'Immunotherapeutic Strategies for Intra-cranial Metastatic Melanoma - a Meta-analysis and Systematic Review'.

Immune-activating anti-CTLA4 and anti-PD1 monoclonal antibodies (alone or in combination) are being used to treat advanced melanoma patients and can lead to durable remissions, and long-term overall survival may be achieved in between 50-60% of patients. Although intracranial metastases are very common in melanoma (about 50-75% of all patients with advanced disease), most of the pivotal prospective clinical trials exclude patients with intra-cranial metastases, certainly if their lesions are symptomatic and steroid-requiring and the degree of sensitivity of intra-cranial melanoma to immunotherapy remains uncertain, and requires further investigation especially in view of the demonstrable activity of RAF-MEK inhibitors in this clinical setting and the emergence of stereotactic radiotherapy. Our study aimed to evaluate the efficacy and toxicity of immunotherapy against advanced melanoma patients with brain metastases. In terms of comparative studies, only retrospective analyses could be identified. Based on 3 retrospective studies, treatment of patients with melanoma brain metastases with immunotherapeutic approaches improves overall survival substantially compared with supportive measures alone (no active anticancer treatment). The efficacy of targeted therapy appeared to be comparable to that of immune therapy in terms of overall survival, based on a small number of patients. The combination of concurrent radiation therapy to the brain and systemic immunotherapy led to improved overall survival compared to radiotherapy alone, suggesting potential synergism between the approaches, and combination treatment could be delivered safely. Our review supports the use of immunotherapeutic strategies for these patients although treatment efficacy appears to be lower for symptomatic lesions. In view of the extremely high efficacy of stereotactic radiotherapy approaches in the brain, understanding the interaction between radiotherapy and immunotherapy is vital and should be an area of active investigation.

A randomised phase 2 study of intermittent versus continuous dosing of dabrafenib plus trametinib in patients with BRAFV600 mutant advanced melanoma (INTERIM).

BACKGROUND: BRAF+MEK inhibitors extend life expectancy of patients with BRAFV600 mutant advanced melanoma. Acquired resistance limits duration of benefit, but preclinical and case studies suggest intermittent dosing could overcome this limitation. INTERIM was a phase 2 trial evaluating an intermittent dosing regimen. METHODS: Patients with BRAFV600 mutant advanced melanoma due to start dabrafenib+trametinib were randomised to receive either continuous (CONT), or intermittent (INT; dabrafenib d1-21, trametinib d1-14 every 28 days) dosing. A composite primary endpoint included progression-free survival (PFS) and quality of life (QoL). Secondary endpoints included response rate (ORR), overall survival (OS) and adverse events (AEs). Mutant BRAFV600E ctDNA was measured by droplet digital PCR (ddPCR), using mutant allele frequency of > 1 % as the detection threshold. RESULTS: 79 patients (39 INT, 40 CONT) were recruited; median age 67 years, 65 % AJCC (7th ed) stage IV M1c, 29 % had brain metastases. With 19 months median follow-up, INT was inferior in all efficacy measures: median PFS 8.5 vs 10.7mo (HR 1.39, 95 %CI 0.79-2.45, p = 0.255); median OS 18.1mo vs not reached (HR 1.69, 95 %CI 0.87-3.28, p = 0.121), ORR 57 % vs 77 %. INT patients experienced fewer treatment-related AEs (76 % vs 88 %), but more grade > 3 AEs (53 % vs 42 %). QoL favoured CONT. Detection of BRAFV600E ctDNA prior to treatment correlated with worse OS (HR 2.55, 95 %CI 1.25-5.21, p = 0.01) in both arms. A change to undetected during treatment did not significantly predict better OS. CONCLUSION: INTERIM findings are consistent with other recent clinical trials reporting that intermittent dosing does not improve efficacy of BRAF+MEK inhibitors.

Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: A 10-year real-world retrospective cohort study.

Background & Aims: Checkpoint inhibitors (CPI) account for increasing numbers of drug-induced liver injury (DILI) cases. We aimed to determine the incidence rate and risk factors associated with checkpoint inhibitor-induced liver injury (ChILI). Methods: Prescription event monitoring was performed on all melanoma and renal cancer patients who received CPI at a tertiary centre between 2011 and 2021. ChILI cases were identified using the definitions, grading, and causality assessment methods validated for DILI. We assessed risk factors associated with ChILI in CPI-naive patients using multivariable logistic regression model. Consecutive patients with suspected ChILI from two other tertiary centres were adjudicated and combined for case characterisation and outcomes of ChILI. Results: Out of 432 patients who received CPI over 10 years, ChILI occurred in 38 (8.8%) with an overall incidence rate of 11.5 per 1,000 person-months (95% CI 8.2-15.8). Probability of ChILI was highest in combination therapy (32%) and no new events occurred beyond 135 days of treatment. Risk factor analysis showed that combination therapy, female sex, higher baseline alanine transferase level and lower baseline alkaline phosphatase level were independently associated with higher risk of ChILI. In total, 99 patients were adjudicated to have ChILI from three centres. Although Common Terminology Criteria for Adverse Events classified 20 patients (20.2%) to have 'life-threatening' grade 4 hepatitis, ChILI severity was graded as mild in 45 (45.5%) and moderate in the remaining 54 (54.5%) cases. Conclusions: The real-world risk of ChILI is higher than previously reported. Among patients receiving dual CPI, this risk falls markedly after 4.5 months. As Common Terminology Criteria for Adverse Events overestimates its clinical severity, case-definition, evaluation and management of ChILI should be revised to harmonise care. Impact and implications: Using prescription event monitoring over a 10-year period, the incidence rate of checkpoint inhibitor induced liver injury (ChILI) based on established case definitions for drug-induced liver injury (DILI) is 11.5 per 1,000 person-months. Formal causality assessment identified an alternative cause in 19% of patients with suspected ChILI highlighting the importance of systematic evaluation by clinicians to minimise unnecessary immunosuppression. Intensity of monitoring in patients receiving combination therapy regime after 4.5 months of therapy can be reduced as the risk of new onset ChILI beyond this point is minimal. Current Common Terminology Criteria for Adverse Events (CTCAE) grading overestimates clinical severity of ChILI and hence contributes to avoidable hospitalisation.

Realizing avalanche criticality in neuromorphic networks on a 2D hBN platform.

Networks and systems which exhibit brain-like behavior can analyze information from intrinsically noisy and unstructured data with very low power consumption. Such characteristics arise due to the critical nature and complex interconnectivity of the brain and its neuronal network. We demonstrate a system comprising of multilayer hexagonal boron nitride (hBN) films contacted with silver (Ag), which can uniquely host two different self-assembled networks, which are self-organized at criticality (SOC). This system shows bipolar resistive switching between the high resistance state (HRS) and the low resistance state (LRS). In the HRS, Ag clusters (nodes) intercalate in the van der Waals gaps of hBN forming a network of tunnel junctions, whereas the LRS contains a network of Ag filaments. The temporal avalanche dynamics in both these states exhibit power-law scaling, long-range temporal correlation, and SOC. These networks can be tuned from one to another with voltage as a control parameter. For the first time, two different neural networks are realized in a single CMOS compatible, 2D material platform.

Highly Efficient Electrochemical Hydrogen Evolution with Ultra-Low Loading of Strongly Adhered Pt Nanoparticles on Carbon.

The development of robust electrocatalysts with low platinum content for acidic hydrogen evolution reaction (HER) is paramount for large scale commercialization of proton exchange membrane electrolyzers. Herein, a simple strategy is reported to synthesize a well anchored, low Pt containing Vulcan carbon catalyst using ZnO as a sacrificial template. Pt containing ZnO (PZ) is prepared by a simultaneous borohydride reduction. PZ is then loaded onto Vulcan carbon to produce a very low Pt content electrocatalyst, PZ@VC. PZ@VC with 2 wt.% Pt shows excellent performance for acidic HER in comparison to the commercial Pt/C (20 wt.%) catalyst. PZ@VC with a very low Pt loading shows significantly low η10 and η100 values (15 and 46 mV, respectively). PZ@VC on coating with Nafion (PZ@VC-N) shows further improvement in its performance (η10 of 7 mV, η100 of 28 mV) with ≈300 h of stability (≈10 mA cm-2 ) with only 4 µgPt cm-2 . PZ@VC-N shows a record high mass activity of 71 A mgPt -1 (32 times larger than Pt/C (20 wt.%) at 50 mV of overpotential. Post reaction characterizations reveal Pt nanoparticles are embedded onto VC with no traces of zinc, suggestive of a strong metal-support interaction leading to this high stability at low Pt loading.

CAR T-Cell Therapy for Cancer: Latest Updates and Challenges, with a Focus on B-Lymphoid Malignancies and Selected Solid Tumours.

Although exponential progress in treating advanced malignancy has been made in the modern era with immune checkpoint blockade, survival outcomes remain suboptimal. Cellular immunotherapy, such as chimeric antigen receptor T cells, has the potential to improve this. CAR T cells combine the antigen specificity of a monoclonal antibody with the cytotoxic 'power' of T-lymphocytes through expression of a transgene encoding the scFv domain, CD3 activation molecule, and co-stimulatory domains. Although, very rarely, fatal cytokine-release syndrome may occur, CAR T-cell therapy gives patients with refractory CD19-positive B-lymphoid malignancies an important further therapeutic option. However, low-level expression of epithelial tumour-associated-antigens on non-malignant cells makes the application of CAR T-cell technology to common solid cancers challenging, as does the potentially limited ability of CAR T cells to traffic outside the blood/lymphoid microenvironment into metastatic lesions. Despite this, in advanced neuroblastoma refractory to standard therapy, 60% long-term overall survival and an objective response in 63% was achieved with anti GD2-specific CAR T cells.

Characterization and application of novel fly ash blended ceramic membrane in MFC for low-cost and sustainable wastewater treatment and power generation.

Field-scale application of the microbial fuel cell (MFC) technology faces a major constraint due to the widely used high-cost proton exchange membrane Nafion, prompting lately, the development of ceramic membranes using different clay minerals. In the present study, the characteristics and applicability of a novel ceramic membrane fabricated using potter's clay (C) blended with varying proportions (0, 5, 10, and 20 wt%) of fly ash (FA), designated as CFA0, CFA5, CFA10, and CFA20, were assessed for cost-effective and sustainable use in MFC. On assessing the properties of the membrane, CFA10 was found to exhibit superior quality with fine pore size distribution (average 0.49 µm) favoring higher water uptake and less oxygen diffusion. The CFA10 membrane showed a maximum proton mass transfer coefficient (4.32 ± 0.04 × 10-5 cm/s) that was about three times that of the control CFA0. The oxygen mass transfer coefficient of CFA10 was 5.13 ± 0.12 × 10-5 cm/s, which was about 40% less than in the control. X-ray diffraction (XRD) analysis of CFA membrane revealed the richness of quartz, which facilitates proton conductance and water retention. The CFA10 membrane fitted MFC demonstrated a peak power output of 4.57 W/m3 (twice that in CFA0) with an average of 80.02 ± 0.86% COD removal and 68.03 ± 0.13% coulombic efficiency in a long-term study indicating its improved applicability and durability. Electrochemical kinetics involving cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) also affirmed the efficacy of CFA10 membrane in MFC showing peak current output of 13.95 mA and low ohmic resistance (74.2 Ω). The novel (CFA10) ceramic membrane amalgamated with the coal fly ash, a waste of concern, shows promise for high MFC performance at a much reduced (98% less) cost that can be used for sustainable scale-up of the technology.

Assessment of bimetallic Zn/Fe0 nanoparticles stabilized Tween-80 and rhamnolipid foams for the remediation of diesel contaminated clay soil.

Diesel contamination of soil due to oil spills, disposal of refinery waste, oil exploration constitutes a major environmental problem. This paper reports the remediation of diesel contaminated clay soil using Zn/Fe0 bimetallic nanoparticle stabilized Rhamnolipid (RMLP) and Tween-80 (TW-80) surfactant foams. Fe0, and Zn (x wt%)/Fe0 (x = 0.2, 2.0, and 10.0) bimetallic nanoparticles are synthesized by using sodium borohydride reduction method. The average particle size (from FESEM) is calculated to be 62, 57, 42 and 35 nm for the Fe0, Zn (0.2)/Fe0, Zn (2)/Fe0 and Zn (10)/Fe0 nanopowders, respectively. The highest foamability and foam stability of 109.6 and 108.5 mL, respectively are observed for the RMLP (12 mg/l) surfactant foam stabilized with 6 mg/l Zn (10)/Fe0 nanoparticles. The surface tension values reduce to the lowest value of 28.1 and 31.4 mN/m with the addition of 6 mg/l of Zn (10)/Fe0 powder in RMLP and TW-80 solutions of 12 mg/l, respectively. The maximum diesel removal efficiency of 83.8 and 59%, is achieved by RMLP (12 mg/l) foam stabilized by Zn (10)/Fe0 nanoparticles (6 mg/l) for the clay soil contaminated with 100 and 500 µl/g of diesel, respectively. The physicochemical properties of the nanoparticles are studied to explain the foam properties and the remediation behavior. These findings regarding the nanoparticle stabilized foams can offer a cost-effective environment friendly commercial solution for soil remediation in the future.

Improvement in Oxygen Evolution Performance of NiFe Layered Double Hydroxide Grown in the Presence of 1T-Rich MoS2.

NiFe layered double hydroxide (NiFe LDH) grown in the presence of MoS2 (rich in 1T phase) shows exceptional performance metrics for alkaline oxygen evolution reaction (OER) in this class of composites. The as-prepared NiFe LDH/MoS2 composite (abbreviated as MNF) exhibits a low overpotential (η10) of 190 mV; a low Tafel slope of 31 mV dec-1; and more importantly, a high stability in its performance manifested by the delivery of current output for 45 h. It is important to note that this could be achieved with an exceedingly low loading of 0.14 mg cm-2. The mass activity of this composite (97 A g-1) is about 14 times greater than that of the conventional RuO2 (7 A g-1) at η = 200 mV. When normalized with respect to the total metal content, a mass activity of 1000 A g-1 (η = 300 mV) was achieved. Impedance analysis further reveals that the significant reduction in charge-transfer resistance and hence high current density (5 times greater as compared to NiFe LDH at η = 300 mV) observed for MNF is associated with interfacial adsorption kinetics of intermediates (R1). Significant enhancement in the intrinsic activity of MNF over LDH has been observed through normalization of current with the electrochemically active surface area. Computational studies suggest that the Ni centers in the composite act as the active sites for OER, which is well-corroborated with the observed postreaction appearance of Ni3+ species.

An artificial synaptic transistor using an α-In2Se3 van der Waals ferroelectric channel for pattern recognition.

Despite being widely investigated for their memristive behavior, ferroelectrics are barely studied as channel materials in field-effect transistor (FET) configurations. In this work, we use multilayer α-In2Se3 to realize a ferroelectric channel semiconductor FET, i.e., FeS-FET, whose gate-triggered and polarization-induced resistive switching is then exploited to mimic an artificial synapse. The FeS-FET exhibits key signatures of a synapse such as excitatory and inhibitory postsynaptic current, potentiation/depression, and paired pulsed facilitation. Multiple stable conductance states obtained by tuning the device are then used as synaptic weights to demonstrate pattern recognition by invoking a hidden layer perceptron model. Detailed artificial neural network (ANN) simulations are performed on binary scale MNIST data digits, invoking 784 input (28 × 28 pixels) and 10 output neurons which are used in the training of 42 000 MNIST data digits. By updating the synaptic weights with conductance weight values on 18 000 digits, we achieved a successful recognition rate of 93% on the testing data. Introduction of 0.10 variance of noise pixels results in an accuracy of more than 70% showing the strong fault-tolerant nature of the conductance states. These synaptic functionalities, learning rules, and device to system-level simulation results based on α-In2Se3 could facilitate the development of more complex neuromorphic hardware systems based on FeS-FETs.

An Unusual Cause of Subacute Headache in a Patient Undergoing Chemotherapy for Advanced Testicular Nonseminomatous Germ Cell Tumour.

Testicular (germ cell) cancer is a model of a chemocurable malignancy and tends to have a favourable prognosis even in advanced stages due to exquisite sensitivity to platinum-based chemotherapy. However, both acute and longer-term toxicities of multiagent chemotherapy remain significant as causes of morbidity, very occasionally mortality, and impaired quality-of-life. Here, we report a case of acute cerebral venous sinus thrombosis occurring within 10 days of chemotherapy initiation in a young patient without comorbidities, whose only predisposing factors were malignancy, chemotherapy, and perhaps mild dehydration. The clinical presentation was also unusual with headache of moderate severity only without focal or global neurologic deficits. We suspect that cisplatin may have had direct vasculotoxic effects. The patient recovered fully after short-duration anticoagulation but oncologists must remain aware of unusual and unpredictable complications of cytotoxic treatment.

Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients.

Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.

Role of sexual behavior in the acquisition of asymptomatic Epstein-Barr virus infection: a longitudinal study.

BACKGROUND: The natural history of Epstein-Barr virus (EBV) infection is poorly defined. We report the prevalence and subsequent incidence of EBV infection in a cohort of sexually active young women and explore the social and sexual determinants of incident infections. METHODS: The study population was drawn from a cohort of young women, who were recruited for a longitudinal study of risk factors for early cervical neoplasia. A case-control analysis, nested within the cohort of 45 women for whom the first EBV sample tested was EBV-negative and who had further follow-up, was undertaken. EBV serostatus was determined in serum with a synthetic peptide-based enzyme-linked immunosorbent assay; EBV DNA was measured in cervical smears with the use of quantitative polymerase chain reaction. RESULTS: Of 1023 women 15-19 years of age included in this analysis, 978 (95.6%) tested positive for antibodies to EBV in their first serum sample. Of 45 women who tested negative, 22 subsequently acquired an asymptomatic EBV infection; the median time to seroconversion was 25 months (range, 1-60 months), and the median age at seroconversion was 18 years (range, 16-21 years). The risk of seroconversion increased with increasing number of sexual partners [compared with 1 partner, odds ratio (OR) was 1.28 for 2 partners and 2.23 for 3 or more; chiTREND 5.02; df 1; P < 0.05] and was greatest when a new sexual partner had been acquired in the 2 years before seroconversion (OR 4.78; chi 4.62; df 1; P < 0.05). EBV DNA was detected in 9 of 14 women who seroconverted and who also provided cervical samples. CONCLUSIONS: In susceptible young women, the acquisition of EBV infection is associated with their sexual behavior.