Elevated sphingosine-1-phosphate lyase leads to increased metabolism and reduced survival in adrenocortical carcinoma.

OBJECTIVE: Adrenocortical carcinomas (ACCs) are invasive tumours arising in the adrenal cortex, and steroidogenic tumours are associated with worse prognostic outcomes. Loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1) cause primary adrenal insufficiency and as a key degradative enzyme in the sphingolipid pathway, SGPL1 also influences the balance of pro-proliferative and pro-apoptotic sphingolipids. We, therefore, hypothesized increased SGPL1 may be linked to increased disease severity in ACC. DESIGN: Analyse SGPL1 expression impact on patient survival and adrenal cancer cell phenotype. We analysed two ACC cohorts with survival and corresponding transcriptomic data, focusing on SGPL1 and sphingolipid pathway genes. In vitro, we generated SGPL1-knockout and overexpressing H295R adrenocortical cells to investigate the role of SGPL1 in cell signalling in ACCs. RESULTS: We found increased expression of several sphingolipid pathway receptors and enzymes, most notably SGPL1 correlated with reduced patient survival in both cohorts. Overexpression of SGPL1 in the H295R cell line increased proliferation and migration while reducing apoptosis, while SGPL1 knockout had the opposite effect. RNA-seq revealed a global increase in the expression of genes in the electron transport chain in overexpressing cells, correlating with increased aerobic respiration and glycolysis. Furthermore, the opposite phenotype was seen in cells lacking SGPL1. We subsequently found the increased proliferation is linked to metabolic substrate availability and increased capacity to use different fuel sources, but particularly glucose, in overexpressing cells. CONCLUSIONS: We, therefore, propose that SGPL1-overexpressing ACC tumours reduce patient survival by increasing fuel usage for anabolism and energy production to facilitate growth and invasion.

Circulating microRNAs and Clinicopathological Findings of Papillary Thyroid Cancer: A Systematic Review.

BACKGROUND/AIM: Papillary thyroid cancer (PTC) is the most common endocrine malignancy with a rising incidence. There is a need for a non-invasive preoperative test to enable better patient counselling. The aim of this systematic review was to investigate the potential role of circulating microRNAs (miRNAs) in the diagnosis and prognosis of PTC. MATERIALS AND METHODS: A systematic literature search was performed using MEDLINE, Cochrane, and Scopus databases (last search date was December 1, 2021). Studies investigating the expression of miRNAs in the serum or plasma of patients with PTC were deemed eligible for inclusion. RESULTS: Among the 1,533 screened studies, 39 studies met the inclusion criteria. In total, 108 miRNAs candidates were identified in the serum, plasma, or exosomes of patients suffering from PTC. Furthermore, association of circulating miRNAs with thyroid cancer-specific clinicopathological features, such as tumor size (13 miRNAs), location (3 miRNAs), extrathyroidal extension (9 miRNAs), pre- vs. postoperative period (31 miRNAs), lymph node metastasis (17 miRNAs), TNM stage (9 miRNAs), BRAF V600E mutation (6 miRNAs), serum thyroglobulin levels (2 miRNAs), 131I avid metastases (13 miRNAs), and tumor recurrence (2 miRNAs) was also depicted in this study. CONCLUSION: MiRNAs provide a potentially promising role in the diagnosis and prognosis of PTC. There is a correlation between miRNA expression profiles and specific clinicopathological features of PTC. However, to enable their use in clinical practice, further clinical studies are required to validate the predictive value and utility of miRNAs as biomarkers.

DLK1/PREF1 marks a novel cell population in the human adrenal cortex.

The adrenal cortex governs fundamental metabolic processes though synthesis of glucocorticoid, mineralocorticoids and androgens. Studies in rodents have demonstrated that the cortex undergoes a self-renewal process and that capsular/subcapsular stem/progenitor cell pools differentiate towards functional steroidogenic cells supporting the dynamic centripetal streaming of adrenocortical cells throughout life. We previously demonstrated that the Notch atypical ligand Delta-like homologue 1 (DLK1)/preadipocyte factor 1 (PREF1) is expressed in subcapsular Sf1 and Shh-positive, CYP11B1-negative and CYP11B2-partially positive cortical progenitor cells in rat adrenals, and that secreted DLK1 can modulate GLI1 expression in H295R cells. Here we show that the human adrenal cortex remodels with age to generate clusters of relatively undifferentiated cells expressing DLK1. These clusters (named DLK1-expressing cell clusters or DCCs) increased with age in size and were found to be different entities to aldosterone-producing cell clusters, another well-characterized and age-dependent cluster structure. DLK1 was markedly overexpressed in adrenocortical carcinomas but not in aldosterone-producing adenomas. Thus, this data identifies a novel cell population in the human adrenal cortex and might suggest a yet-to be identified role of DLK1 in the pathogenesis of adrenocortical carcinoma in humans.

Dwarfs and Giants of Parathyroid Adenomas-No Difference in Outcome After Parathyroidectomy.

BACKGROUD: This study compares the outcome of parathyroidectomy for primary hyperparathyroidism (PHPT) in patients whose adenomas' weights were at the extremes of the distribution curve. As the size of parathyroid adenomas influences the success rate of localization studies for PHPT, it is possible that a difference in cure rate could be observed between subgroups of patients. MATERIALS AND METHODS: Data were retrieved from a prospective database maintained in a large university hospital. RESULTS: From a cohort of 519 patients who underwent parathyroidectomy for PHPT, two subgroups of patients were identified based on the extreme 10% of the distribution curve for adenomas' weight: adenomas <300 mg ("dwarfs", n = 100, median 200 mg) and >3000 mg ("giants", n = 56, median 4300 mg). In comparison with giant adenomas, dwarf adenomas were associated with less severe hypercalcemia (median 2.84 versus 3.00 mmol/L, P < 0.001) and lower PTH (median 11.7 versus 25.6 pmol/L, P < 0.001). The occurrence of dwarf adenomas showed no trend during the study period (23/173 [13%] in 2000-2004 versus 36/217 [17%] in 2007-2011). Scan-directed parathyroidectomy was feasible in more patients with giant adenomas (59% versus 38%). Persistent disease was diagnosed in three patients with dwarf adenomas. Patients with giant adenomas had no recurrence during a follow-up of 40 mo even though eight patients had histological features suggestive of atypical/malignant tumors. CONCLUSIONS: Preoperative biochemistry is a poor predictor of adenomas' size even at the extremes of the distribution curve. Cure can be achieved in all patients with "dwarf" adenomas. Even in the presence of suspicious histological features, "giant" adenomas did not show malignant behavior.

Independent predisposing factors for subcutaneous and deep wound collection after total thyroidectomy, a prospective cohort study.

BACKGROUND: The literature contains diverse and sometimes contradicting results about wound seroma following thyroidectomy. This is probably due to the subjective clinical estimation of seroma, or due to failure to differentiate between the occurrence of subcutaneous (SC) and deep wound collections. This work aimed at objectively investigating the factors affecting subcutaneous and deep wound seroma after thyroidectomy. METHODS: The relation between various operative and clinico-pathological factors and the collection formation was prospectively analyzed in a cohort of 100 patients after conventional thyroidectomy. Wound seroma was assessed clinically and via high-resolution ultrasonography at 24 h, 48 h and two weeks postoperatively. Sonographically detected collections were expressed as SC and/or deep wound collections according to the relation to strap muscles. RESULTS: Operative duration was the only independent factor significantly affecting the incidence of clinical seroma. Older patients (>40ys) showed significantly larger volumes of early SC collections. Early postoperative pain was significantly related to drain insertion, to the occurrence of clinical seroma and to the volume of SC collections.Sonographically, suction drains and shorter operative durations resulted in significantly less amount of deep collections. Suction drains did not result in less amount of SC collections or in a lower incidence of clinical seroma. CONCLUSIONS: Operative duration is the only independent factor significantly related to clinically-detected postoperative seroma with its subsequent postoperative pain. Especially in elderly patients, a flapless technique would be recommended as these patients developed larger volumes of SC collections with subsequent higher pain scores, even if seroma was not clinically detected.

Risk of adrenocortical carcinoma in adrenal tumours greater than 8 cm.

BACKGROUND: Adrenocortical cancer (ACC) is a rare malignancy. In the absence of metastatic disease, the suspicion of ACC is based on size and radiological appearance. The aim of this study was to analyse the long-term outcome of patients with large adrenal cortical tumours (>8 cm). METHODS: A prospective database recorded clinical, biochemical, operative and histological data on patients operated for cortical adrenal tumours between January 2000 and February 2013. Out of 130 patients operated for cortical adrenal tumours, analysis was restricted to 37 cortical tumours >8 cm. RESULTS: There were 31 (84 %) ACCs and 6 (16 %) benign adenomas (p < 0.01). The most common presentation was that of an abdominal mass [17 (55 %) vs. 3 (50 %), ACC vs. benign, respectively]. There was no difference in size between stage II and stage III-IV tumours; however, there was a trend for tumours to be heavier in advanced stages (920 ± 756 vs. 1,435 ± 1,022 g, p = 0.08, stage II vs. stage III-IV, respectively). No mortality was observed in patients with benign tumours during a median follow-up of 70 months (range 36-99 months). Mortality in the ACC group occurred in 17/31 (55 %) patients. Mitotane was administered in 12 (71 %) patients with stage III-IV ACCs with a 5-year survival rate 25 % compared to 20 % in patients who did not receive Mitotane. In stage II ACC, eight (57 %) patients received Mitotane with a 50 % mortality at 5 years. CONCLUSIONS: The high incidence of ACC in cortical tumours >8 cm underlines the need for adequate surgical resection via open surgery aiming to avoid local recurrence. Beyond surgery, the impact of other therapies is not fully characterised and the efficacy of adjuvant Mitotane treatment is yet to be proven.

An unusual diagnosis of splenic rupture.

A 22-year-old woman presented with a 3-day history of worsening epigastric pain, non-productive cough and vomiting. On examination she was pale and had abdominal tenderness predominant in the right upper quadrant. Abdominal ultrasound excluded the presence of gall stones, but was unable to rule out free fluid in the abdomen. CT demonstrated extensive high-density ascites; however, no source of bleeding could be demonstrated. Clinically the patient's condition deteriorated, and an exploratory laparotomy was performed. In theatre the splenic capsule was found to have detached from the splenic body and emergency splenectomy was performed. Virology serology later demonstrated acute cytomegalovirus (CMV) infection, although tissue microscopy and CMV staining were negative. No other cause of rupture was found. The interesting aspects of this case include the poor correlation between initial presenting symptoms and subsequent diagnosis, the difficulty encountered in making a firm diagnosis and the atypical cause of rupture.

Study of serum leptin in well-differentiated thyroid carcinoma: correlation with patient and tumor characteristics.

BACKGROUND: There is a proven relationship between obesity and several cancers including breast, endometrium, colorectal, and esophagus. With the increasing incidence of both obesity and thyroid cancer, we designed the present study to investigate a causal relationship between leptin, which is one of the well known adipokines, and well-differentiated thyroid cancer (WDTC). METHODS: Serum leptin levels were measured in 30 patients with WDTC and compared to 30 healthy control subjects before and 1 month after surgery. Other parameters studied included age, sex, body mass index, menopausal status in women, lymph node status, tumor size, and disease multifocality. RESULTS: There were no differences between the two groups regarding age and sex. Preoperative leptin levels were higher in the WDTC patients when compared to the control patients [19.25 (1.50-109.60) vs 0.90 (0.50-11.80) ng/ml, p < 0.001, group 1 vs group 2, respectively]. A significant drop in leptin levels 1 month after surgery occurred in the WDTC group, falling from 19.25 (1.50-109.60) to 0.90 (0.60-8.90) ng/ml (p < 0.001). This did not occur in the control group (p = 0.274). Lymph node involvement, tumor size, and multifocality had no effect on leptin levels, although trends were observed (p = 0.48, 0.079, and 0.064), respectively. CONCLUSIONS: Serum leptin levels were significantly higher in WDTC patients when compared to control group patients, with a significant drop after surgery. Leptin may play a role in diagnosis of WDTC; however, its prognostic value is still undetermined.