Trabecular Bone Score Change Is Not Predicted by Bone Turnover: Short-term Sequential Follow-up.

BACKGROUND: Trabecular bone score (TBS) reflects vertebrae microarchitecture and assists in fracture risk assessment. The International Society of Clinical Densitometry postulates that the role of TBS in monitoring antiresorptive therapy is unclear. Whether changes in TBS correlate with bone resorption measured by bone turnover markers is not known. OBJECTIVES: To determine whether longitudinal changes in TBS correlate with C-terminal telopeptide (CTX) of type I collagen. METHODS: Examinees with two bone mineral density (BMD) measurements were detected via the institutional database. Over 5.8% change in TBS was considered least significant and patients were grouped accordingly (increment, decrement, or unchanged). CTX, BMD, co-morbidities, incident fractures, and medication exposure were compared between the groups by Kruskal-Wallis. The correlation between TBS and BMD change and CTX in a continuous model was analyzed by Pearson's correlation coefficient. RESULTS: In total, 110 patients had detailed medical records. In 74.5%, TBS change was below least significant change. Two other TBS categories, fracture incidence or medication exposure, did not differ by CTX. In the continuous model, BMD and TBS change was positively correlated (r = 0.225, P = 0.018). A negative correlation was observed between BMD change and CTX. The decrease in BMD level was associated with higher CTX (r = -0.335, P = 0.004). No correlation was observed between CTX and TBS. CONCLUSIONS: No correlation between TBS dynamics and bone resorption marker was found. Clinical interpretation and implication of longitudinal TBS changes should be further explored.

Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours.

Each tumour contains diverse cellular states that underlie intratumour heterogeneity (ITH), a central challenge of cancer therapeutics1. Dozens of recent studies have begun to describe ITH by single-cell RNA sequencing, but each study typically profiled only a small number of tumours and provided a narrow view of transcriptional ITH2. Here we curate, annotate and integrate the data from 77 different studies to reveal the patterns of transcriptional ITH across 1,163 tumour samples covering 24 tumour types. Among the malignant cells, we identify 41 consensus meta-programs, each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many tumours. The meta-programs cover diverse cellular processes including both generic (for example, cell cycle and stress) and lineage-specific patterns that we map into 11 hallmarks of transcriptional ITH. Most meta-programs of carcinoma cells are similar to those identified in non-malignant epithelial cells, suggesting that a large fraction of malignant ITH programs are variable even before oncogenesis, reflecting the biology of their cell of origin. We further extended the meta-program analysis to six common non-malignant cell types and utilize these to map cell-cell interactions within the tumour microenvironment. In summary, we have assembled a comprehensive pan-cancer single-cell RNA-sequencing dataset, which is available through the Curated Cancer Cell Atlas website, and leveraged this dataset to carry out a systematic characterization of transcriptional ITH.

Unique Characteristics of Patients with Von Hippel-Lindau Disease Defined by Various Diagnostic Criteria.

Von Hippel-Lindau (VHL) disease diagnosis is based on two criteria sets: International criteria (IC, two hemangioblastomas, one hemangioblastoma plus one visceral lesion, or VHL family history/pathogenic variant plus hemangioblastoma/visceral lesion); or Danish criteria (DC, two clinical manifestations, or VHL family history/pathogenic variant plus hemangioblastoma/visceral lesion). We aimed to compare the characteristics of patients with VHL-related pancreatic neuroendocrine tumor (vPNET) meeting either the clinical Danish criteria only (DOC) or IC to those with sporadic PNET (sPNET). The cohort included 33 patients with VHL (20 vPNETs) and 65 with sPNET. In terms of genetic testing and family history of VHL, 90.0% of the patients with vPNET in the IC group had a germline VHL pathogenic variant, and 70.0% had a family history of VHL vs. 20% and 10% in the DOC group, respectively (p < 0.05 for both). Patients with vPNET were younger at diagnosis compared with sPNET (51.6 ± 4.1 vs. 62.8 ± 1.5 years, p < 0.05). Patients in the IC group were younger at diagnosis with VHL, vPNET, pheochromocytoma, or paraganglioma (PPGL) and renal-cell carcinoma (RCC) than those in the DOC group (p < 0.05 for all comparisons). The most prevalent presenting manifestations were hemangioblastoma (42.8%) and PPGL (33.3%) vs. RCC (58.3%) and PNET (41.7%) in the IC vs. DOC groups. In conclusion, patients with vPNET meeting DOC criteria show greater similarity to sPNET. We suggest performing genetic testing, rather than solely using clinical criteria, for establishing the diagnosis of VHL.

Non-Interventional Management of Advanced Pancreatic Neuroendocrine Neoplasms in Patients with von Hippel-Lindau Disease.

Von Hippel-Lindau (VHL) is a rare autosomal dominant hereditary cancer predisposition syndrome. Patients with VHL have a high risk for developing retinal and central nervous system hemangioblastoma, pheochromocytoma, renal cell carcinoma, and pancreatic neuroendocrine neoplasms (PNEN). About a fifth of patients with VHL will develop PNEN, and only a tenth of them will develop metastatic or unresectable (advanced) PNEN requiring medical intervention. In this review, we performed a literature search for studies, written in English, on the medical interventions for VHL-related localized and advanced PNENs and their clinical outcomes. We detail the various medical interventions for this rare group of patients, including their mode of action and potential efficacy and toxicity. Finally, based on the current literature, we delineate a possible management algorithm for patients with VHL and advanced PNEN. We can conclude that data on the efficacy of various vascular endothelial growth factor (VEGF) receptor inhibitors, and on the efficacy of belzutifan, a novel hypoxia-inducible factor 2 inhibitor, for the management of advanced PNEN in VHL, are scarce. Hence, deduction from the management of sporadic PNEN is required, and is implemented in the proposed management algorithm provided within this review.

A Case of Metastatic Thymoma Responsive to Treatment With 177 Lu-DOTATATE.

ABSTRACT: We describe a case of a 74-year-old woman with germline BRCA2 mutation, with an incidental diagnosis of metastatic thymoma presenting as a mediastinal mass with cardiac muscle and lymph node involvement. Despite surgical and radiotherapy treatment, there was marked advancement with new lung and liver metastases. All lesions demonstrated 68 Ga-DOTATATE PET/CT uptake, and the patient received 4 peptide receptor radionuclide therapy cycles with 177 Lu-DOTATATE, with pronounced reduction in the size of the liver, cardiac, and pleural lesions. This is the first case to demonstrate partial response to peptide receptor radionuclide therapy in metastatic thymoma, thus suggesting possible treatment option to refractory and advancing metastatic thymoma.

Germline CDKN1B variant type and site are associated with phenotype in MEN4.

Multiple endocrine neoplasia 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome clinically hallmarked by primary hyperparathyroidism (PHPT), pituitary adenoma (PitAd), and neuroendocrine tumors (NET), clinically overlapping MEN1. The underlying mutated gene - CDKN1B, encodes for the cell-cycle regulator p27. Possible genotype-phenotype correlations in MEN4 have not been thoroughly assessed. Prompted by the findings in three Israeli MEN4 kindreds, we performed a literature review on published and unpublished data from previously reported MEN4/CDKN1B cases. Univariate analysis analyzed time-dependent risks for developing PHPT, PitAd, or NET by variant type and position along the gene. Overall, 74 MEN4 cases were analyzed. PHPT risk was 53.4% by age 60 years (mean age at diagnosis age 50.6 ± 13.9 years), risk for PitAd was 23.2% and risk for NET was 16.2% (34.4 ± 21.4 and 52.9 ± 13.9 years, respectively). The frameshift variant p.Q107fs was the most common variant identified (4/41 (9.7%) kindreds). Patients with indels had higher risk for PHPT vs point mutations (log-rank, P = 0.029). Variants in codons 94-96 were associated with higher risk for PHPT (P < 0.001) and PitAd (P = 0.031). To conclude, MEN4 is clinically distinct from MEN1, with lower risk and older age for PHPT diagnosis. We report recurrent CDKN1B frameshift variants and possible genotype-phenotype correlations.

Macrophage Jak2 deficiency accelerates atherosclerosis through defects in cholesterol efflux.

Atherosclerosis is a chronic inflammatory condition in which macrophages play a major role. Janus kinase 2 (JAK2) is a pivotal molecule in inflammatory and metabolic signaling, and Jak2V617F activating mutation has recently been implicated with enhancing clonal hematopoiesis and atherosclerosis. To determine the essential in vivo role of macrophage (M)-Jak2 in atherosclerosis, we generate atherosclerosis-prone ApoE-null mice deficient in M-Jak2. Contrary to our expectation, these mice exhibit increased plaque burden with no differences in macrophage proliferation, recruitment or bone marrow clonal expansion. Notably, M-Jak2-deficient bone marrow derived macrophages show a significant defect in cholesterol efflux. Pharmacologic JAK2 inhibition with ruxolitinib also leads to defects in cholesterol efflux and accelerates atherosclerosis. Liver X receptor agonist abolishes the efflux defect and attenuates the accelerated atherosclerosis that occurs with M-Jak2 deficiency. Macrophages of individuals with the Jak2V617F mutation show increased efflux which is normalized when treated with a JAK2 inhibitor. Together, M-Jak2-deficiency leads to accelerated atherosclerosis primarily through defects in cholesterol efflux from macrophages.

Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism.

X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)-secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes VGLL1, CD40LG, ARHGEF6, RBMX, and GPR101) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. The mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone was previously unclear. Using Hi-C and 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. We showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Next, using 4C-seq with GPR101, RBMX, and VGLL1 viewpoints, we showed that the duplications in multiple X-LAG-affected individuals led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG. We then identified several pituitary active cis-regulatory elements (CREs) within the neo-TAD and demonstrated in vitro that one of them significantly enhanced reporter gene expression. At the same time, we showed that the GPR101 promoter permits the incorporation of new regulatory information. Our results indicate that X-LAG is a TADopathy of the endocrine system in which Xq26.3 duplications disrupt the local chromatin architecture forming a neo-TAD. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in pituitary tumors caused by X-LAG.

Management recommendations for pancreatic manifestations of von Hippel-Lindau disease.

Von Hippel-Lindau disease (VHL) is a multineoplasm inherited disease manifesting with hemangioblastoma of the central nervous system and retina, adrenal pheochromocytoma, renal cell carcinoma, pancreatic neuroendocrine tumors and cysts, and neoplasms/cysts of the ear, broad ligament, and testicles. During 2018-2020, the VHL Alliance gathered several committees of experts in the various clinical manifestations of VHL to review the literature, gather the available evidence on VHL, and develop recommendations for patient management. The current report details the results of the discussion of a group of experts in the pancreatic manifestations of VHL along with their proposed recommendations for the clinical surveillance and management of patients with VHL. The recommendations subcommittee performed a comprehensive systematic review of the literature and conducted panel discussions to reach the current recommendations. The level of evidence was defined according to the Shekelle variation of the Grading of Recommendations, Assessment, Development, and Evaluation grading system. The National Comprehensive Cancer Network Categories of Evidence and Consensus defined the committee members' interpretation of the evidence and degree of consensus. The recommendations encompass the main aspects of VHL-related pancreatic manifestations and their clinical management. They are presented in a clinical orientation, including general planning of screening and surveillance for pancreatic neuroendocrine tumors, utility of biochemical biomarkers, the optimal choice for imaging modality, indirect risk stratification, indications for tissue sampling of VHL-related pancreatic neuroendocrine tumors, and interventions. These recommendations are designed to serve as the reference for all aspects of the screening, surveillance, and management of VHL-related pancreatic manifestations.

Fatty acid-binding protein 4: a key regulator of ketoacidosis in new-onset type 1 diabetes.

AIMS/HYPOTHESIS: Fatty acid-binding protein 4 (FABP4) is an adipokine with a key regulatory role in glucose and lipid metabolism. We prospectively evaluated the role of FABP4 in the pathophysiology of diabetic ketoacidosis (DKA) in new-onset type 1 diabetes. METHODS: Clinical and laboratory data were prospectively collected from consecutive children presenting with new-onset type 1 diabetes. In addition to blood chemistry and gases, insulin, C-peptide, serum FABP4 and NEFA were collected upon presentation and 48 h after initiation of insulin treatment. In a mouse model of type 1 diabetes, glucose, insulin, ß-hydroxybutyrate and weight were compared between FABP4 knockout (Fabp4-/-) and wild-type (WT) mice. RESULTS: Included were 33 children (mean age 9.3 ± 3.5 years, 52% male), of whom 14 (42%) presented with DKA. FABP4 levels were higher in the DKA group compared with the non-DKA group (median [IQR] 10.1 [7.9-14.2] ng/ml vs 6.3 [3.9-7] ng/ml, respectively; p = 0.005). The FABP4 level was positively correlated with HbA1c at presentation and inversely correlated with venous blood pH and bicarbonate levels (p < 0.05 for all). Following initiation of insulin therapy, a marked reduction in FABP4 was observed in all children. An FABP4 level of 7.22 ng/ml had a sensitivity of 86% and a specificity of 78% for the diagnosis of DKA, with an area under the receiver operating characteristic curve of 0.78 (95% CI 0.6, 0.95; p = 0.008). In a streptozotocin-induced diabetes mouse model, Fabp4-/- mice exhibited marked hypoinsulinaemia and hyperglycaemia similar to WT mice but displayed no significant increase in ß-hydroxybutyrate and were protected from ketoacidosis. CONCLUSIONS/INTERPRETATION: FABP4 is suggested to be a necessary regulator of ketogenesis in insulin-deficient states.

Plasma Hemoglobin and Red Blood Cell Mass Levels as Dynamic Prognostic Markers for Progression and Survival in Pancreatic Neuroendocrine Tumors.

There are scarce data on readily available markers enabling immediate risk stratification and personalized management in patients with advanced pancreatic neuroendocrine tumors. This study explores the association of red blood cells-related parameters as prognostic markers in patients harboring pancreatic neuroendocrine tumors. Retrospective analysis of a tertiary medical center database, acquiring data of patients with pancreatic neuroendocrine tumors including demographics, tumor-related parameters and consecutive imaging results, vital status at last follow-up, and red blood cells parameters at baseline, last follow-up, and dynamics (last/baseline ratio). Univariate and multivariable analyses were performed. Sixty-seven patients were identified (mean age at diagnosis of 63±11 years, 56.7% males). Patients with disease progression had lower hemoglobin, red blood cells mass values and hematocrit at the last evaluation (p<0.001 for all comparisons), with red blood cells mass level<3.9 m/µl and a 6% and 9% relative reduction in hemoglobin and hematocrit levels, respectively, associated with an increased risk for disease progression. Similarly, patients deceased during the study period had lower hemoglobin, red blood cells mass values and hematocrit (p<0.03 for all) than those alive, at last follow-up. Eleven percent reduction in hemoglobin level was noted indicating a higher mortality risk (p=0.04). Negative hemoglobin and hematocrit dynamics were independently associated with increased risk for disease progression (p=0.03 and 0.049, respectively). In conclusion, decrease in red blood cells mass, hemoglobin and/or hematocrit levels are all associated with poor prognosis in patients with pancreatic neuroendocrine tumors. We suggest utilizing these parameters as complementary follow-up prognostic markers to radiologic imaging in this patients population.

The adipokine FABP4 is a key regulator of neonatal glucose homeostasis.

During pregnancy, fetal glucose production is suppressed, with rapid activation immediately postpartum. Fatty acid-binding protein 4 (FABP4) was recently demonstrated as a regulator of hepatic glucose production and systemic metabolism in animal models. Here, we studied the role of FABP4 in regulating neonatal glucose hemostasis. Serum samples were collected from pregnant women with normoglycemia or gestational diabetes at term, from the umbilical circulation, and from the newborns within 6 hours of life. The level of FABP4 was higher in the fetal versus maternal circulation, with a further rise in neonates after birth of approximately 3-fold. Neonatal FABP4 inversely correlated with blood glucose, with an approximately 10-fold increase of FABP4 in hypoglycemic neonates. When studied in mice, blood glucose of 12-hour-old WT, Fabp4-/+, and Fabp4-/- littermate mice was 59 ± 13 mg/dL, 50 ± 11 mg/dL, and 43 ± 11 mg/dL, respectively. Similar to our observations in humans, FABP4 levels in WT mouse neonates were approximately 8-fold higher compared with those in adult mice. RNA sequencing of the neonatal liver suggested altered expression of multiple glucagon-regulated pathways in Fabp4-/- mice. Indeed, Fabp4-/- liver glycogen was inappropriately intact, despite a marked hypoglycemia, with rapid restoration of normoglycemia upon injection of recombinant FABP4. Our data suggest an important biological role for the adipokine FABP4 in the orchestrated regulation of postnatal glucose metabolism.

Low risk for all-cause mortality among patients with lung neuroendocrine tumors co-diagnosed with pituitary adenomas.

PURPOSE: Lung neoplasms often co-occur with pituitary adenoma (PA). However, whether co-diagnosis of lung neuroendocrine tumors (LNETs) and PA constitute a unique entity and the impact of such co-diagnosis on patients' outcome is yet to be defined. The study objective was to compare patients' clinical characteristics with LNET to patients co-diagnosed with PA. METHODS: A Retrospective, case-control study based on the Surveillance, Epidemiology, and End Results (SEER) registry database between 2000 and 2016. A total of 2947 patients with LNET, including 2913 with LNET alone ("Sporadic") and 34 patients with both LNET and PA ("LNET-PA"). RESULTS: PA preceded LNET diagnosis in 85.3% of patients and had higher rates among LNET patients (34/2947) than with any cancer (p < 0.00001) and compared to patients with non-small cell lung cancer (NSCLC) (15/2378, p = 0.047). LNET-PA patients were younger at diagnosis compared with NSCLC patients and PA (p = 0.04). Among patients <60 years with LNET, co-diagnosis with PA was associated with lower all-cause mortality (ACM) risk (Log-rank test, p = 0.03). Adjusted ACM risk of patients with LNET-PA was lower than sporadic LNET (hazard ratio 0.553, 95% confidence interval 0.309-0.99, p = 0.046), especially among Caucasians, and lower overall-mortality risk in patients <60 years with borderline statistical significance (p = 0.071). CONCLUSIONS: Patients with both LNET and PA constitute a distinct morbidity and mortality profile than sporadic LNET, possibly suggesting an undefined MEN syndrome. Additional studies to further investigate patients' natural course and genetic profile with these neoplasms are needed.

Distinct Prognostic Factors in Sporadic and Multiple Endocrine Neoplasia Type 1-Related Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PNET) may develop sporadically or in the context of hereditary syndromes. In patients with multiple endocrine neoplasia type 1 (MEN1), PNET is the leading cause of death. Our aim was to compare the mortality risk in sporadic and MEN1-related PNETs and identify high-risk populations. A retrospective Surveillance, Epidemiology, and End Results database analysis of patients with PNET was used. Patients with MEN1 were defined by syn/metachronous pituitary adenoma. Clinical data were retrieved, and all-cause mortality (ACM) risk was compared in univariate and multivariable analyses. The cohort included 569 patients (46.6% males) with sporadic (n=542) and MEN1-related (n=27) PNETs. Age at diagnosis of MEN1-related PNET was significantly younger than with sporadic PNETs (mean age 49.2±16.7 vs. 61.6±12.7 years, respectively; p < 0.001). Survival analysis showed a trend for a better outcome in patients with MEN1-related vs. sporadic PNET (Log-rank, p=0.09) and in subgroup analysis for patients with advanced disease (p=0.08). Furthermore, among patients followed expectantly, those with MEN1-related PNET had lower ACM risk than their sporadic counterparts (p=0.08). Multivariable analysis demonstrated lower ACM risk in patients diagnosed with MEN1 (hazard ratio 0.35, 95% confidence interval 0.11-1.2, p=0.09), further supporting the trend detected in the univariate analysis. In conclusion, our study demonstrates the distinct clinical profile of patients with MEN1-related PNET compared to sporadic disease and emphasizes the expertise required to accurately manage patients with PNET in this rare context. The cautious decision-making required before embarking on surgical intervention is further emphasized in this robust analysis of a large cancer database.

Impact of Pancreatic Neuroendocrine Tumor on Mortality in Patients With von Hippel-Lindau Disease.

OBJECTIVE: The main causes for morbidity and mortality in von Hippel-Lindau (VHL) disease are central nervous system hemangioblastoma and clear cell renal cell carcinoma, but the effect of VHL-related pancreatic neuroendocrine tumors (PNET) on patient outcome is unclear. We assessed the impact of PNET diagnosis in patients with VHL on all-cause mortality (ACM) risk. METHODS: We used the Surveillance, Epidemiology, and End Results database. Of 16 344 patients, 170 had VHL based on clinical diagnostic criteria, and 510 patients had PNET (91 VHL-related and 419 sporadic). RESULTS: Survival analysis demonstrated a lower ACM among patients with VHL-related PNET compared to patients with sporadic PNET (log-rank test, P = .011). Among patients with VHL, ACM risk was higher with vs without PNET (P = .029). The subgroup analysis revealed a higher ACM risk with metastatic PNET (sporadic P = .0031 and VHL-related P = .08) and a similar trend for PNET diameter ≥3 cm (P = .06 and P = 0.1 in sporadic and VHL-related PNET, respectively). In a multivariable analysis of patients with VHL, diagnosis with PNET by itself was associated with a trend of lower risk for ACM, while presence of metastatic PNET was independently associated with increased ACM risk. CONCLUSION: Diagnosis with PNET is not associated with a higher ACM risk in VHL by itself. The independent association of advanced PNET stage with higher mortality risk emphasizes the importance of active surveillance for detecting high-risk PNET at an early stage to allow timely intervention.

Patients With MEN1 Are at an Increased Risk for Venous Thromboembolism.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disorder predisposing the development of multiple functional and nonfunctional neuroendocrine tumors (NETs). Only uncommon MEN1-associated functional NETs such as glucagonomas (<1%) and adenocorticotropic hormone-producing tumors (<5%) are known to be associated with hypercoagulability. It is unknown if patients with MEN1 generally have an increased risk of venous thromboembolism (VTE). METHODS: We queried a prospective natural history study of germline mutation-positive MEN1 patients (n = 286) between 1991 and 2019 for all lifetime events of VTE. The search terms were: DVT, thromb, embol, PE, pulmonary embolism, clot, hematology consult, anticoagulant, coumadin, lovenox, xarelto, warfarin, aspirin, rivaroxaban, and apixaban. Incidence rates were calculated, accounting for age and sex. Comparisons were made to published incidence rates in healthy populations, different types of cancer, and Cushing's syndrome. RESULTS: Thirty-six subjects (median age 45 years, range 16-75) experienced a VTE event, yielding a prevalence rate of 12.9%. The age-sex adjusted incidence rate of VTE is 9.11 per 1000 patient-years, with a sex-adjusted lifetime incidence rate of 2.81 per 1000 patient-years. MEN1-associated lifetime incidence rates are ~2-fold higher than the estimated annual incidence rate in the general population and are comparable to the known risk in the setting of various types of cancer. Approximately 80% of patients who had a VTE were diagnosed with pancreatic NETs, of which 24% were insulinomas. Fourteen patients (42%) experienced perioperative VTE events. CONCLUSIONS: MEN1 patients have an increased risk of VTE. Further mechanistic investigation and validation from other MEN1 cohorts are needed to confirm the increased prevalence of VTE in MEN1.

Pediatric Cushing's syndrome: greater risk of being overweight or obese after long-term remission and its predictive factors.

OBJECTIVE: Due to the rarity of Cushing's syndrome (CS) in children and adolescents, data are scarce about BMI during active disease and following remission. Therefore, our aim was to analyze BMI after long-term remission and determine predictive factors for promptly identifying patients at risk of being overweight or obese after remission for CS. DESIGN: Retrospective cohort study. PATIENTS: 73 patients: 58 (79.4%) had Cushing disease, 40 males (58%), median age of 12 years (IQR: 9-15). The mean follow-up time was 22.4 ± 18.2 months (range: 4-98). METHODS: Main outcome measures: BMI, lipid profile, blood pressure, HOMA-IR. RESULTS: At diagnosis, only eight (11%) patients had a normal weight. Although the BMI z-score at the last follow-up improved (2.0 ± 0.7 to 1.0 ± 1.2, P < 0.001), 44% remained overweight or obese after 2 years of remission according to the Kaplan-Meier curves. The BMI z-scores at the last follow-up correlated only with HOMA-IR levels (r: 0.49, P = 0.027). We found two independent factors related to reaching a normal weight: BMI z-score at diagnosis (HR: 0.156, 95% CI: 0.038-0.644; P = 0.01) and BMI z-score change at 6 ± 2 months (HR: 2.980, 95% CI:1.473-6.028; P = 0.002), which had high accuracy when a cut-off of 0.5 was used for ROC analysis (AUC = 0.828 (0.67-0.97); P < 0.001). CONCLUSIONS: Children and adolescents with CS have a high risk of being overweight or obese after successful treatment for their disease. At risk patients can be identified quickly based on their baseline BMI and initial weight loss after surgery. Efforts should focus on adopting healthy diet and lifestyle in the immediate postoperative period.

Intercellular Transmission of Hepatic ER Stress in Obesity Disrupts Systemic Metabolism.

Endoplasmic reticulum stress (ERS) has a pathophysiological role in obesity-associated insulin resistance. Yet, the coordinated tissue response to ERS remains unclear. Increased connexin 43 (Cx43)-mediated intercellular communication has been implicated in tissue-adaptive and -maladaptive response to various chronic stresses. Here, we demonstrate that in hepatocytes, ERS results in increased Cx43 expression and cell-cell coupling. Co-culture of ER-stressed "donor" cells resulted in intercellular transmission of ERS and dysfunction to ERS-naive "recipient" cells ("bystander response"), which could be prevented by genetic or pharmacologic suppression of Cx43. Hepatocytes from obese mice were able to transmit ERS to hepatocytes from lean mice, and mice lacking liver Cx43 were protected from diet-induced ERS, insulin resistance, and hepatosteatosis. Taken together, our results indicate that in obesity, the increased Cx43-mediated cell-cell coupling allows intercellular propagation of ERS. This novel maladaptive response to over-nutrition exacerbates the tissue ERS burden, promoting hepatosteatosis and impairing whole-body glucose metabolism.