BackgroundPheochromocytomas and paragangliomas (PPGLs) are rare and mostly non-metastatic tumors originating from adrenal medulla and paraganglia. Metastatic PGLs have a worse prognosis, but currently, there are no established criteria to determine PPGL metastatic potential. AimThe aim of this study was to investigate whether SDHB and CDK1 expression is associated with metastatic capacity in PPGL. Material and methodsA tissue microarray (TMA) was constructed from 175 tumors from a total of 149 unique PPGL patients treated at Sahlgrenska University Hospital. SDHB, CDK1, and proliferation index Ki-67 were assessed and correlated to metastatic capacity defined as a confirmed metastatic event. ResultsNegative SDHB expression was more common in patients with metastatic PPGL and displayed a trend toward lower overall survival and correlation with higher Ki-67%. High CDK1 expression was not associated with any of the parameters mentioned above. ConclusionNegative SDHB expression but not high CDK1 expression is associated with metastatic capacity in PPGL.

INTRODUCTION:Several ultrasound risk stratification systems have been developed mainly with the aim of identifying benign lesions and thereby avoiding unnecessary fine needle aspiration (FNA) cytology. This randomized controlled trial assessed whether the use of an ultrasound risk stratification system improved identification of lesions requiring surgical treatment. MATERIAL AND METHODS:This was a multi-centre, unblinded and interventional randomized trial comparing selective and non-selective FNA in Western Sweden. Patients were randomized to either selective cytology according to EU-TIRADS criteria or non-selective cytology. RESULTS:A total of 195 patients were included, 93 in the non-selective group and 102 in the selective group, between February 2022 and December 2023. The frequency of nodules with Bethesda category IV-VI (primary outcome) was higher in the selective group (26% versus 13%, P = 0.039). The rate of malignancy (secondary outcome) was similar in both groups; 8% in the selective group versus 5% in the non-selective group. The frequency of patients undergoing cytology was reduced from 83% in the non-selective group to 71% in the selective group. Considering only patients with at least one nodule yielding EU-TIRADS 3 or higher, cytology was omitted in 7% of patients in the selective group, whereas no cytology was omitted in the non-selective group. CONCLUSION:This randomized controlled trial supports the use of EU-TIRADS to correctly select neoplastic nodules for FNA without missing thyroid cancer. The proportion of patients where FNA can be safely omitted using EU-TIRADS may however be exaggerated, indicating a need for further refinement of risk stratification systems for thyroid cancer diagnostics.The trial was registered at ClinicalTrials.gov (NCT05583097).

Objective: Evaluate the impact of adrenalectomy on metabolic parameters and quality of life (QoL) in patients with mild autonomous cortisol secretion (MACS). Method: A multicenter prospective randomized clinical trial compared adrenalectomy with conservative management. Metabolic parameters and QoL were assessed at baseline and after 2 years. Results: Forty-three MACS patients with a single adrenal adenoma were randomized to either adrenalectomy (n = 21) or conservative management (n = 22). At baseline, 33 patients had hypertension, 13 had type 2 diabetes (T2D), 18 used statins, and nine patients had osteoporosis. After 2 years, normalization of cortisol levels post 1 mg dexamethasone suppression test was achieved in 19/21 adrenalectomy patients compared to 2/22 patients in the conservative group (P < 0.01). All adrenalectomy patients had a significant increase in ACTH and DHEA-S. Office blood pressure and daily defined doses of antihypertensives (DDD) improved in nine of 12 adrenalectomy patients versus four of 15 conservatively treated patients (P = 0.01). Using 24 h blood pressure and DDD, improvement rates were five of 11 in the adrenalectomy group and six of 15 in the conservative group (P = 0.78). Among patients without T2D, the 120 min glucose level during oral glucose tolerance test was lower in the adrenalectomy group (6.2 vs 7.3 mmol/L, P = 0.04), but within-group changes were not different (P = 0.76). There were no statistically significant differences in QoL between the two groups. Conclusion: Adrenalectomy showed trends toward improvement in office blood pressure and glucose metabolism in MACS, suggesting possible reduction in cardiovascular risk and metabolic complications.

Disclosure: G. Ueland: None. O. Ragnarsson: None. A. Heie: None. A. Kjellbom: None. O. Lindgren: None. A. Muth: None. F. Palazzo: None. P.L. Poulsen: None. L. Rolighed: None. H. Thordarson: None. F. Wernig: None. A. Bergenfelz: None. Objective: To evaluate the impact of adrenalectomy on blood pressure and metabolic parameters in patients with mild autonomous cortisol secretion (MACS). Method: A multicenter prospective randomized clinical trial was conducted, comparing adrenalectomy with conservative management. Blood pressure and metabolic parameters were assessed at baseline and after two years. Results: Forty-three patients with MACS and a single adrenal adenoma were randomized to either adrenalectomy (n=21) or conservative management (n=22). At baseline, 33 patients had hypertension, 13 had type 2 diabetes (T2D), 18 were treated with statins, and 9 patients had established osteoporosis. At two-year follow-up, normalization of cortisol levels post 1mg dexamethasone suppression test (DST) was achieved in 19/21 of adrenalectomy patient compared to 2/22 patients in the conservative group (p<0.01). All patients in the adrenalectomy group had a significant increase in ACTH and DHEA-S. Office systolic blood pressure was significantly reduced in the adrenalectomy group (125 vs 140 mmHg, p=0.03), and a higher proportion of patients in the adrenalectomy group had an improved blood pressure compared with those not operated (14/21 vs. 4/22 patients respectively, p=0.03). The relative risk of improvement of blood pressure in the adrenalectomy group was 7.20 (95% CI 1.53-33.8) compared with the conservative group. Among patients without T2D, the 120-minute glucose level during an oral glucose tolerance test was significantly lower in the adrenalectomy group compared with controls (6.2 vs. 7.3 mmol/L, p=0.04). Conclusion: Adrenalectomy significantly improved blood pressure and glucose metabolism in patients with MACS, suggesting that surgery may reduce cardiovascular risk in patients with MACS and metabolic complications. Presentation: Sunday, July 13, 2025

Squamous cell carcinoma (SCC) of the thyroid is a rare tumor that is classified as an anaplastic thyroid cancer (ATC) due to its similar unresponsiveness to chemoradiotherapy and an outstandingly poor prognosis. Due to its rarity, current knowledge about this tumor is mostly based on single-case reports. The tumor-cell-origin and molecular pathogenesis remain unclear, although the presence of BRAF mutations in some cases suggest it may evolve from papillary thyroid carcinoma (PTC). Here we provide direct evidence of derivation of SCC of the thyroid from PTC, based on a unique combination of likely pathogenic mutations in KEAP1 , STK11 ( LKB1 ), and RB1 found in both tumor components, along with loss of one copy of chromosome 11 and additional somatic mutations in the SCC tumor. Transdifferentiation from PTC to SCC was also evident by immunohistochemistry. Out of eight attempted patient-derived xenografts (PDX) from advanced thyroid cancers, only one derived from thyroid SCC successfully engrafted in immunodeficient NOG mice. Untreated PDXs showed high Ki67 indices but did not reproduce the conspicuous stromal invasion of CDH1 low /SNAI2 + /CDH2 + cells that characterized the primary tumor. Based on the mutation profile ( NFE2L2 , PIK3CA , CDKN2A , and TP53 ), experiments were designed to evaluate targeted drug therapy using third-passage PDX transplants. The combination of TRK and PI3K inhibitors, cabozantinib and GDC-0326, additively reduced PDX growth by nearly 90%. Remarkably, CB-839 (telaglenastat), a glutaminase inhibitor targeting metabolic rewiring downstream of NRF2 activation, was equally effective. Both combined treatment with cabozantinib + GDC-0326 and CB-839 monotherapy diminished the expression of NQO1, an NRF2 transcriptional target, in tumor cells. Glutaminase inhibition further promoted squamous differentiation in engrafted tumors. Both investigated SCC tumors were negative for BRAFV600E or any other common driver mutation of thyroid cancer. Collectively, these findings indicate that aberrant activation of the KEAP1/NRF2 pathway due to somatic mutations is a previously unrecognized feature of thyroid SCC and suggest that glutaminase inhibition may serve as a potential therapeutic option for this subgroup of ATC patients. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Disease status in relation to ctDNA levels of tumor-specific and TKI resistance mutations. Black and gray bars indicate treatment duration. Disease status according to imaging. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

IntroductionThe EU-Thyroid Imaging Report and Data System (EU-TIRADS) allows for selective fine needle aspiration cytology (FNAC). In 2017, EU-TIRADS was implemented as part of a nation-wide standardized care bundle for thyroid cancer in Western Sweden with a population of approximately 1.7 million. The objective of this study was to investigate the clinical value of EU-TIRADS attempting to reduce the number of unnecessary FNAC in referred patients with thyroid nodules.Material and MethodsThe study cohort consisted of all patients referred to Sahlgrenska University Hospital due to a palpable, newly detected or growing thyroid nodules or a PET positive finding for examination with thyroid ultrasound and selective cytology between 2018 and 2022. Medical records on EU-TIRADS classification, corresponding FNAC results and histopathological diagnosis were retrospectively collected. Adherence to EU-TIRADS guidelines, use of selective FNAC and rate of malignancy (ROM) in patients undergoing surgery were assessed.ResultsIn total, 1246 thyroid nodules in 990 patients were evaluated. The distribution of EU-TIRADS 2-5 n(%) was: 63(5); 462(37); 443(36); 278(22). FNAC was omitted in 7% of the investigated patients. FNAC was performed in 124 nodules (10%) despite not fulfilling EU-TIRADS criteria or absence of PET positive findings. ROM was 33% and 1/50 in patients undergoing “unnecessary” FNAC.DiscussionImplementation of EU-TIRADS in routine management of thyroid nodules led to selective use of FNAC, but the clinical impact was limited. This study provides real-world data on the value and magnitude of diagnostic improvement by implementing EU-TIRADS in clinical practice.

Patient demographics and tumor details.

ctDNA characteristics in 32 patients diagnosed with GISTs. A, Detailed overview of tumor-specific ctDNA and clinical parameters. ctDNA status in relation to surgery is shown for each patient. Days at the bottom relates to surgical treatment. Red and black samples indicate samples being ctDNA positive and negative, respectively. Gray samples are negative samples, but with less than 50 cfDNA molecules detected. Patients with metastatic disease are shown as bold patient identification (ID). Information about Ki-67, tumor size, TKI treatment, and last known disease status is shown. NED, no evidence of disease; AWD, alive with disease; DBD, dead by disease. B, Tumor cell proliferation rates versus presence of ctDNA. Patients with at least one ctDNA-positive sample were considered positive. Data are shown in log10 scale. n = 32; *, P ≤ 0.05; Student t test on log-transformed values. C, Tumor size versus presence of ctDNA. Patients with at least one ctDNA-positive samples were considered positive. n = 32; **, P ≤ 0.01, Student t test. D, Total ctDNA levels versus presence of ctDNA in each sample. Data are shown in log10 scale. Values out of range (OOR) was in statistical calculation replaced with the value 0.39, which is the lowest detected value divided by two, n = 161. n.s., not significant, Student t test on log-transformed values. E, Type of tumor-specific mutation detected as ctDNA. Frequency of single-nucleotide variations (SNP) and indel. n = 32; **, P ≤ 0.01; Fisher exact test.

Supplementary Table S1 shows detailed sample characteristics. Supplementary Table S2 shows sequences of synthetic spike-in DNA. Supplementary Table S3 shows assay sequences. Supplementary Table S4 shows details related to surgical treatment. Supplementary Table S5 shows resistance events of tyrosine kinase inhibitors in the COSMIC database. Supplementary Table S6 shows patient characteristics. Supplementary Table S7 shows concordance between imaging and ctDNA.

Number of patients with tumor-specific mutations detected in cfDNA.

In this large population-based matched cohort study, patients with primary aldosteronism were at increased risk of hip fracture, particularly subgroups traditionally considered at higher risk of osteoporosis such as women, patients older than 56 years at diagnosis, patients with established cardiovascular disease at diagnosis, and patients treated with MRA. Previous studies suggest that primary aldosteronism (PA) is associated with dysregulated bone homeostasis. The aim of this study was to evaluate the incidence of hip fractures in patients with PA. We studied a nationwide cohort of 2419 patients with PA (1997–2019) and 24 187 age and sex matched controls from the general population. Hip fractures were identified by ICD codes in the Swedish National Patient Register. We estimated hazard ratios (HRs) for incident hip fractures, adjusted for prior fractures, socioeconomic factors, diabetes, osteoporosis, hyperparathyroidism, and cardiovascular disease (CVD). Pairwise subgroup comparisons were performed by age (18–56 and > 56 years), sex, CVD at baseline, and treatment for PA. During a mean follow up of 8 ± 5 years, 64 (2.6

Purpose Data guiding management of pheochromocytoma and paraganglioma (PPGL) in pregnant women is limited, and long-term effects on the child are unknown. The aim of this retrospective registry-based case-cohort study was to assess how maternal PPGL and treatment impacts maternal and fetal outcome, including long-term outcome for the child. The main outcomes were maternal and fetal mortality and morbidity at delivery and relative healthcare consumption in children born by mothers with PPGL during pregnancy. Methods The National Birth Register identified 4,390,869 pregnancies between 1973–2015. Data was crosslinked with three Swedish national registers to identify women diagnosed with pheochromocytoma or paraganglioma within one year before or after childbirth. Hospital records were reviewed and register data was collected for five age-matched controls for each child until age 18. Results 21 women and 23 children were identified (incidence 4.8/1.000.000 births/year), all women with adrenal pheochromocytomas (Pc). The majority (71%) were diagnosed post-partum. Nine women (43%) were hypertensive during pregnancy. Preterm delivery was more common in Pc patients compared to controls (30% vs 6%, p < 0.001). There was no maternal or fetal mortality. Timing of tumor removal did not affect gestational weight or APGAR scores. There was no observed difference in hospital admissions between children affected by maternal Pc and controls. Conclusion Pc was commonly diagnosed after delivery and raised the risk of pre-term delivery, suggesting a need for an increased awareness of this diagnosis. However, reassuringly, there was no fetal or maternal mortality or any observed long-term impact on the children.

Supplementary Figure S1 shows assessment of quality controls when analyzing cfDNA. Supplementary Figure S2 shows a representative electropherogram of assay performance Supplementary Figure S3 shows a the amount of cfDNA in plasma for different risk groups and sample types.

Experimental overview and primary tumor mutations. A, Consort diagram of the eligible patient cohort and study enrollment. The cohort consisted of all patients treated at the Deparment of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden, between November 2016 and March 2019. Forty-three of the 91 initially included patients were excluded. Of the excluded patients, nine patients revealed other diagnoses than GIST by pathology analysis, five patients displayed neither KIT nor PDGFRA mutations (wild-type) in tumor biopsy, three patients had no mutation analysis performed on the tumor material and 26 patients were enrolled after surgery and hence excluded. Thirty-two of 48 patients that were included before surgery were finally analyzed for the presence of ctDNA. Of the 16 additionally excluded patients, five patients were excluded, because sampling was not possible during surgery, samples from two patients were used in workflow optimization and nine patients were excluded as their tumor-specific mutations were not targeted by the developed assays. B, Five SiMSen-Seq assays were used to assess each patient, including one tumor-specific assay targeting the mutation identified in the tumor biopsy combined with four resistance assays. Blood samples were collected during routine visit before and after surgery. At surgery, samples were collected at start of surgery, during mobilization of the tumor and at closure. Extracted cfDNA was analyzed by SiMSen-Seq. Several quality controls were used to monitor the experimental performance. C, Assay overview and detected mutations in tumor biopsy. The length and exon position of each assay are shown. All types of mutations and their position are indicated for all 32 patients. SNV, single-nucleotide variant; indel, insertion or deletion mutation.

Abstract The majority of patients diagnosed with advanced gastrointestinal stromal tumors (GISTs) are successfully treated with a combination of surgery and tyrosine kinase inhibitors (TKIs). However, it remains challenging to monitor treatment efficacy and identify relapse early. Here, we utilized a sequencing strategy based on molecular barcodes and developed a GIST-specific panel to monitor tumor-specific and TKI resistance mutations in cell-free DNA and applied the approach to patients undergoing surgical treatment. Thirty-two patients with GISTs were included, and 161 blood plasma samples were collected and analyzed at routine visits before and after surgery and at the beginning, during, and after surgery. Patients were included regardless of their risk category. Our GIST-specific sequencing approach allowed detection of tumor-specific mutations and TKI resistance mutations with mutant allele frequency < 0.1%. Circulating tumor DNA (ctDNA) was detected in at least one timepoint in nine of 32 patients, ranging from 0.04% to 93% in mutant allele frequency. High-risk patients were more often ctDNA positive than other risk groups (P < 0.05). Patients with detectable ctDNA also displayed higher tumor cell proliferation rates (P < 0.01) and larger tumor sizes (P < 0.01). All patients who were ctDNA positive during surgery became negative after surgery. Finally, in two patients who progressed on TKI treatment, we detected multiple resistance mutations. Our data show that ctDNA may become a clinically useful biomarker in monitoring treatment efficacy in patients with high-risk GISTs and can assist in treatment decision making.

Background Small intestinal neuroendocrine tumors (SI-NET) are highly differentiated and genetically stable malignant tumors, yet they often present with advanced metastatic spread at the time of diagnosis. In contrast to many other types of malignant tumors, primary SI-NET are often asymptomatic and typically smaller in size compared to adjacent lymph node metastases. This study explores the hypothesis that stimulating the chemosensing olfactory receptor 51E1 (OR51E1) decreases SI-NET proliferation suggesting a mechanism that explains a difference in proliferative rate based on tumor location. Methods Clinical data was used to address difference in tumor size depending on location. A SI-NET tissue microarray was used to evaluate expression of OR51E1 and olfactory marker protein (OMP). Primary cultured tumor cells from 5 patients were utilized to determine the effect of OR51E1 agonist nonanoic acid on metabolic activity. The SI-NET cell line GOT1 was used to determine effects of nonanoic acid on the transcriptome as well as long-term effects of nonanoic acid exposure with regards to cell proliferation, serotonin secretion, alterations of the cell-cycle and morphology. Results Tumor size differed significantly based on location. OR51E1 and OMP were generally expressed in SI-NET. Primary SI-NET cells responded to nonanoic acid with a dose dependent altered metabolic activity and this was replicated in the GOT1 cell line but not in the MCF10A control cell line. Nonanoic acid treatment in GOT1 cells upregulated transcripts related to neuroendocrine differentiation and hormone secretion. Long-term nonanoic acid treatment of GOT1 cells decreased proliferation, induced senescence, and altered cell morphology. Conclusion Our results raise the possibility that exposure of intraluminal metabolites could represent a mechanism determining aspects of the SI-NET tumor phenotype. However, we could not causally link the observed effects of nonanoic acid exposure to the OR51E1 receptor.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. PGLs can further be divided into sympathetic (sPGLs) and head-and-neck (HN-PGLs). There are virtually no treatment options, and no cure, for metastatic PCCs and PGLs (PPGLs). Here, we composed a tissue microarray (TMA) consisting of 149 PPGLs, reflecting clinical features, presenting as a useful resource. Mutations in the pseudohypoxic marker HIF-2α correlate to an aggressive tumor phenotype. We show that HIF-2α localized to the cytoplasm in PPGLs. This subcompartmentalized protein expression differed between tumor subtypes, and strongly correlated to proliferation. Half of all sPGLs were metastatic at time of diagnosis. Cytoplasmic HIF-2α was strongly expressed in metastatic sPGLs and predicted poor outcome in this subgroup. We propose that higher cytoplasmic HIF-2α expression could serve as a useful clinical marker to differentiate paragangliomas from pheochromocytomas, and may help predict outcome in sPGL patients.

Abstract Background Techniques for autofluorescence have been introduced to visualize the parathyroid glands during surgery and to reduce hypoparathyroidism after thyroidectomy. Methods This parallel multicentre RCT investigated the use of Fluobeam® LX to visualize the parathyroid glands by autofluorescence during total thyroidectomy compared with no use. There was no restriction on the indication for surgery. Patients were randomized 1 : 1 and were blinded to the group allocation. The hypothesis was that autofluorescence enables identification and protection of the parathyroid glands during thyroidectomy. The primary endpoint was the rate of low parathyroid hormone (PTH) levels the day after surgery. Results Some 535 patients were randomized, and 486 patients received an intervention according to the study protocol, 246 in the Fluobeam® LX group and 240 in the control group. Some 64 patients (26.0 per cent) in the Fluobeam® LX group and 77 (32.1 per cent) in the control group had low levels of PTH after thyroidectomy (P = 0.141; relative risk (RR) 0.81, 95 per cent c.i. 0.61 to 1.07). Subanalysis of 174 patients undergoing central lymph node clearance showed that 15 of 82 (18 per cent) in the Fluobeam® LX group and 31 of 92 (33 per cent) in the control group had low levels of PTH on postoperative day 1 (P = 0.021; RR 0.54, 0.31 to 0.93). More parathyroid glands were identified during operation in patients who had surgery with Fluobeam® LX, and fewer parathyroid glands in the surgical specimen on definitive histopathology. No specific harm related to the use of Fluobeam® LX was reported. Conclusion The use of autofluorescence during thyroidectomy did not reduce the rate of low PTH levels on postoperative day 1 in the whole group of patients. It did, however, reduce the rate in a subgroup of patients. Registration number: NCT04509011 (http://www.clinicaltrials.gov).

Introduction Treatment strategies for primary aldosteronism (PA) include unilateral adrenalectomy and medical treatment with mineralocorticoid receptor (MR) antagonists. Whether these two different treatment strategies are comparable in mitigating the detrimental effect of PA on outcomes is still debated.Objectives The primary aim of this systematic review is to identify, appraise and synthesise existing literature comparing clinical outcomes after treatment in patients with PA.Methods and analysis A systematic and comprehensive search will be performed using PubMed, Web of Science and EMBASE, for studies published until December 2022. Observational and interventional studies will be eligible for inclusion. The quality of observational studies will be assessed using the Newcastle–Ottawa Scale, while interventional studies will be assessed using the Cochrane Effective Practice Organization of Care tool. The collected evidence will be narratively synthesised. We will perform meta-analysis to pool estimates from studies considered to be homogeneous. Reporting of the systematic review and meta-analysis will be in accordance with the Meta-analysis of Observational Studies in Epidemiology Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines.Ethics and dissemination As this study is based solely on the published literature, no ethics approval is required. This review will aim to provide some estimates on outcomes, including survival, rates of clinical and biochemical control, cardiovascular and cerebrovascular events, as well as data on quality of life and renal function, in patients with PA treated surgically or with MR antagonists. The study findings will be presented at scientific meetings and will be published in an international peer-reviewed scientific journal.PROSPERO registration number CRD42022362506.