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.

Influence of Fasting until Noon (Extended Postabsorptive State) on Clock Gene mRNA Expression and Regulation of Body Weight and Glucose Metabolism.

The trend of fasting until noon (omission or delayed breakfast) is increasingly prevalent in modern society. This eating pattern triggers discordance between endogenous circadian clock rhythms and the feeding/fasting cycle and is associated with an increased incidence of obesity and T2D. Although the underlying mechanism of this association is not well understood, growing evidence suggests that fasting until noon, also known as an "extended postabsorptive state", has the potential to cause a deleterious effect on clock gene expression and to disrupt regulation of body weight, postprandial and overall glycemia, skeletal muscle protein synthesis, and appetite, and may also lead to lower energy expenditure. This manuscript overviews the clock gene-controlled glucose metabolism during the active and resting phases and the consequences of postponing until noon the transition from postabsorptive to fed state on glucose metabolism, weight control, and energy expenditure. Finally, we will discuss the metabolic advantages of shifting more energy, carbohydrates (CH), and proteins to the early hours of the day.

Clinical and pathologic characteristics of appendiceal neuroendocrine neoplasms diagnosed during pregnancy.

Introduction: Although appendicitis occurs in approximately 1:1000 pregnancies, appendiceal neuroendocrine neoplasm (ANEN) diagnosis during pregnancy is very rare. Data on presentation, treatment and prognosis is scarce. Aim: To describe ANEN cases diagnosed during pregnancy. Materials and methods: A retrospective appraisal of 7 consecutive ANEN patients diagnosed during pregnancy from four Israeli tertiary medical centers and comparison with 17 cases described in the literature from 1965-2021. Results: Age at ANEN diagnosis was 26.4 ± 3.5 years (range 21-33). Patients were diagnosed between gestational weeks 6-40, most frequently in the third trimester (53%). The most common presenting symptom was abdominal pain. Tumor size was 14.3 ± 8.9mm (range 3-45mm). In patients from our series appendiceal base involvement was reported in 2/7; mesoappendiceal invasion in 5/7; lympho-vascular invasion in 2/7. Ki67 staining was reported in 6/7 cases and ranged from 1-10%. Pathology details were lacking in most of the previously published cases. All 7 pregnancies in our series resulted in term delivery with no complications, whereas in historical cases there were one first trimester abortion, one ectopic pregnancy, and one stillbirth. Right hemicolectomy was performed in 5/7 patients in our series and reported in 2/17 historical cases. All hemicolectomies were performed after delivery, 3-16 months after appendectomy. Local metastases were reported in two cases. Follow-up duration was 7-98 months for our patients and 3-48 months in 5 historical cases. No disease recurrence, distant metastases or mortality were noted. Conclusions: To the best of our knowledge, this is the largest series describing the extremely rare diagnosis of ANEN during pregnancy. Although pathologic characteristics varied, pregnancy outcomes were usually favorable and long-term prognosis was excellent. This data may suggest that a conservative approach to patients with ANEN diagnosis during pregnancy can be considered.

Is there an added value for whole body scan combined with stimulated thyroglobulin testing for follow-up of differentiated thyroid cancer patients?

AIM: The aim of this study was to evaluate the incidence of positive WBS in patients with negative stimulated thyroglobulin (sTg), to define the clinical characteristics of this group, and the association with disease outcome. METHODS: DTC patients who underwent surveillance with simultaneous sTg and WBS were included. RESULTS: Two hundred seventy-two patients were included. Age at diagnosis was 46.5 ± 15.2 years, 79% were female. Mean duration of follow-up was 11.6 ± 6.8 years. Patients were categorised according to stimulation test results: sTg(-)/WBS(-) in 192/272 (70.6%); sTg(+) regardless of WBS results in 33/272 (12.1%); and sTg(-)/WBS(+) in 47/272 (17.3%) subjects. sTg > 10 mg/dl was considered positive. The three groups had similar demographic and pathologic characteristics. During follow-up, additional treatment was given in 77 patients (28.3%). Twelve (4.4%) developed distant metastases; 16 patients (5.8%) died. No deaths were disease-related. There was no difference in mortality rate between categories (P = 0.182). On multivariate analysis, additional treatment was associated with male gender (P = 0.046) and positive stimulation test results, either sTg (P < 0.001) or WBS (P < 0.001). Of the 47 WBS(+)/sTg(-) patients, 7(15%) were treated due to positive WBS results, including two who underwent additional surgery. CONCLUSION: A substantial proportion of stimulation test results were discordant. There was a significant association between WBS results and administration of additional treatment. Routine WBS had additional value for a small proportion of patients with no other evidence for disease and no indication for WBS.

Efficacy and Safety of Intravenous Pamidronate for Parathyroid Hormone-dependent Hypercalcemia in Hospitalized Patients.

CONTEXT: Bisphosphonates are effective for hypercalcemia of malignancy (HOM). Efficacy and safety data for bisphosphonates in parathyroid hormone-related hypercalcemia (PTHRH) are rare, including pamidronate (Pam), which is not indicated for this condition. OBJECTIVE: This work aims to evaluate the efficacy and safety of Pam for moderate-to-severe PTHRH. METHODS: This retrospective case-control study was conducted at a tertiary care medical center. Patients included adults hospitalized with serum calcium levels greater than 12 mg/dL, from October 29, 2013 to December 17, 2019. Etiology was categorized as PTHRH or PTH-independent. Clinical and laboratory data of PTHRH patients treated with Pam (PTHRH-Pam+) were compared to Pam-untreated counterparts (PTHRH-Pam-). RESULTS: Thirty-four patients with 37 hospitalizations for PTHRH (Pam-treated and -untreated) met the inclusion criteria. Pam was given in 24 of 37 cases (64.8%). Admission serum calcium levels for the PTHRH-Pam+ group were higher than for PTHRH-Pam- group (14.4 mg/dL vs 13.0 mg/dL, P = .005). Median total Pam dose was 60 mg (range, 30-180 mg) in the treated group. Serum calcium decreased 3.5 mg/dL for PTHRH-Pam+ vs 1.6 mg/dL for PTHRH-Pam- (P = .003). No PTHRH-Pam+ patients developed hypocalcemia or acute kidney injury. Nadir serum phosphorus levels were lower in the PTHRH-Pam+ vs PTHRH-Pam- group (1.7 mg/dL vs 2.4 mg/dL, respectively, P = .004). Three PTHRH-Pam+ patients developed severe hypophosphatemia; all resolved with intravenous and oral supplementation. Seventeen patients underwent parathyroidectomy, of whom 10 received Pam within 28 days preoperatively. Postoperatively, 4 developed hypocalcemia and 3 hypophosphatemia. CONCLUSION: This study demonstrates that Pam is effective and safe for treating PTHRH, while ensuring close laboratory monitoring of calcium and phosphorus metabolism. Larger, prospective studies are needed to establish the role of Pam and other potent bisphosphonates in moderate-to-severe PTHRH.

Temporal trends in incidence, evaluation and management of neuroendocrine neoplasms of the appendix: 14 years' experience.

BACKGROUND: Information regarding temporal trends in appendiceal neuroendocrine neoplasms (ANEN) is limited. This retrospective study evaluated temporal trends in ANEN incidence and management over a 14-year period. METHODS: Appendectomy pathology reports from a single tertiary center were reviewed. RESULTS: During 2005-2018, 8327 appendectomies were performed and 57 ANENs were diagnosed (average age 31.7 ± 17 years; 70.2% women; 17.5% Arab ethnicity; and 22.8% < 18 years of age). The cohort was divided according to year of diagnosis (Period A 2005-2011; Period B 2012-2018). No differences were found in ANEN incidence (0.75% and 0.62%, respectively, p = 0.104), epidemiologic or pathologic characteristics between periods. In period B, pathology reports were more comprehensive and use of specific imaging and biochemical studies was more prevalent. Hemicolectomy rates and results were similar (8 in Period A, 7 in Period B, p = 0.925). All patients remained alive for the duration of follow-up. CONCLUSIONS: No temporal changes in epidemiological, clinical or pathological features of ANENs were noted. Although clinico-pathological evaluation was more detailed after 2011, there was no change in rates of hemicolectomy or disease prognosis.

Appendiceal tumor incidence and an in-depth look at appendiceal neuroendocrine neoplasm in a cohort of 8,162 appendectomies: Full dataset.

Data describing appendiceal tumor incidence and epidemiology is limited. We collated data from appendectomy pathology reports between 2005 and 2018 in our institution and examined patient epidemiological and appendectomy pathological features [1]. Overall, 8,328 appendectomies were performed at our institution over the pre-specified time period and 8,162 patients had sufficient epidemiological data to be included in the analysis. A total of 153 patients (1.9%) were diagnosed with appendiceal tumors, of which 57 (37.3%) were Appendiceal Neuroendocrine Neoplasm (ANEN), 35 (22.9%) were mucinous cystadenoma and 34 (22.2%) ovarian cancer metastases. We further examined the ANEN cases in order to characterize initial patient and tumor characteristics, to evaluate the performance of further investigations and interventions, and ultimately to study the behavior of these tumors over time.

Indeterminate nodules by the Bethesda system for reporting thyroid cytopathology in Israel: Frequency, and risk of malignancy after reclassification of follicular thyroid neoplasm with papillary-like features.

OBJECTIVE: We aimed to determine the frequency and risk of malignancy (ROM) for indeterminate thyroid nodules, categories III (B3) and IV (B4) of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), at a large institution in Israel. Additionally, we investigated the impact of redefining follicular neoplasm with papillary-like nuclear features (NIFTP) as non-malignant on malignancy rates. METHODS: In this retrospective study of all thyroid fine needle aspirations (FNAs) performed at Tel Aviv-Sourasky Medical Center between January 2013 and December 2015, we assessed ROM for B3 and B4 nodules. Potential risk factors thought to affect a-priori ROM were assessed. Suspected NIFTP lesions were re-examined, and if proven, reclassified as benign. RESULTS: 3701 nodules were sampled in 2919 FNAs performed on 2674 patients. B3 reports comprised 7.7% of all nodules (n = 284); B4 represented 3.6% (n = 132). In multivariate logistic regression, male gender, being of former Soviet Union origin, and smoking increased ROM for B3 nodules by a factor of 7.97 (P = 0.002; CI: 2.2-23.4), 9.15 (P = 0.021; CI:1.4-60.0), and 11.0 (P = 0.001; CI 2.8-44.8), respectively. Reclassifying NIFTP decreased ROM from 14% to 12.5% for B3, and from 26.7% to 25% for B4 nodules. NIFTP comprised 9.5% of previously diagnosed resected malignant tumors. CONCLUSIONS: The relative frequencies of B3 and B4 nodules and their associated malignancy rates were consistent with previous series. Risk factors identified for malignancy may help characterize patients most likely to benefit from surgery. Reclassifying NIFTP had a substantial impact on the ROM in the resected tumors previously diagnosed as malignant.

A RETROPERITONEAL SEMINOMA WITH ENTRAPPED NERVE GANGLION MASQUERADING AS A PARAGANGLIOMA.

OBJECTIVE: The differential diagnosis of retroperito-neal tumors includes lymphoid, germ cell, and neurogenic tumors such as paraganglioma. Paragangliomas are rare neuroendocrine tumors of the autonomic nervous system, which may secrete catecholamines and their metabolites. Clinical features include sustained or paroxysmal hypertension, headaches, sweating, and palpitations. Here we present an unusual case of a retroperitoneal tumor entrapping a sympathetic nerve ganglion and mimicking paraganglioma. METHODS: A 57-year-old man with a history of controlled hypertension presented with paroxysms of tachycardia, flushing, high blood pressure, and headache. Ambulatory blood pressure monitoring showed uncontrolled labile hypertension with a normal nocturnal dip. Abdominal computed tomography (CT) demonstrated a 6.1 cm mass in the right retroperitoneum with adjacent lymphadenopathy. Paraganglioma was suspected and 24-hour urine demonstrated elevated normetanephrines (575 mcg/24 hours; normal, 5 to 290 mcg/24 hours) and vanillylmandelic acid (8.3 mg/24 hours; normal, 0.5 to 6.6 mg/24 hours). 68-Gallium DOTATATE positron emission tomography/CT showed weak uptake in the retroperitoneal mass and no other mass lesions. RESULTS: Following preparation with alpha-adrenergic blockers, surgical excision was performed with diagnostic and curative intent. Postoperatively, hypertension and paroxysmal symptoms resolved completely. The histopathology report described seminoma with an entrapped large ganglion within the tumor. CONCLUSION: We describe a retroperitoneal seminoma with an entrapped ganglion causing hypertension and paroxysmal symptoms, with laboratory and imaging features compatible with paraganglioma. Awareness of the rare possibility of mechanical pressure on a ganglion, within the differential diagnosis of retroperitoneal mass and sympathetic symptoms may aid in clinical decision making in atypical cases.