronic stress.

Chronic stress is a major risk factor for Major Depressive Disorder (MDD), and it has been shown to impact the immune system and cause microglia activation in the medial prefrontal cortex (mPFC) involved in the pathogenesis of depression. The aim of this study is to further investigate cellular and molecular mechanisms underlying persistent depression behavior in sex specific manner, which is observed clinically. Here, we report that both male and female mice exhibited depression-like behavior following exposure to chronic stress. However, only female mice showed persistent depression-like behavior, which was associated with microglia activation in mPFC, characterized by distinctive alterations in the phenotype of microglia. Given these findings, to further investigate the underlying molecular mechanisms associated with persistent depression-like behavior and microglia activation in female mice, we used translating-ribosome affinity purification (TRAP). We find that Toll like receptor 4 (TLR4) signaling is casually related to persistent depression-like behavior in female mice. This is supported by the evidence that the fact that genetic ablation of TLR4 expression in microglia significantly reduced the persistent depression-like behavior to baseline levels in female mice. This study tentatively supports the hypothesis that the TLR4 signaling in microglia may be responsible for the sex differences in persistent depression-like behavior in female.

The Implementation of Precise Point Positioning (PPP): A Comprehensive Review.

High-precision positioning from Global Navigation Satellite Systems (GNSS) has garnered increased interest due to growing demand in various applications, like autonomous car navigation and precision agriculture. Precise Point Positioning (PPP) offers a distinct advantage over differential techniques by enabling precise position determination of a GNSS rover receiver through the use of external corrections sourced from either the Internet or dedicated correction satellites. However, PPP's implementation has been challenging due to the need to mitigate numerous GNSS error sources, many of which are eliminated in differential techniques such as Real-Time Kinematics (RTK) or overlooked in Standard Point Positioning (SPP). This paper extensively reviews PPP's error sources, such as ionospheric delays, tropospheric delays, satellite orbit and clock errors, phase and code biases, and site displacement effects. Additionally, this article examines various PPP models and correction sources that can be employed to address these errors. A detailed discussion is provided on implementing the standard dual-frequency (DF)-PPP to achieve centimeter- or millimeter-level positioning accuracy. This paper includes experimental examples of PPP implementation results using static data from the International GNSS Service (IGS) station network and a kinematic road test based on the actual trajectory to showcase DF-PPP development for practical applications. By providing a fusion of theoretical insights with practical demonstrations, this comprehensive review offers readers a pragmatic perspective on the evolving field of Precise Point Positioning.

The Bioactive Dietary Polyphenol Preparation Alleviates Depression and Anxiety-Like Behaviors by Modulating the Regional Heterogeneity of Microglia Morphology.

SCOPE: The goal of this study is to investigate the effects of a bioactive dietary polyphenol preparation (BDPP), which is made up of grape-derived polyphenols, on microglial responses, as well as the underlying molecular mechanisms in depression and anxiety-like behaviors. METHODS AND RESULTS: The study finds that treatment with BDPP significantly decreases depression-like and anxiety-like behaviors induced by chronic stress in mice, while leaving their locomotor activity unaffected. The study also finds that BDPP treatment reverses microglia activation in the amygdala and hippocampal formation, regions of the brain involved in emotional regulation, from an amoeboid shape to ramified shape. Additionally, BDPP treatment modulates the release of pro-inflammatory cytokines such as interleukin-6 via high mobility box 1 protein and the receptor for advanced glycation end products (HMGB1-RAGE) signaling pathway in activated microglia induced by chronic stress. CONCLUSION: The findings suggest regional heterogeneity in microglial responses following chronic stress in subregions of the corticolimbic circuit. Specifically, activation of the immune-inflammatory HMGB1-RAGE pathway may provide a new avenue for preventing the manifestation of psychiatric impairments including stress-induced anxiety- and depression-like behavior, using bioactive and bioavailable polyphenols.

Impact of an NCCN-Compliant Multidisciplinary Conference on Treatment Decisions for Localized Prostate Cancer.

BACKGROUND: We sought to investigate the impact of an NCCN-compliant multidisciplinary conference on treatment decisions of patients with localized prostate cancer. METHODS: A retrospective review of our quality assurance localized prostate cancer database was performed. All patients with localized prostate cancer who sought a second opinion at Roswell Park Comprehensive Cancer Center between 2009 and 2019 were presented to the multidisciplinary Localized Prostate Cancer Conference (LPCC) that includes urologists, radiation oncologists, pathologists, and patient advocates. Multivariable regression models were fit to evaluate variables associated with concordance between community recommendations, LPCC recommendations, and treatment received by patients. RESULTS: A total of 1,164 patients were identified, of whom 26% had NCCN very low-/low-risk, 27% had favorable intermediate-risk, 25% had unfavorable intermediate-risk, and 22% had high-/very high-risk prostate cancer. Pathology changed in 11% of patients after genitourinary pathologist review, which caused disease reclassification in 9%. Concordance between community and LPCC recommendations occurred in 78%, with lowest concordance for androgen deprivation therapy (21%) and radiotherapy (53%). Concordance between community recommendations and treatment received occurred in 65%, with lowest concordance for androgen deprivation therapy and radiotherapy; among those who were recommended radiotherapy as the only option by their community urologist, only 26% received it. Concordance between LPCC recommendations and treatment received occurred in 92%. CONCLUSIONS: Community recommendations differed from the multidisciplinary NCCN-compliant recommendations in 22% of patients, primarily for radiotherapy. Multidisciplinary recommendations matched the treatment received in 92% of patients compared with 65% for community recommendations.

Inflammasome-Mediated Neuronal-Microglial Crosstalk: a Therapeutic Substrate for the Familial C9orf72 Variant of Frontotemporal Dementia/Amyotrophic Lateral Sclerosis.

Intronic G4C2 hexanucleotide repeat expansions (HRE) of C9orf72 are the most common cause of familial variants of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). G4C2 HREs in C9orf72 undergo non-canonical repeat-associated translation, producing dipeptide repeat (DPR) proteins, with various deleterious impacts on cellular homeostasis. While five different DPRs are produced, poly(glycine-arginine) (GR) is amongst the most toxic and is the only DPR to accumulate in the associated clinically relevant anatomical locations of the brain. Previous work has demonstrated the profound effects of a poly (GR) model of C9orf72 FTD/ALS, including motor impairment, memory deficits, neurodegeneration, and neuroinflammation. Neuroinflammation is hypothesized to be a driving factor in the disease course; microglia activation is present prior to symptom onset and persists throughout the disease. Here, using an established mouse model of C9orf72 FTD/ALS, we investigate the contributions of the nod-like receptor pyrin-containing 3 (NLRP3) inflammasome in the pathogenesis of FTD/ALS. We find that inflammasome-mediated neuroinflammation is increased with microglial activation, cleavage of caspase-1, production of IL-1ß, and upregulation of Cxcl10 in the brain of C9orf72 FTD/ALS mice. Excitingly, we find that genetic ablation of Nlrp3 significantly improved survival, protected behavioral deficits, and prevented neurodegeneration suggesting a novel mechanism involving HRE-mediated induction of innate immunity. The findings provide experimental evidence of the integral role of HRE in inflammasome-mediated innate immunity in the C9orf72 variant of FTD/ALS pathogenesis and suggest the NLRP3 inflammasome as a therapeutic target.

The bioactive dietary polyphenol preparation alleviates depression and anxiety-like behaviors by modulating the regional heterogeneity of microglia morphology.

Scope: The goal of this study is to investigate the effects of a bioactive dietary polyphenol preparation (BDPP), which is made up of grape-derived polyphenols, on microglial responses, as well as the underlying molecular mechanisms in depression and anxiety-like behaviors. Methods and results: We find that treatment with BDPP significantly decreased depression-like and anxiety-like behaviors induced by chronic stress in mice, while leaving their locomotor activity unaffected. We also find that BDPP treatment reversed microglia activation in the amygdala and hippocampal formation, regions of the brain involved in emotional regulation, from an amoeboid shape to ramified shape. Additionally, BDPP treatment modulates the release of pro-inflammatory cytokines such as interleukin-6 via high mobility box 1 protein and the receptor for advanced glycation end products (HMGB1-RAGE) signaling pathway in activated microglia induced by chronic stress. Conclusion: Our findings suggest regional heterogeneity in microglial responses following chronic stress in subregions of the corticolimbic circuit. Specifically, activation of the immune-inflammatory HMGB1-RAGE pathway might provide a new avenue for therapeutic intervention in stress-induced anxiety- and depression-like behavior, using bioactive and bioavailable polyphenols.

Real-Time Safe Landing Zone Identification Based on Airborne LiDAR.

Over the past two decades, there has been a growing demand for generating digital surface models (DSMs) in real-time, particularly for aircraft landing in degraded visual environments. Challenging landing environments can hinder a pilot's ability to accurately navigate, see the ground, and avoid obstacles that may lead to equipment damage or loss of life. While many accurate and robust filtering algorithms for airborne laser scanning (ALS) data have been developed, they are typically computationally expensive. Moreover, these filtering algorithms require high execution times, making them unsuitable for real-time applications. This research aims to design and implement an efficient algorithm that can be used in real-time on limited-resource embedded processors without the need for a supercomputer. The proposed algorithm effectively identifies the best safe landing zone (SLZ) for an aircraft/helicopter based on processing 3D LiDAR point cloud data collected from a LiDAR mounted on the aircraft/helicopter. The algorithm was successfully implemented in C++ in real-time and validated using professional software for flight simulation. By comparing the results with maps, this research demonstrates the ability of the developed method to assist pilots in identifying the safest landing zone for helicopters.

Evaluation of Adjuvant Activity and Bio-Distribution of Archaeosomes Prepared Using Microfluidic Technology.

Archaeosomes, composed of sulfated lactosyl archaeol (SLA) glycolipids, have been proven to be an effective vaccine adjuvant in multiple preclinical models of infectious disease or cancer. They have classically been prepared using a thin-film hydration method with an average particle size of 100-200 nm. In this study, we developed methods to generate SLA archaeosomes at different sizes, i.e., 30 nm and 100 nm, via microfluidic mixing technology and evaluated their physicochemical characteristics, as well as adjuvant activity and in vivo biodistribution in mice. Archaeosomes, prepared using thin-film and microfluidic mixing techniques, had similar nanostructures and physicochemical characteristics, with both appearing stable during the course of this study when stored at 4 °C or 37 °C. They also demonstrated similar adjuvant activity when admixed with ovalbumin antigen and used to immunize mice, generating equivalent antigen-specific immune responses. Archaeosomes, labeled with CellVueTM NIR815, had an equivalent biodistribution with both sizes, namely the highest signal at the injection site at 24 h post injection, followed by liver, spleen and inguinal lymph node. The presence of SLA archaeosomes of either size helped to retain OVA antigen (OVA-Cy5.5) longer at the injection site than unadjuvanted OVA. Overall, archaeosomes of two sizes (30 nm and 100 nm) prepared using microfluidic mixing maintained similar physicochemical properties, adjuvant activity and biodistribution of antigen, in comparison to those compared by the conventional thin film hydration method. This suggests that microfluidics based approaches could be applied to generate consistently sized archaeosomes for use as a vaccine adjuvant.

Correction: Elsheikh et al. Low-Cost Real-Time PPP/INS Integration for Automated Land Vehicles. Sensors 2019, 19, 4896.

The authors wish to make the following corrections in the original paper [...].

Relapses Rates and Patterns for Pathological T0 After Robot-Assisted Radical Cystectomy: Results From the International Robotic Cystectomy Consortium.

OBJECTIVES: To investigate the oncologic outcomes of pT0 after robot-assisted radical cystectomy (RARC). METHODS: A retrospective review of the International Robotic Cystectomy Consortium database was performed. Patients with pT0 after RARC were identified and analyzed. Data were reviewed for demographics and pathologic outcomes. Kaplan-Meier curves were used to depict recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). Multivariate stepwise Cox regression models were used to identify variables associated with RFS and OS. RESULTS: Four hundred seventy-one patients (18%) with pT0 were identified. Median age was 68 years (interquartile range (IQR) 60-73), with a median follow up of 20 months (IQR 6-47). Thirty-seven percent received neoadjuvant chemotherapy and 5% had pN+ disease. Seven percent of patients experienced disease relapse; 3% had local and 5% had distant recurrence. Most common sites of local and distant recurrences were pelvis (1%) and lungs (2%). Five-year RFS, DSS, and OS were 88%, 93%, and 79%, respectively. Age (hazards ratio [HR] 1.05, 95% confidence interval [CI] 1.01-1.09, P = 0.02), pN+ve (HR 11.48, 95% CI 4.47-29.49, P < .01), and reoperations within 30 days (HR 5.53, 95% CI 2.08-14.64, P < .01) were associated with RFS. Chronic kidney disease (HR 3.24, 95% CI 1.45-7.23, P < .01), neoadjuvant chemotherapy (HR 0.41, 95% CI 0.18-0.92, P = .03), pN+ve (HR 4.37, 95% CI 1.46-13.06, P < .01), and reoperations within 30 days (HR 2.64, 95% CI, 1.08-6.43, P = .03) were associated with OS. CONCLUSIONS: Despite pT0 status at RARC, 5% had pN+ disease and 7% of patients relapsed. Node status was the variable strongest associated with RFS and OS in pT0.

Microbubble drug conjugate and focused ultrasound blood brain barrier delivery of AAV-2 SIRT-3.

BACKGROUND: Delivery of viral vectors as gene therapies to treat neurodegenerative diseases has been hampered by the inability to penetrate the blood brain barrier (BBB) and invasive or non-targeted delivery options prone to inducing immune responses. MR guided focused ultrasound (MR-g-FUS) and microbubbles have demonstrated safe, temporary, targeted BBB permeabilization clinically. METHODS: We developed clinically scalable, microbubble drug conjugates (MDCs) for the viral gene therapy, AAV.SIRT3-myc [adeno-associated virus expressing myc-tagged SIRT3], which has previously been shown to have disease modifying effects in animal models of Parkinson's disease (PD). The lipid shells of the perfluorocarbon gas MDCs were covalently conjugated to antibodies with binding specificity to AAVs. Following systemic (iv) delivery of AAV.SIRT3-myc MDCs, MR-g-FUS was used to deliver SIRT3-myc to brain regions affected in PD. SIRT3-myc expression was determined post mortem, using immunohistochemistry. RESULTS: An in vitro, SH-SY5Y cell culture model was used to show that the localized destruction of MDCs using ultrasound exposures within biological safety limits dissociated AAV2-GFP (green fluorescent protein) from the MDCs in the targeted area while maintaining their transduction capacity. In rats, MR-g-FUS resulted in BBB permeabilization in the striatum and substantia nigra (SNc). SIRT3-myc was expressed in the striatum, but not the SNc. CONCLUSION: These studies demonstrate that MDCs combined with MR-g-FUS are an effective method for delivery of viral vector gene therapies, such as AAV.SIRT3, to brain regions affected in PD. This technology may prove useful as a disease-modifying strategy in PD and other neurodegenerative disorders.

Targeting insulin-like growth factor-1 receptor (IGF1R) for brain delivery of biologics.

The blood-brain barrier (BBB) prevents the majority of drugs from crossing into the brain and reaching neurons. To overcome this challenge, safe and non-invasive technologies targeting receptor-mediated pathways have been developed. In this study, three single-domain antibodies (sdAbs; IGF1R3, IGF1R4, and IGF1R5) targeting the extracellular domain of the human insulin-like growth factor-1 receptor (IGF1R), generated by llama immunization, showed enhanced transmigration across the rat BBB model (SV-ARBEC) in vitro. The rate of brain uptake of these sdAbs fused to mouse Fc (sdAb-mFc) in vivo was estimated using the fluorescent in situ brain perfusion (ISBP) technique followed by optical brain imaging and distribution volume evaluation. Compared to the brains perfused with the negative control A20.1-mFc, the brains perfused with anti-IGF1R sdAbs showed a significant increase of the total fluorescence intensity (~2-fold, p < .01) and the distribution volume (~4-fold, p < .01). The concentration curve for IGF1R4-mFc demonstrated a linear accumulation plateauing at approximately 400 µg (~1 µM), suggesting a saturable mechanism of transport. Capillary depletion and mass spectrometry analyses of brain parenchyma post-ISBP confirmed the IGF1R4-mFc brain uptake with ~25% of the total amount being accumulated in the parenchymal fraction in contrast to undetectable levels of A20.1-mFc after a 5-min perfusion protocol. Systemic administration of IGF1R4-mFc fused with the non-BBB crossing analgesic peptide galanin (2 and 5 mg/kg) induced a dose-dependent suppression of thermal hyperalgesia in the Hargreaves pain model. In conclusion, novel anti-IGF1R sdAbs showed receptor-mediated brain uptake with pharmacologically effective parenchymal delivery of non-permeable neuroactive peptides.

Perioperative and Functional Outcomes of Robot-assisted Ureteroenteric Reimplantation: A Multicenter Study of Seven Referral Institutions.

BACKGROUND: Open revision of ureteroenteric strictures (UESs) is associated with considerable morbidity. There is a lack of data evaluating the feasibility of robotic revisions. OBJECTIVE: To analyze the perioperative and functional outcomes of robot-assisted ureteroenteric reimplantation (RUER) for the management of UESs after radical cystectomy (RC). DESIGN SETTING AND PARTICIPANTS: A retrospective multicenter study of 61 patients, who underwent 63 RUERs at seven high-volume institutions between 2009 and 2020 for benign UESs after RC, was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data were reviewed for demographics, stricture characteristics, and perioperative outcomes. Variables associated with being stricture free after an RUER were evaluated using a multivariate Cox regression analysis. RESULTS AND LIMITATIONS: Among 63 RUERs, 22 were right sided (35%), 34 left sided (54%), and seven bilateral (11%). Twenty-seven (44%) had prior abdominal/pelvic surgery and five (8%) radiotherapy (RT). Thirty-two patients had American Society of Anesthesiologists (ASA) scores I-II (52%) and 29 ASA III (48%). Forty-two (68%) RUERs were in ileal conduits, 18 (29%) in neobladders, and two (3%) in Indiana pouch. The median time to diagnosis of a UES from cystectomy was 5 (3-11) mo. Of the UESs, 28 (44%) failed an endourological attempt (balloon dilatation/endoureterotomy). The median RUER operative time was 195 (175-269) min. No intraoperative complications or conversions to open approach were reported. Twenty-three (37%) patients had postoperative complications (20 [32%] were minor and three [5%] major). The median length of hospital stay was 3 (1-6) d and readmissions were 5%. After a median follow-up of 19 (8-43) mo, 84% of cases were stricture free. Lack of prior RT was the only variable associated with better stricture-free survival after RUER (hazard ratio 6.8, 95% confidence interval 1.10-42.00, p = 0.037). The study limitations include its retrospective nature and the small number of patients. CONCLUSIONS: RUER is a feasible procedure for the management of UESs. Prospective and larger studies are warranted to prove the safety and efficacy of this technique. PATIENT SUMMARY: In this study, we investigate the feasibility of a novel minimally invasive technique for the management of ureteroenteric strictures. We conclude that robotic reimplantation is a feasible and effective procedure.

Ileal conduit versus neobladder: A propensity score-matched analysis of the effect on renal function.

OBJECTIVES: To analyze the long-term effects of continent (neobladder) compared with incontinent (ileal conduit) urinary diversion. METHODS: We carried out a retrospective review of our departmental database. Estimated glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Neobladder and ileal conduit patients were matched in a 1:2 ratio and a propensity score-matched analysis was carried out. Data were summarized using descriptive analysis. Trend plots were generated using baseline and follow-up creatinine values to compare estimated glomerular filtration rate at 3 months, then annually for 5 years. Variables associated with estimated glomerular filtration rate were assessed using multivariate linear analysis. RESULTS: Our cohort consisted of 137 patients (neobladder n = 50 and ileal conduit n = 87) with a median follow-up time of 3 years (interquartile range 1-7 years). The ileal conduit group had shorter operative times (352 vs 444 min, P < 0.01), intracorporeal diversions were more common (66% vs 44%, P = 0.01), had prior abdominal surgery (66% vs 38%, P < 0.01) and had radiation (9% vs 0%, P = 0.03). The neobladder group more commonly had recurrent urinary tract infections (22% vs 3%, P < 0.01) and a steeper decrease in estimated glomerular filtration rate in the first year. On multivariate linear analysis, age/year (-0.59), body mass index per kg/m2 (-0.52), preoperative estimated glomerular filtration rate per unit (0.51), recurrent urinary tract infections (-14.03) and time versus day 90 (year 1, -7.52; year 2, -9.06; year 3, -10.78) were significantly associated with estimated glomerular filtration rate. CONCLUSION: Ileal conduits and neobladders showed a similar effect on the estimated glomerular filtration rate up to 5 years after robot-assisted radical cystectomy. Recurrent urinary tract infections were associated with a worse estimated glomerular filtration rate.

Intracorporeal Versus Extracorporeal Neobladder After Robot-assisted Radical Cystectomy: Results From the International Robotic Cystectomy Consortium.

OBJECTIVE: To compare perioperative and oncologic outcomes of intracorporeal (ICNB) and extracorporeal neobladder (ECNB) following robot assisted radical cystectomy (RARC) from a multi-institutional, prospectively maintained database, the International Robotic Cystectomy Consortium (IRCC). METHODS: A retrospective review of IRCC database between 2003 and 2020 (3742 patients from 33 institutions across 14 countries) was performed (I-79606). The Cochran-Armitage trend test was used to assess utilization of ICNB over time. Multivariate logistic regression models were fit to evaluate variables associated with receiving ICNB, overall complications, high-grade complications, and readmissions after RARC. Kaplan Meier curves were used to depict recurrence-free, disease-specific, and overall survival. RESULTS: Four hundred eleven patients received neobladder, 64% underwent ICNB. ICNB utilization increased significantly over time (P <.01). Patients who received ICNB were readmitted and received neoadjuvant chemotherapy more frequently (36% vs 24%, P = .03, 35% vs 8%, P <.01, respectively). ICNB was associated with older age (OR 1.04, 95% CI 1.01-1.07, P = .001), receipt of neoadjuvant chemotherapy (OR 4.63, 95% CI 2.34-9.18, P <.01), and more recent RARC era (2016-2020) (OR 12.6, 95% CI 5.6-28.4, P <.01). On multivariate analysis, ICNB (OR 5.43, 95% CI 2.34-12.58, P <.01), positive surgical margin (OR 4.88, 95% CI 1.29-18.42, P = .019), longer operative times (OR 1.26, 95% CI 1.00-1.58, P = .048), and institutional annual RARC volume (OR 1.09, 95% CI 1.05-1.12, P <.01) were associated with readmissions. CONCLUSION: Utilization of ICNB increased significantly over time. Patients who underwent RARC and ICNB had shorter hospital stays and fewer 30-d reoperations but were readmitted more frequently compared to those who underwent ECNB.

Development and Validation of an Objective Scoring Tool for Robot-Assisted Partial Nephrectomy: Scoring for Partial Nephrectomy.

Objective: To develop a structured and objective scoring tool for assessment of robot-assisted partial nephrectomy (RAPN): Scoring for Partial Nephrectomy (SPaN). Materials and Methods:Content development: RAPN was deconstructed into 6 domains by a multi-institutional panel of 10 expert robotic surgeons. Performance on each domain was represented on a Likert scale of 1 to 5, with specific descriptions of anchors 1, 3, and 5. Content validation: The Delphi methodology was utilized to achieve consensus about the description of each anchor for each domain in terms of appropriateness of the skill assessed, objectiveness, clarity, and unambiguous wording. The content validity index (CVI) of ≥0.75 was set as cutoff for consensus. Reliability: 15 de-identified videos of RAPN were utilized to determine the inter-rater reliability using linearly weighted percent agreement, and Construct validation of SPaN was described in terms of median scores and odds ratios. Results: The expert panel reached consensus (CVI ≥0.75) after 2 rounds. Consensus was achieved for 36 (67%) statements in the first round and 18 (33%) after the second round. The final six-domain SPaN included Exposure of the kidney; Identification and dissection of the ureter and gonadal vessels; Dissection of the hilum; Tumor localization and exposure; Clamping and tumor resection; and Renorrhaphy. The linearly weighted percent agreement was >0.75 for all domains. There was no difference between median scores for any domain between attendings and trainees. Conclusion: Despite the lack of significant construct validity, SPaN is a structured, reliable, and procedure-specific tool that can objectively assesses technical proficiency for RAPN.

Patterns and predictors of relapse in Merkel cell carcinoma: Results from a population-based study.

BACKGROUND AND PURPOSE: Prospective data evaluating the role of adjuvant radiotherapy (RT) for Merkel Cell Carcinoma(MCC) is lacking. To better understand the efficacy of adjuvant RT, a population-based patterns of failure study was conducted. METHODS: We identified MCC patients treated from 1988 to 2018.Primary outcome measures were recurrence-free survival (RFS), overall survival (OS) and MCC-specific survival (MCC-SS). Charlson Co-morbidity Index (CCI) was also calculated. RESULTS: 217 patients with mean age 79 (range: 33-96) were analyzed. The median follow-up was 40 months. Treatments were: surgery(S) alone (n = 101, 45%) or S + RT(n = 116, 55%).Local recurrence (LR) was low in stage I (n = 6, 6.5%) with clear margin of ≥1 cm, negative sentinel lymph node biopsy (SLNB) without high-risk factors, irrespective of adjuvant RT. Tumor size ≥ 2 cm (HR:2.95; p = 0.024) and immunosuppression(HR:3.98; p = 0.001) were associated with high risk of nodal failure. Adjuvant RT was associated with significant reduction in regional failure (HR:0.36; p = 0.002). Distant metastases (DM) were infrequent in stage I (4/90) and stage II (4/34), compared to stage III (32/93). Adjuvant RT improvedRFS but did not influence MCC-SS and OS. CCI was a significant predictor of OS. CONCLUSIONS: Adjuvant RT improvedRFS, withoutimpact on MCC-SS and OS. Co-morbidity rather than RT influenced OS. Adjuvant RT may be avoided instage I patients with negative SLNB and no associated high-risk factors. Prophylactic RNI could be considered in stage II with high risk features, inspite of negative SLNB. Stage III patients benefited from adjuvant RNI, but no impact on prevention of DM.

Changes in polyphenol serum levels and cognitive performance after dietary supplementation with Concord grape juice in veterans with Gulf War Illness.

AIMS: We investigated whether the consumption of Concord grape juice (CGJ) was associated with increased bioavailability of serum metabolites and their potential impact on cognitive performance in Veterans with Gulf War Illness (GWI). MAIN METHODS: Twenty-six veterans were selected from a cohort of 36 enrolled in a 24-week randomized, double-blind, Phase I/IIA clinical trial exploring whether the consumption of Concord grape juice (CGJ) was tolerable and safe in Veterans with GWI and improved cognitive function and fatigue. These 26 veterans were selected based on their completion of the entire 24-week protocol and documented adherence to the study beverage ≥80%. Differences in serum metabolite levels between CGJ and placebo at midpoint and endpoint were evaluated using two-way repeated measures ANOVA with post hoc Sidak's multiple comparison test. Bivariate correlations to assess for possible relationships between change in serum metabolite levels and change in cognitive function as measured by the Halstead Category Test-Russell Revised Version (RCAT) were also conducted. KEY FINDINGS: Seventy-six metabolites were identified and quantified in this study, with three (cyanidin-glucuronide, me-cyanidin-glucuronide, and me-malvidin-glucuronide) found to be significantly higher (p < 0.05) in the CGJ group compared to placebo at 24 weeks. Significant associations between changes in cognitive function and changes in serum levels of epicatechin-sulphate (r = 0.48, p = 0.01) and petunidin-glucuronide (r = 0.53, p < 0.01) from baseline to 24 weeks were also observed. SIGNIFICANCE: Our data suggest that dietary supplementation with CGJ is associated with increased bioavailability of specific phenolic metabolites, some of which may be correlated with cognitive performance.

Dural Follicular Lymphoma: Case Report and Literature Review.

Follicular lymphoma (FL) usually has an indolent course and presents with painless, waxing and waning lymphadenopathy in the absence of systemic symptoms. It is uncommon for FL to present outside of lymph nodes, although it can develop in the gastrointestinal tract, skin, thyroid, and testes. Central nervous system (CNS) involvement in FL is rare. Most CNS lymphomas are diffuse large B-cell lymphoma, although Burkitt lymphoma, lymphoblastic lymphoma, and peripheral T-cell lymphoma are also observed. These tumors usually involve white matter but may also involve gray matter. Lymphomas of the dura are very uncommon and are usually mucosa-associated lymphoid tissue lymphomas. Here, we present a case of FL of the dura arising in a 62-year-old woman that was responsive to chemotherapy. According to a literature review, there have been 15 previously reported cases of FL of the dura. Dural FL has been most frequently treated with radiation and chemotherapy. Patients were still alive in all cases in which follow-up was reported. Although the sample size is small, these data suggest that dural FL, like other forms of FL, is an indolent disease that is associated with prolonged survival despite usually being incurable.