Adrenal Vein Sampling for Primary Aldosteronism: Recommendations From the Australian and New Zealand Working Group.

Adrenal vein sampling (AVS) is the current recommended procedure for identifying unilateral subtypes of primary aldosteronism (PA), which are amenable to surgery with the potential for cure. AVS is a technically challenging procedure usually undertaken by interventional radiologists at tertiary centres. However, there are numerous variations in AVS protocols relating to patient preparation, sampling techniques and interpretation which may impact the success of AVS and patient care. To reduce practice variations, improve the success rates of AVS and optimise patient outcomes, we established an Australian and New Zealand AVS Working Group and developed evidence-based expert consensus recommendations for the preparation, performance and interpretation of AVS. These recommendations can be used by all healthcare professionals in a multidisciplinary team who look after the diagnosis and management of PA.

Accuracy of ethnicity records at primary and secondary healthcare services in Waikato region, Aotearoa New Zealand.

AIMS: Ethnicity is an important variable, and in Aotearoa New Zealand it is used to monitor population health needs, health services outcomes and to allocate resources. However, there is a history of undercounting Maori. The aim of this study was to compare national and primary care ethnicity data to self-reported ethnicity from a Kaupapa Maori research cohort in the Waikato region. METHODS: Through individual record linkage, prospective self-reported ethnicity, collected using New Zealand Census and Ministry of Health - Manatu Hauora ethnicity protocol as a "gold standard", was compared to ethnicity in secondary and primary healthcare datasets. Logistic regression analyses were used to determine if demographic variables such as age, ethnicity and deprivation are associated with inaccuracies in ethnicity recording. RESULTS: Maori were undercounted in secondary NHI (32.5%) and primary care (31.3%) datasets compared to self-reported (34.6%). Between 9.5-11% of individuals had a different ethnicity recorded in health datasets than self-reported. Multiple ethnicities were less often recorded (secondary NHI [5.3%] and primary care [5.8%]) compared to self-reported (8.7%). Maori ethnicity (p=0.039) and multiple ethnicity (p<0.001) were associated with lower ethnicity data accuracy. CONCLUSION: Routine health datasets fail to adequately collect ethnicity, particularly for those with multiple ethnicities. Inaccuracies disproportionately affect Maori and urgent efforts are needed to improve compliance with ethnicity data standards at all levels of the health system.

Genetic testing for familial hyperaldosteronism type 1 in Aotearoa/New Zealand.

BACKGROUND: Primary aldosteronism (PA) is the most common secondary endocrine cause of hypertension with familial hyperaldosteronism type 1 (FH-1), a rare heritable subtype. Timely identification of FH-1 is important because of an increased risk of vascular events in affected individuals and because it provides the opportunity to guide appropriate treatment. Genetic testing is recommended if onset is at a young age (<20 years), there is a family history of PA or early cerebrovascular events occur. AIMS: To assess national rates of testing for FH-1, whether this varied over time and by region. METHODS: De-identified data were obtained on genetic testing performed for FH-1 from 1 April 2010 to 30 October 2023 (163 months) from the Canterbury Health Laboratories database, the sole national testing laboratory for FH-1. RESULTS: A total of 147 tests were performed, of which 19 (12.9%) were positive. Eleven of the positive tests were requested by one region. Testing rates varied from 0.00 to 0.63 per 100 000 people per annum. Most tests were requested by endocrinology services. Testing increased over time from an average of 4.6 tests per annum in the first 5 years of the period studied to 17.7 tests in the most recent 5 years. Limitations include lack of ethnicity data, information on testing indications and testing rates for other familial PA subtypes. CONCLUSIONS: Testing for FH-1 has increased over time but remains low. Testing for familial forms of PA should be considered in those in whom PA was diagnosed at a young age or with a suggestive family history.

Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles.

Hereditary SDHB-mutant pheochromocytomas (PC) and paragangliomas (PG) are rare tumours with a high propensity to metastasize although their clinical behaviour is unpredictable. To characterize the genomic landscape of these tumours and identify metastasis biomarkers, we performed multi-omic analysis on 94 tumours from 79 patients using seven molecular methods. Sympathetic (chromaffin cell) and parasympathetic (non-chromaffin cell) PCPG had distinct molecular profiles reflecting their cell-of-origin and biochemical profile. TERT and ATRX-alterations were associated with metastatic PCPG and these tumours had an increased mutation load, and distinct transcriptional and telomeric features. Most PCPG had quiet genomes with some rare co-operative driver events observed, including EPAS1/HIF-2α mutations. Two mechanisms of acquired resistance to DNA alkylating chemotherapies were also detected - MGMT overexpression and mismatch repair-deficiency causing hypermutation. Our comprehensive multi-omic analysis of SDHB-mutant PCPG therefore identified features of metastatic disease and treatment response, expanding our understanding of these rare neuroendocrine tumours.

Systematic Review-Type B Insulin Resistance With Isolated Hypoglycemia and Suppressed Insulin.

OBJECTIVE: Type B insulin resistance syndrome is a rare autoimmune disorder affecting glucose homeostasis, characterized by serum autoantibodies to the insulin receptor (AIRAbs). Patients typically present with severe insulin resistance. A mixed hyper- and hypoglycemia phenotype may also occur, as may isolated hypoglycemia. The classic biochemical pattern comprises elevated insulin levels despite hypoglycemia; however, a small proportion of cases demonstrate "isolated hypoglycemia with low insulin." The primary objectives of this systematic review were to identify the clinical characteristics and outcome of this subgroup. DESIGN: Systematic review of cases with hypoglycemia with suppressed insulin. Exclusions: hyperglycemia, elevated insulin, AIRAbs not confirmed. METHODS: PubMed, Medline, and Embase databases were searched up until February 2023 and complemented by manual citation search. The Joanna Briggs Institute critical appraisal checklist for case reports was used to assess bias. RESULTS: A total of 5342 articles were identified after duplicate removal. Eleven, all case reports, met all inclusion criteria and were included. Cases belonging to this subgroup were more diverse in sex, age, and ethnicity when compared with type B insulin resistance as a whole. Of the 11 cases, 3 developed lymphoma. High-dose corticosteroid therapy appeared to be effective therapy for the hypoglycemia, with often rapid response. CONCLUSIONS: Isolated hypoglycemia with low insulin forms a rare subgroup of type B insulin resistance. These patients lack the common characteristics of hyperinsulinemic hypoglycemia and hyperglycemia/insulin resistance. Furthermore, while coexisting autoimmune disease is commonly observed, there is potentially an association with aggressive lymphoma, the onset of which may be delayed.

Systematic Review of Therapeutic Agents and Long-Term Outcomes of Familial Hyperaldosteronism Type 1.

BACKGROUND: Familial hyperaldosteronism type 1 (FH1), previously known as glucocorticoid-remediable aldosteronism, was the first identified monogenic cause of primary aldosteronism. Patients classically develop hypertension at a young age and are at risk of premature vascular complications. A systematic review of FH1 was performed to determine long-term treatment outcomes. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted searches with a patient/population, intervention, comparison and outcomes (PICO) framework using Embase, Medline, PubMed, Scopus, and Web of Science databases to identify patients with FH1 prescribed either no treatment with a minimum 3 months follow-up or medical treatment of at least 3 months duration. RESULTS: A total of 99 FH1 cases were identified from 42 studies. Most had early-onset hypertension but variable hypokalemia, hyperaldosteronism, and hyporeninemia. Of the 62 cases with a reported age of FH1 diagnosis, median age was 18 ± 17.6 years old. Of those treated, 72% received a glucocorticoid for long-term treatment compared with 22% receiving a potassium-sparing diuretic. Data on long-term treatment and disease side effects, complications, and outcomes were seldom reported. However, of 20 patients with reported complications, premature vascular complications were evident with the median age of diagnosis for left ventricular hypertrophy and hypertensive retinopathy 15 and 16.5 years old respectively, the youngest age of aortic dissection age 10 years, and those with reported cerebrovascular history had strokes or transient ischemic attacks before age 40 years. CONCLUSIONS: Major gaps in the literature around FH1 patients' long-term treatment and disease outcomes still exist. Long-term outcome data are required to help inform clinicians of the best long-term treatment for FH1.

A Clinicopathologic and Molecular Analysis of Fumarate Hydratase-deficient Pheochromocytoma and Paraganglioma.

Up to 40% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are hereditary. Germline mutations/deletions in fumarate hydratase ( FH ) cause hereditary leiomyomatosis and renal cell carcinoma syndrome which manifests predominantly with FH-deficient uterine/cutaneous leiomyomas and renal cell carcinomas (RCCs)-tumors characterized by loss of immunohistochemical (IHC) expression of FH and/or positive staining for S-(2-succino)-cysteine. Occasional patients develop PCC/PGL. We investigated the incidence, morphologic, and clinical features of FH-deficient PCC/PGL. We identified 589 patients with PCC/PGLs that underwent IHC screening for FH and/or S-(2-succino)-cysteine. Eight (1.4%) PCC/PGLs were FH deficient (1.1% in an unselected population). The median age for FH-deficient cases was 55 (range: 30 to 77 y) with 50% arising in the adrenal. All 4 with biochemical data were noradrenergic. Two (25%) metastasized, 1 dying of disease after 174 months. Germline testing was performed on 7 patients, 6 of whom had FH missense mutations. None were known to have a significant family history before presentation or developed cutaneous leiomyomas, or FH-deficient RCC at extended follow-up. The patient wild-type for FH on germline testing was demonstrated to have somatic FH mutation and loss of heterozygosity corresponding to areas of subclonal FH deficiency in her tumor. One patient did not undergo germline testing, but FH mutation was demonstrated in his tumor. We conclude that FH-deficient PCC/PGL are underrecognized but can be identified by IHC. FH-deficient PCC/PGL are strongly associated with germline missense mutations but are infrequently associated with leiomyoma or RCC, suggesting there may be a genotype-phenotype correlation. FH-deficient PCC/PGL may have a higher metastatic risk.

Ethnic differences in patients undergoing thyroidectomy for non-toxic multinodular goitre.

BACKGROUND: Maori have an increased incidence of thyrotoxicosis when compvared to non-Maori, however there are limited data on benign non-toxic nodular thyroid disease. AIMS: The aims of this study were to determine the rates of non-toxic multinodular goitre (NTMNG) surgery for Maori and non-Maori and to determine if there were differences in thyroid size between Maori and non-Maori undergoing total thyroidectomy for NTMNG. METHODS: Single centre study of patients undergoing thyroidectomy for NTMNG from 1 December 2006 to 30 November 2016. RESULTS: Maori were overrepresented amongst the 427 patients who underwent surgery for NTMNG at 34% compared to the expected ~17% of the background Maori adult population in the region. At the time of surgery, Maori were younger (P = 0.004) and had a larger thyroid gland (P < 0.001) when compared to non-Maori also undergoing total/near total thyroidectomy. Complication rates were low across all ethnic groups. CONCLUSION: Maori have increased rates of surgery for NTMNG compared to non-Maori and thyroid size is larger at the time of surgery. The reasons for this are currently unknown and more research is required.

Systematic Review: Incidence of Pheochromocytoma and Paraganglioma Over 70 Years.

Context: Pheochromocytomas and paragangliomas (PPGLs) are known to be rare. However, there is scant literature reporting their epidemiology, particularly whether the diagnosis of PPGL has increased with advances in medical imaging and biochemical and genetic testing. Objective: The primary objective of this systematic review was to determine the annual incidence of PPGLs and change over time. Design: A systematic review was performed. Medline, Embase, PubMed, and Web of Science Core Collection databases were searched to identify studies reporting PPGL incidence. Studies were eligible for inclusion from the database's inception until August 30, 2021. Results: A total of 6109 manuscripts were identified; 2282 duplicates were excluded, and a further 3815 papers were excluded after abstract and/or full text review. Twelve studies were included in the final review. The incidence of PPGL ranged from 0.04 to 0.95 cases per 100 000 per year. Incidence increased over time, from approximately 0.2/100,000 individuals in studies performed before 2000, to approximately 0.6/100,000 in studies undertaken after 2010. The mode of diagnosis changed over the same time period, with more patients diagnosed from incidental imaging findings, and fewer at autopsy or from symptoms. Conclusion: The annual incidence of PPGL has increased over time. Much of this increase is likely from incidental identification of tumors on imaging. However, the epidemiology of PPGL remains understudied, in particular, in associations with altitude, ethnicity, and genetics. To improve early detection and management guidelines, these gaps should be addressed.

Autosomal Dominant Hypocalcemia Type 1 (ADH1) Associated With Myoclonus and Intracerebral Calcifications.

Autosomal dominant hypocalcemia type 1 (ADH1) is a disorder of extracellular calcium homeostasis caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR). More than 35% of ADH1 patients have intracerebral calcifications predominantly affecting the basal ganglia. The clinical consequences of such calcifications remain to be fully characterized, although the majority of patients with these calcifications are considered to be asymptomatic. We report a 20-year-old female proband with a severe form of ADH1 associated with recurrent hypocalcemic and hypercalcemic episodes, persistent childhood hyperphosphatemia, and a low calcium/phosphate ratio. From the age of 18 years, she had experienced recurrent myoclonic jerks affecting the upper limbs that were not associated with epileptic seizures, extra-pyramidal features, cognitive impairment, or alterations in serum calcium concentrations. Computed tomography (CT) scans revealed calcifications of the globus pallidus regions of the basal ganglia bilaterally, and also the frontal lobes at the gray-white matter junction, and posterior horn choroid plexuses. The patient's myoclonus resolved following treatment with levetiracetam. CASR mutational analysis identified a reported germline gain-of-function heterozygous missense mutation, c.2363T>G; p.(Phe788Cys), which affects an evolutionarily conserved phenylalanine residue located in transmembrane domain helix 5 of the CaSR protein. Analysis of the cryo-electron microscopy CaSR structure predicted the wild-type Phe788 residue to form interactions with neighboring phenylalanine residues, which likely maintain the CaSR in an inactive state. The p.(Phe788Cys) mutation was predicted to disrupt these interactions, thereby leading to CaSR activation. These findings reveal myoclonus as a novel finding in an ADH1 patient with intracerebral calcifications.

A typical presentation of type B insulin resistance syndrome with isolated hypoglycaemia and suppressed insulin.

Type B insulin resistance syndrome is a rare autoimmune disorder affecting glucose homeostasis characterised by the presence of serum autoantibodies to the insulin receptor. Typically, these patients present with severe insulin resistance although a mixed hyperglycaemic and hypoglycaemic phenotype may also occur, as can an exceptionally rare isolated hypoglycaemia presentation. The classic biochemical pattern comprises elevated insulin levels despite significant hypoglycaemia. We report an adult man presenting with isolated hypoglycaemia and suppressed serum insulin and C-peptide levels. He demonstrated evidence of autoimmunity with positive antinuclear antibodies, reactive lymphadenopathy and cytopaenias but did not meet the criteria for systemic lupus erythematosus and underlying malignancy was not identified despite extensive investigation. Insulin receptor antibodies were present. Treatment with prednisone led to resolution of hypoglycaemia, with no recurrence after 36 months of follow-up. However, 42 months after initial presentation, he represented with high-grade lymphoma.

Pituitary function following peptide receptor radionuclide therapy for neuroendocrine tumours.

Peptide receptor radionuclide therapy (PRRT) is an increasingly used treatment for unresectable neuroendocrine tumours (NETs) that express somatostatin receptors. Normal pituitary tissue expresses somatostatin receptors so patients receiving PRRT may be at risk of developing hypopituitarism. The aim was to assess the prevalence of clinically significant hypopituitarism a minimum of 2 years following radioisotope therapy for metastatic NET. This was a multicentre study (Australia and New Zealand). Sixty-six patients with unresectable NETs were included-34 had received PRRT and 32 comparison patients. Median follow-up after PRRT was 68 months. Male hypogonadism was the most common hormonal abnormality (16 of 38 men [42%]) from the total cohort. Of these, seven men had primary hypogonadism (five from PRRT group) and nine had secondary hypogonadism (six in PRRT group). There was no difference in either male hypogonadism or other hormonal dysfunction between patients who had received PRRT and those that had not. Patients who have received PRRT out to 68 months following treatment do not show concerning hypopituitarism although there may be the suggestion of growth hormone deficiency developing. However, hypogonadism is common in men with NETs so the gonadal axis should be assessed in men with suggestive symptoms as the treatment of testosterone deficiency may improve the quality of life.

Thyrotoxicosis in an Indigenous New Zealand Population - a Prospective Observational Study.

BACKGROUND: Reported international incidence rates of thyrotoxicosis vary markedly, ranging from 6 to 93 cases per 100 000 per annum. Along with population demographics, exposures, and study design factors, ethnicity is increasingly being recognized as a potential factor influencing incidence. This study aimed to document the epidemiology and clinical presentation of thyrotoxicosis for Maori, the indigenous population in New Zealand. METHODS: A prospective study of adult patients presenting with a first diagnosis of thyrotoxicosis between January 2013 and October 2014 to a single New Zealand center. Demographic data were collected, and detailed clinical assessment performed. RESULTS: With 375 patients, an incidence rate of thyrotoxicosis of 73.0 per 100 000 per annum was identified. Of these, 353 (94.1%) participated in the study. The median age of the cohort was 47 years, 81% were female, and 58% had Graves disease. The overall incidence of thyrotoxicosis for Maori, the indigenous people of New Zealand, was higher than non-Maori (123.9 vs 57.3 per 100 000 per annum). Rates of both Graves disease and toxic multinodular goiter were higher in Maori as compared to non-Maori (incidence rate ratios of 1.9 [1.4, 2.6] and 5.3 [3.4, 8.3], respectively), with this increase being maintained after controlling for age, deprivation, and smoking. CONCLUSIONS: Maori, the indigenous people of New Zealand, have an increased incidence of thyrotoxicosis compared to non-Maori and, in particular, toxic multinodular goiter. A greater understanding of the epidemiology of thyrotoxicosis in other indigenous and marginalized ethnic groups may help to optimize therapeutic pathways, equitable care and outcomes.

Inequitable Long-Term Outcomes for an Indigenous Population After Definitive Treatment of Patients With Graves Disease.

BACKGROUND: Maori, the indigenous people of Aotearoa/New Zealand, have an increased incidence of Graves disease and often require more than one radioiodine (RAI) dose, raising the question as to whether surgery may be preferable in this population. However, there is a lack of outcome data after definitive therapy in an indigenous population. AIM: To assess ethnic differences in thyroid status after definitive therapy for Graves disease. METHODS: Single-center retrospective review of patients treated by RAI or thyroidectomy from 1 December 2001 to 31 March 2013. TSH levels at 1, 2, 5, and 10 years after treatment were recorded. RESULTS: A total of 798 patients were included: 589 received RAI, and 209 underwent surgery. Overall, 48% of patients were euthyroid at 1 year after definitive treatment, and 63.5% were euthyroid by 10 years. Maori were less likely to be euthyroid when compared with Europeans at all time points (e.g., 29.7% vs 57.3% at 1 year and 52.2% vs 70.9% at 10 years, P < 0.0005). Maori were more likely to receive more than one dose of RAI compared with Europeans (30.2% vs 14.2%, P < 0.0005). Persistent thyrotoxicosis at 1 year after RAI was seen in 25.8% of Maori compared with 8.3% of Europeans (P < 0.0005). CONCLUSIONS: Maori have lower rates of optimal thyroid levels than their European counterparts at all time points studied. Early disparity was associated with a higher RAI failure rate. Late differences were due to higher rates of untreated hypothyroidism. Overall, euthyroid rates were low, indicating the need for improvement in care, particularly for indigenous peoples.

Regulation of murine skeletal muscle growth by STAT5B is age- and sex-specific.

BACKGROUND: Sexually dimorphic growth has been attributed to the growth hormone (GH)/insulin-like growth factor 1 (IGF1) axis, particularly GH-induced activation of the intracellular signal transducer and activator of transcription 5B (STAT5B), because deletion of STAT5B reduces body mass and the mass of skeletal muscles in male mice to that in female mice. However, it remains unclear why these effects are sex- and species-specific, because the loss of STAT5B retards growth in girls, but not in male mice. Our objectives were to determine whether sexually dimorphic growth of skeletal muscle persisted in STAT5B-/- mice and investigate the mechanisms by which STAT5B regulates sexually dimorphic growth. METHODS: Blood and skeletal muscle were harvested from male and female STAT5B-/- mice and their wild-type littermates from the onset of puberty to adulthood. RESULTS: Growth of the skeleton and skeletal muscles was retarded in both sexes of STAT5B-/- mice, but more so in males. Although reduced, sexually dimorphic growth of skeletal muscle persisted in STAT5B-/- mice with an oxidative shift in the composition of myofibres in both sexes. Concentrations of IGF1 in blood and skeletal muscle were reduced in male STAT5B-/- mice at all ages, but only in female STAT5B-/- mice at the onset of puberty. Expression of androgen receptor (AR) and oestrogen receptor alpha (ERα) mRNA and protein was reduced in skeletal muscles of male and female STAT5B-/- mice, respectively. Loss of STAT5B abolished the sexually dimorphic expression of myostatin protein and Igf1, Ar, Erα, suppressor of cytokine signalling 2 (Socs2), and cytokine-inducible SH2-containing protein (Cis) mRNA in skeletal muscle. CONCLUSIONS: STAT5B appears to mediate GH signalling in skeletal muscles of male mice at all ages, but only until puberty in female mice. STAT5B also appears to mediate the actions of androgens and oestrogens in both male and female mice, but sexually dimorphic growth persists in STAT5B-/- mice.

Increased Admissions Due to Cardiac Complications of Thyrotoxicosis in Maori.

BACKGROUND: As thyrotoxicosis is a risk factor for atrial fibrillation, current guidelines recommend measuring a thyroid-stimulating hormone level in patients with this disorder. Hyperthyroidism may also be associated with other heart diseases including cardiac ischaemia and cardiac failure. Currently, the prevalence of thyrotoxicosis in cardiac admissions in the absence of a rhythm disorder is unknown. AIMS: The aims of this study were: 1) to calculate the prevalence of admissions for thyrotoxicosis-associated cardiac disease, 2) determine the type of cardiac disease i.e. dysrhythmic, ischaemic or cardiac failure, and 3) to assess whether Maori are over-represented amongst patients admitted to hospital with cardiac complications of thyrotoxicosis. METHODS: A retrospective review of admissions with both thyrotoxicosis and cardiac disease from 1 January 2005 to 31 December 2012 inclusive. RESULTS: Seventy-two patients were identified as being admitted for a cardiac complication of thyrotoxicosis, giving a mean of nine admissions per year. Dysrhythmia was the cause for admission in 32 patients, ischaemia in 12, cardiac failure in 11 and mixed cardiac disease in 17. Graves' disease and amiodarone-induced were the most common causes of the thyrotoxicosis (25 and 19 cases, respectively). Of the cohort 26 (36.1%) were Maori (compared to 16.8% of all cardiac admissions over the same period). Maori were more likely to present with cardiac failure than non-Maori (57.7% vs. 26.1%, p=0.008 respectively). CONCLUSIONS: Maori are over-represented amongst patients admitted with cardiac complications of thyrotoxicosis and more often present with cardiac failure than non-Maori. Measurement of thyroid function should be considered in patients presenting not only with atrial fibrillation but also in patients presenting with cardiac failure, particularly if they are Maori.

Parafibromin-deficient (HPT-JT Type, CDC73 Mutated) Parathyroid Tumors Demonstrate Distinctive Morphologic Features.

The gene CDC73 (previously known as HRPT2) encodes the protein parafibromin. Biallelic mutation of CDC73 is strongly associated with malignancy in parathyroid tumors. Heterozygous germline mutations cause hyperparathyroidism jaw tumor syndrome,which is associated with a high life-time risk of parathyroid carcinoma. Therefore loss of parafibromin expression by immunohistochemistry may triage genetic testing for hyperparathyroidism jaw tumor syndrome and be associated with malignant behavior in atypical parathyroid tumors. We share our experience that parafibromin-negative parathyroid tumors show distinctive morphology. We searched our institutional database for parathyroid tumors demonstrating complete loss of nuclear expression of parafibromin with internal positive controls. Forty-three parafibromin-negative tumors from 40 (5.1%) of 789 patients undergoing immunohistochemistry were identified. Thirty-three (77%) were external consultation cases; the estimated incidence in unselected tumors was 0.19%. Sixteen (37.2%) fulfilled World Health Organization 2017 criteria for parathyroid carcinoma and 63% had serum calcium greater than 3mmol/L. One of 27 (3.7%) noninvasive but parafibromin-negative tumors subsequently metastasized. Parafibromin-negative patients were younger (mean, 36 vs. 63 y; P<0.001) and had larger tumors (mean, 3.04 vs. 0.62 g; P<0.001). Not all patients had full testing, but 26 patients had pathogenic CDC73 mutation/deletions confirmed in tumor (n=23) and/or germline (n=16). Parafibromin-negative tumors demonstrated distinctive morphology including extensive sheet-like rather than acinar growth, eosinophilic cytoplasm, nuclear enlargement with distinctive coarse chromatin, perinuclear cytoplasmic clearing, a prominent arborizing vasculature, and, frequently, a thick capsule. Microcystic change was found in 21 (48.8%). In conclusion, there are previously unrecognized morphologic clues to parafibromin loss/CDC73 mutation in parathyroid tumors which, given the association with malignancy and syndromic disease, are important to recognize.

GH replacement titrated to serum IGF-1 does not reduce concentrations of myostatin in blood or skeletal muscle.

OBJECTIVE: Traditional weight-based regimens of GH replacement are more effective at reversing the loss of skeletal muscle in GH-deficient adults than currently recommended regimens, where the dose of GH is increased to restore serum concentrations of IGF-1. While weight-based regimens increase concentrations of IGF-1 and decrease concentrations of myostatin, it is not known whether the reduced effectiveness of individually titrated GH regimens is due to ongoing hypersecretion of myostatin. Consequently, the aims of this study were to determine whether concentrations of myostatin in blood and skeletal muscle are increased in GH-deficient adults, and whether these concentrations are decreased by GH replacement regimens titrated to restore serum IGF-1. DESIGN: Twenty-six GH deficient adults (18 men and 8 women) were treated with individualised regimens of recombinant human GH aiming to achieve serum concentrations of IGF-1 within one standard deviation of the age- and gender-adjusted mean. Plasma concentrations of myostatin were measured at baseline and after 6 months of treatment were compared to fifteen healthy controls (9 men and 6 women). Skeletal muscle biopsies were performed in 19 of these GH-deficient adults (15 men and 4 women) and 10 of the healthy controls (6 men and 4 women). Expression of IGF-1 and myostatin mRNA was determined by qPCR. RESULTS: Concentrations of IGF-1 in serum and mRNA in skeletal muscle were reduced, and concentrations of myostatin in plasma and mRNA in skeletal muscle were increased in GH-deficient adults at baseline (P < .05 versus healthy controls). Despite restoring concentrations of IGF-1, GH replacement did not reduce concentrations of myostatin in either blood or skeletal muscle. Concentrations of IGF-1 and myostatin in both blood and skeletal muscle were positively correlated in GH-deficient adults at baseline (P < .05), but not in GH-replete adults. CONCLUSIONS: Concentrations of myostatin in blood and skeletal muscle are increased in GH-deficient adults. Despite normalising concentrations of IGF-1, individualised regimens of GH replacement do not reduce concentrations of myostatin in blood or skeletal muscle. Ongoing hypersecretion of myostatin may explain why individually titrated GH replacement regimens are less effective than higher weight-based regimens in increasing skeletal muscle mass.

Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer.

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic MEN1 inactivation and generally poor clinical outcome. Another ~40% of patients had pNETs that lacked this recurrent LoH pattern but had chromosome 11 LoH, bi-allelic MEN1 inactivation, and universally good clinical outcome. The somatic aneuploidy allowed pathogenic germline variants (e.g., ATM) to be expressed unopposed, with RNA expression patterns showing inactivation of downstream tumor suppressor pathways. No prognostic associations were found with tumor morphology, single gene mutation, or expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. In pNETs, single gene mutations appear to be less important than aneuploidy, with MEN1 the only statistically significant recurrently mutated driver gene. In addition, only one pNET in the series had clearly actionable single nucleotide variants (SNVs) (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two clinically relevant patterns of LoH described here define a novel oncogenic mechanism and a plausible route to genomic precision oncology for this tumor type.