United States

Introduction
In critically ill adults, high plasma free cortisol in face of suppressed plasma ACTH coincides with high plasma pro-opiomelanocortin (POMC), the ACTH precursor (1). Further augmenting the systemic glucocorticoid availability with hydrocortisone treatment further lowered plasma ACTH, while plasma POMC remained unaffected (2). The dynamics of POMC in relation to ACTH and free cortisol prior to intensive care unit (ICU) admission are unknown, as well as the impact hereon of glucocorticoid treatment. Also, elevated plasma POMC concentrations have not yet been confirmed in pediatric ICU (PICU) patients. In pediatric cardiac surgery-induced critical illness, we hypothesized that plasma POMC is elevated and that plasma ACTH transiently rises per-operatively and becomes suppressed once free cortisol has risen on PICU day 1 and 2. In addition, we hypothesized that in patients receiving glucocorticoids per-operatively, plasma ACTH is further suppressed while plasma POMC is unaffected.
Methods
From 53 children aged 0-36 months, who underwent cardiac surgery and were admitted to the PICU, blood samples were taken prior to surgery (pre-operatively, available samples N=51), during surgery (per-operatively, N=47), on the following morning (PICU day 1, N=40) and the day hereafter (PICU day 2, N=24). Blood samples were also collected from 24 age- and gender-matched healthy children. To investigate the impact of synthetic glucocorticoid treatment on the endogenous plasma hormone concentrations, patients were categorized into steroid-naive (total N=38) and steroid-treated patients (total N=15). Plasma hormone concentrations were quantified with highly-specific ELISA (POMC), RIA (ACTH, cortisol, CBG) or colorimetric assays (albumin). Cross reactivity with synthetic glucocorticoids within the used cortisol RIA is minimal (&lt;0.27% for methylprednisolone, &lt;0.1% for dexamethasone). Free cortisol was estimated with the adapted Coolens&#39; formula.
Results
Plasma POMC was increased pre-operatively (p&lt;0.0001) but no longer thereafter (p&gt;0.05), irrespective of steroid treatment. Plasma ACTH in patients was never higher than in healthy children. While in steroid-naive patients, plasma ACTH became suppressed only by PICU day 1 (p&lt;0.0001), steroid-treated patients had already suppressed plasma ACTH per-operatively (p≤0.0001). In steroid-naive patients, plasma free cortisol was increased from per-operatively onwards (p≤0.002), while in steroid-treated patients, plasma free cortisol (endogenous) concentrations always remained comparable to those of healthy children (p&gt;0.05).
Conclusion
Pre-operatively high plasma POMC, not followed by increased ACTH, suggests a centrally-activated HPA-axis already prior to surgery and an immature pituitary processing of POMC into ACTH. Systemic glucocorticoid availability is elevated from surgery onwards, likely driven by ACTH-independent mechanisms. Further increasing systemic glucocorticoid availability exogenously with glucocorticoid administration accelerates the suppression of plasma ACTH. The long-term impact of early glucocorticoid treatment in critically ill children remains to be investigated.
References
(1) Téblick A. et al. Critical Care 2021.
(2) Téblick A. et al. Endocrinology 2022.

ENDO 2022

Pro-opiomelanocortin (POMC), ACTH and Cortisol Responses to Pediatric Cardiac Surgery

**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
In critically ill adults, high plasma free cortisol in face of suppressed plasma ACTH coincides with high plasma pro-opiomelanocortin (POMC), the ACTH precursor (1). Further augmenting the systemic glucocorticoid availability with hydrocortisone treatment further lowered plasma ACTH, while plasma POMC remained unaffected (2). The dynamics of POMC in relation to ACTH and free cortisol prior to intensive care unit (ICU) admission are unknown, as well as the impact hereon of glucocorticoid treatment. Also, elevated plasma POMC concentrations have not yet been confirmed in pediatric ICU (PICU) patients. In pediatric cardiac surgery-induced critical illness, we hypothesized that plasma POMC is elevated and that plasma ACTH transiently rises per-operatively and becomes suppressed once free cortisol has risen on PICU day 1 and 2. In addition, we hypothesized that in patients receiving glucocorticoids per-operatively, plasma ACTH is further suppressed while plasma POMC is unaffected.
Methods
From 53 children aged 0-36 months, who underwent cardiac surgery and were admitted to the PICU, blood samples were taken prior to surgery (pre-operatively, available samples N=51), during surgery (per-operatively, N=47), on the following morning (PICU day 1, N=40) and the day hereafter (PICU day 2, N=24). Blood samples were also collected from 24 age- and gender-matched healthy children. To investigate the impact of synthetic glucocorticoid treatment on the endogenous plasma hormone concentrations, patients were categorized into steroid-naive (total N=38) and steroid-treated patients (total N=15). Plasma hormone concentrations were quantified with highly-specific ELISA (POMC), RIA (ACTH, cortisol, CBG) or colorimetric assays (albumin). Cross reactivity with synthetic glucocorticoids within the used cortisol RIA is minimal (<0.27% for methylprednisolone, <0.1% for dexamethasone). Free cortisol was estimated with the adapted Coolens' formula.
Results
Plasma POMC was increased pre-operatively (p<0.0001) but no longer thereafter (p>0.05), irrespective of steroid treatment. Plasma ACTH in patients was never higher than in healthy children. While in steroid-naive patients, plasma ACTH became suppressed only by PICU day 1 (p<0.0001), steroid-treated patients had already suppressed plasma ACTH per-operatively (p≤0.0001). In steroid-naive patients, plasma free cortisol was increased from per-operatively onwards (p≤0.002), while in steroid-treated patients, plasma free cortisol (endogenous) concentrations always remained comparable to those of healthy children (p>0.05).
Conclusion
Pre-operatively high plasma POMC, not followed by increased ACTH, suggests a centrally-activated HPA-axis already prior to surgery and an immature pituitary processing of POMC into ACTH. Systemic glucocorticoid availability is elevated from surgery onwards, likely driven by ACTH-independent mechanisms. Further increasing systemic glucocorticoid availability exogenously with glucocorticoid administration accelerates the suppression of plasma ACTH. The long-term impact of early glucocorticoid treatment in critically ill children remains to be investigated.
References
(1) Téblick A. et al. Critical Care 2021.
(2) Téblick A. et al. Endocrinology 2022.

technical paper

Purpose. To evaluate deep learning analysis of thyroid nodule ultrasound images as a rule-out test for thyroid malignancy.
Methods. Supervised deep learning (DL) classifier of thyroid nodules was trained on 32,545 thyroid US images from 621 nodules representing all major benign and malignant types of thyroid lesions and tested on an independent set of 145 nodules collected at a different healthcare system in the United States. The Big Transfer BiT-M ResNet-50x1 convolutional neural net architecture was modified to contain 3, 4, 6 and 3 PreActBottleneck units per block 1 through 4. Weights pretrained on the ImageNet-21k dataset were loaded and weights for blocks 3 and 4 were fine-tuned for the binary classification task of distinguishing benign and malignant thyroid nodules.
Results. The deep learning thyroid nodule classifier achieved an area under receiver operating characteristic curve (AUROC) of 0.889 on five-fold cross-validation. The AUROC improved when images were scaled by nodule size and six randomly selected cine clip frames were added to the training set per epoch. GradCAM class activation heatmaps revealed that microcalcifications and spongiform appearance were reliably recognized by the classifier as malignant and benign features, respectively. Spongiform nodules were found to be benign even when microcystic spaces constituted less than 50% of nodule volume.
To investigate the clinical relevance of the benign vs. malignant classifier, the binary classification threshold for the probability of malignancy generated by model was set at 7% to achieve sensitivity and negative predictive value (NPV) comparable to that of the fine needle aspiration biopsy (FNA). At this threshold, cross-validated deep-learning model achieved a sensitivity of 90%, specificity of 63%, positive predictive value (PPV) of 46% and negative predictive value of 94%. When tested on an independent image set that includes 18 classic papillary thyroid cancers (PTC), 5 follicular variant PTC, 4 medullary thyroid cancers, 3 follicular thyroid cancers (FTC), and 1 Hurthle cell thyroid cancer, the DL classifier achieved AUROC of 0.88, sensitivity of 97%, specificity of 61%, PPV of 40% and NPV of 99%. A single minimally-invasive FTC that had no suspicious features on thyroid ultrasound was incorrectly classified as benign.
Conclusions. This study demonstrates that the ultrasound-based deep-learning classifier of thyroid nodules achieves sensitivity and negative predictive value comparable to that of thyroid fine needle aspiration (FNA). Clinicians may use this tool to augment clinical judgment when determining whether to perform FNA procedures.

Deep learning analysis of thyroid nodule ultrasound images has high sensitivity and negative predictive value to rule-out thyroid cancer

Introduction
Hashimoto's thyroiditis raises the risk for differentiated thyroid cancer (DTC) in surgical series, but the role of thyroid peroxidase antibodies (TPO) remains controversial in that regard. We designed the present study to evaluate the effect of preoperative TPO titers in the risk of DTC.
Methods
A comprehensive search was conducted in PubMed, CENTRAL and Scopus databases in November 2021 for the terms "thyroid cancer" and "TPO" or "peroxidase antibodies". We characterized the differential risk found in patients with high titers of TPO (TPO+), as compared to those with low or undetectable titers (TPO-) with regard to DTC. Data are expressed as odds ratio (OR) with 95% confidence interval (CI).
Results
We retrieved and reviewed 408 records; 21 retrospective cohort studies (2006-2022) from 7 countries and n=30,5536 subjects, fulfilled the eligibility criteria: 15 studies in East Asia with n=25,125 subjects (82.2%) and 6 studies in the Western world with n=5,428 subjects (17.8%)]. These comprised n=17,684 subjects with benign disease (57.9%) and n=12,869 with DTC (42.1%). The reference used for TPO+ was 23.6±18.8 (Range 5.1-60.0 IU/ml); n=6,307 patients were TPO+ (20.6%) and n=24,246 were TPO- (79.4%). DTC was present in n=2,960 TPO+ patients (46.9%) and n=9,909 TPO- patients (40.9), OR 1.28, (95%CI 1.21-1.35), p<0.001.
A high titer of TPO was associated with increased risk for DTC in both Asian cohorts, [OR 1.36 (1.28-1.45, p<0.001)] and Western world alike, [OR 1.15 (1.02-1.31), p=0.025]. That risk was statistically significantly higher in the Asian world cohorts as compared to the Western World cohorts, p<0.001.

Conclusions
Thyroid peroxidase antibodies are an integral part of Hashimoto's thyroiditis, which is a well characterized risk factor for thyroid cancer and seem to increase that risk as well. That effect seems significantly higher in East Asia as compared to the Western World region. Further studies are needed to characterize the effects of the immune response, with regard to thyroid cancer risk.

The role of thyroid peroxidase antibodies on the risk of thyroid cancer: a systematic review and meta-analysis of surgical cohort studies.

Introduction: Radiofrequency ablation (RFA) is a promising, non-surgical method, used for the treatment of benign and malignant thyroid nodules (TN). While this minimally invasive technique has been studied extensively in Europe and Asia, it has been recently adopted in Latin America. The aim of our study is to describe the clinical outcomes following the first cohort of TN subjected to ablative radiofrequency in Ecuador.
Methods: This single-center, prospective study, carried out at ITECC (Instituto de la Tiroides y Enfermedades de Cabeza y Cuello) in Ecuador, included adults who underwent RFA for benign and malignant thyroid nodules (TN), between September 2020 and January 2022. The trans-isthmic approach and moving shot technique using the RF Medical equipment with an 18G needle and 5 or 7 mm tip were applied. Nodule size and volume, thyroid function, and complications were evaluated before and after RFA. Initial volume and change in TN volume were calculated with the ATA calculator and the independent-samples T-test.
Results: A total of 26 patients with 28 TNs were included. 25 TNs were benign (Bethesda II) and 3 were micropapillary thyroid cancer (MPTC) (Bethesda VI). In the benign lesions group, most were female (82.6%), <55 years of age (73.9%), euthyroid (62.5%), and symptomatic (95.6%); had a mean maximum diameter of 3.3 ± 1.3 (range: 0.8 – 5.5) cm and a mean initial volume of 13.1 ± 11.6 ml; and had predominantly solid component (36.4%). A substantial volume reduction was observed since the first month after RFA (1 month: mean volume 8.6 ± 4.2 ml, p=0.01; 6 months: mean volume 4.5 ± 3.9 ml, p=0.04; and 12 months: mean volume 4.9 ± 6.9 ml, p=0.25; vs. baseline). All patients were asymptomatic at the last follow-up. In the MPTC group, two patients were males (66.7%); all were <55 years of age (100.0%) and euthyroid (100.0%); most were asymptomatic diagnosed by routine US (66.7%); had a mean maximum diameter of 0.6 ± 0.1 (range: 0.5 – 0.8) cm and a mean initial volume of 0.056 ± 0.001 ml. At 1-month follow-up after RFA all TN were fibrosed and no lymph node or distant metastases were found. Finally, in both groups, no major complications were found and only one patient reported ecchymosis at the puncture site. Thyroid function was not affected.
Conclusions: To the best of our knowledge, we are the pioneers in Ecuador and the third country, after Brazil and Colombia, in Latin America that implemented RFA in the management of TN. In our first experience, RFA was a safe and effective technique. RFA induced a substantial volume reduction, improved symptoms, avoided cosmetic concerns, and did not affect normal thyroid function. Our results are consistent with other series. Data on a longer follow-up are needed to confirm long-term efficacy.

Radiofrequency Ablation for Thyroid Nodules: The First Ecuadorian Prospective Cohort

Background: The incidence of differentiated thyroid cancer (DTC) has tripled over the last 30 years in the US. While most patients respond to conventional treatment, some have an aggressive course with a dismal 5-year survival of 15.3%. There is a need to identify novel markers in addition to clinico-pathologic criteria to better prognosticate DTC patients. In addition, exploration of immunotherapies in advanced DTC underlies the critical need to investigate the immune interface of DTC to identify potential therapeutic targets and those likely to respond to immunotherapies.
Aims: We aimed to identify tumor-infiltrating immune cells and checkpoints [programmed cell death protein 1 (PD-1) and its ligand (PD-L1)] associated with DTC and investigate their association with metastatic and advanced DTC.
Methods: We performed multiplex immunofluorescence on de-paraffinized thyroid tissue collected at initial thyroidectomy from 17 adults with DTC. We identified cell-surface molecules to characterize the tumor immune microenvironment for leukocytes (CD45+), T cells (CD3+), B cells (CD19+), natural killer cells (CD56+), T regulatory cells (CD3+FOXP3+), CD4+ T cells (CD3+CD4+), CD8+ T cells (CD3+CD8+), macrophages (CD68+), M2 macrophages (CD68+CD163+), and immune checkpoints PD-1 and PD-L1. Tonsil tissue was used as positive control. Immunofluorescence staining was quantified by cell counting HALO software. We compared the mean percentage expression of immune markers between tumor and adjacent thyroid tissue from the same patient by paired t-test, and in exploratory analysis between intra-tumoral tissue in patients with versus without distant metastases by student's t-test; p value<0.05 was used for significance.
Results: Overall, in 17 DTC patient samples, most leukocyte infiltrate occurred along the leading edge of the tumor and in the peritumoral thyroid tissue. Immune checkpoints PD-1 and PD-L1 were highly expressed in the tumor as compared to adjacent thyroid tissue (p<0.05). A higher trend for M2 macrophages was observed in the tumor but was not statistically significant. Intra-tumoral expressions of T regulatory cells, macrophages and PD-L1+ cells were more in samples for DTC patients with metastases (n=3) as compared to those without (n=14).
Conclusions: Immune profiling demonstrated significant differences between tumor and adjacent thyroid tissue, particularly for PD-1 and PD-L1, indicating their role in DTC occurrence. Intra-tumor infiltration of T regulatory cells, macrophages and PD-L1+ cells was more in metastatic DTC indicating their potential role in aggressive behavior of DTC. These data suggest that suppressive tumor immune microenvironment portends more aggressive behavior of DTC, and that specific immune suppressive markers may be potential therapeutic targets. We are continuing to expand our sample size to have adequate power for comparing groups with various clinico-pathologic severities and analyzing the role of pro-tumoral M2 macrophages in DTC prognosis.

Suppressive Tumor Immune Microenvironment is Associated with Aggressive Differentiated Thyroid Cancer

"Superhenhanced" transcription of specific oncogenes by aberrant looping of upstream enhancer elements to marked transcriptional regulatory regions is a mechanism of oncogene overexpression. Therefore, compounds that target key positive regulators of RNA polymerase II (RNAPII) activity, such as CDK7 and CDK9, can relatively selectively reduce expression of such superenhanced oncogenes and are in clinical trials. We have previously reported activity of the CDK7 inhibitor THZ1 in medullary thyroid cancer (MTC) along with identification of a superenhancer in RET. CDK7 inhibitors also are reported to be active in anaplastic thyroid cancer cell lines. In the present study, we extend this work to both CDK7 and CDK9 inhibitors, and to a more extensive set of thyroid cancer cell lines. We selected 8 thyroid cancer cell lines (TPC1, FTC133, BCPAP, SW1376; K1, THJ-16T, C643, and 8505C) from a variety of histological subtypes with different driver mutations for treatment with a CDK7 (THZ1) or CDK9 (AZD4573) inhibitors. Cell viability assays were performed to determine IC50 and Western blots were performed for target validation. IC50 values ranged from 5-100 nM for both compounds for all cell lines demonstrating broad activity and robust activity. Unexpectedly, both compounds inhibited both CDK7 RNAPII phosphorylation (Ser5) and CDK9 RNAPII phosphorylation (Ser2) due to a loss of total RNAPII protein levels in all cell lines. Further time course studies two cell lines, 8505C (BRAFV600E) and TPC1 (RET/PTC) showed the loss off RNAPII occurred rapidly (1-3 hours) with stable RNAPII mRNA levels by qRTPCR. We therefore hypothesized that RNAPII stalling induced by inhibition of CDK7 may cause loss of RNAPII protein stability through ubiquitination and proteasome-mediated degradation. Immunoprecipitation-Western blots demonstrated variable baseline levels of RNAPII ubiquitination in 8505C (low) and TPC1 (high) cells. THZ1 treatment induced ubiquitination of RNAPII in 8505C cells signficantly, while a modest increase beyond the higher baseline occurred in TPC1. Bortezomib (proteasome inhibitor) treatment rescued THZ1-reduced RNAPII protein levels in both cell lines. In summary, human thyroid cancer cell lines are broadly sensitive to CDK7 and CDK9 inhibitors. CDK 7 and 9 inhibitors reduce RNAPII levels and THZ1 induces RNAPII ubiquitination and proteasome degradation demonstrating a new mode of action for the reduced RNAPII activity induced by these inhibitors.

CDK7 and CDK9 Inhibition Induces RNA Polymerase II Ubiquitination and Proteasome Degradation in Thyroid Cancer Cells

Introduction: A well-known 'flip flop' phenomenon exists between whole-body scans (WBS) and 18FFDG PET imaging in differentiated thyroid cancer (DTC) such that cancer progression is typically associated with reduced iodine uptake and increased FDG avidity. Patients with FDG avidity have a poor clinical outcome while those with iodine avid lesions are more responsive to radioactive iodine therapy (RAI) and have a better prognosis. A spectrum however exists, as thyroid cancers become less well differentiated, when they will be both iodine and FDG avid. Current scoring systems in thyroid cancer are limited to a single imaging data set.  We propose a new scoring system (I-PET) combining WBS and FDG findings to identify patients more likely to be refractory to RAI, and who may be ideal candidates for 're-differentiation' before RAI treatment.
Methods: Retrospective analysis of 142 patients age > 18 with differentiated thyroid cancer who had a 18FFDG PET and WBS within a 6 month period of each other between 2010 and 2020. Initial pair of 18F FDG PET and WBS were reviewed by two independent nuclear medicine physicians and an IPET score was assigned: IPET [0]: Iodine –ve, FDG –ve, IPET [1]: Iodine +ve, FDG –ve, IPET [2]: Iodine +ve, FDG +ve and IPET [3]: Iodine –ve, FDG +ve. Patients with FDG +ve lesions (I-PET 2 and I-PET 3) were further classified into group 'a' and 'b' if SUVmax was less than or greater than 5 respectively. Follow-up data was obtained by chart review. Progression was defined as either structural recurrence as per RECIST 1.1 or equivalent clinical assessment, or biochemical incomplete response with an unstimulated Tg > 1ug/L. The study was approved by IRB (ETH00674/ STE01494).
Results: Of the 142 patients included in the study 121 patients had follow up data available for review. At baseline, 49 patients were classified as IPET [0], 10 as IPET [1], 16 as IPET [2] and 46 as IPET [3]. Progression was identified in 49% (59/121) patients; of which 54 were structural and 5 biochemical. Patients classified as [2b] and [3b] had a recurrence rate of 88% (7/8) and 78% (25/32) respectively, while IPET [0] patients had 22% (11/49) recurrence (p < 0.001). Patients classified as IPET [3b] were 10.4 times more likely to commence on tyrosine kinase inhibitor therapy (p=0.005) and had a 8.1 times greater mortality rate (p=0.02) than patients in the other IPET groups.
Conclusion: IPET score is a novel scoring system incorporating WBS and 18FFDG PET imaging which predicts progression and death in patients with FDG avid thyroid cancer.

I-PET Score: Combining Whole Body Iodine Scan and 18 Fluorodeoxyglucose Positron Emission Topography to Predict Progression in Thyroid Cancer

Background: Congenital leptin deficiency (CLD) is a rare autosomal recessive form of monogenic obesity caused by loss-of-function mutations in the leptin gene. Targeted therapy is available in the form of recombinant human leptin (metreleptin). We previously reported baseline characteristics of one of the first cases of CLD diagnosed in the United States, a patient with a comorbid diagnosis of Hodgkin lymphoma prior to initiation of therapy. Metreleptin has a black box warning for risk of T-cell lymphoma, which has been reported in acquired generalized lipodystrophy patients, both treated and untreated with metreleptin.
Clinical Case: A 20 yr old female (Pt B) was referred for evaluation of obesity (BMI 45.0 kg/m2) with a history of hyperphagia and excessive weight gain by three months of life. Pt B is of Pakistani origin with a family history of consanguinity. She was treated with combination OCPs in adolescence due to primary amenorrhea and hypogonadotropic hypogonadism. At the time of her initial evaluation, serum leptin levels were undetectable. Pt B was homozygous for the pathogenic variant c398delG in exon 3 of the leptin gene (LEP), which causes a frameshift/premature stop codon. On MR elastography performed for hepatic steatosis, she had an incidental finding of axillary lymphadenopathy. Surgical biopsy and staging work-up confirmed diagnosis of nodular lymphocyte predominant Hodgkin lymphoma, Stage II disease. She was treated with 2 cycles of R-ABVD followed by adjuvant radiation (2000 cGy) to the right supraclavicular and axillary region, achieving clinical remission. Pt B was then treated with 3.75-5 mg metreleptin once daily in an observational treatment protocol for 18 months. With therapy, pt B lost 39.1 kg or 33% of initial body weight. Clinically significant improvements in related parameters were observed, including percent body fat (-18%), estimated visceral adipose tissue (-53%), HOMA2 IR (-80%), ALT (-91%), total cholesterol (-10%), triglycerides (-26%), HDL (+6%), LDL (-19%), and high-sensitivity C-reactive protein (-84%). In addition, prediabetes (with abnormal 2 hour OGTT) resolved, hepatic steatosis improved, bone mineral density increased (+0.6 SD), and pt B developed spontaneous regular menses. She tolerated metreleptin well without serious adverse effects and her lymphoma remained in remission throughout the study.
Conclusion: To our knowledge, this is the first report of lymphoma in a patient with CLD, occurring prior to treatment with metreleptin. Pt B achieved clinical remission prior to initiation of therapy with metreleptin, with no recurrence on 18 months of therapy. She experienced substantial weight loss and marked improvements in body composition, glucose metabolism, insulin sensitivity, lipid metabolism, liver and reproductive health. Untreated CLD has been associated with impaired lymphocyte production and function. The risk for lymphoma associated with metreleptin may relate to preexisting autoimmunity or immunologic abnormalities related to leptin deficiency rather than medication adverse effect.

Lymphoma in Congenital Leptin Deficiency: Comorbidity or Adverse Effect?

Food insecurity, the lack of consistent access to sufficient food for an active and healthy life, is associated with lower diet quality, higher BMI and adiposity, and poor metabolic health. Although lower diet quality is assumed to be responsible for the impact of food insecurity on adiposity, this hypothesis has not been previously investigated.
To test the hypothesis that diet quality mediates the association of food insecurity with adiposity, we used data from the 2015-2016 National Health and Nutrition Examination Survey (NHANES, age ≥18 years, n=5821, weighted N=233,636,542). Anthropometrics included BMI, waist circumference and fat mass (measured by dual X-ray absorptiometry and expressed as percentage of total body weight). Food insecurity was assessed with the 10-item NHANES Food Security Survey Module and defined as ≥3 affirmative responses. Nutrition information was derived from 24h food recalls obtained on 2 separate occasions. Diet quality was estimated by the Healthy Eating Index-2015 (HEI), which includes a total score for overall diet quality, and sub-scores for several dietary components. Mediation analysis was conducted with the Baron and Kenny approach. A p-value <0.05 was considered statistically significant.
The cohort included 52% women, 11% non-Hispanic Black and 15 % Hispanic participants. Eighteen percent were food insecure. They reported a lower energy intake compared to food secure participants, although the difference was not significant after adjusting for demographics and income (difference [95% confidence interval] -84 [-207.36, 38.91] kcal/day, p=0.15). Total HEI and fruit scores were lower in food insecure individuals, suggesting lower diet quality (adjusted difference -1.70 [-3.09, -0.32], p=0.03; and -0.28 [-0.53, -0.02], p=0.04, respectively). Obesity was 22% more prevalent in food insecure individuals (p<0.01). Fat mass and waist circumference were also higher in individuals with food insecurity (adjusted difference 0.95 [0.19, 1.7] %, p=0.02; and 3.81 [1.3, 6.31] cm, p=0.01, respectively). Mediation analysis revealed that total energy intake mediated the effect of food insecurity on fat mass but not BMI or waist circumference, while total HEI partially mediated the effect of food insecurity on waist circumference but not BMI or percent fat mass. No mediation of total fruit score on BMI or adiposity was observed.
In summary, our results confirm a greater prevalence of obesity and higher adiposity in food insecure individuals, despite a similar reported energy intake compared to food secure individuals. Energy intake and measures of diet quality appear to mediate some of the effect of food insecurity on overall and central adiposity, but not on BMI. This suggests that other factors, including the social determinants of health, may also play a role.

Diet Quality and Energy Intake Mediate the Association of Food Insecurity with Adiposity

Well-treated persons living with HIV (PLWH) are predisposed to fat redistribution/visceral adiposity, potentially due to anti-retroviral therapy (ART) use and/or the virus itself, and demonstrate a 2-fold higher risk of cardiovascular disease (CVD) compared to those without HIV. Visceral adipose tissue (VAT) is a metabolically unfavorable ectopic fat depot, which is highly inflamed and dysfunctional. Fat redistribution leading to VAT accumulation is related to increased CVD risk. Current gold standard measures of VAT are obtained using CT and MRI, but are not used clinically. The visceral adiposity index (VAI) is a simple tool combining biochemical measures with anthropometrics that can be easily evaluated by the clinician. VAI may be a surrogate measure of VAT and indeed has been shown to relate to insulin resistance, type 2 diabetes mellitus, metabolic syndrome and CVD among the general population. In this study, we evaluated VAI in PLWH and its relation to VAT, anthropometric measures and other cardiometabolic parameters.
45 PLWH on stable ART with no known CVD were recruited as part of a clinical trial to evaluate CVD indices and were included if they were virologically controlled (HIV viral load <200 copies/mL) and demonstrated increased abdominal VAT (VAT area>110cm²) on CT. For purposes of this study, baseline fasting biochemical, radiologic and anthropometric data were used. VAI was calculated using the standard sex-specific formulas which incorporate waist circumference (WC), BMI, triglycerides and HDL. Presence of coronary plaque was assessed using coronary CT angiography or coronary PET scans. Linear regression was performed to assess relationships with VAI. Non-normally distributed variables were log-transformed for analyses.
Participants were predominantly male (73%), Caucasian (53%), and non-Hispanic (84%) with mean age 55 ± 7 years. Participants had a long duration of HIV and ART use (20 ± 8 and 15 [12,19] years, respectively). The majority of PLWH were obese (BMI 31.9 ± 5.8 kg/m²) with VAT 189 [127,267]cm² and VAI 4.9 [2.8,7.3]. VAI correlated strongly with VAT (r=0.59, P<0.0001), anthropometric measures (BMI r=0.36, P=0.02; WC r=0.43, P=0.004; WHR r=0.33, P=0.03) and ALT (r=0.32, P=0.03), and did not relate to HIV-specific parameters and other metabolic parameters (blood pressure, HbA1c). Participants with coronary plaque tended to have a higher VAI compared to those without coronary plaque (log VAI 0.7 ± 0.3 vs. 0.5 ± 0.3, P=0.056).
These data show VAI, an easily obtained measure, is strongly correlated with abdominal VAT area measured by CT and may be a useful biomarker for visceral adiposity in HIV. Furthermore, VAI may be related to ALT and coronary plaque, which could help identify those PLWH at risk for fatty liver disease (another ectopic fat depot) and heart disease, respectively. Further studies are needed to assess the utility of VAI in evaluating metabolic disease in HIV.

Visceral adiposity index as a measure of cardiometabolic disease in persons living with HIV

Background: While wireless mobile device (WMD) overuse might be perceived as normal behavior in people of all ages, the pathophysiology of WMD addiction is similar to that of substance addiction. Increasing prevalence of disorders related to screentime/sedentary lifestyle such as obesity, dyslipidemia, prediabetes, and type 2 diabetes mellitus calls for comprehensive and cost-effective interventions.
Objectives: We aimed to synthesize existing data on the neuroscience that underlies WMD addiction, its adverse health outcomes and suggest practical strategies to achieve life-technology balance at home and work.
Methods: Comprehensive search of databases (PubMed and MEDLINE) was conducted until May 2021, for smartphone, screentime and phone addiction. The data were collected as part of a population-based educational initiative, Phreedom (Freedom from smartPhone), to inspire individuals to achieve life-technology balance.
Results: From the initial 655 citations, 234 were included. The addictive use of WMDs was linked to the 'incentive sensitization theory of addiction': repeated exposure to potentially addictive stimuli (i.e., notifications) can cause persistent structural and functional brain changes in the prefrontal cortex. As a result, an individual's executive functions and cue-reactivity could be impaired. The hyper-reactive dopamine system could also drive this compulsive behavior in the form of a habit-loop of cue, craving, response, and reward. Each hour/day increase in screentime was associated with 0.05-0.07 increase in body mass index (BMI) (p < 0.001), likely due to food marketing, distracted eating, reduced satiety, and procrastination of physical activity. Overuse of WMDs was associated with insufficient and low-quality sleep, daytime tiredness, daytime sleepiness, depression, and daily cognitive failures. Nine of 10 Americans reported using a technological device in the hour before bed. The more interactive the device, the higher the difficulty falling asleep and unrefreshing sleep (p < 0.05). The younger the age at initial exposure and the longer the duration of exposure, the higher the odds of adverse health outcomes, such as illegal substance use. High users of screens were more likely to have been diagnosed with anxiety or depression, requiring medication. Practical strategies to disrupt the addictive dopamine habit-loop included WMD triage and uncluttering, eliminating redundant notifications, deleting time-consuming applications, modifying the digital environment at home and work, and replacing screentime with greentime. Other tactics could include using an alarm clock, wearing a wristwatch, specifying times to check emails and social media, refocusing teams to decrease reliance on text messages and lowering expectations of immediate responses.
Conclusions: While it would be irrational to suggest complete avoidance of all WMDs, moderation, balance, and real-life engagement together with strategies aimed at disrupting the dopamine habit loop will be critical components of any intervention plan. Educating patients about the neuroscience of WMD addiction and empowering them with tips to curb WMD use might impact their behavior substantially.

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