United States

Introduction: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder of progressive heterotopic ossification, resulting in cumulative loss of joint function and severe disability. We present results from an international, cross-sectional FOP Burden of Illness Survey (NCT04665323) demonstrating the impact of loss of joint function on quality of life (QoL) for patients and their family members. Methods: Individuals with FOP (survey proxy-completed for patients aged &lt;13 years), their primary caregivers, and other family members (aged ≥18 years) were eligible to participate. Family members who acted as a proxy could also participate themselves, as a family member. The survey was available online from 18Jan21–30Apr21 in 15 countries and 11 languages. The Patient­-Reported Mobility Assessment (PRMA) evaluated range of motion across 12 joints and 3 body regions (total scores range from 0–30; higher scores reflect more severe limitations). PRMA total scores were categorized into four Levels: Level 1, 0–6; Level 2, 7–12; Level 3, 13–18; Level 4, ≥19. To assess the impact of FOP on QoL, patients ≥13 years and their family members completed the EuroQoL health-related QoL questionnaire (EQ-5D-5L; index ranges from &lt;0 [worst health] to 1 [full health]). Descriptive analyses of EQ-5D-5L index scores were performed for each population and by patients&#39; PRMA Level. Linear regression analyses (adjusted for geographic region) were used to evaluate the relationship between patients&#39; degree of joint impairment (PRMA total score) and patient or family member EQ-5D-5L index score. Results: 463 survey responses were received from 405 individuals: patient/proxy population, n=219 (patients ≥13 years, n=161; proxies for patients &lt;13 years, n=58); family member population, n=244, of whom 163 identified as primary caregivers. Mean (standard deviation [SD]) EQ-5D-5L index score was 0.24 (0.36) for patients ≥13 years, 0.83 (0.22) for primary caregivers, and 0.85 (0.21) across all family members. For the patient population, mean (SD) EQ-5D-5L index score decreased as PRMA Level increased: Level 1, 0.61 (0.26); Level 2, 0.46 (0.34); Level 3, 0.21 (0.30); Level 4, 0.05 (0.26). There was a significant negative association between PRMA total score and EQ­-5D-5L index score for patients, such that for every 1-unit increase in the PRMA total score of the patient, there was a mean (standard error [SE]) decrease of 0.029 (0.003; p&lt;0.0001) in EQ-5D-5L adjusted for geographic region. For all family members, there was no significant association between EQ-5D-5L and the PRMA total score of the patient (p=0.6737). Conclusion: Loss of joint function (as represented by PRMA Level) has a significant, detrimental impact on QoL for patients with FOP. These findings increase understanding of the impact of FOP on patients and their family members, and may help to improve quality of care and access to support for the FOP community. Funding: Sponsored by Ipsen.

ENDO 2022

Joint Function and Quality of Life in Fibrodysplasia Ossificans Progressiva: Results from an International Burden of Illness Survey of Patients and Family Members

**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. 

Introduction: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder of progressive heterotopic ossification, resulting in cumulative loss of joint function and severe disability. We present results from an international, cross-sectional FOP Burden of Illness Survey (NCT04665323) demonstrating the impact of loss of joint function on quality of life (QoL) for patients and their family members. Methods: Individuals with FOP (survey proxy-completed for patients aged <13 years), their primary caregivers, and other family members (aged ≥18 years) were eligible to participate. Family members who acted as a proxy could also participate themselves, as a family member. The survey was available online from 18Jan21–30Apr21 in 15 countries and 11 languages. The Patient­-Reported Mobility Assessment (PRMA) evaluated range of motion across 12 joints and 3 body regions (total scores range from 0–30; higher scores reflect more severe limitations). PRMA total scores were categorized into four Levels: Level 1, 0–6; Level 2, 7–12; Level 3, 13–18; Level 4, ≥19. To assess the impact of FOP on QoL, patients ≥13 years and their family members completed the EuroQoL health-related QoL questionnaire (EQ-5D-5L; index ranges from <0 [worst health] to 1 [full health]). Descriptive analyses of EQ-5D-5L index scores were performed for each population and by patients' PRMA Level. Linear regression analyses (adjusted for geographic region) were used to evaluate the relationship between patients' degree of joint impairment (PRMA total score) and patient or family member EQ-5D-5L index score. Results: 463 survey responses were received from 405 individuals: patient/proxy population, n=219 (patients ≥13 years, n=161; proxies for patients <13 years, n=58); family member population, n=244, of whom 163 identified as primary caregivers. Mean (standard deviation [SD]) EQ-5D-5L index score was 0.24 (0.36) for patients ≥13 years, 0.83 (0.22) for primary caregivers, and 0.85 (0.21) across all family members. For the patient population, mean (SD) EQ-5D-5L index score decreased as PRMA Level increased: Level 1, 0.61 (0.26); Level 2, 0.46 (0.34); Level 3, 0.21 (0.30); Level 4, 0.05 (0.26). There was a significant negative association between PRMA total score and EQ­-5D-5L index score for patients, such that for every 1-unit increase in the PRMA total score of the patient, there was a mean (standard error [SE]) decrease of 0.029 (0.003; p<0.0001) in EQ-5D-5L adjusted for geographic region. For all family members, there was no significant association between EQ-5D-5L and the PRMA total score of the patient (p=0.6737). Conclusion: Loss of joint function (as represented by PRMA Level) has a significant, detrimental impact on QoL for patients with FOP. These findings increase understanding of the impact of FOP on patients and their family members, and may help to improve quality of care and access to support for the FOP community. Funding: Sponsored by Ipsen.

technical paper

Background: Hypercalcemia during pregnancy is rare. The true incidence, however, is difficult to estimate as routine calcium screening is not recommended. Hypercalcemia is linked with various maternal and fetal outcomes but overall, the literature is conflicting.
Aims: Aim of this study is to determine the frequency of hypercalcemia in pregnancy and to determine association with early maternal and fetal outcomes.
Methods: This retrospective cohort study included all confirmed gestations with expected date of delivery (EDD) between 2017-2019 at a large tertiary maternity unit. Baseline demographic, biochemical, and clinical data collected as part of a clinical-administrative dataset was retrieved. Maternal and fetal outcomes studied were incidence of fetal loss (miscarriage/stillbirth), pre-term delivery, emergency C-section, hypertension, blood loss during delivery, neonatal intensive care unit (NICU) admission, and fetal birth weight (for term deliveries).
Results: Total number of gestations and livebirths recorded between 2017-2019 were 33,118 and 20,969, respectively, with median age of 30.1 [IQR 25.6-34.3] years. Two-thirds of pregnancies were in Caucasian women (65.9%) followed by Asians (9.6%), Afro-Caribbean (5%), and others (19.5%). 15.7% (n=5195) of all gestations had calcium tested in the preceding ten months of EDD. Of these, the hypercalcemia and hypocalcemia were noted in 42 (0.81%) and 499 gestations (9.61%) respectively. The median adjusted calcium in the hypercalcemic group was 2.75 mmol/L [IQR 2.65-2.88] and underlying diagnoses were primary hyperparathyroidism (n=17), transient hypercalcemia (n=12), suspected familial hypocalciuric hypercalcemia (n=2), sarcoidosis (n=1), and unknown (n=10). Of maternal and fetal outcomes, the incidence of pre-term delivery (20.0% v 9.2%; P=0.042), emergency C-section (42.4% v 21.4%; P=0.021), neonatal intensive care unit (NICU) admission (19.4% v 8.2%; P=0.024), and blood loss during delivery (1252 v 526 mL; P<0.001) was higher in the hypercalcemic group. The incidence of fetal loss (22.5% v 18.9%; P=0.560) and hypertension (0% v 1%; P =0.561) was not different between hyper and normocalcemic groups. Interestingly, the hypocalcemic group also demonstrated higher incidence of pre-term delivery (24.2% v 9.2%; P=<0.001), emergency C-section (28.6% v 21.4%; P=0.025), NICU admission (15.9% v 8.2%; P<0.001), and blood loss (627 v 526 mL; P<0.001), but not of fetal loss (21.0% v 18.9%; P=0.281) or hypertension (2.2% v 1.0%; P =0.054) compared to the eucalcemic group.
Conclusion: The incidence of hypercalcemia in pregnancy is low (0.81%). However, abnormal calcium levels are associated with worse maternal and fetal outcomes. Research needs to focus on whether routine calcium estimations are necessary and if treatment of these conditions improves maternal and fetal outcomes. We recommend that calcium testing should be considered in women who are at risk of worse outcomes during current or previous pregnancies.

Hypercalcemia and hypocalcemia during pregnancy are associated with worse maternal and fetal outcomes

Introduction
We used a machine-learning algorithm (gradient boosting) to test the association of genetic risk for 11 glycemic traits with osteoporosis and fractures in the UK Biobank population.
Methods
The study was performed with 409,633 caucasian participants in the UKBIobank. We identified 4626 SNPs associated with 11 glycemic traits from the NGHRI catalogue for GWAS studies. Weighted genetic risk scores (wGRS) were calculated using the effect estimates from the GWAS studies. We used a gradient-boosting machine-learning (GBM) model to identify the relative influence (RI) of baseline variables and wGRS of the glycemic traits on osteoporosis and all-cause fractures in the UK Biobank population. We split the data into training (2/3) and testing set (1/3) and calculated the discriminatory power of the models using the area under the curve (AUC) with the testing model.
Results
The study consisted of 409,633 individuals (53% females) with a median age of 58 (51-63) years and a median BMI of 26.7 (24.1-29.8) kg/m². The study population had 41954 (10.2%) all-cause fractures and 4995 (1.2%) participants with osteoporosis. In the GBM model, top wGRS associated with all-cause fractures were wGRS for Type 1 diabetes (RI=4.49) and fasting glucose (4.17). In contrast, the top wGRS associated with osteoporosis were wGRS for acute insulin response to glucose (RI=6.74) and Type 1 diabetes (RI=5.62). Both models showed low to moderate discriminatory power with the area under the AUC of 0.57(CI: 0.56-0.57) for fractures and 0.75(CI: 0.74-0.76) for osteoporosis.
Conclusion
We showed a differential effect of wGRS for various glycemic traits on the risk of fractures and osteoporosis in the UK Biobank population. However, the machine-learning model with wGRS for glycemic traits demonstrated limited capacity to predict fractures and osteoporosis in the general population.

Estimating the relative influence (RI) of genetic risk of 11 glycemic traits on osteoporosis and fractures in 409633 participants in the UK Biobank using Machine learning

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

Bone Quality in Lean Adults with Metabolic Syndrome

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.

Joint Function and Quality of Life in Fibrodysplasia Ossificans Progressiva: Results from an International Burden of Illness Survey of Patients and Family Members

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