Extent of investigation and management of cases of 'unexplained' mismatch repair deficiency (u-dMMR): a UK Cancer Genetics Group consensus.

BACKGROUND: Mismatch repair deficiency (dMMR) is a characteristic feature of cancers linked to Lynch syndrome. However, in most cases, it results from sporadic somatic events rather than hereditary factors. The term 'Lynch-like syndrome' (LLS) has been used to guide colorectal cancer surveillance for relatives of individuals with a dMMR tumour when somatic and germline genomic testing is uninformative. As the assessment of mismatch repair through immunohistochemistry and/or microsatellite instability is increasingly applied across various tumour types for treatment planning, dMMR is increasingly detected in tumours where suspicion of hereditary aetiology is low. Our objective was to establish current practices and develop national guidance for investigating, and managing relatives of, patients with cancers demonstrating unexplained dMMR. METHODS: This was achieved through a virtual consensus meeting involving key stakeholders from the UK, through premeeting surveys, structured discussions and in-meeting polling to formulate best practice guidance. RESULTS: We identified variability in the availability of diagnostic technologies across specialist centres. It was agreed that equitable access to baseline testing is required, acknowledging the need for a pragmatic approach to investigating dMMR cancers not traditionally associated with Lynch syndrome. Factors such as family history, age, tumour type, protein loss pattern and extent of the investigation were deemed crucial in guiding family management. The term 'unexplained dMMR' was recommended over LLS. CONCLUSION: Decisions regarding investigations and future cancer risk management in patients and relatives should be nuanced, considering factors like clinical suspicion of hereditary predisposition to allocate limited resources efficiently and avoid unnecessary investigations in low-suspicion families.

High performance of the DNA methylation-based WID-qEC test for detecting uterine cancers independent of sampling modalities.

Endometrial cancer (EC) is the most prevalent gynaecological cancer in high-income countries and its incidence is continuing to rise sharply. Simple and objective tools to reliably detect women with EC are urgently needed. We recently developed and validated the DNA methylation (DNAme)-based women's cancer risk identification-quantitative polymerase chain reaction test for endometrial cancer (WID-qEC) test that could address this need. Here, we demonstrate that the stability of the WID-qEC test remains consistent regardless of: (i) the cervicovaginal collection device and sample media used (Cervex brush and PreservCyt or FLOQSwab and eNAT), (ii) the collector of the specimen (gynaecologist- or patient-based), and (iii) the precise sampling site (cervical, cervicovaginal and vaginal). Furthermore, we demonstrate sample stability in eNAT medium for 7 days at room temperature, greatly facilitating the implementation of the test into diagnostic laboratory workflows. When applying FLOQSwabs (Copan) in combination with the eNAT (Copan) sample collection media, the sensitivity and specificity of the WID-qEC test to detect uterine (i.e., endometrial and cervical) cancers in gynaecologist-taken samples was 92.9% (95% confidence interval [CI] = 75.0%-98.8%) and 98.6% (95% CI = 91.7%-99.9%), respectively, whilst the sensitivity and specificity in patient collected self-samples was 75.0% (95% CI = 47.4%-91.7%) and 100.0% (95% CI = 93.9%-100.0%), respectively. Taken together these data confirm the robustness and clinical potential of the WID-qEC test.

The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2.

BACKGROUND: Our study aimed to establish 'real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO). METHODS: Our study recruited 875 female BRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation. RESULTS: Our study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9-100), 75% (34.9-96.8) and 99.9% (99.9-100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of -£102,496/QALY. CONCLUSION: OC surveillance for women deferring RRSO in a 'real-world' setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery.

CAR Peer Learning Guide.

Peer learning is a quality initiative used to identify potential areas of practice improvement, both on a patient level and on a systemic level. Opportunities for peer learning include review of prior imaging studies, evaluation of cases from multidisciplinary case conferences, and review of radiology trainees' call cases. Peer learning is non-punitive and focuses on promoting life-long learning. It seeks to identify and disseminate learning opportunities and areas for systems improvement compared to traditional peer review. Learning opportunities arise from peer learning through both individual communication of cases reviewed for routine work, as well as through anonymous presentation of aggregate cases in an educational format. In conjunction with other tools such as root cause analysis, peer learning can be used to guide future practice improvement opportunities. This guide provides definitions of terms and a synthetic evidence review regarding peer review and peer learning, as well as medicolegal and jurisdictional considerations. Important aspects of what makes an effective peer learning program and best practices for implementing such a program are presented. The guide is intended to be a living document that will be updated regularly as new data emerges and peer learning continues to evolve in radiology practices.

A selective small molecule NOP (ORL-1 receptor) partial agonist for the treatment of anxiety.

Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind the classical δ, µ and κ opioid receptors with high affinity. The synthesis of 1 involved using a molecular diversity approach, to rapidly advance a library of compounds for biological testing. A lead selective potent partial agonist (35-fold ORL-1/Mu) progressed to ORL-1 (NOP or OP4) proof of concept testing in advanced studies. The synthetic approach and biological data for the related chemical series will be presented.

The Fixion nailing system for stabilising diaphyseal fractures of the humerus: a two-year clinical experience.

Previous studies have shown that the expandable nail system (Fixion) can provide rapid stabilisation of long bone fractures with reduced operative time and low complication rates. Patients with humeral shaft fracture were treated consecutively over a two-year period in our institution with the Fixion nail. Nineteen Fixion nailings were performed in 16 patients over a 2 year period. All fractures were diaphyseal and closed. Eight primary fracture stabilisations were performed and we recorded 2 nonunions in this group, both associated with rotational instability at the fracture site. Six nailings were performed in 4 patients for fracture non-union with a mean operative time of 127.5 minutes. One case did not unite despite 3 separate Fixion nailing procedures. Five operations were performed for a pathological fracture, with a mean operative time of 79 minutes; they all united. We did not experience advantages of this nail as mentioned in previous studies and the complication rate was higher than previously stated.

2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead.

A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.

The second galanin receptor GalR2 plays a key role in neurite outgrowth from adult sensory neurons.

Expression of the neuropeptide galanin is markedly upregulated within the adult dorsal root ganglion (DRG) after peripheral nerve injury. We demonstrated previously that the rate of peripheral nerve regeneration is reduced in galanin knock-out mice, with similar deficits observed in neurite outgrowth from cultured mutant DRG neurons. Here, we show that the addition of galanin peptide significantly enhanced neurite outgrowth from wild-type sensory neurons and fully rescued the observed deficits in mutant cultures. Furthermore, neurite outgrowth in wild-type cultures was reduced to levels observed in the mutants by the addition of the galanin antagonist M35 [galanin(1-13)bradykinin(2-9)]. Study of the first galanin receptor (GalR1) knock-out animals demonstrated no differences in neurite outgrowth compared with wild-type animals. Similarly, use of a GalR1-specific antagonist had no effect on neuritogenesis. In contrast, use of a GalR2-specific agonist had equipotent effects on neuritogenesis to galanin peptide, and inhibition of PKC reduced neurite outgrowth from wild-type sensory neurons to that observed in galanin knock-out cultures. These results demonstrate that adult sensory neurons are dependent, in part, on galanin for neurite extension and that this crucial physiological process is mediated by activation of the GalR2 receptor in a PKC-dependent manner.

In-phantom characterisation studies at the Birmingham Accelerator-Generated epIthermal Neutron Source (BAGINS) BNCT facility.

A broad experimental campaign to validate the final epithermal neutron beam design for the BNCT facility constructed at the University of Birmingham concluded in November 2003. The final moderator and facility designs are overviewed briefly, followed by a summary of the dosimetric methods and presentation of a small subset of the results from this campaign. The dual ionisation chamber technique was used together with foil activation to quantify the fast neutron, photon, and thermal neutron beam dose components in a large rectangular phantom exposed to the beam with a 12 cm diameter beam delimiter in place. After application of a normalisation factor, dose measurements agree with in-phantom MCNP4C predictions within 10% for the photon dose, within 10% for thermal neutron dose, and within 25% for the proton recoil dose along the main beam axis.

Synthesis of (-)-5,8-dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydronaphthalene: an inhibitor of beta-amyloid(1-42) aggregation.

A concise synthesis of the beta-amyloid(1-42 )aggregation inhibitor (-)-5,8-dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydronaphthalene [(-)-2] has been developed. The key step is a regio- and diastereoselective hydroboration-amination sequence to convert alkene into amine. Enantiomeric resolution was achieved by recrystallization of amine as the dibenzoyl-D-tartaric acid salt. Hydroquinone is a potent inhibitor of the fibrillar aggregation of beta-amyloid as determined in two different assay systems.

2,3-Diaryl-5-anilino[1,2,4]thiadiazoles as melanocortin MC4 receptor agonists and their effects on feeding behavior in rats.

The melanocortin-4 receptor (MC4) modulates physiological functions such as feeding behavior, nerve regeneration, and drug addiction. Using a high throughput screen based on (125)I-NDP-MSH binding to the human MC4 receptor, we discovered 2,3-diaryl-5-anilino[1,2,4]thiadiazoles 3 as potent and selective MC4 receptor agonists. Through SAR development on the three attached aryl rings, we improved the binding affinity from 174 nM to 4.4 nM IC(50). When delivered intraperitoneally, compounds 3a, 3b, and 3c induced significant inhibition of food intake in a fasting-induced feeding model in rats. When delivered orally, these compounds lost activity, mainly due to rapid metabolism to inactive imidoylthiourea reduction products.