Presentation and management of patients with adrenal masses:a large tertiary centre experience

Background: Adrenal masses are found in up to 5-7% of adults. The 2016 European guidelines on the management of adrenal incidentalomas have standardised the workup of these patients, but evidence of their impact on clinical practice is lacking.Methods: Retrospective review of clinical presentation, radiological characteristics, and final diagnosis of a large cohort of patients with adrenal masses referred to a tertiary care centre 1998 to 2022. Sub-analysis compares outcomes before and after implementing the 2016 guidelines.Results: 1397 patients (55.7% women; median age 60 years [interquartile range, IQR, 49-70]) were included. Incidental discovery was the most frequent mode of presentation (63.7%) and 30.6% of patients had masses ≥4 cm (median 2.9 cm [IQR, 1.9-4.7]). Unenhanced computed tomography (CT) Hounsfield Units (HU) were available for 763 patients; of these, 32.9% had heterogeneous masses or &gt;20 HU. The most common diagnoses were adrenocortical adenoma (ACA, 56.0%), phaeochromocytoma (12.7%), adrenocortical carcinoma (10.6%), and metastases (5.7%). At multivariable analysis, significant predictors of malignancy included HU &gt;20 or heterogeneous density (Odds Ratio, OR 28.40), androgen excess (OR 27.67), detection during cancer surveillance (OR 11.34), size ≥4 cm (OR 6.11) and male sex (OR 3.06). After implementing the 2016 guidelines, the number of adrenalectomies decreased (6.1% pre-2016 vs. 4.5% post-2016) and the number of patients discharged increased (4.4% pre-2016 vs. 25.3% post-2016) for benign non-functioning adrenal masses. Conclusion: Implementing the 2016 guidelines positively impacted clinical practice, reducing unnecessary surgeries and increasing the discharge rate for benign adrenal masses, thereby preserving healthcare resources and patient burden. <br/

Inflammation-based scores in patients with pheochromocytoma

Background: Pheochromocytoma is associated with systemic inflammation, but the underlying mechanisms are unclear. Therefore, we investigated the relationship between plasma metanephrine levels and haematological parameters – as a surrogate of inflammation – in patients with pheochromocytoma and the influence of preoperative α-blockade treatment.Design and Methods: We retrospectively studied 68 patients with pheochromocytoma who underwent adrenalectomy (median age 53 years, 64.7% females) and two control groups matched for age, sex, and body mass index (BMI): 68 patients with non-functioning adrenocortical tumors (NFAT) and 53 with essential hypertension (EAH). The complete blood count (CBC) and several inflammation-based scores [Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR), Systemic-Immune-Inflammation Index (SII), Prognostic-Nutrition Index (PNI)] were assessed in all patients and, in a subset of pheochromocytomas, after adrenalectomy (n=26) and before and after preoperative α-blockade treatment (n=29).Results: A higher inflammatory state, as indicated by both CBC and inflammation-based scores, was observed in patients with pheochromocytoma compared to NFAT and EAH. Plasma metanephrine levels showed a positive correlation with NLR (r=0.4631), PLR (r=0.3174), SII (r=0.3709), and a negative correlation with LMR (r=0.4368) and PNI (r=0.3741), even after adjustment for age, sex, ethnicity, BMI and tumor size (except for PLR). After adrenalectomy, we observed a reduction in NLR (p=0.001), PLR (p=0.003), SII (p=0.004) and a concomitant increase in LMR (p=0.0002). Similarly, α-blockade treatment led to a reduction in NLR (p=0.007) and SII (p=0.03).Conclusions: Inflammation-based scores in patients with pheochromocytoma showed pro-inflammatory changes that correlated with plasma metanephrine levels and are ameliorated by adrenalectomy and α-blockade

Pheochromocytomas Most Commonly Present As Adrenal Incidentalomas:A Large Tertiary Center Experience

Context: Pheochromocytomas are increasingly diagnosed in incidentally detected adrenal masses. However, the characteristics of incidental pheochromocytomas are unclear.Objective: We aimed to assess the proportion and clinical, biochemical, radiological, genetic, histopathological, and follow-up characteristics of incidental pheochromocytomas.Methods: A retrospective review was conducted of patients with pheochromocytoma seen between January 2010 and October 2022 at a large UK tertiary care center. The diagnosis was confirmed histologically or by the combined presence of increased plasma and/or urinary metanephrines (MN), indeterminate adrenal mass on cross-sectional imaging, and metaiodobenzylguanidine avidity.Results: We identified 167 patients with pheochromocytoma; 144 (86.2%) underwent adrenalectomy, for 23 (13.8%) surgery was either awaited, deemed unsuitable due to frailty or other metastatic malignancy, or declined by the patients. Excluding pheochromocytomas diagnosed via screening genetically predisposed individuals (N = 20), 37 of 132 (28.0%) presented with adrenergic symptoms and/or uncontrolled hypertension, while 91 of 132 (69.0%) patients presented with an incidentally detected adrenal mass. Incidentally detected patients were older (median age 62 years) than those detected due to clinical suspicion (aged 42 years) or after genetic screening (aged 33 years) (all P &lt; .05). Incidentally detected pheochromocytomas were smaller (median 42 mm) than tumors detected due to adrenergic symptoms/uncontrolled hypertension (60 mm), but larger than tumors identified by genetic screening (30 mm) (all P &lt; .05). Increased MN excretion showed a similar pattern (symptomatic/uncontrolled hypertension &gt; incidental &gt; genetic screening) (all P &lt; .05). Hereditary predisposition was detected in 20.4% of patients (incidental, 15.3%; symptomatic/uncontrolled hypertension, 42.9%).Conclusion: The majority of pheochromocytomas are diagnosed incidentally and have distinct clinical, radiological, biochemical, and genetic features. Their detection at older age but smaller size may point to a different underlying tumor biology

Circulating cell-free DNA-based biomarkers for prognostication and disease monitoring in adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a rare aggressive cancer with heterogeneous behaviour. Disease surveillance relies on frequent imaging, which comes with significant radiation exposure. The aim of the study was to investigate the role of circulating cell-free DNA (ccfDNA)-related biomarkers (BM) for prognostication and monitoring of ACC.We investigated 34 patients with ACC and 23 healthy subjects (HS) as controls. ccfDNA was extracted by commercial kits and ccfDNA concentrations quantified by fluorimeter (BM1). Targeted sequencing was performed using a customised panel of 27 ACC-specific genes. Leucocyte DNA was used to discriminate somatic variants (BM2), while tumour DNA was sequenced in 22/34 cases for comparison. Serial ccfDNA samples were collected during follow-up in 19 ACC patients (median period 9 months) and analysed in relationship with standard radiological imaging.ccfDNA concentrations were higher in ACC than HS (mean±SD, 1.15±1.56 vs 0.05±0.05 ng/µl, P&lt;0.0001), 96% of them being above the cut-off of 0.146 ng/µl (mean HS+2SD, positive BM1). At ccfDNA sequencing, 47% of ACC showed at least one somatic mutation (positive BM2). A combined ccfDNA-BM score was strongly associated with both progression-free and overall survival (HR=2.63, 95%CI=1.13-6.13, P=0.010, and HR=5.98, 95%CI=2.29-15.6, P=0.0001, respectively). During disease monitoring, positive BM2 showed the best specificity (100%) and sensitivity (67%) to detect ACC recurrence or progress compared to BM1.In conclusion, ccfDNA-related BMs are frequently detected in ACC patients and represent a promising, minimally invasive tool to predict clinical outcome and complement surveillance imaging. Our findings will be validated in a larger cohort of ACCs with long-term follow-up

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Spatio-temporal analyses of cropland degradation in the irrigated lowlands of Uzbekistan using remote-sensing and logistic regression modeling

Advancing land degradation in the irrigated areas of Central Asia hinders sustainable development of this predominantly agricultural region. To support decisions on mitigating cropland degradation, this study combines linear trend analysis and spatial logistic regression modeling to expose a land degradation trend in the Khorezm region, Uzbekistan, and to analyze the causes. Time series of the 250-m MODIS NDVI, summed over the growing seasons of 2000–2010, were used to derive areas with an apparent negative vegetation trend; this was interpreted as an indicator of land degradation. About one third (161,000 ha) of the region’s area experienced negative trends of different magnitude. The vegetation decline was particularly evident on the low-fertility lands bordering on the natural sandy desert, suggesting that these areas should be prioritized in mitigation planning. The results of logistic modeling indicate that the spatial pattern of the observed trend is mainly associated with the level of the groundwater table (odds = 330 %), land-use intensity (odds = 103 %), low soil quality (odds = 49 %), slope (odds = 29 %), and salinity of the groundwater (odds = 26 %). Areas, threatened by land degradation, were mapped by fitting the estimated model parameters to available data. The elaborated approach, combining remote-sensing and GIS, can form the basis for developing a common tool for monitoring land degradation trends in irrigated croplands of Central Asia