Effects of primary hyperparathyroidism on oral health. A longitudinal register-based study.

OBJECTIVES: To analyze the effects of primary hyperparathyroidism on oral health and to investigate if the effects are linked to severity of the disease. SUBJECTS AND METHODS: This prospective cohort study involved 6151 primary hyperparathyroidism patients registered in the Scandinavian Quality Registry of Thyroid, Parathyroid, and Adrenal surgery and the National Cancer Register after parathyroidectomy (exposure) during 2011-2017 (patient cohort) and 60,654 individuals without primary hyperparathyroidism (reference cohort), matched by age, gender, and county of resident at the date of parathyroidectomy. The outcomes were tooth extractions and periodontal interventions. The risk for the outcomes was assessed by Poisson regression models. RESULTS: After adjusting for covariates, the patient cohort had a higher incidence rate of tooth extraction during the two-year period after parathyroidectomy (IRR = 1.15; 95% CI = 1.01-1.31), but a lower incidence rate of periodontal interventions during the four- to six-year period after parathyroidectomy (IRR = 0.88; 95% CI = 0.79-0.99). Furthermore, patients with more severe primary hyperparathyroidism were more likely to have tooth extractions and periodontal interventions after parathyroidectomy. CONCLUSIONS: The risk of tooth extraction increased slightly during the first two years after parathyroidectomy. Thereafter, the oral health effects subsided. Pre-surgical serum ionized calcium levels and adenoma weight may indicate negative dental outcomes after parathyroidectomy.

Direct interaction of the ATP-sensitive K+ channel by the tyrosine kinase inhibitors imatinib, sunitinib and nilotinib.

The ATP-regulated K+ channel (KATP) plays an essential role in the control of many physiological processes, and contains a ATP-binding site. Tyrosine kinase inhibitors (TKI) are commonly used drugs, that primarily target ATP-binding sites in tyrosine kinases. Herein, we used the patch-clamp technique to examine the effects of three clinically established TKIs on KATP channel activity in isolated membrane patches, using a pancreatic ß-cell line as a KATP channel source. In excised inside-out patches, the activity of the KATP channel was dose-dependently inhibited by imatinib with half-maximal concentration of approximately 9.4 µM. The blocking effect of imatinib was slow and reversible. No effect of imatinib was observed on either the large (KBK) or the small (KSK) conductance, Ca2+-regulated K+ channel. In the presence of ATP/ADP (ratio 1) addition of imatinib increased channel activity approximately 1.5-fold. Sunitinib and nilotinib were also found to decrease KATP channel activity. These findings are compatible with the view that TKIs, designed to interact at the ATP-binding pocket on the tyrosine receptor, also interact at the ATP-binding site on the KATP channel. Possibly, this might explain some of the side effects seen with TKIs.

Phase I trial evaluating safety and efficacy of intratumorally administered inflammatory allogeneic dendritic cells (ilixadencel) in advanced gastrointestinal stromal tumors.

BACKGROUND: The majority of patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Ilixadencel (allogeneic inflammatory dendritic cells) is a cell-based immune primer injected intratumorally that previously has been clinically investigated in metastatic renal cell carcinoma and hepatocellular carcinoma. METHODS: The trial was a single arm phase I trial assessing safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Three patients were progressing while on sunitinib (second line), one on regorafenib (third line), and two on pazopanib (fourth line). TKI treatment was maintained throughout, while two intratumoral injections of ilixadencel (10 × 106 viable and HLA-DR expressing cells per dose) were administered. RESULTS: No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. One patient (on third line regorafenib) had stable disease for 9 months and another patient (on second line sunitinib) had stable disease at end of study (12 months) as per RECIST 1.1. These two patients developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. The median progression-free survival (PFS) was 4.0 months. CONCLUSION: Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial registration www.clinicaltrials.gov ; NCT: 02432846; registration date: February 22, 2016.

Sarcoma of the breast: breast cancer history as etiologic and prognostic factor-A population-based case-control study.

PURPOSE: Sarcomas of the breast account for about 1% of all breast malignancies. The aim of this national survey was to explore etiologic and prognostic factors. METHODS: Utilizing national Swedish registers, all patients registered with mesenchymal tumors in the breast during the period 1993-2013 (n = 344) were identified and compared to up to ten age and gender matched controls. Cancer history was retrieved for cases and controls. Conditional Poisson regression models were used for calculation of odds ratios. RESULTS: Previous breast cancer was overrepresented among patients with angiosarcoma. The highest risk occurred ≥ 5 years after treatment for breast cancer (OR 73.9, 95% confidence interval, CI, 25.4-215; P < 0.001). An increase in incidence of angiosarcoma was observed during the study period (1.10, 95% CI 1.05-1.16; P < 0.001). The overall incidence of breast sarcoma increased from 1.52 to 2.04 cases per million per year. Angiosarcoma of the breast was associated with a significant excess mortality compared to age-matched controls (HR 4.65, 95% CI 3.01-7.19; P < 0.001). CONCLUSIONS: Angiosarcoma increased in incidence and displayed a more severe clinical course, with significantly shorter survival. The strong association between a history of breast cancer 5 years or more prior to the diagnosis of angiosarcoma points to radiotherapy as a contributing factor.

Parafibromin immunostainings of parathyroid tumors in clinical routine: a near-decade experience from a tertiary center.

The cell division cycle 73 gene is mutated in familial and sporadic forms of primary hyperparathyroidism, and the corresponding protein product parafibromin has been proposed as an adjunct immunohistochemical marker for the identification of cell division cycle 73 mutations and parathyroid carcinoma. Here, we present data from our experiences using parafibromin immunohistochemistry in parathyroid tumors since the marker was implemented in clinical routine in 2010. A total of 2019 parathyroid adenomas, atypical adenomas, and carcinomas were diagnosed in our department, and parafibromin staining was ordered for 297 cases with an initial suspicion of malignant potential to avoid excessive numbers of false positives. The most common inclusion criteria for immunohistochemistry were marked tumor weight (146 cases) and/or fibrosis (77 cases) and/or marked pleomorphism (58 cases). In total, 238 cases were informatively stained, and partial or complete loss of nuclear parafibromin immunoreactivity was noted in 40 cases; 10 out of 182 adenomas (5%), 27 out of 46 atypical adenomas (59%), and 7 out of 10 carcinomas (70%), with positive and negative predictive values of 85 and 90%, respectively for the detection of atypical adenomas/carcinomas versus adenomas, and 18 and 98%, respectively for carcinomas versus atypical adenomas/adenomas. Male patients with high-proliferative tumors were overrepresented among cases with aberrant parafibromin immunohistochemistry, and carcinomas more frequently harbored parafibromin aberrancies than atypical adenomas and adenomas (p < 0.001). We conclude that parafibromin immunohistochemistry is a useful marker in the clinical routine when applied on a pre-selected material of cases, with positive immunoreactivity as a confident rule out marker of malignancy.

Wide Surgical Margin Improves the Outcome for Patients with Gastrointestinal Stromal Tumors (GISTs).

BACKGROUND: Surgical resection is still the main treatment for gastrointestinal stromal tumor (GIST), and R0 excision, regardless of surgical margins, is considered sufficient. METHODS: A cohort of 79 consecutive GIST cases treated at the Karolinska University Hospital, who were without metastasis at diagnosis and who had not received any pre-or postoperative treatment with tyrosine kinase inhibitors, was included. Surgical margins were evaluated at the time of surgery and classified as wide, marginal or intralesional. Time to local/peritoneal recurrence, distant metastasis, and survival were recorded. Cox regression analysis was used to investigate the association between surgical margin, and recurrence and survival. RESULTS: Local/peritoneal recurrence was diagnosed in 2/39 cases with wide margins, in 7/22 cases with marginal margins, and in 13/18 cases with intralesional surgery. Compared to wide margins this gives a hazard ratio of 6.8 (confidence interval 1.4-32.7) for marginal margins and 13.5 (3-61) for intralesional margins. In multivariate analysis, adjusting for size, site, and mitotic index, surgical margin remained an independent significant predictor of risk for recurrence. When classifying patients according to R0/R1 surgery, patients with R0 surgery showed longer time to peritoneal recurrence and better recurrence-free and disease-specific survival as compared to those with R1 resection. However, when excluding patients operated with wide surgical margin, no significant difference was observed. CONCLUSION: Wide surgical margins are of significant prognostic importance, supporting the strategy of en bloc resection with good margin and careful handling of the tumor to avoid damaging the peritoneal surface in surgical resection of GIST.

Intracellular concentration of the tyrosine kinase inhibitor imatinib in gastrointestinal stromal tumor cells.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm in the gastrointestinal tract. In most GISTs, the underlying mechanism is a gain-of-function mutation in the KIT or the PDGFRA gene. Imatinib is a tyrosine kinase inhibitor that specifically blocks the intracellular ATP-binding sites of these receptors. A correlation exists between plasma levels of imatinib and progression-free survival, but it is not known whether the plasma concentration correlates with the intracellular drug concentration. We determined intracellular imatinib levels in two GIST cell lines: the imatinib-sensitive GIST882 and the imatinib-resistant GIST48. After exposing the GIST cells to imatinib, the intracellular concentrations were evaluated using LC-MS (TOF). The concentration of imatinib in clinical samples from three patients was also determined to assess the validity and reliability of the method in the clinical setting. Determination of imatinib uptake fits within detection levels and values are highly reproducible. The GIST48 cells showed significantly lower imatinib uptake compared with GIST882 in therapeutic doses, indicating a possible difference in uptake mechanisms. Furthermore, imatinib accumulated in the tumor tissues and showed intratumoral regional differences. These data show, for the first time, a feasible and reproducible technique to measure intracellular imatinib levels in experimental and clinical settings. The difference in the intracellular imatinib concentration between the cell lines and clinical samples indicates that drug transporters may contribute toward resistance mechanisms in GIST cells. This highlights the importance of further clinical studies to quantify drug transporter expression and measure intracellular imatinib levels in GIST patients.

Regional variations in the management of primary hyperparathyroidism in Sweden: population-based case-control study.

BACKGROUND: Substantial disparities in the utilization of parathyroidectomy for primary hyperparathyroidism have been reported. This study aimed to analyse regional variations in parathyroidectomy incidence with respect to the patient's disease burden and socioeconomic status. METHODS: A population-based case-control study included all patients with primary hyperparathyroidism who underwent parathyroidectomy in Sweden between 2008 and 2017 and 10 matched controls. Data on demographic and socioeconomic variables, co-morbidities and drug prescriptions were collected from relevant national registers. Conditional logistic regression was used to analyse predictors of parathyroidectomy. RESULTS: A total of 8626 patients with primary hyperparathyroidism (77% women) underwent parathyroidectomy during the study interval. The annual incidence of parathyroidectomy was 9.0 per 100 000 persons. The annual age-adjusted regional incidences of parathyroidectomy varied between 3.3 and 16.9 operations per 100 000 inhabitants. Except for a small underrepresentation of patients with lower education, no effect of socioeconomic variables was observed. Compared with matched controls, the parathyroidectomy group had increased odds ratios of having developed classical symptoms of primary hyperparathyroidism and being prescribed medication against cardiovascular disorders and psychiatric illness at the time of parathyroidectomy. Increased risks of kidney stones and osteoporosis were observed 5 years before parathyroidectomy. Patients with primary hyperparathyroidism selected for parathyroidectomy from regions with a low incidence of operations had a higher prevalence of kidney stones, osteoporosis and hypertension, as well as larger adenomas and higher calcium levels at the time of parathyroidectomy compared with patients in high-incidence regions. CONCLUSION: The considerable variation in parathyroidectomy seems more likely associated with different clinical thresholds for detection of primary hyperparathyroidism and referral to surgery than socioeconomic disparities.

BRAF-induced EHF expression affects TERT in aggressive papillary thyroid cancer.

CONTEXT: BRAFV600E and TERT promoter mutations in papillary thyroid carcinoma (PTC) have a synergistic effect on prognosis. This effect is believed to arise from MAPK activation triggered by BRAFV600E, leading to the upregulation of ETS transcription factors that bind to the mutant TERT promoter. OBJECTIVE: To explore the role of ETS factors in relation to clinical features, BRAFV600E and TERT promoter mutations in PTC. DESIGN: Transcriptomic data for 28 ETS factors were analyzed in the PTC cohort of The Cancer Genome Atlas (TCGA, n=399) and subsequently validated in a local cohort (n=93). In vitro experiments were performed to investigate the regulatory role in relation to BRAFV600E and TERT expression. RESULTS: TCGA identified ETS1, ERG, FLI1, GABPA, EHF, ETV6 and SPDEF as differentially expressed genes between stages I+II and III+IV. In both cohorts, EHF was consistently associated with adverse clinical features, BRAFV600E and TERT promoter mutation/expression. Notably, in BRAFV600E mutated PTC, high EHF expression was associated with shorter disease-free survival. Cases harboring concurrent BRAFV600E, TERT promoter mutations and high EHF expression exhibited the shortest disease-free survival. In cells harboring concurrent BRAFV600E and TERT promoter mutation, over-expression of EHF significantly increased TERT expression while knockdown or pharmacological inhibition of BRAF significantly decreased both EHF and TERT expression. In addition, ChIP-qPCR analysis suggested a potential binding of EHF in TERT promoter mutant cells but not in TERT promoter wild-type cells. CONCLUSION: The ETS transcription factor EHF is associated with poor prognosis in PTC. This is potentially mediated by BRAF-induced upregulation of EHF which in turn increases TERT expression in TERT promoter mutated cells.

Anaplastic carcinoma of the thyroid gland: treatment and outcome over 13 years at one institution.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy of the thyroid gland. Patients at our institution are treated with external radiotherapy up to 46 Gray (Gy) and low-dose doxorubicin prior to surgery. We retrospectively evaluated the outcome of ATC patients over a 13-year period. METHODS: Clinical, histopathological, and follow-up data for 59 patients diagnosed between 1997 and 2010 were collected and analyzed. RESULTS: Median age at diagnosis was 77 years. Female-male ratio was 2.5:1. Median survival from time of diagnosis was 3.3 months. Thirty-six patients completed the treatment protocol (including surgery), of whom one succumbed due to local tumor growth. In multivariate analysis, the only factor significantly associated with longer survival among operated patients was absence of metastases at diagnosis (P = 0.031). No impact on survival time was found for gender, extent of surgical resection, and absence of extrathyroidal invasion. CONCLUSIONS: Despite aggressive treatment, survival rates in ATC patients remain low. Locoregional control is feasible for most patients, underscoring the importance of an intense, multimodal treatment regimen. Further oncological intervention is of crucial importance to achieve a better prognosis for ATC patients.

Primary hyperparathyroidism, a machine learning approach to identify multiglandular disease in patients with a single adenoma found at preoperative Sestamibi-SPECT/CT.

Objective: Successful preoperative image localisation of all parathyroid adenomas (PTA) in patients with primary hyperparathyroidism (pHPT) and multiglandular disease (MGD) remains challenging. We investigate whether a machine learning classifier (MLC) could predict the presence of overlooked PTA at preoperative localisation with 99mTc-Sestamibi-SPECT/CT in MGD patients. Design: This study is a retrospective study from a single tertiary referral hospital initially including 349 patients with biochemically confirmed pHPT and cured after surgical parathyroidectomy. Methods: A classification ensemble of decision trees with Bayesian hyperparameter optimisation and five-fold cross-validation was trained with six predictor variables: the preoperative plasma concentrations of parathyroid hormone, total calcium and thyroid-stimulating hormone, the serum concentration of ionised calcium, the 24-h urine calcium and the histopathological weight of the localised PTA at imaging. Two response classes were defined: patients with single-gland disease (SGD) correctly localised at imaging and MGD patients in whom only one PTA was localised on imaging. The data set was split into 70% for training and 30% for testing. The MLC was also tested on a subset of the original data based on CT image-derived PTA weights. Results: The MLC achieved an overall accuracy at validation of 90% with an area under the cross-validation receiver operating characteristic curve of 0.9. On test data, the MLC reached a 72% true-positive prediction rate for MGD patients and a misclassification rate of 6% for SGD patients. Similar results were obtained in the testing set with image-derived PTA weight. Conclusions: Artificial intelligence can aid in identifying patients with MGD for whom 99mTc-Sestamibi-SPECT/CT failed to visualise all PTAs.

Thyroid incidentaloma detected by fluorodeoxyglucose positron emission tomography/computed tomography: practical management algorithm.

BACKGROUND: Our aim was to design a practical algorithm for management of an increasing number of incidental findings of thyroid lesions identified by (18)F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT). METHODS: The reports of 3641 patients examined by FDG-PET/CT for evaluation of nonthyroid cancer were reviewed. The anatomic locations and standardized uptake values (SUV) of any focally increased thyroid FDG uptake were reanalyzed and related to surrounding normal thyroid ((T)SUV(max)/(thy)SUV(mean) ratio) and liver ((T)SUV(max)/(liver)SUV(mean)). RESULTS: Focal FDG uptakes in the thyroid were reported in 37 cases (1%; 26 women). Neoplastic thyroid lesions were diagnosed in 16 patients: papillary thyroid cancer in 9, follicular neoplasia in 5, and metastatic lesions (lung cancer and squamous cell carcinoma) in 2. Benign lesions were diagnosed in 11 patients. Ten patients with malignancy elsewhere did not undergo thyroid examination. In all, 11 patients underwent thyroid surgery (8 with papillary cancer, 3 with follicular adenoma); the median tumor size was 12 mm (8-40 mm). The (T)SUV(max)/(thy)SUV(mean) ratio was higher for the malignant lesions [median 5.53 (2.75-30.81) vs. 3.70 (1.82-31.70); P < 0.05], albeit with a considerable overlap between individual patients. The (T)SUV(max) and (T)SUV(max)/(liver)SUV(mean) did not differ between groups. The (T)SUV(max)/(thy)SUV(mean) and / (thy)SUV(mean) ratios correlated with the tumor size (r = 0.64 and r = 0.66; P < 0.05). CONCLUSIONS: An incidental finding of focal uptake of FDG in the thyroid is associated with a significant risk of thyroid cancer. If the patient would benefit from thyroidectomy if a malignancy were identified, further diagnostic workup with ultrasonography-guided fine-needle aspiration and cytology is recommended.

Institutional characterisation of water clear cell parathyroid adenoma: a rare entity often unrecognised by TC-99m-sestamibi scintigraphy.

Parathyroid lesions exhibiting a water clear cell morphology are exceedingly rare manifestations in primary hyperparathyroidism (PHPT), and the phenomenon has been reported both for uniglandular (water clear cell adenoma; WCCA) and multiglandular disease (water clear cell hyperplasia; WCCH). In all, only 24 previous descriptions of WCCA exist in the literature. Herein, we present seven cases with water clear cell morphology (6 WCCAs and 1 case of WCCH) in an institutional series of approximately 4000 parathyroid lesions spanning 29 years in a tertiary centre setting. Major histological attributes and clinical parameters associated with this morphological subtype were reviewed, and a literature search was conducted. WCCA and WCHH exhibited an institutional prevalence of 0.15% and 0.025%, respectively. All cases displayed histological hallmarks of water clear cell morphology, with cells exhibiting abundant cytoplasm filled with vacuoles. Atypical findings or unequivocal evidence of invasive behaviour were not observed. The gender distribution was 6:1 (F:M), patients were generally symptomatic with mild hypercalcaemia, and the median age at surgery was 53 years (range 38-78). The preoperative localisation was inconclusive in four of seven, and neck exploration of all four glands was undertaken in five cases. The excised WCCAs exhibited an average weight of 1215 mg, markedly higher than conventional adenomas, and all patients were cured of PHPT following parathyroidectomy. Interestingly, previous reports mirror our observations that these lesions often are large, in relation to their sizes biochemically fairly indolent, and indecisively localised using scintigraphy, providing correlations of possible clinical value when pre-operatively assessing these rare lesions.

A single parathyroid hormone measurement two hours after a thyroidectomy reliably predicts permanent hypoparathyroidism.

INTRODUCTION: Hypoparathyroidism is the most common complication following thyroidectomy, and various algorithms for early detection have been suggested. The aim of this study was to evaluate the predictive value of measuring the parathyroid hormone level 2 h after thyroidectomy and whether determination of the perioperative decline in parathyroid hormone added diagnostic value. METHODS: Patients subjected to thyroidectomy for benign thyroid disorders were analyzed in (1) a retrospective register-based study (366 consecutive patients treated during 2015-2016) and (2) a prospective observational study (39 patients treated during 2018). Optimal cut-off values for postoperative parathyroid hormone and perioperative decline (%) in parathyroid hormone were determined by receiver operating characteristics and area under the curve. Sensitivity, specificity, positive and negative predictive values were calculated using cross tabulation. RESULTS: The prevalence of hypoparathyroidism the first day after thyroidectomy was higher among patients treated for hyperthyroidism (30% vs 20%; P = 0.03). The optimal cut-off level for postoperative parathyroid hormone was 1.1 pmol/L (area under the curve = 0.887, 95% confidence interval: 0.839-0.934; positive predictive value: 88%, negative predictive value: 93%) for the entire cohort. When the groups were analyzed separately, the optimal cut-off was 1.05 for the non-hyperfunctioning group and 1.55 pmol/L for the group with hyperthyroidism. Twelve months after thyroidectomy, 3% were defined as having permanent hypoparathyroidism. Measurement of parathyroid hormone decline added diagnostic value for one patient with preoperative parathyroid-hormone-elevation associated with vitamin D deficiency. CONCLUSIONS: For patients with vitamin D sufficiency, the diagnostic accuracy of a single measurement of parathyroid hormone 2 h after thyroidectomy is an excellent indicator for predicting transient hypoparathyroidism.

The preoperative localisation of small parathyroid adenomas improves when adding Tc-99m-Sestamibi SPECT to multiphase contrast-enhanced CT.

OBJECTIVES: To investigate the incremental value of Sestamibi SPECT combined with a non-enhanced and contrast-enhanced CT, using SPECT/CT, for the preoperative localisation of small parathyroid adenomas (PTA). METHODS: Retrospectively, 147 patients surgically cured from primary hyperparathyroidism, as verified by biochemistry 6 months postoperatively, were included. All patients had preoperatively undergone a dual time 99mTechnetium-Sestamibi SPECT (S) with multiphase CT including native (N), arterial (A) and venous (V) phases. Independently, two radiologists blinded from both the surgical and the preoperative imaging reports, sequentially performed PTA localisation starting with either [A] or [V], thereafter [A + N] or [V + N] and finally with the complete [A + N + S] or [V + N + S]. PTA localisation was reported for each image-set. The readers results were combined and the diagnostic performance for each image set was determined. Sensitivity was also calculated for the different quartiles of PTA weight distribution. RESULTS: The median adenoma weight was 315 mg. No statistically significant differences in diagnostic performance between arterial and venous based image sets were found. The net effect of adding [N] was to increase specificity. Sestamibi SPECT significantly increased the overall diagnostic accuracy for arterial- and venous-based image sets, p = 0.0008 and p = 0.001, respectively. [A + N + S] was found to have the highest diagnostic performance with 86.5% sensitivity and 94.9% overall accuracy. [A + N + S] was particularly advantageous for locating PTA in the lower weight quartiles. CONCLUSIONS: Native CT-phase and dual time point Sestamibi SPECT increase specificity and sensitivity, respectively. These, in combination with a single contrast-enhanced CT-phase is the most optimal examination protocol for preoperative localisation of PTA using SPECT/CT.

Lipoadenoma of the Parathyroid Gland: Characterization of an Institutional Series Spanning 28 Years.

Parathyroid lipoadenomas (PLAs) are rare tumors, and case descriptions are limited, < 80 to date. As a consequence, scarce information regarding the etiology of these enigmatic lesions is available. We searched our departmental pathology database for PLAs diagnosed between 1992 and 2020, reexamined the histology of each case, and recorded clinical parameters from the patients' medical charts. As the diagnostic criteria of this lesion vary over this time period, we defined PLA as an enlarged parathyroid gland with > 50% fat on histologic examination with preoperative evidence of primary hyperparathyroidism (PHPT). A total of 8 bona fide PLA cases and 2 equivocal PLAs (close to 50% fat) were included. As approximately 4000 conventional parathyroid adenomas were diagnosed at our department during the same time interval, the prevalence of PLA was 0.20%. PLA patients were predominately female (63%) and presented with classical PHPT-related symptoms. Majority of cases were successfully located preoperatively and had an average tumor weight of 445 mg. Histologically, all PLAs consisted of > 50% mature adipose tissue, except a single case with brown fat. Of note, PLA patients exhibited a body mass index in line with PHPT patients in general, but a relatively high, near-significant prevalence of arterial hypertension was observed when compared to tumors with less fat (P = 0.0584). Future studies on this finding might be warranted. To summarize, we present one of the largest institutional PLA case series to date, and conclude that PLAs are rare, sporadic tumors mirroring many clinical aspects of conventional adenomas-with a potential coupling to hypertension worthy of follow-up studies.

Metastatic Anaplastic Thyroid Carcinoma in Complete Remission: Morphological, Molecular, and Clinical Work-Up of a Rare Case.

Anaplastic thyroid carcinoma (ATC) exhibits an exceedingly poor prognosis, and the current treatment options are, for most cases, palliative by nature. Few reports of long-time survivors exist, although in these patients, tumors often were limited to the thyroid and/or regional lymph nodes. We describe a 64-year-old male who developed a rapidly growing mass in the left thyroid lobe. A fine-needle aspiration biopsy (FNAB) was consistent with ATC, and the patient underwent preoperative combined chemo- and radiotherapy followed by a hemithyroidectomy. The ensuing histopathological investigation was consistent with ATC adjoined by an oxyphilic well-differentiated lesion, likely a Hürthle cell carcinoma. Tumor margins were negative, and no extrathyroidal extension was noted. Focused next-generation sequencing analysis of the primary tumor tissue identified a TP53 gene mutation but could not identify any potential druggable targets. Additional Sanger sequencing detected a C228T TERT promoter mutation. The tumor was found to be microsatellite stable and displayed PDL1 expression in 80% of tumor cells. Following a CT scan 1 month postoperatively, metastatic deposits were suspected in the lung as well as in the left adrenal gland, of which FNAB verified the latter. Remarkably, upon radiological follow-up, the disease had gone into apparent complete remission. The patient is alive and well with no signs of residual disease after 12 months of follow-up. We here summarize the clinical, histological, and molecular data of this highly interesting patient case and review the literature for possible common denominators with other patients with disseminated ATC.

Multiphase Iodine Contrast-Enhanced SPECT/CT Outperforms Nonenhanced SPECT/CT for Preoperative Localization of Small Parathyroid Adenomas.

PURPOSE: The aim of this study was to assess the value of intravenously contrast-enhanced CT in conjunction with Tc-MIBI SPECT for preoperative localization of parathyroid adenoma. METHODS: One hundred ninety-two patients with primary hyperparathyroidism were enrolled in the study between May 2015 and May 2017. The patients underwent a preoperative "one-stop shop" examination with Tc-MIBI SPECT/CT by using dual time-point (10 and 90 minutes) protocol and both nonenhanced CT and contrast-enhanced CT acquisition in the arterial and venous phase, 35 and 75 seconds, respectively, after contrast medium injection start. For 149 patients, the imaging results could be correlated to those at surgery and histopathology. RESULTS: The median adenoma weight was 330 mg. The addition of contrast-enhanced CT increased the sensitivity from 81.1% to 89.9% (P = 0.003). The specificity of nonenhanced SPECT/CT was similar to contrast-enhanced CT (96.1% vs 97.9%; P = 0.077). For patients with uniglandular disease (n = 140, 94.0%), the sensitivity increased from 86.4% to 93.6% (P = 0.021) and the specificity from 96.2% to 97.9% (P = 0.118) by adding contrast-enhanced CT. In patients with multiglandular disease (n = 9, 6.0%), adding contrast-enhanced CT improved detection sensitivity from 42.1% to 63.2%. However, these patients were few and significance was not reached (P = 0.125). CONCLUSIONS: In this cohort, with generally small parathyroid adenomas, the sensitivity in preoperative localization was greatly improved by adding contrast-enhanced CT to Tc-MIBI SPECT/CT.

Biochemical Inhibition of DOG1/TMEM16A Achieves Antitumoral Effects in Human Gastrointestinal Stromal Tumor Cells In Vitro.

BACKGROUND/AIM: DOG1 is a calcium-activated chloride channel that has gained attention as a promising drug target due to its involvement in several processes essential for tumor development and progression. DOG1 is overexpressed in >95% of gastrointestinal stromal tumors (GIST). The aim was to determine DOG1 inhibition antitumoral effects on GIST. MATERIALS AND METHODS: Human GIST (GIST-T1 and GIST882) cell lines were used to study the effect of DOG1 inhibitors on chloride currents, viability, colony formation, and cell cycle. RESULTS: CaCCinh-A01 decreased chloride currents. CaCCinh-A01 and T16inh-A01 reduced GIST cell viability and CaCCinh-A01 affected cell cycle distribution leading to G1 cell-cycle arrest. CaCCinh-A01 also increased the sub-G1 phase population, indicative of apoptosis, in GIST882. CaCCinh-A01 strongly reduced the colony forming ability of the cells, whereas T16inh-A01 did not. CONCLUSION: DOG1 inhibition has antitumoral effects in GIST cells in vitro, and could potentially serve as a target for GIST therapy.

GABPA inhibits invasion/metastasis in papillary thyroid carcinoma by regulating DICER1 expression.

The ETS family transcription factor GABPA is suggested as an oncogenic element, which is further supported by the recent reporting of it as the sole ETS member to activate the mutant TERT promoter in thyroid carcinomas (TC). However, it remains unclear how GABPA contributes to TC pathogenesis. The present study is designed to address this issue. TERT expression was significantly diminished in TERT promoter-mutated TC cells upon GABPA inhibition. Surprisingly, GABPA depletion led to robustly increased cellular invasion independently of TERT promoter mutations and TERT expression. DICER1, a component of the microRNA machinery, was identified as a downstream effector of GABPA. GABPA facilitated Dicer1 transcription while its depletion reduced Dicer1 expression. The mutation of the GABPA binding site in the DICER1 promoter led to diminished basal levels of DICER1 promoter activity and abolishment of GABPA-stimulated promoter activity as well. The forced DICER1 expression abrogated the invasiveness of GABPA-depleted TC cells. Consistently, the analyses of 93 patients with papillary thyroid carcinoma (PTC) revealed a positive correlation between GABPA and DICER1 expression. GABPA expression was negatively associated with TERT expression and promoter mutations, in contrast to published observations in cancer cell lines. Lower GABPA expression was associated with distant metastasis and shorter overall/disease-free survival in PTC patients. Similar results were obtained for PTC cases in the TCGA dataset. In addition, a positive correlation between GABPA and DICER1 expression was seen in multiple types of malignancies. Taken together, despite its stimulatory effect on the mutant TERT promoter and telomerase activation, GABPA may itself act as a tumor suppressor rather than an oncogenic factor to inhibit invasion/metastasis in TCs and be a useful predictor for patient outcomes.