United States

Purpose: Metabolic syndrome (MetS) comprises a constellation of risk factors for cardiovascular disease, which are thought to be derived from truncal obesity. Adipose tissue can have positive effects on bone density through mechanical stimulation on weight bearing sites and can have hormonal influences which affect bone cells, however in obesity this relationship is inversed as the deleterious effects of excess fat mass predominate. It is unclear how MetS and the regional distribution of fat relate with bone density and bone quality in lean individuals who do not benefit from increased weight bearing.
Methods: We performed a cross sectional analysis of adults who underwent bone density and body composition by dual energy x-ray absorptiometry (DXA) at a university health system bone clinic, and had laboratory and demographic data available in the electronic medical record. We included adults with BMI below 24.9 kg/m2 in the analysis. Individuals were classified as being metabolically unhealthy lean (MUL) when they fulfilled at least 2 of the following criteria: blood pressure &gt; 130/85, triglyceride &gt;150 mg/dL, HDL &lt; 50 mg/dL for women and &lt; 40 mg/dL for men, fasting plasma glucose &gt;100mg/dL (or HbA1c &gt;=5.7), and metabolically healthy lean (MHL) when they did not fit the criteria. Linear regression was used to evaluate the association of body composition fat parameters with trabecular bone score (TBS), and bone mineral density (BMD) at the total hip (TH).
Results: Among the 119 (100%) lean adults, 50 (42%) were classified as being MUL. Mean age was 62 ±14 years old and mean BMI was 22 ±1.9kg/m2. The population was mostly white 105 (88%) and 70 (41%) were Hispanics. Additionally, 43 subjects (40%) had a history of a previous fracture. Total body fat was similar between the two groups (mean,%) MHL 33.5, MUL 34.1 (p=0.32), as were age (mean, years) MHL 62.3 vs MUL 62.5 (p=0.48), BMI (mean, kg/m2) MHL 22.2, MUH 22.2 (p=0.49), TH BMD (mean, g/cm2) MHL 0.74, MUL 0.72 (p=0.140) and TBS (mean, unitless) MHL 1.34, MUL 1.33 (p=0.308). However, visceral adipose tissue area (VAT) (mean, cm2) was statistically significantly different between the groups (MHL 69.0, MUL 86.7, p=0.004). In linear regression analyses total body fat had negative association with TBS (B=-0.44, p&lt;0.001) and TH BMD (B= -0.37, p&lt;0.001) while VAT had negative association with TBS (B=-0.26, p=0.02) but not TH BMD (B=-0.17, p=0.08).
Conclusion: In our sample of older lean individuals body fat distribution varied by classification of metabolic health. Total body fat amount was associated with decreasing bone density and quality, while higher truncal fat as measured by VAT area was associated with decreasing bone quality. Our findings suggest that excess body fat may have deleterious effects on bone health even in lean individuals

ENDO 2022

Bone Quality in Lean Adults with Metabolic Syndrome

**Program**
ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

**What Programming Is Included in My Virtual Meeting Registration?**
As you build your schedule during the conference, you can select the sessions that are tagged with 'Livestreamed', so you can view virtually. These sessions are being livestreamed, so they are available in real time to our virtual audience. In addition, our in-person and livestreamed sessions will be recorded, so you can access them on demand after 72 hours. We will have over 200 hours available on demand for Standard and Premium pass registrants.

Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

Purpose: Metabolic syndrome (MetS) comprises a constellation of risk factors for cardiovascular disease, which are thought to be derived from truncal obesity. Adipose tissue can have positive effects on bone density through mechanical stimulation on weight bearing sites and can have hormonal influences which affect bone cells, however in obesity this relationship is inversed as the deleterious effects of excess fat mass predominate. It is unclear how MetS and the regional distribution of fat relate with bone density and bone quality in lean individuals who do not benefit from increased weight bearing.
Methods: We performed a cross sectional analysis of adults who underwent bone density and body composition by dual energy x-ray absorptiometry (DXA) at a university health system bone clinic, and had laboratory and demographic data available in the electronic medical record. We included adults with BMI below 24.9 kg/m2 in the analysis. Individuals were classified as being metabolically unhealthy lean (MUL) when they fulfilled at least 2 of the following criteria: blood pressure > 130/85, triglyceride >150 mg/dL, HDL < 50 mg/dL for women and < 40 mg/dL for men, fasting plasma glucose >100mg/dL (or HbA1c >=5.7), and metabolically healthy lean (MHL) when they did not fit the criteria. Linear regression was used to evaluate the association of body composition fat parameters with trabecular bone score (TBS), and bone mineral density (BMD) at the total hip (TH).
Results: Among the 119 (100%) lean adults, 50 (42%) were classified as being MUL. Mean age was 62 ±14 years old and mean BMI was 22 ±1.9kg/m2. The population was mostly white 105 (88%) and 70 (41%) were Hispanics. Additionally, 43 subjects (40%) had a history of a previous fracture. Total body fat was similar between the two groups (mean,%) MHL 33.5, MUL 34.1 (p=0.32), as were age (mean, years) MHL 62.3 vs MUL 62.5 (p=0.48), BMI (mean, kg/m2) MHL 22.2, MUH 22.2 (p=0.49), TH BMD (mean, g/cm2) MHL 0.74, MUL 0.72 (p=0.140) and TBS (mean, unitless) MHL 1.34, MUL 1.33 (p=0.308). However, visceral adipose tissue area (VAT) (mean, cm2) was statistically significantly different between the groups (MHL 69.0, MUL 86.7, p=0.004). In linear regression analyses total body fat had negative association with TBS (B=-0.44, p<0.001) and TH BMD (B= -0.37, p<0.001) while VAT had negative association with TBS (B=-0.26, p=0.02) but not TH BMD (B=-0.17, p=0.08).
Conclusion: In our sample of older lean individuals body fat distribution varied by classification of metabolic health. Total body fat amount was associated with decreasing bone density and quality, while higher truncal fat as measured by VAT area was associated with decreasing bone quality. Our findings suggest that excess body fat may have deleterious effects on bone health even in lean individuals

technical paper

While anorexia nervosa is associated with impaired skeletal integrity, less is known about the skeletal effects of atypical anorexia nervosa, in which psychological criteria for anorexia nervosa are met, but affected individuals are not low weight. Mean bone mineral density (BMD) is higher in atypical anorexia nervosa than in low-weight anorexia nervosa but lower than in healthy controls. However, it is unknown whether bone microarchitecture and strength are affected. We hypothesized that bone microarchitecture and estimated strength would be impaired in women with atypical anorexia nervosa.
This was a cross-sectional study of women ages 21-46 years (n=55): n=28 with atypical anorexia nervosa (body mass index (BMI) >18.5 kg/m²), n=27 healthy, normal weight, eumenorrheic controls. Exclusion criteria included use of oral contraceptives. Areal BMD (aBMD) was assessed by DXA. Volumetric BMD (vBMD), microarchitecture, and failure load (a bone strength estimate) at the distal tibia and radius were assessed by high-resolution peripheral quantitative CT.
Median(IQR) BMI was lower [19.4(18.6,20.2) vs 22.2(21.5,23.0), p<0.0001] and median serum 25OH vitamin D level was higher [31(24,39) vs 22(17,25), p=0.0001] in atypical anorexia nervosa than healthy controls. In the atypical anorexia nervosa group, 89% had a history of low weight, 21% had a history of overweight/obesity, 31% had current amenorrhea, and 88% had a history of amenorrhea; median duration of anorexia nervosa was 11(5,14) years.
Median lateral spine, total hip, femoral neck, and total radius aBMD Z-scores were lower in atypical anorexia nervosa than healthy controls [lateral spine: -1.1(-2.0,-0.1) vs -0.4(-0.7,0.4), total hip: -0.8(-1.3,0.2) vs 0.2(-0.4,0.7), femoral neck: -0.9(-1.4,0.1) vs -0.1(-0.9,0.6), radius: -0.2(-0.9,0.3) vs 0.1(-0.4,0.6); p≤0.04 for all]. At the tibia, median total, cortical, and trabecular vBMD; cortical thickness; trabecular bone volume fraction; and failure load were lower in atypical anorexia nervosa than healthy controls (p<0.05). At the radius, median trabecular number was lower and trabecular separation was higher in atypical anorexia nervosa than healthy controls (p≤0.04), but there was no difference in failure load between the groups. After controlling for baseline BMI, differences at the radius but not tibia remained significant. At the tibia and radius, median total vBMD, cortical vBMD, and cortical thickness were lower in atypical anorexia nervosa subjects with amenorrhea compared to healthy controls and to atypical anorexia nervosa subjects with eumenorrhea (p≤0.04).
Conclusions: We demonstrate that, despite normal weight, women with atypical anorexia nervosa have impaired vBMD, microarchitecture, and estimated strength compared to healthy controls, with differences more pronounced at the weight-bearing tibia vs non-weight-bearing radius. Individuals with amenorrhea had additional impairments in the non-weight-bearing radius, suggesting an effect of systemic estrogen deficiency. Our data suggest that current normal weight is not protective against impaired bone structure and strength in atypical anorexia nervosa.

Impairments in volumetric bone mineral density, bone microarchitecture, and estimated strength in women with atypical anorexia nervosa

Introduction: Hypercalciuria is one of the reported complications in patients with primary hyperparathyroidism (PHPT). Profound hypercalciuria in the settings of renal stones is considered to be one of the indications for parathyroidectomy. However, limited data is available to describe the rate of hypercalciuria resolution following successful parathyroidectomy in patients with PHPT who had elevated pre-op 24 hour urine calcium levels.
Objective: To describe efficacy of successful parathyroidectomy (defined as normalization of serum calcium) in patients with primary hyperparathyroidism and hypercalciuria (defined as 24 hour urine calcium > 250 mg/24 hr) on resolution of hypercalciuria (defined as 24 hour urine calcium < 200 mg/24hr).
Design: This is a retrospective study in which 51 eligible patients (with parathyroidectomies performed from August 2015 to June 2021) were chart reviewed. Twenty nine patients with complete records pre and post parathyroidectomy were included in the analysis.
Setting: Single outpatient endocrinology center in Las Vegas, Nevada.
Participants: A population of 29 adults aged 29 to 72 years with confirmed primary hyperparathyroidism and hypercalciuria who had a complete resolution of hypercalcemia status post parathyroidectomy.
Main outcome measure: Resolution of hypercalciuria.
Results: 12 patients (41%) had complete resolution of  hypercalciuria after parathyroidectomy. The mean age among patients with resolution was 61.4 years (SD 6.7 years) at the time of surgery vs. 50.5 (SD 11.9 years) among not responders (p= 0.008). There was no significant difference between the resolved and not resolved groups with regard to sex, history of renal stones, history of osteoporosis, location of parathyroid adenoma, pre-op PTH, calcium, and 24 hour urine calcium (p >0.05). Nephrolithiasis occured in 34% of cases. Osteoporosis occurred in 24% of cases. Average pre-op 24 hour urine calcium was 427 mg/24hr (SD  134 mg/24hr, collected on average at 5 months pre-op). Average post-op 24 hour urine calcium was 204 mg/24hr  (SD 83 mg/24hr, collected on average at 22 months post-op).
In a multivariate analysis, for each year of age (at the time of surgery) increase, the odds of resolution of hypercalciuria increased by 37% (p= 0.036, 95% CI [1.020-1.840];  stepwise logistic regression). For each 1 mg increase in pre-op urine calcium odds of resolution of hypercalciuria decreased by 1.7% after successful parathyroidectomy (p=0.033, 95% CI [0.967, 0.999]).
Conclusions: These results suggest that hypercalciuria is less likely to resolve in younger patients with PHPT after successful parathyroidectomy compared to older adults. Our data also suggests that resolution of hypercalciuria in primary hypercalciuria is inversely related to the pre-op 24 hour urine calcium levels (the higher the pre-op 24 hour urine calcium level, the less likely the hypercalciuria to resolve after successful parathyroidectomy).

Hypercalciuria in Young Adults With Primary Hyperparathyroidism Is Less Likely to Resolve After a Successful Parathyroidectomy Compare to Older Adults

Pancreatic ductal adenocarcinoma (PDAC) comprises more than 90% of pancreatic cancer cases and commonly harbors mutations in KRAS and TP53. PDAC is the third leading cause of cancer-related deaths in the US with approximately 10% 5-year relative survival rate. The poor survival rate largely pertains to aggressive growth following metastasis and limited understanding of prognostic factors. Accumulated evidence indicates that PDAC survival rates are inversely correlated with the pancreatic gene expression of INHBA, which encodes inhibin βA, and circulating levels of activin A (a dimer of inhibin βA), which is overexpressed in pancreatic cancer cells. However, potential mechanisms supporting the correlations have remained unclear. PDAC is etiologically related to sustained metaplasia of acinar cells to ductal-like cells (ADM). Therefore, in this study, we tested the hypothesis that activin A plays a tumor-promoting role via ADM. We implanted mouse PDAC KPC (KrasG12D and Tp53R172H) cells into the pancreata of C57BL/6 male mice and divided them into four groups; sham and three groups of orthotopic mice intraperitoneally (IP) injected with either no (TO), scramble (sc) or inhba siRNA (inhba) packaged with CPX nanoparticles, which previously exhibited tumor-targeted delivery, starting on postoperative day 4. On day 16, blood and tissues were harvested for analyses of tumor-related prognostic blood markers and tumor histology. Implanted KPC cells significantly elevated serum activin A levels and induced tumors as demonstrated by the accumulation of SOX9-positive ADM and a-SMA-positive fibroblasts when compared to sham group. Also, metastases occurred to the liver, spleen, kidney, and intestine. No differences were observed between TO and sc groups. However, when compared to sc group, inhba group had significantly suppressed serum activin A levels and reduced tumor size. Statistically, inhba group had fewer metastases and longer survival rates. Histologically, inhba group exhibited more amylase-positive acini conserved and less accumulation of a-SMA-positive cells in the pancreas. Further, the expression of activin A receptor type 2B (ACVR2B) was greatly induced on the acinar cells undergoing ADM transition in sc group, whereas such expression was subdued in inhba group. Collectively, our data indicate that inhba suppression impedes ADM mediated by KPC cells in mice and suggests activin A as one of tumor-initiating factors. It warrants further investigations in human PDAC models and clinical settings to test the potential therapeutic roles of targeting tumor INHBA in early PDAC development.

Potential Role of Activin A During Pancreatic Acinar-to-Ductal Metaplasia of Orthotopic Pancreatic Tumor Mice

Lymphangioleiomyomatosis (LAM) is an estrogen-sensitive lung disease found almost exclusively in women. LAM is characterized by the hyperproliferation of smooth muscle cells creating small tumors throughout the lungs, resulting in the formation of large cysts that replace normal alveolar space. Growth of these tumors and progression of cyst development leads to loss of pulmonary function, and sometimes subsequent lung transplantation. LAM tumor cells contain mutations in one of the tuberous sclerosis genes (TSC1 or TSC2), leading to constitutive activation of the mTORC1 pathway. In fact, mTOR inhibitors are commonly used to treat LAM; however, these drugs are not always effective and have significant side effects, suggesting the need for new therapeutic targets. Additionally, tumors recur even after lung transplantation and LAM cells are found in circulating body fluids, suggesting a metastatic nature of LAM, and a question of the origin of the LAM cell. Due to LAM's estrogen sensitivity, female specificity, and metastatic nature, we previously proposed that LAM cells originate from the uterine myometrium. We therefore designed a uterine-specific TSC2-null mouse model where all of the mice generate uterine tumors characteristic of LAM and half develop lung metastases, suggesting that indeed LAM tumors may be derived from the uterus. Notably, our collaborators recently utilized single cell RNA sequencing with human LAM lung lesions, and found that TSC2-null cells have a strong uterine profile. Using bulk RNASeq analysis of uterine tissue from our mouse model, when focusing on genes regulated by estrogen and TSC2, we discovered increased expression of melanocytic markers, including Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB). GPNMB is known to be oncogenic in other cancers and has been shown to be expressed intracellularly in benign cells, but both intracellularly and on the cell surface of tumor cells making GPNMB a good cell surface drug target. This melanocytic marker was not only highly expressed in our mouse model, it was also expressed in TSC2-null cell lines, as well as in human LAM patient lung and uteri samples. Knocking down GPNMB expression by siRNA directed against GPNMB mRNA decreased proliferation, migration, and invasion in TSC2-null cells. We also found that GPNMB's large ectodomain is released from the cell surface of TSC2-null cells and potentially mediated by the protease, Adam10. The ectodomain specifically is implicated in mediating GPNMB's effects on tumor growth. Finally, knocking out GPNMB in TSC2-null cells using CRISPR/Cas9 decreased xenograft tumor growth in mice. Overall, our data thus far demonstrate that GPNMB promotes TSC2-null tumor growth and metastasis. Importantly, the GPNMB ectodomain is a potential biomarker of human LAM, as we detect a significant difference in GPNMB ectodomain levels in patient blood as compared with healthy controls.

Glycoprotein-NMB (GPNMB) is Pro-Tumorigenic in Lymphangioleiomyomatosis (LAM)

Introduction: Paragangliomas (PGL) are rare neuroendocrine tumours and account for approximately 10% of all chromaffin tumours. They may occur in the retroperitoneum, mediastinum, skull and the urinary bladder. Paragangliomas of the urinary bladder are rare entities accounting for 10% of all paragangliomas and 0.06% of all bladder tumours. Approximately 10% of urinary bladder paragangliomas are malignant. Bladder paragangliomas can be either functional or non-functional. Main symptoms of functional PGLs are due to catecholamine excess with palpitations, paroxysmal hypertension during micturition, sweating and headaches. Functional bladder PGL are diagnosed on biochemical analysis. Non-functional bladder PGLs present with haematuria and are often misdiagnosed as bladder cancer as they may cystoscopically and histologically resemble a urothelial neoplasm. Clinical cases: We present a case series of 4 surgically treated patients with urinary bladder paragangliomas who presented to Cambridge University Hospital over the last 3 years. All patients were female with an age range between 21 and 44 years. All four patients had SDHB deficient tumours, and all four patients were diagnosed with a pathogenic variant in the SDHB gene. Three patients had no family history of SDHx associated neoplasia whereas one had a paternal aunt who died from a metastatic pheochromocytoma. Three patients had presented with palpitations and hypertensive episodes, one of whom experienced symptoms while micturating. Biochemical analysis revealed elevated plasma normetadrenaline levels in all patients. On presentations, one patient had a synchronous paratracheal paraganglioma while two patients had lymph node metastasis. All patients were surgically treated with two patients undergoing fertility preserving cystectomy and bladder substitution, one undergoing partial cystectomy, radical hysterectomy and ureteric implantation and one managed with robot-assisted partial cystectomy. None of the patients have evidence of biochemical or radiological tumour recurrence on follow-up with a mean follow-up time of 23 months (range 12 to 40 months). Conclusion and points for discussion: The diagnosis of urinary bladder PGL is challenging. Biochemical assessment to assess catecholamine production and imaging studies like CT, MRI and NM Ga68 DOTATATE PET CT are helpful modalities in diagnosis. Patients presenting with extra adrenal paragangliomas including bladder paragangliomas require genetic testing because of the strong hereditary predisposition, with mutations in the SDHx genes being most common with this clinical phenotype. The surgical approach should be tailored to the individual patient, agreed by a multi-disciplinary team and the risk of malignancy should be weighed against the potential morbidity associated with a curative oncological surgery. As urinary bladder PGLs have malignant potential and are frequently hereditary (as demonstrated in this series), lifelong follow-up is required to screen for synchronous tumours and tumour recurrence.

Urinary bladder Paragangliomas – A Case series

Multiple studies have shown that approximately 50-70% of patients with MEN1 die of causes directly related to MEN1 particularly gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). While non-functional GEP-NETs are the most common in the general population, gastrinomas (40%) are the most common functional GEP-NETs in patients with MEN1. c-MET is a proto-oncogene that encodes for c-MET, a tyrosine kinase receptor which promotes tumor cell motility, proliferation, survival, invasion, and metastasis. Studies in patients with sporadic gastrinomas and pancreatic NETs (PNETs) have shown that c-MET expression correlates with decreased survival.
While c-MET inhibitors are currently in various stages of investigation for treatment of carcinoids and sporadic PNETs, data regarding their efficacy in patients with MEN1-related GEP NETs is lacking. The majority of trials in patients with GEP-NETs exclude or do not report the number of patients with MEN1. Importantly, somatic MEN1 mutations are observed in 20-40% of sporadic NETs (gastrinomas, PNETs, lung NETs, etc. ) but correlation of cMET expression with the presence of somatic or germline MEN1 mutations has not been reported. We sought to investigate the expression of c-MET in tumor tissue from germline MEN1 patients with metastatic GEP-NETs.
Methods
We identified subjects with a germline positive MEN1 mutation and pathologically confirmed distant metastasis who had a follow-up visit between 2018-2020. Of these, we selected subjects with available tissue specimens (including either multiple organ sources or different tumor types). Where available, we identified specimens from multiple source or tumor types. Immunohistochemistry (IHC) to detect c-MET was performed with anti-MET (Cell Signaling) using the DAKO IHC kit (Agilent). IHC slides were imaged and observed to score the level of c-MET staining (-, 1+ to 5+). A score of 3+ or higher was considered consistent with overexpression. We investigated if age at initial GEP-NET presentation, tumor type, tissue source, tumor grade, total number of surgeries for GEP-NET, number of sites of distant metastasis and disease status from overall GEP-NET burden over the preceding 12 months (stable/progressive) predicted c-MET expression.
Results
Eight subjects with available tissue specimens were identified, of which six had tissue from multiple organs while five had tissue from multiple tumor types. Six subjects (75%) showed increased expression of c-MET in one or more tumor specimen(s). The frequency of c-MET overexpression varied with tumor types – carcinoids (n=2/2; 100%), gastrinomas (n=3/5; 60%) and non-functional tumors (n=3/6; 50%). c-MET expression also varied among different tumors in the same patient. Tumor tissue from liver (n=2/2), duodenum (n=3/4), stomach (n=1/1), ovary (n=1/1), pancreas (n= 1/5), and lymph nodes (n=1/3), all showed over-expression of c-MET. No clear predictors of c-MET overexpression emerged.
Conclusion
Our finding suggests a role for c-MET expression in personalizing therapy for patients with MEN1-related NETs with distant metastases.

c-MET expression in MEN1-associated neuroendocrine tumors

Adrenocortical carcinoma (ACC) can occur as part of hereditary cancer syndromes, particularly Lynch syndrome and Li-Fraumeni syndrome. Here we describe 5 patients (3 women) with adrenal tumors and Birt-Hogg-Dubé syndrome (BHDS). BHDS is a hereditary tumor syndrome characterized by fibrofolliculomas/trichodiscomas, renal tumors, lung cysts, and spontaneous pneumothoraces.
All five patients had a confirmed germline FLCN pathogenic variant. One case was previously reported by our institution. Age of diagnosis (AD) ranged from 36 to 62 years with a mean AD of 46 years. All patients identified as Caucasian. Three patients had non-functioning adrenal tumors, while the remaining two patients did not undergo biochemical assessment preoperatively but did not have symptoms or history of adrenal hormone excess.
Histologically, four patients had confirmed ACC while one had an adrenocortical tumor of uncertain malignant potential, most consistent with an oncocytoma. All patients were initially treated with mitotane. Three patients developed metastatic disease requiring additional systemic chemotherapy, immunotherapy, and/or radiation.
A total of 8 confirmed ACCs in patients with BHDS have been reported to date, raising suspicions that these tumors might be a part of the BHDS tumor spectrum. When BHDS patients are screened for renal malignancies, special attention should be paid to the adrenal glands. Adrenal nodules should undergo prompt assessment as >50% of reported cases developed metastatic disease. Given possible association with BHDS, testing for FLCN pathogenic variants should be considered during the genetic evaluation of patients with ACC.

Adrenocortical Carcinoma as a Rare Manifestation of Birt-Hogg-Dubé Syndrome

Introduction:Insulinoma is a rare pancreatic neuroendocrine tumor (PNET) accounting for 1-2% of pancreatic neoplasms. Usually benign, even small tumors can cause significant morbidity due to hypoglycemia. Surgical resection is preferable choice of treatment, but diagnosis is usually delayed and localization can be evasive. We present a case of insulinoma in a patient who battled his symptoms with high carbohydrate intake leading to massive weight gain associated with severe insulin resistance.Case:A 70 year old male presented to the ED after being found unconscious in his home. Blood glucose was 34 mg/dl after missing a meal. He had a remote history of diabetes mellitus, which gradually resolved. Five years ago, he began experiencing sweats, tremors, headaches and confusion early in the morning or when fasting that improved with eating. He was hospitalized four years ago due to hypoglycemia where he was suspected to have endogenous hyperinsulinemia. CT abdomen at that time was unremarkable. Possibility of insulinoma was raised, but patient did not pursue further investigations. In the last 4 years, he avoided severe hypoglycemic events with frequents meals, but had gained more than 50 lbs with resultant BMI of 51 kg/m2. While admitted, he underwent a 72h fasting test showed glucose 42 mg/dl, insulin level was 84.8 IU/L (range <3), proinsulin was 105.7 (pmol/l) and C-peptide was 4.83 ng/ml (ref <0.2). EUS revealed 7 mm x 4 mm mass in pancreatic body. FNAB confirmed well differentiated PNET, grade 1. CT abdomen remained unrevealing. He was started on weight based diazoxide therapy with resolution of hypoglycemic events and persistent hyperglycemia, which required high dose insulin therapy and improved with significant decrease in diazoxide dose. Hospitalization was complicated by hypoxic hypercarbic respiratory failure due to obesity hypoventilation syndrome, COVID19 infection and new onset rapid atrial fibrillation. Patient was deemed not to be a surgical candidate due to multiple comorbidities and his medical management was switched to octreotide with low dose insulin therapy, which patient tolerated well.Conclusion:Diagnosis of insulinoma can be significantly delayed in cases with mild or slowly progressive course of the disease. We suggest that progressive development of severe insulin resistance in patients with baseline obesity and insulin resistance-driven DM2 can mask endogenous hyperinsulinemia for extended period of time. This gives a false sense of slower progression or even resolution of symptomatology, as well as diversion to alternative diagnoses, like postprandial hypoglycemia. We also argue that "resolution" of diabetes with significant weight gain, especially when associated with increased calorie intake through frequent meals and symptomatology suggestive of hypoglycemia should be a red flag for workup towards possible insulinoma, akin to suspecting adrenal insufficiency in diabetic patients with an unexplained decrease in insulin requirements.

Surviving Insulinoma: Severe Insulin Resistance in the Face of Endogenous Hyperinsulinemia

Introduction: There is a clinical need to develop novel and better biomarkers to monitor patients with neuroendocrine neoplasms (NENs). Circulating cell free tumor derived DNA (ctDNA), a form of liquid biopsy, is finding clinical utility in an ever increasing number of malignancies however has not been widely tested in patients with NENs.Aims: Our aim was to identify and track plasma ctDNA in a cohort of patients with NENs using a personalized, patient specific approach.Materials and methods: A total of 35 serial plasma samples were collected from 9 patients with metastatic, well differentiated NENs (6 small intestinal and 1 lung, 1 ovarian and 1 pelvic; range 2-5 plasma samples per patient) over the space of 2-25 months. For each patient, NEN specific somatic mutations (single nucleotide variants and insertions/deletions) were identified through whole exome sequencing of paired tumor-leucocyte DNA and were used to design a bespoke multi-variant Ampliseq™ HD ctDNA panel (5-20 variants per patient) for targeted next generation sequencing. Imaging and treatment were provided as per usual clinical care.Results: ctDNA was detectable in 6/9 patients and in 19/35 plasma samples. A rise in the number of ctDNA target variants and/or variant allele frequency was seen in 4/6 patients who experienced disease progression. Two of these patients received peptide receptor radionuclide therapy after which ctDNA disappeared in one patient and substantially reduced in the other, which correlated with treatment response. The 3 patients who did not have detectable ctDNA at any time point all had grade 1 small intestinal NENs with stable disease during the observation period.Discussion: Our data provide exciting evidence for the feasibility of using ctDNA as a biomarker in NENs. By targeting multiple individualized variants using next generation sequencing, we have demonstrated that ctDNA can track changes in disease burden and can monitor response to treatment in patients. Of equal importance, ctDNA was not detectable in patients with quiescent disease. This could help identify patients who do not need intensive monitoring. Targeting bespoke, multiple variants per patient is a novel and powerful approach for NENs, especially given their heterogenous genetic landscape. This study provides important early evidence that ctDNA may be a clinically useful biomarker for detection and surveillance of NENs.

Liquid Biopsies - Detecting and Tracking Circulating Cell Free Tumor Derived DNA in Patients with Neuroendocrine Neoplasms

Background: The 5-year survival for metastatic pancreatic neuroendocrine tumours (PNETs) is <50%, and current therapies are not effective. Thus, there is an unmet clinical need for new therapies for patients with PNETs. PNETs frequently have mutations in chromatin remodelling genes, including in Multiple Endocrine Neoplasia type 1 (MEN1), encoding menin, which is mutated in up to 40% of sporadic PNETs, and is part of multiple histone modifying complexes including the SET1/MLL methyltransferases.Aim: To examine multiple classes of epigenetic inhibitors and determine which may be effective in treating PNETs.Methods: BON1 and QGP1 PNET cell lines, the bronchial NET cell line H727, and the non-NET cell line HEK293T were utilised to assess >150 small molecule inhibitors targeting: histone deacetylases (HDACs); histone acetyltransferases; histone demethylases (KDMs); histone methyltransferases; bromodomain-containing proteins; menin; and DNA methyltransferases (DNMTs). MTOR inhibitors, already used clinically for PNET patients, as well as drugs targeting other tumorigenic pathways e.g. the proto-oncogene SRC, were used as comparators. Efficacy of compounds was evaluated using the Cell Titer Blue cell viability assay, and the Caspase Glo 3/7 apoptosis assay.Results: At a dose of 1mM for 7 days, 26 compounds (including HDAC, KDM, bromodomain and mTOR inhibitors) significantly decreased the viability of both the BON1 and QGP1 cell lines by >50%, compared to DMSO control treated cells. Upon increasing the dose to 10mM for 7 days, 34 additional compounds, making a total of 60 compounds (including inhibitors of menin and DNMTs), decreased viability of both BON1 and QGP1 cells by >50%; and 56 and 46 compounds also reduced viability of H727 and HEK293 cells by >50%, respectively. Apoptosis assays utilising the 60 above compounds, at 10mM for 7 days, revealed that 25, 18, 14, and 9 of them could increase apoptosis by >4-fold of BON1, QGP1, H727 and HEK293 cells, respectively. Ten compounds (2 KDM, 5 HDAC and 3 bromodomain inhibitors) that were effective in reducing viability by >50% as well as increasing apoptosis by >4-fold of NET cells, were selected for further dosing (0.1-10mM) and time course investigations (3-7 days). All 10 compounds significantly reduced viability of BON1 and QGP1 cells (p<0.01) after 3 days of treatment. The KDM and HDAC inhibitors showed the greatest efficacy, by significantly (p<0.05) reducing BON1 and QGP1 cell viability at as low as 25nM treatment for 3 days. The efficacy of bromodomain inhibitors was not attained until 1000nM treatment, however these inhibitors had very little effect on the non-NET HEK293 cells.Conclusions: Compounds targeting HDACs, KDMs or bromodomain-containing proteins are effective in reducing viability by >50% and increasing apoptosis by >4-fold of NET cells , and thus provide novel agents for studying anti-cancer mechanisms and potential therapeutic options for PNETs.

Bone Quality in Lean Adults with Metabolic Syndrome

Downloads

Next from ENDO 2022

Impairments in volumetric bone mineral density, bone microarchitecture, and estimated strength in women with atypical anorexia nervosa

Similar lecture

Treatment of Heart Failure with Preserved Ejection Fraction (HFpEF) with Low and High Dose of Triiodothyronine: an Animal Model of Metabolic Syndrome with HFpEF

Stay up to date with the latest Underline news!

PRESENTATIONS

CONFERENCES

COMPANY

RESOURCES