Combined photodynamic therapy and transpupillary thermotherapy for small choroidal melanoma.

OBJECTIVE: The objective of this study was to determine whether combining verteporfin-based photodynamic therapy (PDT) and transpupillary thermotherapy (TTT) achieves adequate tumour control while maintaining visual acuity in individuals with small choroidal melanoma of amelanotic, melanotic, and variable pigmentation. DESIGN: Individuals with posterior choroidal melanomas up to 3 mm in height underwent verteporfin-based PDT followed by immediate TTT. Further combined laser therapy was performed if a poor response was noted at 12 weeks or beyond. Tumours that demonstrated significant further growth were treated with brachytherapy or enucleation. A total of 37 eyes of 37 patients from the Terrace Eye Centre in Brisbane, Australia were studied. Average age of participants was 59.62 ± 12.45 years, and 17 of 37 participants were female (46%). METHODS: This was a retrospective, noncomparative interventional study. RESULTS: Seven of the 37 participants (19%) had recurrence of their tumour requiring further brachytherapy or enucleation. There was no statistically significant difference in visual acuity before and after treatment. There were no baseline characteristics that predicted treatment outcome. Ten individuals developed complications including epiretinal membrane (16%), scotoma (8%), cataract (3%), and macular edema (3%). No individuals experienced extraocular extension or progressed to metastatic disease. The mean follow-up time was 49 months. CONCLUSION: Combined PDT and TTT achieved 81% tumour control in this study while preserving visual acuity. However, higher rates of local recurrence compared with brachytherapy warrant close follow-up to identify recurrences early.

Quality assurance for focused ultrasound-induced blood-brain barrier opening procedure using passive acoustic detection.

BACKGROUND: Focused ultrasound (FUS) combined with microbubbles is a promising technique for noninvasive, reversible, and spatially targeted blood-brain barrier opening, with clinical trials currently ongoing. Despite the fast development of this technology, there is a lack of established quality assurance (QA) strategies to ensure procedure consistency and safety. To address this challenge, this study presents the development and clinical evaluation of a passive acoustic detection-based QA protocol for FUS-induced blood-brain barrier opening (FUS-BBBO) procedure. METHODS: Ten glioma patients were recruited to a clinical trial for evaluating a neuronavigation-guided FUS device. An acoustic sensor was incorporated at the center of the FUS device to passively capture acoustic signals for accomplishing three QA functions: FUS device QA to ensure the device functions consistently, acoustic coupling QA to detect air bubbles trapped in the acoustic coupling gel and water bladder of the transducer, and FUS procedure QA to evaluate the consistency of the treatment procedure. FINDINGS: The FUS device passed the device QA in 9/10 patient studies. 4/9 cases failed acoustic coupling QA on the first try. The acoustic coupling procedure was repeatedly performed until it passed QA in 3/4 cases. One case failed acoustic coupling QA due to time constraints. Realtime passive cavitation monitoring was performed for FUS procedure QA, which captured variations in FUS-induced microbubble cavitation dynamics among patients. INTERPRETATION: This study demonstrated that the proposed passive acoustic detection could be integrated with a clinical FUS system for the QA of the FUS-BBBO procedure. FUNDING: National Institutes of Health R01CA276174, R01MH116981, UG3MH126861, R01EB027223, R01EB030102, and R01NS128461.

Focused Ultrasound-Mediated Delivery of Anti-Programmed Cell Death-Ligand 1 Antibody to the Brain of a Porcine Model.

Immune checkpoint inhibitor (ICI) therapy has revolutionized cancer treatment by leveraging the body's immune system to combat cancer cells. However, its effectiveness in brain cancer is hindered by the blood-brain barrier (BBB), impeding the delivery of ICIs to brain tumor cells. This study aimed to assess the safety and feasibility of using focused ultrasound combined with microbubble-mediated BBB opening (FUS-BBBO) to facilitate trans-BBB delivery of an ICI, anti-programmed cell death-ligand 1 antibody (aPD-L1) to the brain of a large animal model. In a porcine model, FUS sonication of targeted brain regions was performed after intravenous microbubble injection, which was followed by intravenous administration of aPD-L1 labeled with a near-infrared fluorescent dye. The permeability of the BBB was evaluated using contrast-enhanced MRI in vivo, while fluorescence imaging and histological analysis were conducted on ex vivo pig brains. Results showed a significant 4.8-fold increase in MRI contrast-enhancement volume in FUS-targeted regions compared to nontargeted regions. FUS sonication enhanced aPD-L1 delivery by an average of 2.1-fold, according to fluorescence imaging. In vivo MRI and ex vivo staining revealed that the procedure did not cause significant acute tissue damage. These findings demonstrate that FUS-BBBO offers a noninvasive, localized, and safe delivery approach for ICI delivery in a large animal model, showcasing its potential for clinical translation.

First-in-human prospective trial of sonobiopsy in high-grade glioma patients using neuronavigation-guided focused ultrasound.

Sonobiopsy is an emerging technology that combines focused ultrasound (FUS) with microbubbles to enrich circulating brain disease-specific biomarkers for noninvasive molecular diagnosis of brain diseases. Here, we report the first-in-human prospective trial of sonobiopsy in high-grade glioma patients to evaluate its feasibility and safety in enriching plasma circulating tumor biomarkers. A nimble FUS device integrated with a clinical neuronavigation system was used to perform sonobiopsy following an established clinical workflow for neuronavigation. Analysis of blood samples collected before and after FUS sonication showed that sonobiopsy enriched plasma circulating tumor DNA (ctDNA), including a maximum increase of 1.6-fold for the mononucleosome cell-free DNA (cfDNA) fragments (120-280 bp), 1.9-fold for the patient-specific tumor variant ctDNA level, and 5.6-fold for the TERT mutation ctDNA level. Histological analysis of surgically resected tumors confirmed the safety of the procedure. Transcriptome analysis of sonicated and nonsonicated tumor tissues found that FUS sonication modulated cell physical structure-related genes. Only 2 out of 17,982 total detected genes related to the immune pathways were upregulated. These feasibility and safety data support the continued investigation of sonobiopsy for noninvasive molecular diagnosis of brain diseases.

First-in-human prospective trial of sonobiopsy in glioblastoma patients using neuronavigation-guided focused ultrasound.

Sonobiopsy is an emerging technology that combines focused ultrasound (FUS) with microbubbles to enrich circulating brain disease-specific biomarkers for noninvasive molecular diagnosis of brain diseases. Here, we report the first-in-human prospective trial of sonobiopsy in glioblastoma patients to evaluate its feasibility and safety in enriching circulating tumor biomarkers. A nimble FUS device integrated with a clinical neuronavigation system was used to perform sonobiopsy following an established clinical workflow for neuronavigation. Analysis of blood samples collected before and after FUS sonication showed enhanced plasma circulating tumor biomarker levels. Histological analysis of surgically resected tumors confirmed the safety of the procedure. Transcriptome analysis of sonicated and unsonicated tumor tissues found that FUS sonication modulated cell physical structure-related genes but evoked minimal inflammatory response. These feasibility and safety data support the continued investigation of sonobiopsy for noninvasive molecular diagnosis of brain diseases.

Cement-in-cement versus uncemented modular stem revision for Vancouver B2 periprosthetic fractures.

Background: To compare outcomes of revision to a long uncemented stem with cement-in-cement revision for Vancouver B2 periprosthetic fracture (PPF). Methods: Patients undergoing surgery for a Vancouver B2 PPF in a cemented stem from 2008 to 2018 were identified using our prospectively collated database. Results: We identified 43 uncemented and 29 cement-in-cement revisions. Cement-in-cement revision had a shorter operative time, reduction in certain complications, no increased rate of non-union, lower degree of stem subsidence and no difference in re-revision rate. Conclusion: With appropriate patient selection, both cement-in-cement and long uncemented stem revision represent appropriate treatment options for Vancouver B2 fractures.

Alumina ceramic-on-ceramic hybrid total hip arthroplasty. A median of 15 years follow-up.

INTRODUCTION: The optimum choice of bearing surfaces in total hip replacement (THR) in the younger and active patient remains controversial. The aim of this study was to report the 10 year clinical outcomes, and a median of 15 year implant survival and incidence of complications in a series of Alumina ceramic-on-ceramic THRs utilising an uncemented shell and cemented stem. METHODS: From January 2004 to December 2007, 175 consecutive patients (195 hips) underwent primary THR. The acetabular components was Trident Peripheral Self Locking (Stryker Orthopaedics) with a third-generation ceramic head and liner (Alumina ceramic, Stryker Orthopaedics). The stem utilised was an Exeter V-40 (Stryker Orthopaedics). Data were collated on demographics, surgical factors, clinical outcomes, radiographic outcomes and revision. RESULTS: 23 patients (27 THRs) died during the follow-up period at a median of 7.8 (3.8 to 9.0) years post-operatively due to causes unrelated to the THR. Median age at time of surgery was 55 (interquartile range 48-60) years. Median follow-up for surviving patients was 15.2 years. Survivorship for all-cause revision was 97.2%. Increasing patient age at time of surgery was associated with a higher OHS at 10 years (p = 0.022). 32 mm head diameter had an improved OHS at 3 months (p = 0.014) and 10 years (p = 0.030). Posterior surgical approach had a statistically significant better OHS at 3 months (p = 0.015) and 1 year (p < 0.001), but the effect was not significant at 10 years (p = 0.440). CONCLUSION: The findings of this study support excellent long-term outcomes and survivorship of Alumina ceramic-on-ceramic bearing in a hybrid THR in a younger population. Surgical factors leading to a more favourable outcome were the use of a 32 mm femoral head and a posterior approach. Increasing age at surgery demonstrated the most sustained improvement in 10 year clinical outcomes.

A systematic analysis of hypermucoviscosity and capsule reveals distinct and overlapping genes that impact Klebsiella pneumoniae fitness.

Hypervirulent K. pneumoniae (hvKp) is a distinct pathotype that causes invasive community-acquired infections in healthy individuals. Hypermucoviscosity (hmv) is a major phenotype associated with hvKp characterized by copious capsule production and poor sedimentation. Dissecting the individual functions of CPS production and hmv in hvKp has been hindered by the conflation of these two properties. Although hmv requires capsular polysaccharide (CPS) biosynthesis, other cellular factors may also be required and some fitness phenotypes ascribed to CPS may be distinctly attributed to hmv. To address this challenge, we systematically identified genes that impact capsule and hmv. We generated a condensed, ordered transposon library in hypervirulent strain KPPR1, then evaluated the CPS production and hmv phenotypes of the 3,733 transposon mutants, representing 72% of all open reading frames in the genome. We employed forward and reverse genetic screens to evaluate effects of novel and known genes on CPS biosynthesis and hmv. These screens expand our understanding of core genes that coordinate CPS biosynthesis and hmv, as well as identify central metabolism genes that distinctly impact CPS biosynthesis or hmv, specifically those related to purine metabolism, pyruvate metabolism and the TCA cycle. Six representative mutants, with varying effect on CPS biosynthesis and hmv, were evaluated for their impact on CPS thickness, serum resistance, host cell association, and fitness in a murine model of disseminating pneumonia. Altogether, these data demonstrate that hmv requires both CPS biosynthesis and other cellular factors, and that hmv and CPS may serve distinct functions during pathogenesis. The integration of hmv and CPS to the metabolic status of the cell suggests that hvKp may require certain nutrients to specifically cause deep tissue infections.

Genomic analysis of adult case of ocular surface giant congenital melanocytic nevus and associated clinicopathological findings.

INTRODUCTION: Conjunctival nevi are the most common tumor of the ocular surface. There are some rare reports of so-called 'giant' conjunctival nevi. We report a case of a 47-year-old female with a cutaneous and ocular surface giant congenital melanocytic nevus and describe her clinical course. CASE DESCRIPTION: This is a retrospective case report of a single patient. A 47-year-old female with a history of biopsy-proven periorbital congenital melanocytic nevus, with an associated giant conjunctival nevus presented for structural and functional rehabilitation. Serial surgeries were performed and excised tissue was sent for histopathological and genetic examination. The conjunctival nevus had a low tumor mutation burden, and of the 647 somatic mutations, only one occurred within a protein coding region, namely NRAS p.Gln61Arg. CONCLUSION: This is the first reported adult case including genomic analysis of an ocular surface giant congenital melanocytic nevus. The case shows a possible association between periorbital congenital melanocytic nevi and giant conjunctival nevi, and underscores the possible role that targeted drug therapies may have in malignant transformation of these conditions.

Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours.

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE).

A Panel of Circulating MicroRNAs Detects Uveal Melanoma With High Precision.

PURPOSE: To determine if a circulating microRNA (miRNA) panel could be used to distinguish between uveal melanoma and uveal nevi. METHODS: We report on a multicenter, cross-sectional study conducted between June 2012 and September 2015. The follow-up time was approximately 3 to 5 years. Blood was drawn from participants presenting with a uveal nevus (n = 10), localized uveal melanoma (n = 50), or metastatic uveal melanoma (n = 5). Levels of 17 miRNAs were measured in blood samples of study participants using a sensitive real-time PCR system. RESULTS: A panel of six miRNAs (miR-16, miR-145, miR-146a, miR-204, miR-211, and miR-363-3p) showed significant differences between participants with uveal nevi compared with patients with localized and metastatic uveal melanoma. Importantly, miR-211 was able to accurately distinguish metastatic disease from localized uveal melanoma (P < 0.0001; area under the curve = 0.96). When the six-miRNA panel was evaluated as a group it had the ability to identify uveal melanoma when four or more miRNAs (93% sensitivity and 100% specificity) reached or exceeded their cut-point. CONCLUSIONS: This miRNA panel, in tandem with clinical findings, may be suited to confirm benign lesions. In addition, due to the panel's high precision in identifying malignancy, it has the potential to augment melanoma detection in subsequent clinical follow-up of lesions with atypical clinical features. TRANSLATIONAL RELEVANCE: Uveal nevi mimic the appearance of uveal melanoma and their transformation potential cannot be definitively determined without a biopsy. This panel is most relevant at the nevus stage and in lesions with uncertain malignant potential as a companion diagnostic tool to assist in clinical decision-making.

Discovery of a Thiadiazole-Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models.

Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers by blocking the tumor cell's ability to produce glutamine-derived nutrients. Starting from the known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe the medicinal chemistry evolution of a series from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic properties to cell potent examples with reduced molecular weight and lipophilicity, leading to compounds with greatly improved oral exposure that demonstrate in vivo target engagement accompanied by activity in relevant disease models.

Correction to: Prolonged stable disease in a uveal melanoma patient with germline MBD4 nonsense mutation treated with pembrolizumab and ipilimumab.

The authors regret that the online version of this article contains an error. The MBD4 mutation in sample MM138 was given an incorrect dbSNP ID. The correct ID is rs769076971.

Prolonged stable disease in a uveal melanoma patient with germline MBD4 nonsense mutation treated with pembrolizumab and ipilimumab.

There is currently no effective treatment for metastasised uveal melanoma (UM). Recently, it was reported that a UM patient was responsive to checkpoint inhibitor (CI) treatment, due to a high tumour mutation burden correlated with a germline loss-of-function MBD4 mutation. Here, we report on another UM patient who carried an MBD4 germline nonsense variant (p.Leu563Ter) and her tumour showed a fivefold higher than average mutation burden. We confirmed the association between germline loss-of-function variant in MBD4 and CI response. The patient experienced stable disease (10 months) and survived 2 years with metastatic disease, which is twice as long as median survival. Additionally, the frequency of MBD4 loss-of-function variants in reported UM cohorts was > 20 times higher than in an aggregated population genome database (P < 5 × 10-5), implying a potential role as UM predisposition gene. These findings provide a strong basis for the inclusion of MBD4 in the screening of potential UM-prone families as well as stratification of immunotherapy.

Noise characteristics in ceramic-on-ceramic vs. metal-on-polyethylene total hip arthroplasty: a comparative study.

INTRODUCTION: A comparison of noise in ceramic-on-ceramic (CoC) bearings and metal-on-polyethylene (MoP) bearings after total hip arthroplasty (THA) was undertaken. Noise associated with MoP implants is rarely reported and has not been linked to squeaking. METHODS: A noise characterising hip questionnaire and Oxford Hip Score (OHS) was sent to 1,000 THA patients; there were 509 respondents 282 CoC and 227 MoP; mean age 63.7 years (range 45-92 years), mean follow up 33 months (range 6-156 months). RESULTS: Of 282 repsondents 47 (17%) of the CoC patients reported noise compared to 19 (8%) of the MoP patients (p = 0.048); 9 CoC patients and 4 MoP patients reported squeaking. Overall, 27% patients with noise reported avoiding recreational activities because of it and patients with noisy hips scored on average 5 points less on the OHS (CoC: p = 0.04 and MoP: p = 0.007). DISCUSSION: This is the first study to report squeaking from MoP THAs. The squeaking hip phenomenon is not exclusive to CoC THAs. Noisy hip implants may have social implications, and patients should be aware of this. We have shown a relationship between noise and a lower OHS. However, longer follow-up is needed to link noise to a poorly functioning implant.

Advanced signaling technologies for high-speed digital fiber-optic links.

We summarize the most recent research of the Georgia Tech Terabit Optical Networking Consortium and the state-of-the-art in fiber telecommunications. These results comprise high-capacity single-mode fiber systems with digital coherent receivers and shorter-reach multimode fiber links with vertical cavity surface emitting lasers. We strongly emphasize the capabilities that sophisticated digital signal processing and electronics add to these fiber-based data transport links.

Joint digital signal processing for superchannel coherent optical communication systems.

Ultra-high-speed optical communication systems which can support ≥ 1Tb/s per channel transmission will soon be required to meet the increasing capacity demand. However, 1Tb/s over a single carrier requires either or both a high-level modulation format (i.e. 1024QAM) and a high baud rate. Alternatively, grouping a number of tightly spaced "sub-carriers" to form a terabit superchannel increases channel capacity while minimizing the need for high-level modulation formats and high baud rate, which may allow existing formats, baud rate and components to be exploited. In ideal Nyquist-WDM superchannel systems, optical subcarriers with rectangular spectra are tightly packed at a channel spacing equal to the baud rate, thus achieving the Nyquist bandwidth limit. However, in practical Nyquist-WDM systems, precise electrical or optical control of channel spectra is required to avoid strong inter-channel interference (ICI). Here, we propose and demonstrate a new "super receiver" architecture for practical Nyquist-WDM systems, which jointly detects and demodulates multiple channels simultaneously and mitigates the penalties associated with the limitations of generating ideal Nyquist-WDM spectra. Our receiver-side solution relaxes the filter requirements imposed on the transmitter. Two joint DSP algorithms are developed for linear ICI cancellation and joint carrier-phase recovery. Improved system performance is observed with both experimental and simulation data. Performance analysis under different system configurations is conducted to demonstrate the feasibility and robustness of the proposed joint DSP algorithms.

Outcome after femoral revision using the restoration cone/conical femoral revision stem.

Despite improvements in implant technology and surgical technique, failure of total hip arthroplasty (THA) remains a persistent problem. This article reports clinical outcomes at a mean follow-up of 42 months using the Restoration cone/conical modular femoral revision stem (Stryker, Newbury, United Kingdom). A prospective cohort study was performed of 46 consecutive patients who underwent revision THA between January 2004 and June 2007. Patients were reviewed pre- and postoperatively at regular intervals for clinical and radiological assessment. Forty-six patients (17 men, 29 women) with a mean age of 72 years (range, 44-93 years) were observed for a mean of 42 months (range, 28-66 months). Indications for surgery included aseptic loosening/osteolysis (38/46 [83%]), periprosthetic fracture (4/46 [9%]), and infection (4/46 [8%]). Median time from index procedure was 16 years (range, 1-26 years). No patient was lost to follow-up. Two patients (4%) with well-fixed asymptomatic stems died during follow-up. Three patients (7%) sustained an early postoperative dislocation. One patient sustained a periprosthetic fracture after a fall. This was treated by osteosynthesis, and stem revision was not required. Mean Oxford Hip Score improved from 42 points (range, 24-57 points) to 28 points (range, 18-51 points) at 3-month follow-up (P=.003). Median stem subsidence was 1.0 mm (standard error of the mean, ±1.7 mm; range, 0-7mm) at last follow-up. No patient developed loosening or osteolysis around the stem. The Restoration femoral revision system has favorable clinical and radiological outcomes at a mean follow-up of 42 months.

Optical head tracking for functional magnetic resonance imaging using structured light.

An accurate motion-tracking technique is needed to compensate for subject motion during functional magnetic resonance imaging (fMRI) procedures. Here, a novel approach to motion metrology is discussed. A structured light pattern specifically coded for digital signal processing is positioned onto a fiduciary of the patient. As the patient undergoes spatial transformations in 6 DoF (degrees of freedom), a high-resolution CCD camera captures successive images for analysis on a computing platform. A high-speed image processing algorithm is used to calculate spatial transformations in a time frame commensurate with patient movements (10-100 ms) and with a precision of at least 0.5 microm for translations and 0.1 deg for rotations.