Exploring the impact of clients’ disclosures of trauma on psychologists working in the National Health service: a qualitative study

Objective: Given the identified gaps and inconsistencies in the literature the current study: (1) uses the conceptualisation of VT to investigate and highlight the potential effects of exposure to clients’ traumatic disclosures on psychologists working in the NHS, (2) employs a qualitative methodology for an in-depth exploration of participants’ experiences and (3) recruits a relatively homogeneous sample to improve the accuracy and quality of the resultant data. Methods: Nine qualified psychologists with working experience in the NHS were recruited through snowball sampling and personal networks. Qualitative data was collected using semi-structured interviews. Interviews were audio recorded, transcribed and analysed using Interpretative Phenomenological Analysis (IPA). Results: Two superordinate themes emerged entitled ‘The impact of clients’ traumatic disclosures on the psychologist’ and ‘Dealing with clients’ traumatic disclosures in the National Health Service context’. The first superordinate theme produced 4 subordinate themes entitled ‘Psychological and physical reactions’, ‘Questioning belief systems’, ‘Social and relational impact’ and ‘Coping mechanisms’. The second superordinate theme produced six subordinate themes entitled ‘Job expectations’, ‘Support systems’, ‘Caseload’, ‘Sense of safety’, ‘Culture influence’ and ‘Considerations of improving systems’. The participants had experienced vicarious trauma symptoms such as disruptions in their cognitive schemas, nightmares, intrusive thoughts and images, alterations in their sense of safety for themselves and significant others, changes in their worldviews and loss of trust. Conclusions: The participants reported symptoms that suggest the presence of VT. They mentioned cognitive disruptions and alterations of their beliefs, sense of safety, worldviews, trust towards others, job satisfaction and, sometimes, motivation, among others. In addition, participants reported organisational environment challenges such as heavy caseloads, lack of cultural awareness, decreased sense of safety at work, unmet job expectations, lack of space and time for reflection and a general lack of specialised support within organisations

Guanylyl cyclase activation reverses resistive breathing–induced lung injury and inflammation

Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure–volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC–cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases

What Causes Desmoplastic Reaction in Small Intestinal Neuroendocrine Neoplasms?

PURPOSE OF REVIEW: Mesenteric desmoplasia in small intestinal neuroendocrine neoplasms (SINENs) is associated with increased morbidity and mortality. In this paper, we discuss the development of desmoplasia in SINENs. RECENT FINDINGS: The fibrotic reactions associated with these tumours could be limited to the loco-regional environment of the tumour and/or at distant sites. Mesenteric fibrotic mass forms around a local lymph node. Formation of desmoplasia is mediated by interactions between the neoplastic cells and its microenvironment via number of profibrotic mediators and signalling pathways. Profibrotic molecules that are mainly involved in the desmoplastic reaction include serotonin, TGFβ (transforming growth factor β) and CTGF (connective tissue growth factor), although there is some evidence to suggest that there are a number of other molecules involved in this process. Desmoplasia is a result of autocrine and paracrine effects of multiple molecules and signalling pathways. However, more research is needed to understand these mechanisms and to develop targeted therapy to minimise desmoplasia

Evaluation of circulating transcript analysis (NETest) in small intestinal neuroendocrine neoplasms after surgical resection

PURPOSE: Surgical resection is the only effective curative strategy for small intestinal neuroendocrine neoplasms (SINENs). Nevertheless, the evaluation of residual disease and prediction of disease recurrence/progression remains a problematic issue. METHODS: We evaluated 13 SINENs that underwent surgical resection of the primary tumour and/or mesenteric mass. Patients were divided in three groups: (a) Group 1: SINENs that underwent resection with curative intent, (b) Group 2: SINENs treated with resection in the setting of metastatic disease, which remained stable and (c) Group 3: SINENs treated with resection in the setting of metastatic disease, with evidence of any progression at follow-up. NETest and chromogranin A were measured pre-operatively and post-operatively during a 22-month median follow-up period and compared with imaging studies. NETest score <20% was determined as normal, 20-40% low, 41-79% intermediate and ≥80% high score. RESULTS: NETest score was raised in all (100%) SINENs pre-operatively. Surgery with curative intent resulted in NETest score reduction from 78.25 ± 15.32 to 25.25 ± 1.75 (p < 0.05). Low NETest scores post-operatively were evident in all cases without clinical evidence of residual disease (Group 1). However, the low disease activity score suggested the presence of microscopic residual disease. In three cases (75%) with stable disease (Group 2) the NETest score was low consistent with indolent disease. In the progressive disease group (Group 3), a high NETest score was present in three cases (60%) and an intermediate NETest score in the remainder (40%). CONCLUSIONS: Blood NETest scores accurately identified SINENs and were significantly decreased by curative surgery. Monitoring NETest post-operatively may facilitate management by identifying the presence of residual/progressive disease

Endoscopic ultrasound-guided fine-needle aspiration vs fine-needle biopsy for the diagnosis of pancreatic neuroendocrine tumors

Background and study aims Endoscopic ultrasoundguided fine-needle aspiration (EUS-FNA) as a method of obtaining preoperative diagnosis of pancreatic neuroendocrine tumors (PanNETs) has been reported in several series. Fine-needle biopsies (FNB) are increasingly employed to obtain core specimens during EUS. However, the differences in efficacy between these sampling methods in the diagnosis of PanNETs still needs to be defined. Patients and methods Over a 13-year period, all patients who underwent EUS-guided tissue sampling of suspicious pancreatic lesions with clinical, endoscopic and pathologic details were entered into an electronic database. Lesions underwent EUS-FNA or FNB sampling, or a combination of the two. The accuracy and safety of different EUS-guided sampling methods for confirmed PanNETs were investigated. Results A total of 91 patients (M/F: 42/49, median age: 57 years), who underwent 102 EUS procedures had a final diagnosis of PanNET. Both EUS-guided sampling modalities were used in 28 procedures, EUS-FNA alone was used in 61 cases, while EUS-FNB alone in 13 cases. Diagnostic yield of EUS-FNA and EUS-FNB alone, including the inadequate specimens, was 77.5 % (95 %CI: 68.9 – 86.2%) and 85.4 % (95 % CI: 74.6 – 96.2 %), respectively. The combination of both sampling modalities established the diagnosis in 96.4 % of cases (27/28) (95 %CI: 89.6 – 100%), significantly superior to EUS-FNA alone (P = 0.023). Diagnostic sensitivity among the adequate samples for EUS-FNA, EUS-FNB and for the combination of the two methods was 88.4 % (95 %CI: 80.9 – 96.0 %), 94.3% (95 %CI: 86.6 – 100%) and 100% (95% CI: 100 – 100 %). There was one reported complication, a post-FNA bleeding, treated conservatively. Conclusions EUS-FNB improves diagnostic sensitivity and confers additional information to cytological assessment of PanNETs

Expression of somatostatin receptors 2 and 5 in circulating tumour cells from patients with neuroendocrine tumours.

BACKGROUND: Neuroendocrine tumours (NET) overexpress somatostatin receptors (SSTR) that can be targeted for therapy. Somatostatin receptor expression is routinely measured by molecular imaging but the resolution is insufficient to define heterogeneity. We hypothesised that SSTR expression could be measured on circulating tumour cells (CTCs) and used to investigate heterogeneity of expression and track changes during therapy. METHODS: MCF-7 cells were transfected with SSTR2 or 5 and spiked into donor blood for analysis by CellSearch. Optimum anti-SSTR antibody concentration and exposure time were determined, and flow cytometry was used to evaluate assay sensitivity. For clinical evaluation, blood was analysed by CellSearch, and SSTR2/5 immunohistochemistry was performed on matched tissue samples. RESULTS: Flow cytometry confirmed CellSearch was sensitive and that detection of SSTR was unaffected by the presence of somatostatin analogue up to a concentration of 100 ng ml(-l). Thirty-one NET patients were recruited: grade; G1 (29%), G2 (45%), G3 (13%), primary site; midgut (58%), pancreatic (39%). Overall, 87% had SSTR-positive tumours according to somatostatin receptor scintigraphy or 68-Ga-DOTATE PET/CT. Circulating tumour cells were detected in 21 out of 31 patients (68%), of which 33% had evidence of heterogeneous expression of either SSTR2 (n=5) or SSTR5 (n=2). CONCLUSIONS: Somatostatin receptors 2 and 5 are detectable on CTCs from NET patients and may be a useful biomarker for evaluating SSTR-targeted therapies and this is being prospectively evaluated in the Phase IV CALMNET trial (NCT02075606)

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

Prognostic Threshold for Circulating Tumor Cells in Patients With Pancreatic and Midgut Neuroendocrine Tumors

BACKGROUND: Circulating tumour cells (CTCs) are detectable in patients with NET and are accurate prognostic markers although the optimum threshold has not been defined. OBJECTIVE: To define optimal prognostic CTC threshold in pancreatic and midgut NET. PATIENTS AND METHODS: CellSearch was used to enumerate CTCs in 199 patients with metastatic pancreatic (PanNET) (90) or midgut NET (109). Patients were followed for progression free survival (PFS) and overall survival (OS) for a minimum of 3 years or until death. RESULTS: AUROC for progression at 12 months in PanNET and midgut NET identified the optimal CTC threshold as ≥1 and ≥2 respectively. In multivariate logistic regression analysis, these thresholds were predictive for 12 month progression with OR of 6.69 (p< 0.01) for PanNET and 5.88 (p<0.003) for midgut. The same thresholds were found to be optimal for predicting death at 36 months with an OR of 2.87 (p< 0.03) and 5.09 (p<0.005) for PanNET and midgut NET respectively. In multivariate Cox hazard regression analysis for PFS in PanNET, ≥ 1 CTC had HR 2.6 (p <0.01) whilst ≥ 2 CTCs had HR 2.25 (p < 0.01) in midgut NET. In multivariate analysis OS in PanNET, ≥ 1 CTC had HR 3.16 (p < 0.01) and in midgut NET, ≥ 2 CTCs had HR of 1.73 (p < 0.06). CONCLUSIONS: The optimal CTC threshold to predict PFS and OS in metastatic PanNET and midgut NET is 1 and 2, respectively. These thresholds can be used to stratify patients in clinical practice and clinical trials

Clinicopathological correlations of mesenteric fibrosis and evaluation of a novel biomarker for fibrosis detection in small bowel neuroendocrine neoplasms

PURPOSE: Mesenteric fibrosis (MF) in small intestinal neuroendocrine neoplasms (SINENs) is often associated with significant morbidity and mortality. The detection of MF is usually based on radiological criteria, but no previous studies have attempted a prospective, multidimensional assessment of mesenteric desmoplasia to determine the accuracy of radiological measurements. There is also a lack of non-invasive biomarkers for the detection of image-negative MF. METHODS: A multidimensional assessment of MF incorporating radiological, surgical and histological parameters was performed in a prospective cohort of 34 patients with SINENs who underwent primary resection. Pre-operative blood samples were collected in 20 cases to evaluate a set of five profibrotic circulating transcripts-the "fibrosome"-that is included as an "omic" component of the NETest. RESULTS: There was a significant correlation between radiological and surgical assessments of MF (p < 0.05). However, there were several cases of image-negative MF. The NETest-fibrosome demonstrated an accuracy of 100% for the detection of microscopic MF. CONCLUSIONS: The detection of MF by radiological criteria has limitations. The NETest-fibrosome is a promising biomarker for fibrosis detection and further validation of these results would be needed in larger, multicentre studies

High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms and Improved Prognostic Stratification With the New World Health Organization 2019 Classification A Validation Study From a Single-Institution Retrospective Analysis

Objectives: There is a pressing need to develop clinical management pathways for grade 3 (G3) gastroenteropancreatic neuroendocrine neoplasms (GEP NEN). Methods: We performed a retrospective study on patients with metastatic G3 GEP NEN. The relationship between baseline characteristics and progression-free survival and overall survival was analyzed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model. Results: We included 142 patients (74 well-differentiated neuroendocrine tumors [WDNETs], 68 poorly differentiated neuroendocrine carcinomas [PDNECs]). Patients with WDNET had prolonged survival compared with PDNEC (median, 24 vs 15 months, P = 0.0001), which persisted in both pancreatic and nonpancreatic cohorts. Well-differentiated morphology, Ki-67 <50% and positive somatostatin receptor imaging were independently associated with prolonged survival. Of the subgroup treated with first-line platinum-based chemotherapy, response rates were favorable (partial response, 47%; stable disease, 30%); there was no significant difference in response rates nor progression-free survival between WDNET and PDNEC despite significantly prolonged overall survival in the WDNET cohort. Conclusions: Our study corroborates the knowledge of 2 prognostically distinct subgroups within the World Health Organization 2019 G3 GEP NEN population, observed in both pancreatic and nonpancreatic gastrointestinal cohorts. Definitive management pathways are needed to reflect the differences between G3 WDNET and PDNEC