United States

One of the oldest and most common therapies for endometrial complex atypical hyperplasia (CAH) and low-stage, low-grade endometrioid endometrial carcinoma (EEC) is the use of progestins. Importantly, the use of progestins remains the only fertility-sparing treatment available. Despite frequent initial response to progestins, relapse rates are high (35-50%). Currently, there are no biomarkers available for predicting a woman’s likelihood of successful progestin therapy.?Primary samples (n = 63) were obtained from a total of 31 patients with either CAH or EEC who underwent progestin therapy and were acquired pre- and post-treatment with progestins. Pathological review of the FFPE samples was performed to identify regions of high hyperplastic or neoplastic content for core punches and RNA extraction. RNA-seq was then performed on the FFPE RNA using the TruSeq RNA Exome approach, a method that uses targeted capture to improve sequencing from fragmented samples. Differential expression analysis was performed using two methods: DESeq2 a parametric method and Noiseq a non-parametric method. Both methods were used to obtain an overlapping subset of genes to reduce spurious results due to samples with outlier expression.?Analysis of all samples identified 137 genes significantly associated with outcome. These 137 genes were largely increased in post-treatment samples from progestin responders and were highly enriched for progestogen and estrogen responsive genes, indicating a strong hormonal gene expression response to progestin therapy. Importantly, post-treatment samples from non-responding patients did not show this expression pattern, demonstrating that this set of genes may indicate successful hormone response in post-treatment samples. We also identified a 61 gene signature that remains high in non-responders after treatment compared to responders. Overall, we find that responders show a coordinated change in expression during progestin therapy that is missing from non-responders and this signature could be used in the early evaluation of progestin treatment success.?Focusing solely on pre-treatment samples, we identified more variable expression differences across tumors, suggesting multiple reasons for progestin success/failure. We found that the combined expression of estrogen receptor alpha and progesterone receptor was predictive of progestin therapy success. In addition, non-responding tumors had increased expression of several immune-related genes that we are currently exploring. Overall, these results show that progestin therapy response could be predicted using gene expression signatures and that multiple factors may underlie progestin success/failure.?? 

ENDO 2021

Identification of Genes and Pathways Differentially Expressed in Progestin Responsive Endometrial Cancer and Hyperplasia

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ENDO 2020

ENDO is the place where leading experts, researchers, and the most respected clinicians in the field come together to share the latest findings in hormone science and discuss breakthroughs in clinical care.

technical paper

ENDO is the leading meeting for endocrinology research and clinical care worldwide. 

Obesity is associated with increased severity of viral illnesses, but its impact on outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is yet to be elucidated. We sought to determine the association of obesity and other clinical factors with outcomes among patients hospitalized for severe coronavirus disease (COVID-19). This study included patients hospitalized between March 1, 2020 and September 17, 2020 in a 5-hospital health care system in Northeast United States, who had a positive RT-PCR assay of nasopharyngeal swabs for SARS-CoV-2 performed during hospitalization. Body mass index (BMI) was calculated using admission weight and height, and the WHO classification was used to define obesity. Both bivariate and multivariate logistic regression analyses were performed to determine the association of obesity and other clinical parameters with mortality (defined as in-hospital death or transition to hospice care) and intensive care use (defined by transfer to intensive care unit [ICU]). Multivariate model was adjusted for demographics and 8 pertinent comorbidities. Among 3246 patients hospitalized with COVID-19, median age was 65 years (interquartile range, 51-78), 49.9% were female, 30.5% overweight, and 43.2% had obesity (20.8%, 12.1%, and 10.4% with class I, II, and III obesity, respectively). A total of 542 (16.7%) patients died or received hospice care, and 811 (25.0%) required ICU care. In unadjusted analyses, patients with obesity had lower mortality compared with normal weight adults (13.0% vs. 23.1%) but a higher risk of ICU care (26.5% vs. 22.5%) and longer duration of ICU stays (9.5±10.6 vs. 6.6±8.5 [days]; all p-values <0.05). Obesity was associated with a higher incidence of hypoxic respiratory failure requiring invasive (17.8% vs. 9.3%) and noninvasive (22.7% vs. 14.0%) ventilatory support. In multivariate analysis, older age, male sex, and diabetes were significantly associated with both mortality and ICU care. In contrast, obesity was not associated with a significantly higher mortality (adjusted odds ratio [OR] 1.14; 95% CI, 0.91-1.43) but was associated with a higher risk of ICU care (OR 1.27; 95% CI 1.07-1.51 for all obesity and OR 2.07; 95% CI 1.51-2.82 for class III obesity compared with normal weight). The association of underweight with mortality (OR 1.56; 95% CI 0.93 - 2.60) and ICU care (OR 1.20; 95% CI, 0.71-1.99) was not statistically significant. This retrospective study of hospitalized patients suggests that obesity is associated with intensive care use and longer duration of ICU stay but not with mortality due to COVID-19. These findings underscore the vulnerability of individuals with obesity during the current pandemic.?? 

Obesity Is Associated With Intensive Care Use and Duration of ICU Stay but Not Mortality Among 3246 Patients Hospitalized With COVID-19

BACKGROUND: In Spring 2020 the severe acute respiratory syndrome coronavirus 2 pandemic disease (Covid-19) badly affected Northern Italy. We have described for the first time the occurrence of thyrotoxicosis due to atypical subacute thyroiditis in 15% of patients hospitalised for Covid-19 pneumonia, compared with only 1% among patients hospitalised in the same wards during Spring 2019, thus before the Covid-19 pandemic. The whole group of Covid-19 patients also had median serum TSH concentrations significantly lower compared with the control group. The atypical thyroiditis induced by Covid-19 is not associated with neck pain, affects more men than women and especially those severely ill, thus coexists with non-thyroidal illness syndrome. Subacute thyroiditis is classically followed by subsequent occurrence of permanent thyroid dysfunction and autoimmunity, thus we have started a systematic follow-up program of these patients.?METHODS: Longitudinal follow-up study of survived Covid-19 patients without previous known history of thyroid disorders and/or medications, assessing serum thyroid function and autoantibodies, C reactive protein (CRP), full blood count (FBC) and thyroid ultrasound (US) every 3 months. Patients showing baseline (at hospitalisation for Covid-19) thyroid dysfunction and/or focal hypoechoic areas suggestive for subacute thyroiditis at US performed 3 months post-infection, also underwent thyroid 99mTc or I123uptake.?RESULTS: To date, 53 patients have been included in the follow-up study. At 3 months post-infection, all of them presented with increased median (IQR) serum TSH concentrations compared with baseline: 1.3 (0.9-2.0) mIU/L versus 0.9 (0.5-1.8) mIU/L (p=0.0001). Similarly, serum concentrations of free-thyroxine, free-triiodothyronine, CRP and FBC had normalised compared with baseline. All patients had negative autoantibodies to TSH receptor; autoantibodies to thyroglobulin and to thyroid peroxidase were positive in 6/53 (11%) and 5/53 (9%) of patients, respectively. The thyroid US showed the presence of focal hypoechoic areas of thyroiditis in 16/51 (32%) patients, with thyroid uptake normal in 6/16 (37%), focally reduced in 8/16 (50%) and diffusely reduced in 2/16 (12%).?CONCLUSIONS: At 3 months after Covid-19 disease all patients had a normalised thyroid function, however imaging findings suggestive for subacute thyroiditis were still present in about one third of cases. The thyroid dysfunction induced by Covid-19 seems not mediated by autoimmunity. It is important to continue to follow these patients since they might develop thyroid dysfunction during the following months.?? 

Early Follow-up of Atypical Thyroiditis Induced by SARS-CoV-2

Background:There is some data available in adults which suggests that Type 1 diabetes may be associated with higher risk with Covid-19 (1). Limited data has been available in pediatric Type 1 diabetes with Covid-19 Methods: We used TriNetX, with a large COVID-19 database, collecting real-time electronic medical records data. We compared children (0-18 years) who were diagnosed with Covid-19 with and without Type 1 diabetes. This database collected information from 54 health care organizations Results: Mortality rate in children with Covid-19 and Type 1 diabetes was 0.618% (10/1618). Mortality rate in children with Covid-19 without Type 1 diabetes was 0.102% (257/251517). Relative risk of mortality for children with Covid-19 and Type 1 diabetes was 6.05 with a p value of < 0.0001. Endotracheal intubation rate in children with Covid-19 and Type 1 diabetes was 0.618% (10/1618). Endotracheal intubation rate in children with Covid-19 without Type 1 diabetes was 0.071% (178/251517). Relative risk of endotracheal intubation for children with Covid-19 and Type 1 diabetes was 8.73 with a p value of < 0.0001. Pneumonia rate in children with Covid-19 and Type 1 diabetes was 0.804% (13/1618). Pneumonia rate in children with Covid-19 without Type 1 diabetes was 0.562% (1414/251517). Relative risk of pneumonia for children with Covid-19 and Type 1 diabetes was 1.43 with a p value of < 0.1959. Septic shock rate in children with Covid-19 and Type 1 diabetes was 1.05% (17/1618). Septic shock rate in children with Covid-19 without Type 1 diabetes was 0.293% (737/251517). Relative risk of septic shock for children with Covid-19 and Type 1 diabetes was 3.59 with a p value of < 0.00001. Conclusion: Mortality rate, endotracheal and septic shock were increased in children with Type 1 diabetes and Covid-19 versus children with Covid-19 and no Type 1 diabetes. Further studies with larger sample size are needed to study complication rate of Covid-19 and Type 1 diabetes. References 1) Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. Lancet Diabetes Endocrinol 2020 Oct;8(10):813-822. doi: 10.1016/S2213-8587(20)30272-2. Epub 2020 Aug 13.?? 

Risk of Complications in Children With Type 1 Diabetes and Covid-19

Enzalutamide Downregulates TMPRSS2 in Lung Cells and Reduces Cellular Entry of SARS-CoV-2

Persistent and stable growth promoting effects of vosoritide in children with achondorplasia for up to 2 years: Results from the ongoing Phase 3 extension study

Introduction: Setmelanotide is a melanocortin 4 receptor (MC4R) agonist being investigated for chronic weight management in patients with rare genetic diseases of obesity caused by impairment of the MC4R pathway. The objective of this analysis was to assess the efficacy and safety of setmelanotide in patients with partial insufficiency in the MC4R pathway due to heterozygous mutations in the POMC, PCSK1, or LEPR genes. Methods: This was an open-label, single-arm, Phase 2 study of setmelanotide in rare genetic diseases of obesity, including proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) heterozygous deficiency obesity (NCT03013543). Patients aged ≥6 years with POMC, PCSK1, or LEPR heterozygous deficiency obesity received once-daily setmelanotide, which was titrated for 4 weeks to establish the therapeutic dose of 3 mg daily. Treatment at the therapeutic dose continued for an additional 12 weeks. The primary endpoint was mean percent change from baseline in body weight at Month 3. Hunger scores and adverse events (AEs) were secondary endpoints. A responder was defined as having ≥5% weight loss from baseline at Month 3. Results: A total of 35 patients were included in this analysis, with mean (standard deviation) age of 39.5 (17.6) years and body mass index of 50.3 (9.4) kg/m2. Across all patients, the mean percent change in body weight from baseline to Month 3 was −3.7% (90% confidence interval [CI], −5.3% to −2.1%; n=35). A total of 34.3% of patients (12/35) achieved the responder threshold of ≥5% weight loss from baseline at Month 3. The mean percent change in body weight from baseline to Month 3 was −10.1% (90% CI, −12.4% to −7.9%; n=12) and −0.4% (90% CI, −1.2% to −0.5%; n=23) for responders and nonresponders, respectively. The mean percent change in most hunger score from baseline to Month 3 was −4.4% (90% CI, −5.7% to −3.2%; n=10) and −2.3% (90% CI, −3.2% to −1.5%; n=23) for responders and nonresponders, respectively. Among responders, 4 (33%) had variants that were considered pathogenic/likely pathogenic per American College of Medical Genetics criteria. All patients experienced at least?1 AE. Overall, the most common treatment-emergent AEs were skin hyperpigmentation (51.4%), nausea (48.6%), and injection site pruritis (37.8%). One patient had serious AEs of acute myocardial infarction and gastrointestinal hemorrhage that were considered unrelated to setmelanotide. No AEs led to death.Conclusions: Setmelanotide was associated with reduced body weight and hunger scores in patients with POMC, PCSK1, or LEPR heterozygous deficiency obesity. While the overall mean percent decrease in body weight may have been less than that previously reported in patients with homozygous or compound heterozygous variants, setmelanotide may be a viable treatment option for some patients with POMC, PCSK1, or LEPR heterozygous deficiency obesity.?? 

Effects of Setmelanotide in Patients with POMC, PCSK1, or LEPR Heterozygous Deficiency Obesity in a Phase 2 Study

Primary Results From MATCH: Is Metomidate PET-CT superior to Adrenal venous sampling in predicting ouTCome from adrenalectomy in patients with primary Hyperaldosteronism

Identification of Genes and Pathways Differentially Expressed in Progestin Responsive Endometrial Cancer and Hyperplasia

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