Clinical characteristics of a large familial cohort with Medullary thyroid cancer and germline Cys618Arg RET mutation in an Israeli multicenter study.

Objective: To determine genealogical, clinical and pathological characteristics of a cohort with Cys618Arg mutation from an Israeli multicenter MTC study. Methods: Retrospective database analysis examining RET mutations and comparing Cys618Arg and Cys634Arg/Thr/Tyr subgroups. Results: Genetic testing was performed in 131/275 MTC patients (47.6%). RET mutations were found in 50/131 (38.2%), including Cys618Arg (28/50 cases,56%), and Cys634Arg/Thr/Tyr (15/50,30%). Through genealogical study, 31 MTC patients were found descendants of one family of Jewish Moroccan descent, accounting for 27/28 patients with documented Cys618Arg mutation and 4 patients without available genetic testing. Familial Cys618Arg cases (n=31) and Cys634Arg/Thr/Tyr cases (n=15, from 6 families) were compared. Although surgical age was similar (25.7 vs 31.3 years, p=0.19), the Cys618Arg group had smaller tumors (8.9mm vs 18.5mm, p=0.004) and lower calcitonin levels (33.9 vs 84.5 X/ULN, p=0.03). Youngest ages at MTC diagnosis were 8 and 3 years in Cys618Arg and Cys634Arg/Thr/Tyr cohorts, respectively. Long-term outcome was similar between groups. The Cys618Arg cohort had lower rates of pheochromocytoma (6.5% vs 53.3%, p=0.001) and primary hyperparathyroidism (3.2% vs 33.3%, p=0.01). Conclusion: This is the first description of RET mutation distribution in Israel. Of 131 tested MTC patients, Cys618Arg was the predominant mutation. To the best of our knowledge, this is the largest cohort of Cys618Arg mutation described. For Cys618Arg and Cys634Arg/Thr/Tyr cohorts, MTC was diagnosed earlier than expected, likely due to familial genetic screening, and MTC outcomes were similar between groups. International studies are necessary to further characterize the clinical features of Cys618 mutations due to their relative rarity.

Clinical Outcomes of Diabetic Ketoacidosis in Type 2 Diabetes Patients with and without SGLT2 Inhibitor Treatment: A Retrospective Study.

AIM: This study aimed to compare the clinical course and outcomes of DKA in T2DM patients who received treatment with SGLT2 inhibitors versus those who did not. METHODS: A retrospective analysis was conducted on T2DM patients who were admitted to the Rambam Health Care Campus with DKA between 7/2015 and 9/2020. Demographic, clinical, and laboratory data were obtained from electronic medical records. Outpatient mortality was monitored until 12/2022. RESULTS: Of 71 T2DM patients admitted with DKA, 16 (22.5%) were on SGLT2 inhibitor treatment upon admission. SGLT2 inhibitor users had a higher BMI and were less likely to be treated with insulin. During hospitalization, the rates of acute kidney injury, concomitant infections, and inpatient mortality among SGLT2 inhibitor users were comparable to non-users. The median follow-up period was 35.1 months for the SGLT2 inhibitor users and 36.7 months for non-users. The long-term mortality from any cause was lower among the SGLT2 inhibitor users (12.5% vs. 52.7%, p = 0.004). In Cox regression analysis, SGLT2 inhibitor use was associated with a lower risk of long-term mortality from any cause (HR = 0.19, p = 0.04). CONCLUSION: T2DM patients with DKA who received SGLT2 inhibitors had lower long-term mortality from any cause compared to those who did not receive SGLT2 inhibitors.

Validation of TIRADS ACR Risk Assessment of Thyroid Nodules in Comparison to the ATA Guidelines.

OBJECTIVES: The prevalence of thyroid nodules in adults, detected by ultrasound (US), is reported as high as 68%. US-guided fine-needle aspiration biopsy (FNAB) is the test of choice used to determine the nature of the nodules. However, not more than 15% are found to be malignant. Reducing the number of unnecessary FNAB while identifying clinically significant malignant nodules is imperative. There are several guidelines suggested for risk stratification of thyroid nodules by US. The aim of our study was to validate and compare Thyroid Imaging Reporting and Data System (TIRADS) American College of Radiology (ACR) and American Thyroid Association (ATA) risk stratification, specifically pertaining to reduction of unnecessary biopsies. MATERIAL AND METHODS: The study included 281 nodules in 245 patients who underwent FNAB between May 2018 and June 2019. Statistical analysis was performed only on 235 nodules that according to the TIRADS ACR and/ or ATA guidelines were eligible for FNAB. Data collected included nodule characteristics with corresponding TIRADS and ATA grading and cytological results using Bethesda scoring. RESULTS: An agreement was found between the two criteria methods in 58.2% (137/235) of the cases. In 35.3% (83/235), ATA recommended FNAB while TIRADS did not. The specificity for ATA criteria was 7% (15/221) and for TIRADS was 37% (81/221). The sensitivity was 100% (14/14) for ATA and 86% (12/14) for TIRADS. CONCLUSION: Application of ACR TIRADS criteria can reduce the number of US-guided FNAB performed on benign nodules compared to ATA criteria, by 35%, with a cost of only two missed carcinomas that remained on further follow-up.

Metallothionein protein and minichromosome maintenance protein-2 expression in adrenocortical tumors.

AIM: Some resected adrenal-confined adrenocortical carcinomas metastasize and others not. The present study was designed to evaluate the expression of metallothionein protein (MT) and minichromosome maintenance protein-2 (MCM2) in adrenocortical carcinomas and adrenocortical adenomas, and to test the correlation between this and adrenocortical carcinoma aggressiveness. MATERIALS AND METHODS: The study comprised 14 patients operated on for adrenocortical carcinoma, 15 operated on for adrenocortical adenoma and 2 with normal adrenals. Hematoxylin-eosin staining was used for histological evaluation under light microscopy, and sequential sections were used for MCM2 and MT staining. RESULTS: In normal adrenals, positive staining was weak for MT and zero for MCM2. Rates of positive staining for MT and MCM2 were significantly higher in adrenocortical carcinomas than in adrenocortical adenomas (P=0.008 and P<0.001, respectively). In adrenocortical carcinomas, a significant positive correlation was found between MCM2 staining and Weiss revisited score (P=0.022) but not for Weiss score, and a significant positive correlation was found between MCM2 and mitotic rate on histology (P=0.033). MCM2 but not MT staining was also shown to correlate significantly with stage IV carcinoma (P=0.008 and P=0.165, respectively). CONCLUSION: MCM2 and MT are overexpressed in adrenocortical carcinoma, and MCM2 expression correlates significantly with metastatic disease.

Management of cystic prolactinomas: a review.

INTRODUCTION: Cystic prolactinoma is a variant of prolactin-secreting pituitary adenoma. The strategies for the management of cystic prolactinoma have not been addressed thoroughly in clinical guidelines. METHODS: A literature search was performed using Pubmed to review the current approaches to the treatment of cystic prolactinoma. RESULTS: Transsphenoidal resection is an effective and relatively safe approach for the treatment of cystic prolactinoma, however, morbidity of surgery is dependent on the skill of the surgeon. Emerging studies allude to the efficacy and safety of dopamine agonists in the management of cystic prolactinoma. Dopamine agonists are associated with considerable rates of clinical improvement and tumor shrinkage, hence reducing the need for surgical intervention. CONCLUSIONS: Recent studies suggest that dopamine agonist therapy may be an effective and safe treatment option in a considerable portion of patients with cystic prolactinomas. We suggest that dopamine agonists should be considered as a first-line therapy for cystic prolactinoma in the absence of indications for early surgical intervention.

Post-translational Regulation of Radioactive Iodine Therapy Response in Papillary Thyroid Carcinoma.

Background: Radioactive iodine (RAI) is the mainstay of treatment for differentiated thyroid carcinoma (DTC). Nevertheless, the mechanism of RAI resistance that occurs in many patients with DTC remains unknown. We aimed to elucidate the role of post-translational regulation of radioiodine uptake. Methods: We analyzed the expression pattern of the ribosomal glycosylphosphatidylinositol transamidase (GPIT) complex in freshly excised tumors from 10 patients with DTC. We used functional RAI uptake assays to assess the role of GPIT in iodine uptake both in vivo and in vitro. The effects of MEK inhibition on the GPIT subunit PIGU and the sodium iodide symporter (NIS) were assessed in three DTC cell lines and in four human DTC biopsies. We used a multivariable logistic regression model to study the role of PIGU in the response to RAI treatment in advanced DTC. All statistical tests were two-sided. Results: Expression profiling of different GPIT complex subunits revealed statistically significantly lower expression of PIGU in papillary carcinomas than in matched normal thyroid tissue (P < .001). Expression of PIGU in the K1 human papillary carcinoma cell line resulted in a robust increase in NIS glycosylation and trafficking to the cell membrane, accompanied by a robust increase in I125 uptake both in vitro (465 200 ± 56 343 vs 1236 ± 156 counts per million, P < .001) and in vivo (128 945 ± 28 556 vs 7963 ± 192 counts per million, P < .001, n = 5 mice per group). Treatment with the MEK inhibitors U0126 and PD302 rescued PIGU expression. Finally, the PIGU expression levels in tumors of 18 patients with recurrent DTC were associated with a biochemical response to RAI treatment (hazard ratio = 8.06, 95% confidence interval = 3.72 to 12.3, P = .001). Conclusions: We showed that downregulation of PIGU in DTC determines NIS function and RAI avidity. This represents a novel mechanism for RAI resistance.

Homozygous LIPE mutation in siblings with multiple symmetric lipomatosis, partial lipodystrophy, and myopathy.

Despite considerable progress in identifying causal genes for lipodystrophy syndromes, the molecular basis of some peculiar adipose tissue disorders remains obscure. In an Israeli-Arab pedigree with a novel autosomal recessive, multiple symmetric lipomatosis (MSL), partial lipodystrophy and myopathy, we conducted exome sequencing of two affected siblings to identify the disease-causing mutation. The 41-year-old female proband and her 36-year-old brother reported marked accumulation of subcutaneous fat in the face, neck, axillae, and trunk but loss of subcutaneous fat from the lower extremities and progressive distal symmetric myopathy during adulthood. They had increased serum creatine kinase levels, hypertriglyceridemia and low levels of high-density lipoprotein cholesterol. Exome sequencing identified a novel homozygous NC_000019.9:g.42906092C>A variant on chromosome 19, leading to a NM_005357.3:c.3103G>T nucleotide change in coding DNA and corresponding p.(Glu1035*) protein change in hormone sensitive lipase (LIPE) gene as the disease-causing variant. Sanger sequencing further confirmed the segregation of the mutation in the family. Hormone sensitive lipase is the predominant regulator of lipolysis from adipocytes, releasing free fatty acids from stored triglycerides. The homozygous null LIPE mutation could result in marked inhibition of lipolysis from some adipose tissue depots and thus may induce an extremely rare phenotype of MSL and partial lipodystrophy in adulthood associated with complications of insulin resistance, such as diabetes, hypertriglyceridemia and hepatic steatosis. © 2016 Wiley Periodicals, Inc.

Genetic Testing in Differentiated Thyroid Carcinoma: Indications and Clinical Implications.

Differentiated thyroid cancer (DTC) is a common and diverse endocrine malignancy. In most patients DTC results in an indolent and curable disease. Nevertheless, disease recurrence rates are relatively high (10%-30%), while 5% of the patients are resistant to conventional treatment and some of these patients are incurable. Over the past 20 years much progress has been made in identifying genetic changes that occur in DTC. In addition, studies aimed to understand the role of these genetic changes in tumorigenesis and their effects on the clinical characteristics of the disease have been conducted. The accrued knowledge has set the stage for development of genetic tests aimed to identify these changes in samples obtained from DTC patients and use this information in the clinical decision process. This paper reviews genetic changes that were identified in DTC, and how the emerging data obtained by genetic testing are currently used to gain key information on the diagnosis, risk stratification, and personalized care of DTC patients.

Metabolic profiling in personalized medicine: bridging the gap between knowledge and clinical practice in Type 2 diabetes.

Type 2 diabetes mellitus (DM2) is the most commonly diagnosed metabolic disease and its prevalence is expected to increase. Epidemiological studies clearly show excess mortality associated with DM2, as well as an increased risk of DM2-related complications. Advances in personalized medicine would greatly improve patient care in the field of diabetes and other metabolic diseases. Prediction of the disease in asymptomatic patients as well as its harsh complications in patients already diagnosed is becoming a necessity, with the considerable increase in the cost of the treatment. In the current article, we review the known clinical, molecular metabolic and genetic biomarkers that should be integrated in a future bioinformatic platform to be used at the point-of-care, and discuss the challenges we face in applying this vision of personalized medicine for diabetes into reality.