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Purpose Small intestinal neuroendocrine tumours (SI-NETs) are the most common malignancy of the small bowel. Curative treatment is surgical, with exploratory laparotomy considered the standard approach. This study aimed to assess the outcomes of minimally invasive surgery compared to open approach for SI-NETs at the Endocrine surgical unit at Uppsala University Hospital. Methods This retrospective cohort study included patients who underwent surgery for SI-NET between 2013 and 2023 at Uppsala University Hospital. Variables such as operative time, length of hospital stay, use of analgesia and radicality were compared between groups of patients operated on before and after 2019, when hand-port assisted laparoscopic surgery (HALS) for SI-NETs was introduced at our unit. Outcomes were further compared between open and hand-port assisted laparoscopic approaches. The primary outcome was the rate of radicality achieved for stage II-III patients. Secondary outcomes included operative time, the length of hospital stay and the use of epidural and patient-controlled analgesia. Results Of 97 patients, 58 (59.8%) underwent open surgery and 39 (40.2%) underwent hand-port assisted laparoscopic surgery. There was no significant difference in operative time (121 min [91.3-150.3] vs 108 min [83-141]), length of hospital stay, 6 days [4-7] vs 5 days [4-8]), and surgical radicality in patients with stage II-III, 85.2% vs 100%, (p = 0.079). 86.2% of patients with explorative laparotomy required epidural analgesia compared to only 23.1% with HALS (p < 0.001). Conclusion Hand-port assisted laparoscopic surgery of SI-NETs is a feasible approach that preserves radical resection while enhancing postoperative recovery, with a lower requirement of epidural analgesia.

Hereditary SDHB-mutant pheochromocytomas (PC) and paragangliomas (PG) are rare tumours with a high propensity to metastasize although their clinical behaviour is unpredictable. To characterize the genomic landscape of these tumours and identify metastasis biomarkers, we perform multi-omic analysis on 94 tumours from 79 patients using seven molecular methods. Sympathetic (chromaffin cell) and parasympathetic (non-chromaffin cell) PCPG have distinct molecular profiles reflecting their cell-of-origin and biochemical profile. TERT and ATRX-alterations are associated with metastatic PCPG and these tumours have an increased mutation load, and distinct transcriptional and telomeric features. Most PCPG have quiet genomes with some rare co-operative driver events, including EPAS1/HIF-2 alpha mutations. Two mechanisms of acquired resistance to DNA alkylating chemotherapies are identifiable; MGMT overexpression and mismatch repair-deficiency causing hypermutation. Our comprehensive multi-omic analysis of SDHB-mutant PCPG therefore identifies features of metastatic disease and treatment response, expanding our understanding of these rare neuroendocrine tumours.

Objective: Primary aldosteronism (PA) is a common cause of hypertension. It entails elevated morbidity and mortality that do not sufficiently improve with conventional antihypertensive therapy. Screening for PA by plasma aldosterone–renin ratio (ARR) enables discovery and specific treatment of affected patients. By screening primary care patients with hypertension and evaluating them further according to the Endocrine Society guidelines, we aimed to assess the prevalence of PA, the factors affecting biochemical diagnostics, and the outcome of lateralization studies and of specific treatment of the discovered PA cases.

Design, patients, and methods: Prospective evaluation of screening for PA was conducted in 1,181 patients. Screening by ARR was performed under current therapy, but without mineralocorticoid receptor antagonists (MRA), under normokalemia, and confirmed by the intravenous saline suppression test, SST#1. Those with results in a defined gray zone underwent therapy adjustment and then completed SST#2. Plasma aldosterone and ARR were compared under different stages of the diagnostic process. All patients with PA were offered adrenal venous sampling, or, in certain cases, adrenocortical-specific positron emission tomography. Lateralizing cases were offered laparoscopic adrenalectomy. Patients with bilateral disease were treated with MRA. Treatment results were assessed after a minimum of 6 months.

Results: A total of 53 discovered cases of (mostly mild) PA corresponded to its prevalence of 4.5%. Initial seated ARR was higher than recumbent ARR before SST#1. At SST#2, initial ARR and final aldosterone were higher than at SST#1. Localizing studies (accepted by 45 patients) found 14 lateralized cases. Of the 11 operated cases, 4 had aldosterone-producing adenoma, and the remainder had micro- and macronodular histopathology. A total of 31 patients had bilateral PA. Both surgical and conservative treatments were well tolerated and led to improved blood pressure and higher renin, indicating risk amelioration.

Conclusions: PA is prevalent among primary care patients with hypertension and can be screened for under current antihypertensive therapy. Aldosterone-producing adenoma was rare in this cohort. The study results support active screening of primary care patients with hypertension for PA in order to offer appropriate treatment options.

Background: Primary aldosteronism (PA) is the principal cause of secondaryhypertension; it leads to significantly elevated cardiovascular morbidity andmortality, but only a fraction of its cases ever get detected, partially due todiagnostic procedures that are difficult to perform and to interpret. Morestraightforward diagnostic methods are needed. Lateralized, or unilateral PA(uPA), is best treated by surgery. Bilateral PA (bPA) is treated medically.Aim: The aim of our study was to explore microRNA (miRNA) in peripheral bloodas markers of PA, uPA and bPA.

Methods: In groups of subjects with primary hypertension (HT, n = 11), bPA (n =12), and uPA (n = 16), peripheral serum was used for isolation of total RNA, librarypreparation, and NGS sequencing to achieve a comparative analysis of miRNAexpression. Five-fold cross-validation support vector machine learning (ML)models were employed to search for miRNA that could be used as markers ofPA and its forms.

Results: In our cohort of patients, the discovered combinations of miRNAs could,with a high level of accuracy, sensitivity, and specificity, characterize thedifference between HT and PA, as well as between a combined group of HT +bPA vs. uPA. The differentiating parameters were moderately good forcomparison of bPA vs. uPA.

Conclusion: Within our patient cohort, and using ML, the study identifieddistinctly different miRNA profiles between HT and PA, as well as between bPAand uPA. Further validation studies may lead to the emergence of a new tool forclinical diagnostics of PA.

Objective Hereditary pheochromocytoma (hPCC) commonly develops bilaterally, causing adrenal insufficiency when standard treatment, radical adrenalectomy (RA), is performed. Partial adrenalectomy (PA) aims to preserve adrenal function, but with higher recurrence rates. This study compares outcomes of PA versus RA in hPCC.Methods Patients with hPCC due to pathogenic variants in RET, VHL, NF1, MAX, and TMEM127 from 12 European centers (1974-2023) were studied retrospectively. Stratified analysis based on surgery type and initial presentation was conducted. The main outcomes included recurrence, adrenal insufficiency, metastasis, and mortality.Results The study included 256 patients (223 RA, 33 PA). Ipsilateral recurrence rates were 9/223 (4%) after RA versus 5/33 (15%) after PA (P = 0.02). Metastasis and mortality did not differ between groups. Overall, 103 patients (40%) underwent bilateral adrenalectomy either synchronously or metachronously (75 RA, 28 PA). Of these, 46% developed adrenal insufficiency after PA. In total, 191 patients presented with initial unilateral disease, of whom 50 (26%) developed metachronous contralateral disease, most commonly in RET, VHL, and MAX. In patients with metachronous bilateral disease, adrenal insufficiency developed in 3/4 (75%) when PA was performed as the first operation followed by RA, compared to 1/7 (14%) when PA was performed as the second operation after prior RA (P = 0.09).Results The study included 256 patients (223 RA, 33 PA). Ipsilateral recurrence rates were 9/223 (4%) after RA versus 5/33 (15%) after PA (P = 0.02). Metastasis and mortality did not differ between groups. Overall, 103 patients (40%) underwent bilateral adrenalectomy either synchronously or metachronously (75 RA, 28 PA). Of these, 46% developed adrenal insufficiency after PA. In total, 191 patients presented with initial unilateral disease, of whom 50 (26%) developed metachronous contralateral disease, most commonly in RET, VHL, and MAX. In patients with metachronous bilateral disease, adrenal insufficiency developed in 3/4 (75%) when PA was performed as the first operation followed by RA, compared to 1/7 (14%) when PA was performed as the second operation after prior RA (P = 0.09).Conclusion In patients with hPCC undergoing PA, local recurrence rates are higher than after RA, but metastasis and disease-specific mortality are similar. Therefore, PA seems a safe method to preserve adrenal function in patients with hPCC, in cases of both synchronous and metachronous bilateral disease, when performed as a second operation.

Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular may progress from a low/intermediate to a high-grade disease. The aim of this work was to understand the molecular mechanisms underlying metastatic progression as well as PanNET transformation from a low/intermediate to a high-grade disease. We performed multi-omics analysis (genome/exome sequencing, total RNA-sequencing and methylation array) of 32 longitudinal samples from six patients with metastatic low/intermediate grade PanNET. The clonal composition of tumour lesions and underlying phylogeny of each patient were determined with bioinformatics analyses. Findings were validated in post-alkylating chemotherapy samples from 24 patients with PanNET using targeted next generation sequencing. We validate the current PanNET evolutionary model with MEN1 inactivation that occurs very early in tumourigenesis. This was followed by pronounced genetic diversity on both spatial and temporal levels, with parallel and convergent tumour evolution involving the ATRX/DAXX and mechanistic target of the rapamycin (mTOR) pathways. Following alkylating chemotherapy treatment, some PanNETs developed mismatch repair deficiency and acquired a hypermutational phenotype. This was validated among 16 patients with PanNET who had high-grade progression after alkylating chemotherapy, of whom eight had a tumour mutational burden >50 (50%). In comparison, among the eight patients who did not show high-grade progression, 0 had a tumour mutational burden >50 (0%; odds ratio ‘infinite’, 95% confidence interval 1.8 to ‘infinite’, p = 0.02). Our findings contribute to broaden the understanding of metastatic/high-grade PanNETs and suggests that therapy driven disease evolution is an important hallmark of this disease.

Purpose

[¹¹C]Metomidate positron emission tomography (PET) is currently used for staging of adrenocortical carcinoma and for lateralization in primary aldosteronism (PA). Due to the short half-life of carbon-11 and a high non-specific liver uptake of [¹¹C]metomidate there is a need for improved adrenal imaging methods. In a previous pre-clinical study para-chloro-2-[¹⁸F]fluoroethyletomidate has been proven to be a specific adrenal tracer. The objective is to perform a first evaluation of para-chloro-2-[¹⁸F]fluoroethyletomidate positron emission computed tomography ([¹⁸F]CETO-PET/CT) in patients with adrenal tumours and healthy volunteers.

Methods

Fifteen patients underwent [¹⁸F]CETO-PET/CT. Five healthy volunteers were recruited for test-retest analysis and three out of the five underwent additional [¹⁵O]water PET/CT to measure adrenal blood flow. Arterial blood sampling and tracer metabolite analysis was performed. The kinetics of [¹⁸F]CETO were assessed and simplified quantitative methods were validated by comparison to outcome measures of tracer kinetic analysis.

Results

Uptake of [¹⁸F]CETO was low in the liver and high in adrenals. Initial metabolization was rapid, followed by a plateau. The kinetics of [¹⁸F]CETO in healthy adrenals and all adrenal pathologies, except for adrenocortical carcinoma, were best described by an irreversible single-tissue compartment model. Standardized uptake values (SUV) correlated well with the uptake rate constant K₁. Both K₁ and SUV were highly correlated to adrenal blood flow in healthy controls. Repeatability coefficients of K₁, SUV_65–70, and SUV₁₂₀ were 25, 22, and 17%.

Conclusions

High adrenal uptake combined with a low unspecific liver uptake suggests that ¹⁸F]CETO is a suitable tracer for adrenal imaging. Adrenal SUV, based on a whole-body scan at 1 h p.i., correlated well with the net uptake rate K_i.

Trial registration

ClinicalTrials.gov, NCT05361083 Retrospectively registered 29 April 2022. at, https://clinicaltrials.gov/ct2/show/NCT05361083

Core needle biopsy (CNB) has been used with caution in pheochromocytoma and paraganglioma (PPGL) due to concerns about catecholamine-related complications. While it is unclear what scientific evidence supports this claim, it has limited the acquisition of biological samples for diagnostic purposes and research, especially in metastatic PPGL. We performed a systematic review and individual patient meta-analysis to evaluate the risk of complications after CNB in PPGL patients. The primary and secondary objectives were to investigate the risk of death and the occurrence of complications requiring intervention or hospitalization, respectively. Fifty-six articles describing 86 PPGL patients undergoing CNB were included. Of the patients (24/71), 34% had metastases and 53.4% (31/58) had catecholamine-related symptoms before CNB. Of the patients (14/41), 34.1% had catecholamine excess testing prior to the biopsy. No CNB-related deaths were reported. Four patients (14.8%, 4/27) experienced CNB-related complications requiring hospitalization or intervention. One case had a temporary duodenal obstruction caused by hematoma, two cases had myocardial infarction, and one case had Takotsubo cardiomyopathy. Eight patients (32%, 8/25) had CNB-related catecholamine symptoms, mainly transient hypertension, excessive diaphoresis, tachycardia, or hypertensive crisis. The scientific literature does not allow us to make any firm conclusion on the safety of CNB in PPGL. However, it is reasonable to argue that CNB could be conducted after thorough consideration, preparation, and with close follow-up for PPGL patients with a strong clinical indication for such investigation.

Longitudinal changes in pancreatic neuroendocrine tumor (panNET) cell proliferation correlate with fast disease progression and poor prognosis. The optimal treatment strategy for secondary panNET grade (G)3 that has progressed from a previous low- or intermediate-grade to high-grade panNET G3 is currently unknown. This was a single-center retrospective cohort study aimed to characterize treatment patterns and outcomes among patients with secondary panNET-G3. Radiological responses were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. A total of 22 patients were included and received a median of 2 (range, 1–4) treatment lines in 14 different combinations. Median overall survival (OS) was 9 months (interquartile range (IQR): 4.25–17.5). For the 15 patients who received platinum–etoposide chemotherapy, median OS was 7.5 months (IQR: 3.75–10) and median progression-free survival (PFS) was 4 months (IQR: 2.5–5.5). The 15 patients who received conventional panNET therapies achieved a median OS of 8 months (IQR: 5–16.75) and median PFS was 5.5 months (IQR: 2.75–8.25). We observed one partial response on ¹⁷⁷Lu DOTA-TATE therapy. In conclusion, this hypothesis-generating study failed to identify any promising treatment alternatives for patients with secondary panNET-G3. This demonstrates the need for both improved biological understanding of this particular NET entity and for designing prospective studies to further assess its treatment in larger patient cohorts.