A Multimodal Approach to the Management of Neuroendocrine Tumour Liver Metastases

Neuroendocrine tumours (NETs) are often indolent malignancies that commonly present with metastatic disease in the liver. Surgical, locoregional, and systemic treatment modalities are reviewed. A multidisciplinary approach to patient care is suggested to ensure all therapeutic options explored

Circulating tumor cells and tumor biomarkers in functional midgut neuroendocrine tumors

CALM-NET was a phase IV exploratory study in the UK that aimed to evaluate if the presence of circulating tumour cells (CTCs) at baseline predicted symptomatic response in patients with midgut neuroendocrine tumours (NETs) treated with lanreotide autogel (LAN). Adults with functional, well/moderately differentiated (Ki-67 0. Primary endpoint was the clinical value of baseline CTCs to predict symptomatic response (decrease in diarrhoea or flushing of ≥50% frequency, or ≥1 severity level). Other endpoints included progression-free survival (PFS) and correlations between plasma and urinary biomarkers (including 5-hydroxyindoleacetic acid [5-HIAA]). Fifty patients were enrolled; 40 completed the study. Baseline CTCs were present in 22 (45.8%) patients (missing baseline CTC status n = 2). Overall, 87.5% (95% confidence interval [CI]: 73.9; 94.5) of patients had a symptomatic response; a 5.9-fold higher odds of symptomatic response in patients without CTC versus patients with CTC at baseline was observed, although this was not statistically significant (odds ratio: 0.17 [95% CI: 0.02; 1.65], p = .126). One-year PFS rate was 66.4% (95% CI: 48.8; 79.2). Biomarker concentrations did not correlate to baseline CTC status. However, there was a strong correlation between plasma and urinary 5-HIAA (Spearman correlation coefficients ≥0.87 [p < .001], all time points). In conclusion, patients without CTC at baseline may be more likely to achieve a symptomatic response following LAN treatment than patients with CTC. Plasma 5-HIAA correlated with urinary 5-HIAA during LAN treatment. ClinicalTrials.gov identifier: NCT02075606

Sex Differences in Survival from Neuroendocrine Neoplasia in England 2012–2018:A Retrospective, Population-Based Study

Pre-clinical studies have suggested sex hormone signalling pathways may influence tumorigenesis in neuroendocrine neoplasia (NEN). We conducted a retrospective, population-based study to compare overall survival (OS) between males and females with NEN. A total of 14,834 cases of NEN diagnosed between 2012 and 2018, recorded in England’s National Cancer Registry and Analysis Service (NCRAS), were analysed. The primary outcome was OS with 5 years maximum follow-up. Multivariable analysis, restricted mean survival time and mediation analysis were performed. Appendiceal, pulmonary and early-stage NEN were most commonly diagnosed in females; stomach, pancreatic, small intestinal, colonic, rectal and later-stage NEN were more often diagnosed in males. Females displayed increased survival irrespective of the stage, morphology or level of deprivation. On average, they survived 3.62 (95% CI 1.73–5.90) to 10.26 (6.6–14.45) months longer than males; this was statistically significant in NEN of the lung, pancreas, rectum and stomach (p &lt; 0.001). The stage mediated improved survival in stomach, lung, and pancreatic NEN but not in rectal NEN. The reasons underlying these differences are not yet understood. Overall, females diagnosed with NEN tend to survive longer than males, and the stage at presentation only partially explains this. Future research, as well as prognostication and treatment, should consider sex as an important factor.</p

Validation of the EORTC QLQ-GINET21 questionnaire for assessing quality of life of patients with gastrointestinal neuroendocrine tumours

Background:Quality of life is an important end point in clinical trials, yet there are few quality of life questionnaires for neuroendocrine tumours.Methods:This international multicentre validation study assesses the QLQ-GINET21 Quality of Life Questionnaire in 253 patients with gastrointestinal neuroendocrine tumours. All patients were requested to complete two quality of life questionnaires - the EORTC Core Quality of Life questionnaire (QLQ-C30) and the QLQ-GINET21 - at baseline, and at 3 and 6 months post-baseline; the psychometric properties of the questionnaire were then analysed.Results:Analysis of QLQ-GINET21 scales confirmed appropriate aggregation of the items, except for treatment-related symptoms, where weight gain showed low correlation with other questions in the scale; weight gain was therefore analysed as a single item. Internal consistency of scales using Cronbach's α coefficient was >0.7 for all parts of the QLQ-GINET21 at 6 months. Intraclass correlation was >0.85 for all scales. Discriminant validity was confirmed, with values <0.70 for all scales compared with each other.Scores changed in accordance with alterations in performance status and in response to expected clinical changes after therapies. Mean scores were similar for pancreatic and other tumours.Conclusion:The QLQ-GINET21 is a valid and responsive tool for assessing quality of life in the gut, pancreas and liver neuroendocrine tumours

Calcitonin secreting neuroendocrine neoplasms of the lung : a systematic review and narrative synthesis

Calcitonin-secreting neuroendocrine neoplasms of the lung are rare, with few cases reported in the literature. Differentiating between medullary thyroid carcinoma and an ectopic source of calcitonin secretion can represent a complex diagnostic conundrum for managing physicians, with cases of unnecessary thyroidectomy reported in the literature. This manuscript reports a case of ectopic hypercalcitonaemia from a metastatic neuroendocrine neoplasm of the lung with concurrent thyroid pathology and summarises the results of a systematic review of the literature. Medical Literature Analysis and Retrieval System Online, Excerpta Medica, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and SCOPUS databases were systematically and critically appraised for all peer reviewed manuscripts that suitably fulfilled the inclusion criteria established a priori. The protocol for this systematic review was developed according to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols, and followed methods outlined in The Cochrane Handbook for Systematic Reviews of Interventions. This systematic review is registered with PROSPERO. It is vital to consider diagnoses other than medullary thyroid carcinoma when presented with a patient with raised calcitonin, as it is not pathognomonic of medullary thyroid carcinoma. Lung neuroendocrine neoplasms can appear similar to medullary thyroid carcinoma histologically, they can secrete calcitonin and metastasize to the thyroid. Patients with medullary thyroid carcinoma may show stimulated calcitonin values over two or more times above the basal values, whereas calcitonin-secreting neuroendocrine neoplasms may or may not show response to stimulation tests. The present review summarises existing evidence from cases of ectopic hypercalcitonaemia to lung neuroendocrine neoplasms

Thresholds for clinical importance were defined for the European Organisation for Research and Treatment of Cancer Computer Adaptive Testing Core-an adaptive measure of core quality of life domains in oncology clinical practice and research

Objectives The aim of this article was to establish thresholds for clinical importance (TCIs) for the European Organisation for Research and Treatment of Cancer (EORTC) Computer Adaptive Testing (CAT) Core measure, the new adaptive version of the EORTC QLQ-C30. Study Design and Setting For our diagnostic study, we recruited cancer patients with mixed diagnoses and treatments from six European countries. Patients completed the EORTC CAT Core and a questionnaire with anchor items assessing criteria for clinical importance (limitations in everyday life, need for help/care, and worries by the patient/family/partner) for each EORTC CAT Core domain. We used a binary variable summarizing the anchor items for determining TCIs and for calculating the area under the curve (AUC) in receiving operator characteristic analysis as a measure of diagnostic accuracy. Results Using data from 498 cancer patients (mean age 60.4 years, 55.2% women), we established TCIs for the 14 domains of the EORTC CAT Core. Median AUC across domains was 0.93 (range 0.84–0.94). Median sensitivity and specificity of the TCIs were 0.91 (range 0.80–0.96) and 0.77 (range 0.66–0.84), respectively. TCIs and AUCs were largely consistent across patient groups. Conclusion We have generated TCIs for the 14 functional health and symptom domains of the EORTC CAT Core. The EORTC CAT Core showed high diagnostic accuracy in identifying clinically important symptoms and functional impairments

Thresholds for clinical importance were established to improve interpretation of the EORTC QLQ-C30 in clinical practice and research

To establish thresholds for clinical importance (TCIs) for the five functioning and nine symptom scales of the EORTC QLQ-C30 questionnaire

Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs)

These guidelines update previous guidance published in 2005. They have been revised by a group who are members of the UK and Ireland Neuroendocrine Tumour Society with endorsement from the clinical committees of the British Society of Gastroenterology, the Society for Endocrinology, the Association of Surgeons of Great Britain and Ireland (and its Surgical Specialty Associations), the British Society of Gastrointestinal and Abdominal Radiology and others. The authorship represents leaders of the various groups in the UK and Ireland Neuroendocrine Tumour Society, but a large amount of work has been carried out by other specialists, many of whom attended a guidelines conference in May 2009. We have attempted to represent this work in the acknowledgements section. Over the past few years, there have been advances in the management of neuroendocrine tumours, which have included clearer characterisation, more specific and therapeutically relevant diagnosis, and improved treatments. However, there remain few randomised trials in the field and the disease is uncommon, hence all evidence must be considered weak in comparison with other more common cancers

Multi-omic approach identifies hypoxic tumor-associated myeloid cells that drive immunobiology of high-risk pediatric ependymoma.

Ependymoma (EPN) is a devastating childhood brain tumor. Single-cell analyses have illustrated the cellular heterogeneity of EPN tumors, identifying multiple neoplastic cell states including a mesenchymal-differentiated subpopulation which characterizes the PFA1 subtype. Here, we characterize the EPN immune environment, in the context of both tumor subtypes and tumor cell subpopulations using single-cell sequencing (scRNAseq, n = 27), deconvolution of bulk tumor gene expression (n = 299), spatial proteomics (n = 54), and single-cell cytokine release assays (n = 12). We identify eight distinct myeloid-derived subpopulations from which a group of cells, termed hypoxia myeloid cells, demonstrate features of myeloid-derived suppressor cells, including IL6/STAT3 pathway activation and wound healing ontologies. In PFA tumors, hypoxia myeloid cells colocalize with mesenchymal-differentiated cells in necrotic and perivascular niches and secrete IL-8, which we hypothesize amplifies the EPN immunosuppressive microenvironment. This myeloid cell-driven immunosuppression will need to be targeted for immunotherapy to be effective in this difficult-to-cure childhood brain tumor. [Abstract copyright: © 2023 The Author(s).

One step closer to understanding the role of bacteria in diabetic foot ulcers: characterising the microbiome of ulcers

Background: The aim of this study was to characterise the microbiome of new and recurrent diabetic foot ulcers using 16S amplicon sequencing (16S AS), allowing the identification of a wider range of bacterial species that may be important in the development of chronicity in these debilitating wounds. Twenty patients not receiving antibiotics for the past three months were selected, with swabs taken from each individual for culture and 16S AS. DNA was isolated using a combination of bead beating and kit extraction. Samples were sequenced on the Illumina Hiseq 2500 platform. Results: Conventional laboratory culture showed positive growth from only 55 % of the patients, whereas 16S AS was positive for 75 % of the patients (41 unique genera, representing 82 different operational taxonomic units (OTU’s). S. aureus was isolated in 72 % of culture-positive samples, whereas the most commonly detected bacteria in all ulcers were Peptoniphilusspp., Anaerococcus spp. and Corynebacterium spp., with the addition of Staphylococcus spp. in new ulcers. The majority of OTU’s residing in both new and recurrent ulcers (over 67 %) were identified as facultative or strict anaerobic Gram-positive organisms. Principal component analysis (PCA) showed no difference in clustering between the two groups (new and recurrent ulcers). Conclusions: The abundance of anaerobic bacteria has important implications for treatment as it suggests that the microbiome of each ulcer “starts afresh” and that, although diverse, are not distinctly different from one another with respect to new or recurrent ulcers. Therefore, when considering antibiotic therapy the duration of current ulceration may be a more important consideration than a history of healed ulcer