Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up F. Pacini, M. G. Castagna, L. Brilli & G. Pentheroudakis On behalf of the ESMO Guidelines Working Group* Section of Endocrinology and Metabolism, Department of Internal Medicine, Endocrinology and Metabolism and Biochemistry, Section of Endocrinology and Metabolism, University of Siena, Siena, Italy; Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greec

Activity of platinum and cetuximab in cutaneous squamous cell cancer not amenable to curative treatment

Background: Unresectable or metastatic cutaneous squamous cell cancers (cSCCs) are rare but potentially life-threatening diseases. In this setting, systemic therapy has a palliative intent with limited benefit, but there is no established consensus regarding the proper management of this tumour. This retrospective study aimed to review outcomes in patients with non-curable cSCC treated with platinum-based chemotherapy and cetuximab. Methods: We considered 12 consecutive patients treated between June 2010 and March 2016. All patients had received previous treatment for the local disease. Results: The overall response rate was 50%, and the disease control rate was 67%. Median progression-free survival and overall survival were 6.6 (95% confidence interval [CI]: 1.9-8.4) and 14.6 (95% CI: 9.4-20.1) months, respectively. The median duration of response was 4.8 months (95% CI: 1.2-5.9). The most frequent toxicities were skin reactions (58%; grade 3: 25%) and anaemia (10%). No grade 4 toxicities were observed. Conclusions: Cetuximab and platinum-based chemotherapy were shown to be feasible and active in cSCC, with an acceptable toxicity profile, even if with a limited duration of response

Genotype-Phenotype Correlation in a Family with Brugada Syndrome Harboring the Novel p.Gln371* Nonsense Variant in the SCN5A Gene

Brugada syndrome (BrS) is marked by coved ST-segment elevation and increased risk of sudden cardiac death. The genetics of this syndrome are elusive in over half of the cases. Variants in the SCN5A gene are the single most common known genetic unifier, accounting for about a third of cases. Research models, such as animal models and cell lines, are limited. In the present study, we report the novel NM_198056.2:c.1111C>T (p.Gln371*) heterozygous variant in the SCN5A gene, as well as its segregation with BrS in a large family. The results herein suggest a pathogenic effect of this variant. Functional studies are certainly warranted to characterize the molecular effects of this variant

RANK expression in EBV positive nasopharyngeal carcinoma metastasis: A ready-to-treat target?

Epstein Barr Virus (EBV) related Nasopharyngeal Carcinoma (NPC), is an highly chemo- and radiosensitive endemic malignancy in southeast Asia. More than one third of locally advanced cases relapse after curative treatment, especially because of bone, liver and lung metastases. Lymphocyte sub-populations favour EBV-associated carcinogenesis and tumour progression and several strategies aim to reverse this phenomenon. Receptor activator of NF-kB (RANK) and its Ligand (RANKL), key regulator of bone metabolisms, are expressed in several malignancies and tumorinfiltrating Tregs. We collected 17 paired FFPE specimen of primary and metachronous metastatic or regionally relapsed EBV related NPC and evaluated RANK expression by immunohistochemistry. All primary tumour specimens resulted not evaluable whereas all metastatic specimens, regardless of sites, showed high RANK IHC expression in the tumor with no staining in normal surrounding tissues. This observation deserves further clarifications and could open the way to trials testing the hypotesis that targeting the RANK/RANKL pathway with denosumab, an already available, clinically approved monoclonal antibody for metastatic bone lesions, might restore proper antitumor immune response in NPC metastatic patients

The impact of electronic versus paper-based data capture on data collection logistics and on missing scores in thyroid cancer patients.

The purpose of this study was to investigate the impact of the type of data capture on the time and help needed for collecting patient-reported outcomes as well as on the proportion of missing scores. In a multinational prospective study, thyroid cancer patients from 17 countries completed a validated questionnaire measuring quality of life. Electronic data capture was compared to the paper-based approach using multivariate logistic regression. A total of 437 patients were included, of whom 13% used electronic data capture. The relation between data capture and time needed was modified by the emotional functioning of the patients. Those with clinical impairments in that respect needed more time to complete the questionnaire when they used electronic data capture compared to paper and pencil (OR <sub>adj</sub> 24.0; p = 0.006). This was not the case when patients had sub-threshold emotional problems (OR <sub>adj</sub> 1.9; p = 0.48). The odds of having the researcher reading the questions out (instead of the patient doing this themselves) (OR <sub>adj</sub> 0.1; p = 0.01) and of needing any help (OR <sub>adj</sub> 0.1; p = 0.01) were lower when electronic data capture was used. The proportion of missing scores was equivalent in both groups (OR <sub>adj</sub> 0.4, p = 0.42). The advantages of electronic data capture, such as real-time assessment and fewer data entry errors, may come at the price of more time required for data collection when the patients have mental health problems. As this is not uncommon in thyroid cancer, researchers need to choose the type of data capture wisely for their particular research question

The observational clinical registry (cohort design) of the European Reference Network on Rare Adult Solid Cancers: The protocol for the rare head and neck cancers

Care for head and neck cancers is complex in particular for the rare ones. Knowledge is limited and histological heterogeneity adds complexity to the rarity. There is a wide consensus that to support clinical research on rare cancer, clinical registries should be developed within networks specializing in rare cancers. In the EU, a unique opportunity is provided by the European Reference Networks (ERN). The ERN EURACAN is dedicated to rare adults solid cancers, here we present the protocol of the EURACAN registry on rare head and neck cancers (ClinicalTrials.gov Identifier: NCT05483374). Study design Registry-based cohort study including only people with rare head and neck cancers. Objectives 1.To help describe the natural history of rare head and neck cancers; 2.To evaluate factors that influence prognosis; 3.To assess treatment effectiveness; 4.To measure indicators of quality of care. Methods Settings and participants It is an hospital based registry established in hospitals with expertise in head and neck cancers. Only adult patients with epithelial tumours of nasopharynx; nasal cavity and paranasal sinuses; salivary gland cancer in large and small salivary glands; and middle ear will be included in the registry. This registry won t select a sample of patients. Each patient in the facility who meets the above mentioned inclusion criteria will be followed prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for the patient follow-up. Variables Data will be collected on patient characteristics (eg. patient demographics, lifestyle, medical history, health status); exposure data (eg. disease, procedures, treatments of interest) and outcomes (e.g. survival, progression, progression-free survival, etc.). In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will be also collected. Statistical methods The data analyses will include descriptive statistics showing patterns of patients and cancers variables and indicators describing the quality of care. Multivariable Cox s proportional hazards model and Hazard ratios (HR) for all-cause or cause specific mortality will be used to determine independent predictors of overall survival, recurrence etc. Variables to include in the multivariable regression model will be selected based on the results of univariable analysis. The role of confounding or effect modifiers will be evaluated using stratified analysis or sensitivity analysis. To assess treatment effectiveness, multivariable models with propensity score adjustment and progression-free survival will be performed. Adequate statistical (eg. marginal structural model) methods will be used if time-varying treatments/ confounders and confounding by indication (selective prescribing) will be present. Results The registry initiated recruiting in May 2022. The estimated completion date is December 2030 upon agreement on the achievement of all the registry objectives. As of October 2022, the registry is recruiting. There will be a risk of limited representativeness due to the hospital-based nature of the registry and to the fact that hospital contributing to the registry are expert centres for these rare cancers. Clinical Follow-up could also be an issue but active search of the life status of the patients will be guaranteed

Amyotrophic lateral sclerosis transcriptomics reveals immunological effects of low-dose interleukin-2

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease causing upper and lower motor neuron loss and currently no effective disease-modifying treatment is available. A pathological feature of this disease is neuroinflammation, a mechanism which involves both CNS-resident and peripheral immune system cells. Regulatory T-cells are immune-suppressive agents known to be dramatically and progressively decreased in patients with amyotrophic lateral sclerosis. Low-dose interleukin-2 promotes regulatory T-cell expansion and was proposed as an immune-modulatory strategy for this disease. A randomized placebo-controlled pilot phase-II clinical trial called Immuno-Modulation in Amyotrophic Lateral Sclerosis was carried out to test safety and activity of low-dose interleukin-2 in 36 amyotrophic lateral sclerosis patients (NCT02059759). Participants were randomized to 1MIU, 2MIU-low-dose interleukin-2 or placebo and underwent one injection daily for 5 days every 28 days for three cycles. In this report, we describe the results of microarray gene expression profiling of trial participants' leukocyte population. We identified a dose-dependent increase in regulatory T-cell markers at the end of the treatment period. Longitudinal analysis revealed an alteration and inhibition of inflammatory pathways occurring promptly at the end of the first treatment cycle. These responses are less pronounced following the end of the third treatment cycle, although an activation of immune-regulatory pathways, involving regulatory T-cells and T helper 2 cells, was evident only after the last cycle. This indicates a cumulative effect of repeated low-dose interleukin-2 administration on regulatory T-cells. Our analysis suggested the existence of inter-individual variation amongst trial participants and we therefore classified patients into low, moderate and high-regulatory T-cell-responders. NanoString profiling revealed substantial baseline differences between participant immunological transcript expression profiles with the least responsive patients showing a more inflammatory-prone phenotype at the beginning of the trial. Finally, we identified two genes in which pre-treatment expression levels correlated with the magnitude of drug responsiveness. Therefore, we proposed a two-biomarker based regression model able to predict patient regulatory T-cell-response to low-dose interleukin-2. These findings and the application of this methodology could be particularly relevant for future precision medicine approaches to treat amyotrophic lateral sclerosis

Critical appraisal of technologies to assess electrical activity during atrial fibrillation: a position paper from the European Heart Rhythm Association and European Society of Cardiology Working Group on eCardiology in collaboration with the Heart Rhythm Society, Asia Pacific Heart Rhythm Society, Latin American Heart Rhythm Society and Computing in Cardiology

We aim to provide a critical appraisal of basic concepts underlying signal recording and processing technologies applied for (i) atrial fibrillation (AF) mapping to unravel AF mechanisms and/or identifying target sites for AF therapy and (ii) AF detection, to optimize usage of technologies, stimulate research aimed at closing knowledge gaps, and developing ideal AF recording and processing technologies. Recording and processing techniques for assessment of electrical activity during AF essential for diagnosis and guiding ablative therapy including body surface electrocardiograms (ECG) and endo- or epicardial electrograms (EGM) are evaluated. Discussion of (i) differences in uni-, bi-, and multi-polar (omnipolar/Laplacian) recording modes, (ii) impact of recording technologies on EGM morphology, (iii) global or local mapping using various types of EGM involving signal processing techniques including isochronal-, voltage- fractionation-, dipole density-, and rotor mapping, enabling derivation of parameters like atrial rate, entropy, conduction velocity/direction, (iv) value of epicardial and optical mapping, (v) AF detection by cardiac implantable electronic devices containing various detection algorithms applicable to stored EGMs, (vi) contribution of machine learning (ML) to further improvement of signals processing technologies. Recording and processing of EGM (or ECG) are the cornerstones of (body surface) mapping of AF. Currently available AF recording and processing technologies are mainly restricted to specific applications or have technological limitations. Improvements in AF mapping by obtaining highest fidelity source signals (e.g. catheter–electrode combinations) for signal processing (e.g. filtering, digitization, and noise elimination) is of utmost importance. Novel acquisition instruments (multi-polar catheters combined with improved physical modelling and ML techniques) will enable enhanced and automated interpretation of EGM recordings in the near future

Chemokine receptors (version 2019.5) in the IUPHAR/BPS Guide to Pharmacology Database

Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [426, 425, 32]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibiotics, among others. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and "Atypical chemokine receptors", which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [32].Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-chemokines; n= 28), CXC (also known as α-chemokines; n= 17) and CX3C (n= 1) chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C chemokines (n= 2) have only the second and fourth cysteines found in other chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high-affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most chemokines bind to more than one receptor subtype. Receptors for inflammatory chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled chemokine receptors are named acccording to the class of chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors [33]. There can be substantial cross-species differences in the sequences of both chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and microbial non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard chemokine receptor names [675] and aliases

L’indagine macrosismica: metodologia, parametri del terremoto, questioni aperte

Subito dopo l’evento del 6 aprile 2009, come di consueto è stata realizzata una lunga e complessa indagine macrosismica, promossa dal gruppo operativo QUEST, che ha avuto inizialmente l’obiettivo di delimitare l’area di danneggiamento, a supporto delle attività di pronto intervento della Protezione Civile, e successivamente quello di classificare nel modo più accurato e capillare possibile, gli effetti prodotti dall’evento, particolarmente nelle aree danneggiate. A questo scopo è stata prodotta una stima utilizzando la scala MCS (Sieberg, 1930); in un secondo momento è stata rifinita l’indagine per una cinquantina di località dell’area maggiormente danneggiata (Is MCS>VII), raccogliendo ed elaborando i dati in termini di scala macrosismica EMS98 (Grünthal, 1998). Per la complessità e la dimensione dei problemi affrontati, questo terremoto ha costituito un banco di prova di grande importanza per la macrosismologia italiana. In questo testo viene descritto il lavoro realizzato, discutendo in particolare alcuni aspetti che hanno messo alla prova le metodologie di indagine tradizionali (sistematiche irregolarità degli insediamenti monitorati, forti divergenze degli scenari di danno rispetto a quelli previsti dalle scale, difficile comparabilità con scenari storici, ecc.) e presentandone i risultati, in relazione ai parametri epicentrali che ne risultano e il loro contributo più diretto alla comprensione complessiva della sismicità dell’area