Delivered relative dose intensity in adolescent and young adult germ cell tumours in England: Assessment of data quality and consistency from clinical trials compared to national cancer registration data.

Adolescent and young adults (AYA) with germ cell tumours (GCT) have poorer survival rates than children and many older adults with the same cancers. There are several likely contributing factors to this, including the treatment received. The prognostic benefit of intended dose intensity is well documented in GCT from trials comparing regimens. However, evidence specific to AYA is limited by poor recruitment of AYA to trials and dose delivery outside trials not being well examined. We examined the utility of cancer registration data and a clinical trials dataset to investigate the delivery of relative dose intensity (RDI) in routine National Health Service practice in England, compared to within international clinical trials. Linked data from the Cancer Outcomes and Services Dataset (COSD) and the Systemic Anti-Cancer Therapy (SACT) dataset, and data from four international clinical trials were analysed. Survival over time was described using Kaplan-Meier estimation; overall, by age category, International Germ-Cell Cancer Collaborative Group (IGCCCG) classification, stage, tumour subtype, primary site, ethnicity and deprivation. Cox regression models were used to determine the fully adjusted effect of RDI on mortality risk. The quality of both datasets was critically evaluated and clinically enhanced. RDI was found to be well maintained in all datasets with higher RDIs associated with improved survival outcomes. Real-world data demonstrated several strengths, including population coverage and inclusion of sociodemographic variables and comorbidity. It is limited in GCT however, by the poor completion of data items enabling risk classification of patients and a higher proportion of missing data.

Small-molecule factor B inhibitor for the treatment of complement-mediated diseases.

Dysregulation of the alternative complement pathway (AP) predisposes individuals to a number of diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy. Moreover, glomerular Ig deposits can lead to complement-driven nephropathies. Here we describe the discovery of a highly potent, reversible, and selective small-molecule inhibitor of factor B, a serine protease that drives the central amplification loop of the AP. Oral administration of the inhibitor prevents KRN-induced arthritis in mice and is effective upon prophylactic and therapeutic dosing in an experimental model of membranous nephropathy in rats. In addition, inhibition of factor B prevents complement activation in sera from C3 glomerulopathy patients and the hemolysis of human PNH erythrocytes. These data demonstrate the potential therapeutic value of using a factor B inhibitor for systemic treatment of complement-mediated diseases and provide a basis for its clinical development.

An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient.

MALT1 paracaspase is central for lymphocyte antigen-dependent responses including NF-κB activation. We discovered nanomolar, selective allosteric inhibitors of MALT1 that bind by displacing the side chain of Trp580, locking the protease in an inactive conformation. Interestingly, we had previously identified a patient homozygous for a MALT1 Trp580-to-serine mutation who suffered from combined immunodeficiency. We show that the loss of tryptophan weakened interactions between the paracaspase and C-terminal immunoglobulin MALT1 domains resulting in protein instability, reduced protein levels and functions. Upon binding of allosteric inhibitors of increasing potency, we found proportionate increased stabilization of MALT1-W580S to reach that of wild-type MALT1. With restored levels of stable MALT1 protein, the most potent of the allosteric inhibitors rescued NF-κB and JNK signaling in patient lymphocytes. Following compound washout, MALT1 substrate cleavage was partly recovered. Thus, a molecular corrector rescues an enzyme deficiency by substituting for the mutated residue, inspiring new potential precision therapies to increase mutant enzyme activity in other deficiencies.

A Case of Recurrent Painful Ophthalmoplegic Neuropathy with Associated Oculomotor Nerve Tumour.

Recurrent painful ophthalmoplegic neuropathy (RPON) replaced the term 'ophthalmoplegic migraine' as the condition behaves more like an inflammatory cranial neuropathy than a primary headache disorder. RPON may be associated with cranial nerve thickening on MR imaging and persistent oculomotor paresis. Oculomotor tumours have rarely been described in cases of relapsing painful ophthalmoplegia with and without persistent paresis. Here, we present a case of relapsing painful left ophthalmoplegia that gradually became persistent. MR imaging after 14 years of symptoms revealed an enhancing tumour of the left oculomotor nerve. It is unclear whether the tumour was the cause of the attacks or whether repeated cycles could lead to tumour development. MR imaging is indicated in patients with RPON who develop persistent deficits to screen for associated oculomotor tumour.

Whole-body MRI of bone marrow: A review.

Technical advances in the last two decades have allowed rapid, high-resolution whole-body magnetic resonance imaging (WBMRI). MRI allows unparalleled visualization and detail in the imaging of bone marrow and surrounding soft tissues. The properties of nuclear magnetic resonance allow superb characterization of bone marrow constituents. WBMRI allows superb characterization of the different types of bone marrow and their natural evolution during the life cycle. Diffusion-weighted WBMRI is an exciting development that adds functional information to anatomical detail. The mainstay of WBMRI for bone marrow abnormalities to date has centered upon staging multiple myeloma and other hematologic bone marrow conditions, and as a valuable tool in quantifying skeletal metastases. Increasingly, WBMRI is being utilized in a variety of additional malignant and nonmalignant conditions. Due to the absence of ionizing radiation, WBMRI represents a valuable screening tool in areas such as malignant transformation in hereditary multifocal exostoses or for the development of ischemic marrow insult in at-risk patients. An additional novel area of use includes postmortem WBMRI for characterization of skeletal injuries. This article provides a state-of-the-art and current review of WBMRI of the bone marrow and highlights potential future areas of development. Level of Evidence: 5 Technical Efficacy Stage: 3 J. MAGN. RESON. IMAGING 2019. J. Magn. Reson. Imaging 2019;50:1687-1701.

Small-molecule factor D inhibitors targeting the alternative complement pathway.

Complement is a key component of the innate immune system, recognizing pathogens and promoting their elimination. Complement component 3 (C3) is the central component of the system. Activation of C3 can be initiated by three distinct routes-the classical, the lectin and the alternative pathways-with the alternative pathway also acting as an amplification loop for the other two pathways. The protease factor D (FD) is essential for this amplification process, which, when dysregulated, predisposes individuals to diverse disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinuria (PNH). Here we describe the identification of potent and selective small-molecule inhibitors of FD. These inhibitors efficiently block alternative pathway (AP) activation and prevent both C3 deposition onto, and lysis of, PNH erythrocytes. Their oral administration inhibited lipopolysaccharide-induced AP activation in FD-humanized mice. These data demonstrate the feasibility of inhibiting the AP with small-molecule antagonists and support the development of FD inhibitors for the treatment of complement-mediated diseases.

Therapeutic Intervention in Musculoskeletal Radiology: Current Practice and Future Directions.

Over the last several decades, the volume and range of therapeutic musculoskeletal (MSK) interventions that radiologists can offer their patients has dramatically increased. With new materials and improving imaging modalities, as well as significant investment in research, the field of MSK interventional radiologic intervention will likely continue to expand. In this article, we summarize the range of interventions currently available to the MSK radiologist. We also seek to explore new and emerging techniques that may become commonplace in the near future while considering the challenges that may lie ahead in the field of MSK radiology.

Sonographic differences between conventional and follicular variant papillary thyroid carcinoma.

Follicular variant papillary thyroid carcinoma (FVPTC) may pose a diagnostic challenge due to higher likelihood of lower risk cytology compared to conventional papillary thyroid carcinoma (CPTC). Recent guidelines have recommended the use of sonographic features to guide decisions to biopsy thyroid nodules. The purpose of this study was to evaluate the sonographic features of CPTC and FVPTC. This is a retrospective study design done in an Academic teaching hospital setting. Preoperative ultrasounds of 79 patients with conventional CPTC (48) and FVPTC (31) were reviewed by a radiologist blinded to histological diagnosis. Sonographic features of nodules were classified according to the British Thyroid Association (BTA) U-classification system as normal (U1), benign (U2), indeterminate (U3), suspicious (U4), and malignant (U5). Pathology slides of patients with FVPTC were reviewed by two pathologists and subclassified into encapsulated, well circumscribed/partly encapsulated, and infiltrative subtypes. FVPTC had a significantly lower incidence of any calcifications (p = 0.0005), microcalcifications (p = 0.002), and irregular or lobulated margins (p = 0.03) than CPTC. Differences in hypoechogenicity (p = 0.06), taller > wide shape (p = 0.17) and presence of halo (p = 0.07) were not significant. FVPTC was significantly less likely to be classified sonographically as malignant (U5) (p = 0.006) or suspicious/malignant (U4/5) (p = 0.009) than conventional PTC. Among FVPTC cases, infiltrative FVPTC were more likely to be sonographically classified as suspicious/malignant (U4/5) than non-infiltrative FVPTC. FVPTC nodules are less likely to show sonographic features of malignancy than conventional PTC. Reliance solely on sonographic features for thyroid nodule evaluation may not be sufficient to exclude FVPTC.

Structure-based design and optimization of potent inhibitors of the adenoviral protease.

Adenoviral infections are associated with a wide range of acute diseases, among which ocular viral conjunctivitis (EKC) and disseminated disease in immunocompromised patients. To date, no approved specific anti-adenoviral drug is available, but there is a growing need for an effective treatment of such infections. The adenoviral protease, adenain, plays a crucial role for the viral lifecycle and thus represents an attractive therapeutic target. Structure-guided design with the objective to depeptidize tetrapeptide nitrile 1 led to the novel chemotype 2. Optimization of scaffold 2 resulted in picomolar adenain inhibitors 3a and 3b. In addition, a complementary series of irreversible vinyl sulfone containing inhibitors were rationally designed, prepared and evaluated against adenoviral protease. High resolution X-ray co-crystal structures of representatives of each series proves the successful design of these inhibitors and provides an excellent basis for future medicinal chemistry optimization of these compounds.

Patient and public involvement to inform priorities and practice for research using existing healthcare data for children's and young people's cancers.

BACKGROUND: In the United Kingdom, healthcare data is collected on all patients receiving National Health Service (NHS) care, including children and young people (CYP) with cancer. This data is used to inform service delivery, and with special permissions used for research. The use of routinely collected health data in research is an advancing field with huge potential benefit, particularly in CYP with cancer where case numbers are small and the impact across the life course can be significant. Patient and public involvement (PPI) exercise aims: Identify current barriers to trust relating to the use of healthcare data for research. Determine ways to increase public and patient confidence in the use of healthcare data in research. Define areas of research importance to CYP and their carers using healthcare data. METHODS: Young people currently aged between 16 and 25 years who had a cancer diagnosis before the age of 20 years and carers of a young person with cancer were invited to take part via social media and existing networks of service users. Data was collected during two interactive online workshops totalling 5 h and comprising of presentations from health data experts, case-studies and group discussions. With participant consent the workshops were recorded, transcribed verbatim and analysed using thematic analysis. RESULTS: Ten young people and six carers attended workshop one. Four young people and four carers returned for workshop two. Lack of awareness of how data is used, and negative media reporting were seen as the main causes of mistrust. Better communication and education on how data is used were felt to be important to improving public confidence. Participants want the ability to have control over their own data use. Late effects, social and education outcomes and research on rare tumours were described as key research priorities for data use. CONCLUSIONS: In order to improve public and patient trust in our use of data for research, we need to improve communication about how data is used and the benefits that arise.

Everyday data is collected on all patients treated within the National Health Service, including children and young people with cancer (CYP). This data is used routinely to improve how services are run and with special permissions, can also be used for research. Negative reporting in the media about this use of data can lead to mistrust and some people choosing not to share their data. This can reduce the quality and accuracy of research looking at rare diseases or populations with small numbers. In addition, many barriers exist to researchers when trying to access this data such as laws around data sharing, making it difficult and sometimes impossible to carry out such research. We invited CYP and carers to two workshops to: Learn about how healthcar e data is used for research. Consider ways to increase public and patient confidence in this use of healthcare data. Describe areas of research importance to CYP and their carers using healthcare data. Ten young people and six carers attended the first workshop. Four young people and four carers returned for workshop two. Workshops consisted of interactive presentations, case studies and group discussions. Overall participants felt that lack of awareness and negative media reporting led to mistrust in data use for research. It was believed that greater education about how the data is used, including positive examples of the benefits of the research, was needed to improve public confidence. Key research priorities for data use included late-effects, social and educational outcomes and rare tumours.

TLR3 and Rig-like receptor on myeloid dendritic cells and Rig-like receptor on human NK cells are both mandatory for production of IFN-gamma in response to double-stranded RNA.

Cross-talk between NK cells and dendritic cells (DCs) is critical for the potent therapeutic response to dsRNA, but the receptors involved remained controversial. We show in this paper that two dsRNAs, polyadenylic-polyuridylic acid and polyinosinic-polycytidylic acid [poly(I:C)], similarly engaged human TLR3, whereas only poly(I:C) triggered human RIG-I and MDA5. Both dsRNA enhanced NK cell activation within PBMCs but only poly(I:C) induced IFN-gamma. Although myeloid DCs (mDCs) were required for NK cell activation, induction of cytolytic potential and IFN-gamma production did not require contact with mDCs but was dependent on type I IFN and IL-12, respectively. Poly(I:C) but not polyadenylic-polyuridylic acid synergized with mDC-derived IL-12 for IFN-gamma production by acting directly on NK cells. Finally, the requirement of both TLR3 and Rig-like receptor (RLR) on mDCs and RLRs but not TLR3 on NK cells for IFN-gamma production was demonstrated using TLR3- and Cardif-deficient mice and human RIG-I-specific activator. Thus, we report the requirement of cotriggering TLR3 and RLR on mDCs and RLRs on NK cells for a pathogen product to induce potent innate cell activation.

Radiation Recall Pneumonitis on FDG PET/CT Triggered by COVID-19 Vaccination.

ABSTRACT: A 67-year-old man with metastatic lung adenocarcinoma was initially treated with whole-brain radiotherapy for intracranial metastases, followed by chemotherapy and pembrolizumab. After completing 2 years of systemic therapy, the primary right lung lesion was biopsy-proven to have residual adenocarcinoma, which was then treated with radiation (6000 cGy in 15 fractions). Follow-up serial FDG PET/CT showed radiation fibrosis. Eighteen months after radiotherapy, the patient received 2 doses of an mRNA COVID-19 vaccine. FDG PET/CT performed 4 days following his second vaccine dose showed FDG-avid multistation lymphadenopathy and radiation recall pneumonitis, likely vaccination-induced and mimicking recurrent disease. This resolved spontaneously without therapy.

Recommendations on qPCR/ddPCR assay validation by GCC.

Gene therapy, cell therapy and vaccine research have led to an increased use of qPCR/ddPCR in bioanalytical laboratories. CROs are progressively undertaking the development and validation of qPCR and ddPCR assays. Currently, however, there is limited regulatory guidance for the use of qPCR and a complete lack of any regulatory guidelines for the use of the newer ddPCR to support regulated bioanalysis. Hence, the Global CRO Council in Bioanalysis (GCC) has issued this White Paper to provide; 1) a consensus on the different validation parameters required to support qPCR/ddPCR assays; 2) a harmonized approach to their validation and 3) a consistent development of standard operating procedures (SOPs) for all the bioanalytical laboratories using these techniques.

Recommendations on ELISpot assay validation by the GCC.

Gene therapy, cell therapy and vaccine research have led to an increased need to perform cellular immunity testing in a regulated environment to ensure the safety and efficacy of these treatments. The most common method for the measurement of cellular immunity has been Enzyme-Linked Immunospot assays. However, there is a lack of regulatory guidance available discussing the recommendations for developing and validating these types of assays. Hence, the Global CRO Council has issued this white paper to provide a consensus on the different validation parameters required to support Enzyme-Linked Immunospot assays and a harmonized and consistent approach to Enzyme-Linked Immunospot validation among contract research organizations.

PET Imaging for Hematologic Malignancies.

Hematologic malignancies are a broad category of cancers arising from the lymphoid and myeloid cell lines. The 2016 World Health Organization classification system incorporated molecular markers as part of the diagnostic criteria and includes more than 100 subtypes. This article focuses on the subtypes for which imaging with positron emission tomography/computed tomography (PET/CT) has become an integral component of the patient's evaluation, that is, lymphoma and multiple myeloma. Leukemia and histiocytic and dendritic cell neoplasms are also discussed as these indications for PET/CT are less common, but increasingly seen in clinic.

Risk stratification of young adult survivors of cancer to estimate hospital morbidity burden: applicability of a pediatric therapy-based approach.

PURPOSE: Children and young adults (CYA) are at risk of late morbidity following cancer treatment, with risk varying by disease type and treatment received. Risk-stratified levels of aftercare which stratify morbidity burden to inform the intensity of long-term follow-up care, are well established for survivors of cancer under the age of 18 years, utilizing the National Cancer Survivor Initiative (NCSI) approach. We investigated the applicability of risk-stratified levels of aftercare in predicting long-term morbidity in young adults (YA), aged 18-29 years. METHODS: Long-term CYA survivors followed-up at a regional center in the North of England were risk-stratified by disease and treatments received into one of three levels. These data were linked with local cancer registry and administrative health data (Hospital Episode Statistics), where hospital activity was used as a marker of late morbidity burden. RESULTS: Poisson modelling with incident rate ratios (IRR) demonstrated similar trends in hospital activity for childhood (CH) and YA cancer survivors across NCSI risk levels. NCSI levels independently predicted long-term hospitalization risk in both CH and YA survivors. Risk of hospitalization was significantly reduced for levels 1 (CH IRR 0.32 (95% CI 0.26-0.41), YA IRR 0.06 (95% CI 0.01-0.43)) and 2; CH IRR 0.46 (95% CI 0.42-0.50), YA IRR 0.49 (95% CI 0.37-0.50)), compared with level 3. CONCLUSIONS: The NCSI pediatric late-effects risk stratification system can be effectively and safely applied to cancer patients aged 18-29, independent of ethnicity or socioeconomic position. IMPLICATIONS FOR CANCER SURVIVORS: To enhance quality of care and resource utilization, long-term aftercare of survivors of YA cancer can and should be risk stratified through adoption of approaches such as the NCSI risk-stratification model.

Crystal Structure of NLRP3 NACHT Domain With an Inhibitor Defines Mechanism of Inflammasome Inhibition.

The NLRP3 inflammasome assembles in response to a variety of pathogenic and sterile danger signals, resulting in the production of interleukin-1ß and interleukin-18. NLRP3 is a key component of the innate immune system and has been implicated as a driver of a number of acute and chronic diseases. We report the 2.8 Å crystal structure of the NLRP3 NACHT domain in complex with an inhibitor. The structure defines a binding pocket formed by the four subdomains of the NACHT domain, and shows the inhibitor acts as an intramolecular glue, which locks the protein in an inactive conformation. It provides further molecular insight into our understanding of NLRP3 activation, helps to detail the residues involved in subdomain coordination within the NLRP3 NACHT domain, and gives molecular insights into how gain-of-function mutations de-stabilize the inactive conformation of NLRP3. Finally, it suggests stabilizing the auto-inhibited form of the NACHT domain is an effective way to inhibit NLRP3, and will aid the structure-based development of NLRP3 inhibitors for a range of inflammatory diseases.

2020 White Paper on Recent Issues in Bioanalysis: BMV of Hybrid Assays, Acoustic MS, HRMS, Data Integrity, Endogenous Compounds, Microsampling and Microbiome (Part 1 - Recommendations on Industry/Regulators Consensus on BMV of Biotherapeutics by LCMS, Advanced Application in Hybrid Assays, Regulatory Challenges in Mass Spec, Innovation in Small Molecules, Peptides and Oligos).

The 14th edition of the Workshop on Recent Issues in Bioanalysis (14th WRIB) was held virtually on June 15-29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14th WRIB included three Main Workshops, seven Specialized Workshops that together spanned 11 days in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccine. Moreover, a comprehensive vaccine assays track; an enhanced cytometry track and updated Industry/Regulators consensus on BMV of biotherapeutics by Mass Spectrometry (hybrid assays, LCMS and HRMS) were special features in 2020. As in previous years, this year's WRIB continued to gather a wide diversity of international industry opinion leaders and regulatory authority experts working on both small and large molecules to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance and achieving scientific excellence on bioanalytical issues. This 2020 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the Global Bioanalytical Community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2020 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication covers the recommendations on (Part 1) Hybrid Assays, Innovation in Small Molecules, & Regulated Bioanalysis. Part 2A (BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation), Part 2B (Regulatory Input) and Part 3 (Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity) are published in volume 13 of Bioanalysis, issues 5, and 6 (2021), respectively.

Subperiosteal hematoma of the iliac wing presenting with leg weakness in a young adult footballer.

We present the case of a 17 year old football player with a 2 week history of left leg weakness and difficulty weight-bearing. Magnetic resonance imaging revealed a well-circumscribed lesion deep to the left iliacus muscle. The patient proceeded to computed tomography-guided biopsy. The likely diagnosis was that of a subperiosteal haematoma of the iliac wing, which was exerting mass effect upon the left femoral nerve resulting in leg pain and weakness. Imaging was repeated at an interval of 1 month, at which time the lesion had almost entirely resolved. Subperiosteal haematoma of the iliac bone is a rare entity but should be considered as a potential diagnosis in young adults, particularly where there is a history of trauma or recent sports injury.

Combining structural and textural assessments of volumetric FDG-PET uptake in NSCLC.

Numerous studies have reported the prognostic utility of texture analyses and the effectiveness of radiomics in PET and PET/CT assessment of non-small cell lung cancer (NSCLC). Here we explore the potential, relative to this methodology, of an alternative model-based approach to tumour characterization, which was successfully applied to sarcoma in previous works. The spatial distribution of 3D FDG-PET uptake is evaluated in the spatial referential determined by the best-fitting ellipsoidal pattern, which provides a univariate uptake profile function of the radial position of intratumoral voxels. A group of structural features is extracted from this fit that include two heterogeneity variables and statistical summaries of local metabolic gradients. We demonstrate that these variables capture aspects of tumour metabolism that are separate to those described by conventional texture features. Prognostic model selection is performed in terms of a number of classifiers, including stepwise selection of logistic models, LASSO, random forests and neural networks with respect to two-year survival status. Our results for a cohort of 93 NSCLC patients show that structural variables have significant prognostic potential, and that they may be used in conjunction with texture features in a traditional radiomics sense, towards improved baseline multivariate models of patient overall survival. The statistical significance of these models also demonstrates the relevance of these machine learning classifiers for prognostic variable selection.