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 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.

A Comparison of Outcomes in Medullary Thyroid Carcinoma Patients With and Without a Preoperative Diagnosis: A Multicenter Retrospective Cohort Study.

Background: Cytological limitations pose a challenge to preoperative diagnosis of medullary thyroid carcinoma (MTC) and therefore, a significant subset of patients is only diagnosed postoperatively. The objective of this study was to investigate the impact of knowledge of a preoperative MTC diagnosis on disease management and outcomes. Methods: Multicenter, retrospective, cohort study of MTC patients treated in Israel from January 2000 to June 2021. We compared cohorts of patients according to the presence or absence of a preoperative MTC diagnosis. Results: Ninety-four patients with histologically confirmed MTC were included (mean age 56.2 ± 14.3 years, 43% males). Fifty-three patients (56%) had a preoperative MTC diagnosis (preop-Dx group), and 41 (44%) were confirmed only postoperatively (no-Dx group). The extent of surgical resection, including completion procedures, was as follows: total thyroidectomy in 83% versus 100% (p = 0.002), central lymph node dissection (LND) in 46% versus 98% (p < 0.001), ipsilateral lateral LND in 36% versus 79% (p < 0.001), and contralateral lateral LND in 17% versus 28% (NS), in the no-Dx versus the preop-Dx group, respectively. Pathology confirmed a smaller median tumor size of 16 ± 17.4 mm versus 23 ± 14.0 mm (p = 0.09), a higher proportion of micro-MTC (size ≤10 mm) 32% versus 15% (p = 0.03), and a higher rate of co-occurrence of follicular cell-derived carcinoma 24% versus 4% (p = 0.003), in the no-Dx compared to the preop-Dx group, respectively. The rates of extrathyroidal and extranodal tumor extension were not significantly different between the groups. At the last follow-up, the biochemical cure was attained in 55% [CI 0.38-0.71] compared to 64% [CI 0.50-0.77] of the no-Dx and the preop-Dx group, respectively (p = 0.41). After the exclusion of patients with micro-MTC, biochemical cure was more commonly achieved in the preop-Dx group (33% [CI 0.14-0.52] vs. 62% [CI 0.46-0.77], p = 0.04). Preop-Dx patients had improved overall survival compared to the no-Dx group (log-rank p = 0.04) over a median follow-up of 82 months (interquartile range [IQR] 30-153). Conclusions: Preoperatively, the diagnosis of MTC is often missed. An accurate preoperative diagnosis of MTC may enable guideline-concordant surgical treatment and ultimately contribute to an overall survival benefit in MTC patients.

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.

The prognostic value of lymph node ratio in Medullary thyroid carcinoma: A multi-center study.

INTRODUCTION: The lymph node ratio (LNR), which represents the proportion of metastatic lymph nodes resected, has been found to be a prognostic variable in several cancers, but data for Medullary thyroid carcinoma (MTC) are sparse. The aim of this study was to determine the value of the LNR in predicting outcome in patients with MTC. MATERIALS AND METHODS: A retrospective multicenter study design of 107 patients with MTC who underwent total thyroidectomy with neck dissection between 1984 and 2016. The association of LNR with patient and tumor characteristics and prognostic factors was evaluated. RESULTS: Study population consisted of 53.3% female, mean age at diagnosis was 50.3 ± 18.4 years; 16.8% had inherited MTC. LNR was positively correlated with tumor size (p = 0.018) and inversely correlated with age at diagnosis (p = 0.024). A higher LNR was associated with extrathyroidal extension (p < 0.001), multifocality (p = 0.001), bilateral tumor (p = 0.002), distant metastases (p < 0.001), and tumor recurrence (OR = 14.7, p < 0.001). LNR was also correlated to postoperative calcitonin levels (p < 0.001) and carcinoembryonic antigen (p = 0.011). LNR >0.1 was associated with shorter disease-specific survival in patients at risk: tumor larger than 20 mm at diagnosis (p = 0.013), sporadic MTC (p = 0.01), and age above 40 years at diagnosis (p = 0.004). Cox multivariate survival analysis revealed LNR as the only significant independent factor for disease free survival (p = 0.005). CONCLUSIONS: This study showed that LNR correlates well with patient and tumor characteristics and prognostic variables. We suggest that LNR should be considered an important parameter for predicting outcome in MTC.

Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study.

Introduction: The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN <2 cm of diameter. Several retrospective series demonstrated that a non-operative management is safe and feasible, but no prospective studies are available. Aim of the ASPEN study is to evaluate the optimal management of asymptomatic NF-PanNEN ≤2 cm comparing active surveillance and surgery. Methods: ASPEN is a prospective international observational multicentric cohort study supported by ENETS. The study is registered in ClinicalTrials.gov with the identification code NCT03084770. Based on the incidence of NF-PanNEN the number of expected patients to be enrolled in the ASPEN study is 1,000 during the study period (2017-2022). Primary endpoint is disease/progression-free survival, defined as the time from study enrolment to the first evidence of progression (active surveillance group) or recurrence of disease (surgery group) or death from disease. Inclusion criteria are: age >18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at 68Gallium DOTATOC-PET scan. Conclusion: The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach.

Clinico-pathologic and dynamic prognostic factors in sporadic and familial medullary thyroid carcinoma: an Israeli multi-center study.

OBJECTIVE: Multiple clinical, pathological and biochemical variables, including the response to initial treatment, are associated with medullary thyroid carcinoma (MTC) prognosis. Studies that include separate analyses of familial and sporadic MTC patients followed for long period are scarce. This study evaluated the association between baseline clinico-pathologic variables and response to initial treatment and short- and long-term disease outcomes in sporadic and familial MTC. METHODS: Patients treated for MTC at four tertiary medical centers were retrospectively analyzed. Clinical and pathological data were collected. The outcomes measured included disease persistence 1 year after diagnosis, disease persistence at last follow-up, disease-related mortality (DRM) and all-cause mortality. RESULTS: The study enrolled 193 patients (mean age: 48.9 ± 18.7, 44.7% males), of whom 18.1% were familial cases. The mean follow-up period was 10.1 ± 9.4 years (8.5 ± 8.1 in sporadic and 16.9 ± 11.6 in familial MTC). Disease persistence 1-year after diagnosis and at last follow-up was detected in 56.1 and 60.4% patients, respectively. All-cause and DRM were 28.5 and 12.6%, respectively. Extra-thyroidal extension (ETE) and distant metastases (DM) were associated with disease persistence at last follow-up. ETE and DM were also significantly associated with DRM. Complete remission 1 year after diagnosis had high correlation with no evidence of disease at last follow-up (Cramer's V measure of association 0.884, P < 0.001) and with 100% disease-specific survival (Cramer's V measure of association 0.38, P < 0.001). CONCLUSIONS: Apart from clinico-pathologic parameters, close correlation was found between 1-year status and long-term prognosis. These results underscore the importance of combining classical and dynamic factors for both sporadic and familial MTC prognostication and treatment decision making.

Vitamin D diminishes the high platelet aggregation of type 2 diabetes mellitus patients.

Platelet activation is found in inflammatory conditions and implicated in the pathogenesis of chronic medical conditions, such as atherosclerosis, coronary vascular disease, cerebrovascular disease, and diabetes mellitus (DM). HbA1c is inversely related to vitamin D25 levels in individuals with and without DM. This study aimed to determine the relation between platelet aggregation, vitamin D and HbA1c among healthy individuals and those with Type 2 DM (T2DM). The direct effect of vitamin D1, 25 (calcitriol) on platelet aggregation was also investigated. The study included four groups: A. normoglycemic Control group: HbA1c<5.7%; B. Pre-diabetes (DM): 5.7% ≥ HbA1c ≤ 6.4%; C. DM on aspirin therapy: HbA1c>6.4%(+)Asp.; and D. DM not on aspirin therapy: HbA1c > 6.4%(-)Asp. Platelet aggregation was tested with and without calcitriol or saline pre-treatment, using collagen or adenosine diphosphate (ADP) as agonists. Platelet aggregation was higher in DM(-)Asp group compared to normoglycemic and DM(+)Asp, and higher, but not significant compared to pre-DM. The entire study population exhibited negative correlation between HbA1c and serum concentration of vitamin D25. Excluding DM(+)Asp, aggregation induced by collagen was significantly higher in patients with insufficient (<76 nmol/L) vitamin D25 compared to sufficient (≥76 nmol/L) vitamin D25. In this cohort, a negative correlation was found between serum concentrations of vitamin D25 and collagen-induced percent maximum (%max) aggregation and area under curve (AUC) aggregation. In the DM(-)Asp group, collagen-induced aggregation was reduced by approximately 25% after calcitriol treatment. Calcitriol decreased ADP-induced aggregation of control and DM(+)Asp groups to approximately 85% of saline treatment. We conclude that glycemic control is inversely associated with high platelet aggregation and low vitamin D25 levels. This elevated aggregation could be regulated by a novel, direct effect of calcitriol, indicating a beneficial effect of vitamin D on vascular complications related to diabetes. We offer a possible non-genomic mechanism for the vitamin D/Vitamin D receptor (VDR) pathway.

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.

Temporal Trends in the Presentation, Treatment, and Outcome of Medullary Thyroid Carcinoma: An Israeli Multicenter Study.

BACKGROUND: The widespread use of neck sonography in recent years has led to a dramatic increase in the detection of thyroid cancer, accompanied by changes in the clinicopathologic features of the disease. However, small papillary carcinomas account for the bulk of this increase, while little is known about temporal changes in medullary thyroid carcinoma (MTC). The aim of this study was to evaluate trends in the presentation, treatment, and outcome of MTC. METHODS: Patients treated for MTC at four medical centers in Israel were divided into three groups by year of diagnosis: 19811995 (period A), 1996-2005 (period B), and 2006-2016 (period C). Clinicopathologic and survival data were collected retrospectively from the medical files and compared between the groups. RESULTS: The cohort included 182 patients (54.9% female) with a mean age of 49.2 ± 18.7 years: 43 (23.6%) diagnosed in period A, 54 (29.7%) in period B, and 85 (46.7%) in period C. No significant differences were found between the groups in primary tumor size (25.7 ± 18.9 mm, 26.6 ± 18 mm, and 23.7 ± 17.6 mm, respectively), proportion of micro-MTC (30.8%, 20.0%, and 25.3%, respectively), or TNM staging. Age at diagnosis significantly increased over time (38.7 ± 17.2 years, 51.7 ± 18.4 years, and 53.7 ± 17.7 years, respectively; p < 0.001), and the rate of familial MTC significantly decreased (41.9%, 14.8%, and 8.2%, respectively; p = 0.002). Although the implementation of cervical lymph node dissection increased (62.1%, 78.4%, and 85%, respectively; p = 0.01), detection of metastatic lymph nodes decreased from 88.9% in period A to 65.0% in periods B and C (p = 0.06). There was no difference between the groups in disease-specific survival or disease-free state at one year from diagnosis (37.5%, 43.1%, and 50%, respectively) and last follow-up (27%, 41.2%, and 48%, respectively). Similar findings on MTC presentation and outcomes were obtained when only patients with non-familial MTC were analyzed. CONCLUSIONS: Unlike differentiated thyroid cancer, most of the presenting features of MTC have not changed over time. The most significant temporal change is a decreased rate of familial MTC. Despite more extensive surgery and the use of new treatment modalities in recent years, significant improvement in disease-related outcomes were not found.

VARIATIONS IN CLINICAL AND IMAGING FINDINGS BY TIME OF DIAGNOSIS IN FEMALES WITH HYPOPITUITARISM ATTRIBUTED TO LYMPHOCYTIC HYPOPHYSITIS.

OBJECTIVE: To describe the various patterns of presentation, including assisting analyses, associated with the timing of diagnosis of females with hypopituitarism and suspected clinical diagnosis of lymphocytic hypophysitis. METHODS: A retrospective study of 9 consecutive females with pituitary dysfunction developed during or after pregnancy. All subjects were treated in our clinics between 2008 and 2014. Data were collected on clinical characteristics, pituitary hormone levels, and imaging findings. RESULTS: The study group included 9 patients with a mean age 33.7 ± 7.8 years at delivery. The probable cause of disease was lymphocytic hypophysitis. Headache or specific symptoms/signs of hypopituitarism appeared within 1 year of delivery. Five patients had headache, and 8 had difficulty breastfeeding or amenorrhea. Laboratory findings included central hypocortisolism (8/9 patients), hypogonadotropic hypogonadism (8/9), and central hypothyroidism (6/7). Insulin-like growth factor-1 (IGF-1) levels were low in 8/8 patients. Prolactin levels were low in 3/9 patients, and 1 patient had diabetes insipidus. Seven patients were diagnosed less than 1 year from symptom onset; 4 (57%) complained of headaches, and 5 (71%) had panhypopituitarism. Two patients were diagnosed later. Both had difficulty breastfeeding and amenorrhea, and one also had headaches. Both had panhypopituitarism and reduced pituitary volume. None of the patients fully recovered pituitary function. Normalization of the thyrotroph axis occurred in 3 patients, gonadotroph function in 3, the corticotroph axis in 2, and IGF-1 normalized in 1 subject. CONCLUSION: Hypopituitarism attributed to lymphocytic hypophysitis may present during pregnancy or early postpartum period with a clear clinical picture, or later, with indolent and nonspecific symptoms and signs.

New-onset diabetes in elderly subjects: association between HbA1c levels, mortality, and coronary revascularization.

OBJECTIVE: New-onset diabetes mellitus (DM) in elderly patients is associated with increased risk of diabetes complications and mortality. It is unknown whether glycemic control in this population influences the mortality risk. RESEARCH DESIGN AND METHODS: The current study was conducted using the computerized database of the Sharon-Shomron District of Clalit Health Services in Israel. Included in the study were subjects 65 years of age and above with new-onset DM. The primary outcome measures were all-cause mortality and coronary revascularization procedures with either percutaneous coronary intervention or coronary artery bypass grafting. RESULTS: Participants (n = 2,994) were stratified into four groups according to their mean HbA1c levels during the follow-up period (<6.5% [48 mmol/mol], 6.5-6.99% [48-52 mmol/mol], 7-7.49% [53-57 mmol/mol], and ≥7.5% [58 mmol/mol]). During a mean follow-up of 5.54 ± 2.1 years, 1,173 (39.17%) participants died and 285 (9.51%) underwent coronary revascularization. An HbA1c level >7.5% (58 mmol/mol) was associated with a significantly increased all-cause mortality rate (hazard ratio [HR] 1.74 [95% CI 1.2-1.8], P < 0.0001). This difference remained statistically significant after a multivariate model adjusted for the conventional cardiovascular risk factors and for the use of hypoglycemic agents and statins. Kaplan-Meier survival plots revealed lower survival rates in this group of patients. Coronary revascularization rates were highest among subjects with HbA1c 6.5-6.99% (48-52 mmol/mol) (HR 1.6 [1.01-2.4], P < 0.05) and lowest in patients with HbA1c ≥7.5% (58 mmol/mol). CONCLUSIONS: An HbA1c level >7.5% (58 mmol/mol) is associated with increased risk for all-cause mortality and with a lower revascularization rate in elderly patients with new-onset DM.