Germline CDKN1B variant type and site are associated with phenotype in MEN4.

Multiple endocrine neoplasia 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome clinically hallmarked by primary hyperparathyroidism (PHPT), pituitary adenoma (PitAd), and neuroendocrine tumors (NET), clinically overlapping MEN1. The underlying mutated gene - CDKN1B, encodes for the cell-cycle regulator p27. Possible genotype-phenotype correlations in MEN4 have not been thoroughly assessed. Prompted by the findings in three Israeli MEN4 kindreds, we performed a literature review on published and unpublished data from previously reported MEN4/CDKN1B cases. Univariate analysis analyzed time-dependent risks for developing PHPT, PitAd, or NET by variant type and position along the gene. Overall, 74 MEN4 cases were analyzed. PHPT risk was 53.4% by age 60 years (mean age at diagnosis age 50.6 ± 13.9 years), risk for PitAd was 23.2% and risk for NET was 16.2% (34.4 ± 21.4 and 52.9 ± 13.9 years, respectively). The frameshift variant p.Q107fs was the most common variant identified (4/41 (9.7%) kindreds). Patients with indels had higher risk for PHPT vs point mutations (log-rank, P = 0.029). Variants in codons 94-96 were associated with higher risk for PHPT (P < 0.001) and PitAd (P = 0.031). To conclude, MEN4 is clinically distinct from MEN1, with lower risk and older age for PHPT diagnosis. We report recurrent CDKN1B frameshift variants and possible genotype-phenotype correlations.

High Prevalence of Acromegaly in Different Industrial Areas: A Population-based Study from Haifa and Western Galilee District in Northern Israel.

BACKGROUND: National registries for acromegaly and population-based data make an important contribution to disease understanding and management. Data concerning the epidemiology of acromegaly in Israel is scanty. OBJECTIVES: To evaluate the epidemiology of acromegaly in different industrial areas in northern Israel. METHODS: Data from adult patients diagnosed with acromegaly from 2000 to 2020, living in Haifa and the western Galilee District were collected using the electronic database and medical records from Clalit Health Services. The prevalence of acromegaly in three distinct areas and overall were reported. In addition, other epidemiological data including associated co-morbidities, pituitary tumor size, and treatment modalities were collected. RESULTS: We identified 77 patients with a confirmed diagnosis of acromegaly. The overall prevalence was 155 cases/106 inhabitants without statistically significant differences between the three areas. The mean age at diagnosis was 50 ± 1.8 years and the male to female ratio was 1.1. Macroadenoma and microadenoma were identified in 44 (57%) and 25 (33%), respectively. The frequency rate of acromegaly-associated co-morbidities such as diabetes, hypertension, carpal tunnel syndrome, and osteoporosis was similar to previously reported studies. The mean body mass index (BMI) was 29 ± 5.6 kg/m2 .Obesity, with a BMI ≥ of 30 kg/m2, was found in 29 patients (38%). The majority of patients underwent transsphenoidal surgery 67 (87%). Normalized insulin-like growth factor 1 was reported in 64 (83%). CONCLUSIONS: A high prevalence of acromegaly was found in northern Israel. The pituitary microadenoma frequency rate is the highest reported.

Long-term safety and efficacy of long-acting pasireotide in acromegaly.

BACKGROUND: Pasireotide long acting (LAR) can be effective in normalizing insulin-like growth factor (IGF)-1 level in acromegaly patients inadequately controlled by octreotide or lanreotide. OBJECTIVE: Determine the long-term efficacy and safety of pasireotide, including time to biochemical control and time to best response, and risk for diabetes mellitus. METHODS: A retrospective multicenter study investigating the efficacy and safety of pasireotide LAR treatment in patients with active acromegaly treated for >12 months. RESULTS: The study included 19 patients (10 men; mean age ± SD, 48.0 ± 12.9 years) treated with pasireotide for a mean of 50 ± 36 months. During the follow-up, 4 patients discontinued pasireotide treatment. Pasireotide LAR produced a tolerable and long-term significant biochemical response in 15 of 19 patients (79.0%). Mean time to IGF-1 normalization from pasireotide LAR initiation was 13.6 ± 16.9 months with early biochemical normalization (<12 months) evident in 11 (64.7%) patients and delayed IGF-1 normalization in 6 (35.2%) patients. Nadir IGF-1 values were recorded within the first 12 months in 6 patients (35.3%), while in 11 patients (64.7%) lowest values were reported after >12 months of treatment, including 4 of 11 patients with early IGF-1 normalization. New-onset diabetes was documented in 5 of 7 patients with pre-diabetes and in 1 of 5 patients with normal glucose homeostasis at baseline. Among patients with pre-diabetes or diabetes mellitus prior to initiating pasireotide, mean HbA1c increase was 0.56 ± 1.0%. CONCLUSIONS: The results support the long-term efficacy and safety of pasireotide LAR for acromegaly and support the potential delayed effect of treatment on IGF-1 normalization.

Safety and Efficacy of Oral Human Parathyroid Hormone (1-34) in Hypoparathyroidism: An Open-Label Study.

The standard treatment of primary hypoparathyroidism (hypoPT) with oral calcium supplementation and calcitriol (or an analog), intended to control hypocalcemia and hyperphosphatemia and avoid hypercalciuria, remains challenging for both patients and clinicians. In 2015, human parathyroid hormone (hPTH) (1-84) administered as a daily subcutaneous injection was approved as an adjunctive treatment in patients who cannot be well controlled on the standard treatments alone. This open-label study aimed to assess the safety and efficacy of an oral hPTH(1-34) formulation as an adjunct to standard treatment in adult subjects with hypoparathyroidism. Oral hPTH(1-34) tablets (0.75 mg human hPTH(1-34) acetate) were administered four times daily for 16 consecutive weeks, and changes in calcium supplementation and alfacalcidol use, albumin-adjusted serum calcium (ACa), serum phosphate, urinary calcium excretion, and quality of life throughout the study were monitored. Of the 19 enrolled subjects, 15 completed the trial per protocol. A median 42% reduction from baseline in exogenous calcium dose was recorded (p = .001), whereas median serum ACa levels remained above the lower target ACa levels for hypoPT patients (>7.5 mg/dL) throughout the study. Median serum phosphate levels rapidly decreased (23%, p = .0003) 2 hours after the first dose and were maintained within the normal range for the duration of the study. A notable, but not statistically significant, median decrease (21%, p = .07) in 24-hour urine calcium excretion was observed between the first and last treatment days. Only four possible drug-related, non-serious adverse events were reported over the 16-week study, all by the same patient. A small but statistically significant increase from baseline quality of life (5%, p = .03) was reported by the end of the treatment period. Oral hPTH(1-34) treatment was generally safe and well tolerated and allowed for a reduction in exogenous calcium supplementation, while maintaining normocalcemia in adult patients with hypoparathyroidism. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Increased Risk of Antithyroid Drug Agranulocytosis Associated with Amiodarone-Induced Thyrotoxicosis: A Population-Based Cohort Study.

BACKGROUND: Agranulocytosis occurs in 0.2-0.5% of patients treated with the antithyroid drugs (ATDs) methimazole and propylthiouracil. The objectives of this study were to evaluate the risk of ATD-related agranulocytosis in patients with amiodarone-induced thyrotoxicosis (AIT), and to compare it with the agranulocytosis risk in patients with thyrotoxicosis due to other etiologies treated with ATDs. METHODS: This was a retrospective cohort study. Participants were 14,781 adult patients with thyrotoxicosis, newly treated with an ATD between January 1, 2002, and December 31, 2015. Among them were 593 patients treated by ATDs due to AIT. The main outcome measures were incidence rates and crude and adjusted hazard ratios using univariate and multivariable Cox regression models for ATD-related agranulocytosis within one year of treatment initiation, in association with AIT. RESULTS: Agranulocytosis occurred in 28 (0.19%) of patients newly treated with methimazole or propylthiouracil during the first year of follow-up. Of these 28 patients, 8/593 (1.35%) were AIT patients and 20/14,188 (0.14%) were thyrotoxic patients that was not AIT related (p < 0.001). Incidence rates were 22 (9.47-43.36) cases/1000 person-years of follow-up in AIT, and 1.79 (1.09-2.76)/1000 person-years of follow-up in non-AIT thyrotoxicosis (p < 0.0001). In univariate Cox regression analysis, risk for ATD agranulocytosis associated with AIT was 9.71 (4.28-22.05) compared to the risk in non-AIT thyrotoxicosis. In a multivariable model, adjusting for age, sex, body mass index, smoking history, year of cohort entry, diabetes mellitus, hypertension, renal failure, beta blockers, calcium channel blockers, anti-aggregants, and dose of ATDs, the risk associated with AIT was 5.70 (2.14-15.21). In a model adjusted for a propensity score to receive amiodarone, risk for ATD agranulocytosis associated with AIT was 6.32 (1.22-32.70). CONCLUSIONS: ATD use is associated with a higher risk for agranulocytosis in patients with AIT.

Efficacy and safety of long-acting pasireotide in patients with somatostatin-resistant acromegaly: a multicenter study.

INTRODUCTION: Pasireotide, a multi-somatostatin receptor (SSTR)-ligand with high affinity for SSTR5 was recently approved for acromegaly treatment. PATIENTS AND METHODS: A retrospective multicenter study investigating the efficacy and safety of long-acting (LAR) pasireotide treatment in 35 patients (20 males) with active acromegaly (28 macroadenomas). RESULTS: Mean baseline insulin-like growth factor-1 (IGF-1) at diagnosis was 3.1 ± 1.3 × ULN. All but five patients have undergone pituitary surgery and six received sellar radiotherapy. All remained with active acromegaly despite first-generation somatostatin analogue (SSA) treatment. Immediately before pasireotide-LAR initiation, eighteen patients were under SSA monotherapy and one with pegvisomant. The remaining patients received combination therapy with SSA and pegvisomant, n = 9 (two received cabergoline also); SSA and cabergoline, n = 4; pegvisomant and cabergoline, n = 1. Two were untreated. Mean IGF-1 was 1.76 ± 0.9 ULN before pasireotide. Pasireotide-LAR starting dose was 40 mg/4 weeks in most patients. IGF-1 normalized in 19 patients, IGF-1 between 1-1.2 × ULN was reached in five, and in additional two patients IGF-1 was significantly suppressed. No effect was seen in nine patients. Pasireotide dose was reduced by 20 mg in six patients with excellent response, with preserved IGF-1 control in five. Severe headaches in six patients disappeared or improved with pasireotide. Side effects consisted of symptomatic cholelithiasis in one patient and deterioration of glucose control in 22 patients, requiring initiation or intensification of antidiabetic treatment in seventeen. One patient developed diabetic ketoacidosis. CONCLUSIONS: In the real-life scenario ~54% of patients with acromegaly resistant to first-generation SSA, may normalize IGF-1 with pasireotide; however, 63% experienced glucose control deterioration.

"ECG variability contour" method reveals amplitude changes in both ischemic patients and normal subjects during Dipyridamole stress: a preliminary report.

To detect and quantify consistent ECG amplitude changes, the "ECG variability contour" (EVC) method was proposed. Using this method we investigated amplitude changes in subjects undergoing myocardial perfusion imaging (MPI) with Dipyridamole (Dp). Fifty-three patients having reversible perfusion defects and 19 normal subjects (NS) who were free of: perfusion defects on their MPI, standard ST-T changes during Dp stress, and a negative clinical follow up. Mean ∏¹(<∏¹>) was similar for the NS and patient group (6.2 ± 6.1 vs. 6.3 ± 6.2, P = 0.95). <∏¹> was 4.6 ± 3.0 in patients not having ST-T changes during Dp stress (n = 42), whereas in patients having ST-T changes (n = 11) it was 13.1 ± 10.2 (P < 0.001). For both groups <∏(QRS)> was smaller than <∏(ST)>, which in turn was smaller than <∏(T)>. The values of <∏(QRS)>, <∏(ST)>, and <∏(T)> for the NS, patients without and with ST-T changes were: 26.8 ± 28.6, 42.6 ± 41.8, 44.9 ± 36.5; 19.6 ± 20.8, 26.4 ± 31.4, 38.7 ± 27.3; 51.0 ± 30.0, 71.0 ± 36.8, 75.1 ± 20.9, respectively (P < 0.05 for all comparisons of patients with versus without ST-T changes). This study showed that Dp stress, with or without hypoperfusion, had a clear effect on myocyte electrophysiology, expressed by consistent ECG amplitude changes, detected by the EVC method. The EVC method did not distinguish between NS and patients in this clinical setting.

Changes in the initial slope of the QRS in ischemic patients and normal subjects undergoing scintigraphy with dipyridamole.

The effect of dipyridamole (Dp) on the linear portion of the first major deflection of the QRS in human electrocardiograms (which we refer to as Fslope) was investigated in the context of myocardial perfusion imaging (MPI), in normal subjects (NS, n=19) and in patients with cardiovascular ischemia (as manifested by a positive MPI scan, n=53). In the majority of participants, Fslope decreased (84% of 19 NS and 77% of 53 patients, p=0.69). The decrease in Fslope was more pronounced in patients with ST-T deviation as compared to those without (32.6±24.5 vs. 22.4±23.1, p=0.24), and in patients vs. NS (24.9±23.5 vs. 19.6±23.4, p=0.44). A change in Fslope is a sensitive (but not specific) measure for detecting the effect of Dp on the myocardium in the setting of scintigraphy.

Efficacy of long-term lanreotide treatment in patients with acromegaly.

We investigated the effectiveness of lanreotide for the treatment of active acromegaly in a retrospectively multicenter case series including 53 patients (24 male, 29 female; mean age at diagnosis, 49.5 +/- 13.9 years) with acromegaly treated with lanreotide in nine different centers. Mean tumor diameter was 20 +/- 13 mm; mean basal levels of growth hormone (GH) and insulin-like growth factor I (IGF-I) were 21.3 +/- 26.3 and 579 +/- 177 mug/l, respectively. The primary mode of treatment was surgery in 70% of patients. Twenty-nine patients received only lanreotide (Prolonged Release, Autogel), whereas 24 subjects were also treated with octreotide at another treatment stage. Primary therapy with lanreotide was administered in five patients. Maximal monthly dose of lanreotide Autogel (n = 44) was 60 mg in 45%, 90 mg in 26%, 120 mg in 21% and 180 mg in 8%. During 36 months of lanreotide treatment, mean IGF-I levels decreased from 443 +/- 238 to 276 +/- 147 mug/l (P < 0.001), and mean GH levels, from 5.2 +/- 6.4 to 3.2 +/- 3.0 mug/l (P < 0.001). IGF-I levels normalized in 51% of patients and decreased by >50% towards normal in 32%; the normalization rate was higher in women (65%) than men (33%, P = 0.04). Safe random GH levels (