Publications by authors named "Emily J Gallagher"

44 Publications

Association between somatostatin analogues and diabetes mellitus in gastroenteropancreatic neuroendocrine tumor patients: A Surveillance, Epidemiology, and End Results-Medicare analysis of 5235 patients.

Cancer Rep (Hoboken) 2021 Apr 9:e1387. Epub 2021 Apr 9.

Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are increasingly common malignancies and tend to have favorable long-term prognoses. Somatostatin analogues (SSA) are a first-line treatment for many NETs. Short-term experiments suggest an association between SSAs and hyperglycemia. However, it is unknown whether there is a relationship between SSAs and clinically significant hyperglycemia causing development of diabetes mellitus (DM), a chronic condition with significant morbidity and mortality.

Aim: In this study, we aimed to compare risk of developing DM in patients treated with SSA vs no SSA treatment.

Methods And Results: Using the Surveillance, Epidemiology, and End Results (SEER) database and linked Medicare claims (1991-2016), we identified patients age 65+ with no prior DM diagnosis and a GEP-NET in the stomach, small intestine, appendix, colon, rectum, or pancreas. We used χ tests to compare SSA-treated and SSA-untreated patients and multivariable Cox regression to assess risk factors for developing DM. Among 8464 GEP-NET patients, 5235 patients had no prior DM and were included for analysis. Of these, 784 (15%) patients received SSAs. In multivariable analysis, the hazard ratio of developing DM with SSA treatment was 1.19, which was not statistically significant (95% CI 0.95-1.49). Significant risk factors for DM included black race, Hispanic ethnicity, prior pancreatic surgery, prior chemotherapy, tumor size >2 cm, pancreas tumors, and higher Charlson scores.

Conclusion: DM was very common in GEP-NET patients, affecting 53% of our cohort. Despite prior studies suggesting an association between SSAs and hyperglycemia, our analysis found similar risk of DM in SSA-treated and SSA-untreated GEP-NET patients. Further studies are needed to better understand this relationship. As NET patients have increasingly prolonged survival, it is crucial to identify chronic conditions such as DM that these patients may be at elevated risk for.
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http://dx.doi.org/10.1002/cnr2.1387DOI Listing
April 2021

Association of Insulin Resistance and Higher Oncotype DX™ Recurrence Score.

Ann Surg Oncol 2021 Apr 3. Epub 2021 Apr 3.

Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute at Mount Sinai, New York, NY, USA.

Background: Black women with breast cancer have a worse overall survival compared with White women; however, no difference in Oncotype DX™ (ODX) recurrence scores has been observed to explain this health disparity. Black women are also disproportionately affected by insulin resistance. We evaluated whether insulin resistance is associated with a higher ODX recurrence score and whether there is a difference between White and Black women to explain disparate clinical outcomes.

Methods: A subgroup analysis of patients in a multi-institutional cross-sectional study evaluating differences in insulin resistance between White and Black women was performed. Women diagnosed with a new hormone receptor-positive, HER2/neu-negative breast cancer with an ODX recurrence score were identified. Fasting blood glucose and insulin measurements were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) score, a method for assessing insulin resistance, and compared against ODX scores.

Results: Overall, 412 women (358 White women, 54 Black women) were identified. Compared with White women, Black women had a higher body mass index (30 vs. 26 kg/m, p < 0.0001), higher HOMA-IR score (2.4 vs. 1.4, p = 0.004), and more high-grade tumors (30% vs. 16%, p = 0.01). There was a direct positive association with an increasing ODX score and HOMA-IR (p = 0.014). On subset analysis, this relationship was seen in White women (p = 0.005), but not in Black women (p = 0.55).

Conclusion: In women with newly diagnosed breast cancer, increasing insulin resistance is associated with a higher recurrence score; however, this association was not present in Black women. This lack of association may be due to the small number of Black women in the cohort, or possibly a reflection of a different biological disease process of the patient's tumor.
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http://dx.doi.org/10.1245/s10434-021-09748-8DOI Listing
April 2021

Hyperglycemia is Associated With Increased Mortality in Critically Ill Patients With COVID-19.

Endocr Pract 2021 Feb 9;27(2):95-100. Epub 2021 Jan 9.

Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Objective: To explore the relationship between hyperglycemia in the presence and absence of diabetes mellitus (DM) and adverse outcomes in critically ill patients with coronavirus disease 2019 (COVID-19).

Methods: The study included 133 patients with COVID-19 admitted to an intensive care unit (ICU) at an urban academic quaternary-care center between March 10 and April 8, 2020. Patients were categorized based on the presence or absence of DM and early-onset hyperglycemia (EHG), defined as a blood glucose >180 mg/dL during the first 2 days after ICU admission. The primary outcome was 14-day all-cause in-hospital mortality; also examined were 60-day all-cause in-hospital mortality and the levels of C-reactive protein, interleukin 6, procalcitonin, and lactate.

Results: Compared to non-DM patients without EHG, non-DM patients with EHG exhibited higher adjusted hazard ratios (HRs) for mortality at 14 days (HR 7.51, CI 1.70-33.24) and 60 days (HR 6.97, CI 1.86-26.13). Non-DM patients with EHG also featured higher levels of median C-reactive protein (306.3 mg/L, P = .036), procalcitonin (1.26 ng/mL, P = .028), and lactate (2.2 mmol/L, P = .023).

Conclusion: Among critically ill COVID-19 patients, those without DM with EHG were at greatest risk of 14-day and 60-day in-hospital mortality. Our study was limited by its retrospective design and relatively small cohort. However, our results suggest the combination of elevated glucose and lactate may identify a specific cohort of individuals at high risk for mortality from COVID-19. Glucose testing and control are important in individuals with COVID-19, even those without preexisting diabetes.
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http://dx.doi.org/10.1016/j.eprac.2020.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796656PMC
February 2021

Risk Factors for Emergency Room and Hospital Care Among Patients With Solid Tumors on Immune Checkpoint Inhibitor Therapy.

Am J Clin Oncol 2021 03;44(3):114-120

Tisch Cancer Institute, Division of Hematology/Oncology.

Objectives: Immune checkpoint inhibitors (ICIs) are being increasingly used across cancer types. Emergency room (ER) and inpatient (IP) care, common in patients with cancer, remain poorly defined in this specific population, and risk factors for such care are unknown.

Methods: We retrospectively reviewed charts for patients with solid tumors who received >1 ICI dose at 1 of 2 sites from January 1, 2011 to April 28, 2017. Demographics, medical history, cancer diagnosis/therapy/toxicity details, and outcomes were recorded. Descriptive data detailing ER/IP care at the 2 associated hospitals during ICI therapy (from first dose to 3 mo after last dose) were collected. The Fisher exact test and multivariate regression analysis was used to study differences between patients with versus without ER/IP care during ICI treatment.

Results: Among 345 patients studied, 50% had at least 1 ER visit during ICI treatment and 43% had at least 1 IP admission. Six percent of ER/IP visits eventually required intensive care. A total of 12% of ER/IP visits were associated with suspected or confirmed immune-related adverse events. Predictors of ER care were African-American race (odds ratio [OR]: 3.83, P=0.001), Hispanic ethnicity (OR: 3.12, P=0.007), and coronary artery disease (OR: 2.43, P=0.006). Predictors of IP care were African-American race (OR: 2.38, P=0.024), Hispanic ethnicity (OR: 2.29, P=0.045), chronic kidney disease (OR: 3.89, P=0.006), angiotensin converting enzyme inhibitor/angiotensin receptor blocker medication use (OR: 0.44, P=0.009), and liver metastasis (OR: 2.32, P=0.003).

Conclusions: Understanding demographic and clinical risk factors for ER/IP care among patients on ICIs can help highlight disparities, prospectively identify high-risk patients, and inform preventive programs aimed at reducing such care.
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http://dx.doi.org/10.1097/COC.0000000000000793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902456PMC
March 2021

Characterization of hyperglycemia in patients receiving immune checkpoint inhibitors: Beyond autoimmune insulin-dependent diabetes.

Diabetes Res Clin Pract 2021 Feb 23;172:108633. Epub 2020 Dec 23.

Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Aims: Immune-mediated beta cell destruction is known to cause hyperglycemia in patients receiving immune checkpoint inhibitor (ICI) cancer therapy. However, it is uncommon, and little is known about the full spectrum of hyperglycemia in patients receiving ICIs. We aimed to characterize the prevalence and factors associated with hyperglycemia in patients treated with ICIs.

Methods: We retrospectively analyzed patients receiving ICIs at an NCI-designated Cancer Center. We assessed the proportion of patients with new onset hyperglycemia (random glucose >11.1 mmol/L) after starting ICIs and used logistic regression to determine hyperglycemia predictors in patients without known diabetes.

Results: Of 411 patients, 385 had post-ICI glucose data. 105 (27%) had hyperglycemia. Of this group, 29 (28%) had new onset hyperglycemia, 19 of whom had glucocorticoid-associated hyperglycemia. The remaining 10 had unexplained hyperglycemia and none had known autoimmune diabetes. Among patients without known diabetes, race/ethnicity, obesity, and pre-ICI hyperglycemia were significantly associated with hyperglycemia after starting ICIs.

Conclusions: We found that new hyperglycemia in patients receiving ICIs was most commonly related to glucocorticoids. A small patient subset had new unexplained hyperglycemia, suggesting ICIs might have a role in promoting hyperglycemia. Recognizing factors associated with hyperglycemia in this population is crucial for appropriate management.
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http://dx.doi.org/10.1016/j.diabres.2020.108633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940559PMC
February 2021

Durable disease control with local treatment for oligoprogression of metastatic solid tumors treated with immune checkpoint blockade.

Cancer Treat Res Commun 2020 8;25:100216. Epub 2020 Oct 8.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: While the concept of oligometastatic disease is increasingly recognized as a distinct clinical disease state, the concept of oligoprogression is less well-characterized. Oligoprogression may be particularly relevant in the context of immune checkpoint inhibitors (CPI) given the underlying mechanism of action and insights regarding acquired resistance. In this study, we sought to characterize the incidence of oligoprogression in patients on CPI and explore the impact of local therapy.

Materials And Methods: We performed a retrospective analysis of all patients with advanced solid tumors (excluding glioblastoma multiforme) who received a PD-1, PD-L1, or CTLA-4 inhibitor at a single institution between 2011 and 2017. Oligoprogression was defined as progression at ≤3 metastatic lesions outside of the brain after achieving at least stable disease on CPI for 3 months. Progression-free survival (PFS) was calculated using the Kaplan-Meier method.

Results: Among 425 patients treated with CPI, 390 had advanced primary solid tumors outside of the central nervous system. 321 of these patients were evaluable for response, among whom 102 achieved at least stable disease. Oligoprogression was observed in 4.1% of the entire cohort and 15.7% of patients achieving at least stable disease on CPI. Among 16 patients experiencing oligoprogression, 15 received local therapy to the oligoprogressive lesions, many of whom continued CPI. At a median follow-up of 25.8 months, the median PFS for patients with oligoprogression after local therapy was 15.4 months.

Conclusions: Oligoprogression occurs in a subset of patients after an initial response to CPI. However, patients receiving local therapy to oligoprogressive sites may experience durable disease control. Further study is warranted.

Microabstract: Oligoprogression was observed in 4.1% of the entire cohort of patients on immune checkpoint inhibitors in this study and 15.7% of patients achieving at least stable disease. Among 16 patients experiencing oligoprogression, 15 received local therapy. At a median follow-up of 25.8 months, the median progression-free survival for patients with oligoprogression after local therapy was 15.4 months and zero patients had died. Oligoprogression occurs in a subset of patients after an initial response to CPI and local therapy to oligoprogressive sites may result in durable disease control.
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http://dx.doi.org/10.1016/j.ctarc.2020.100216DOI Listing
October 2020

The ontogeny of Na uptake in larval rainbow trout reared in waters of different Na content.

J Comp Physiol B 2021 Jan 24;191(1):29-42. Epub 2020 Sep 24.

Department of Zoology, The University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.

Teleost fish have a remarkable capacity to maintain ion homeostasis against diffusion gradients in hypo-ionic freshwater. In adult teleosts the gills are the primary site for ion uptake; however, in larvae, the gills are underdeveloped, and as ion-regulation is primarily cutaneous, branchial mechanisms of plasticity are not yet available. In larval rainbow trout, the gills become the primary site for Na uptake at ~ 15 days post hatch (dph). To address how Na uptake develops in response to differences in water [Na], the present study characterised the ontogeny of Na uptake in rainbow trout larvae, at a time when ion regulation transitions from being a primarily cutaneous to a primarily branchial process. Results indicate that initially (0-15 dph), when ion-regulation is cutaneous, low-[Na] reared larvae had a higher Na affinity (lower K) compared to the high-[Na] treatment. In addition, larvae reared in low-[Na] water had a lower internal Na content, despite similar Na-uptake rates ([Formula: see text]) across treatments. But, once the gills became the dominant site for ion-regulation (> 15 dph), larvae in all treatments maintained the same Na content, despite large differences in [Formula: see text], indicating plasticity in those mechanisms that control Na efflux ([Formula: see text]). The mechanisms of Na uptake in larval rainbow trout showed plasticity during all stages of development. However, in young larvae that relied on cutaneous Na uptake, the internal Na content was significantly affected by the [Na] in the water, perhaps revealing challenges to ion homeostasis and a period of heightened vulnerability to external stressors during early larval development.
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http://dx.doi.org/10.1007/s00360-020-01311-3DOI Listing
January 2021

The ontogeny of Na balance during rapid smoltification in pink salmon (Oncorhynchus gorbuscha).

J Comp Physiol B 2021 Jan 24;191(1):17-28. Epub 2020 Sep 24.

Department of Zoology, The University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.

Pink salmon hatch in fresh water, but their highly anadromous life history requires them to migrate into the ocean immediately after gravel-emergence, at a very small size. During their down-river migration these larvae undergo rapid smoltification that completely remodels their osmoregulatory physiology. At this time, the larvae reportedly have high whole-body Na contents and we hypothesised that the active accumulation of internal Na occurs in preparation for ocean entry. Using a comparative approach, the present study characterised the ontogeny of Na regulation in larvae of the anadromous pink salmon and the fresh-water rainbow trout. Our results indicate that larvae from both species actively accumulated Na; however, whole-body Na content was higher in rainbow trout larvae compared to pink salmon. The time-course of this response was similar in the two species, with highest Na-uptake rates ([Formula: see text]) shortly after yolk sac absorption, but the mechanism of Na accumulation differed between the species. Rainbow trout larvae greatly increased [Formula: see text] to overcompensate for a large simultaneous increase in Na-efflux rate ([Formula: see text]), whereas pink salmon mounted a smaller increase in [Formula: see text] while maintaining tight control over [Formula: see text], which is supported by a significantly lower paracellular permeability. Our results indicate that the transient accumulation of internal Na is not a unique feature of the highly anadromous life history in pink salmon and may be a common ontogenetic pattern during larval development in salmonids; and perhaps it is associated with the development of the cardiovascular system during the larvae's transition to a more active lifestyle.
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http://dx.doi.org/10.1007/s00360-020-01309-xDOI Listing
January 2021

Hyperinsulinaemia in cancer.

Nat Rev Cancer 2020 11 9;20(11):629-644. Epub 2020 Sep 9.

Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Elevated circulating insulin levels are frequently observed in the setting of obesity and early type 2 diabetes, as a result of insensitivity of metabolic tissues to the effects of insulin. Higher levels of circulating insulin have been associated with increased cancer risk and progression in epidemiology studies. Elevated circulating insulin is believed to be a major factor linking obesity, diabetes and cancer. With the development of targeted cancer therapies, insulin signalling has emerged as a mechanism of therapeutic resistance. Although metabolic tissues become insensitive to insulin in the setting of obesity, a number of mechanisms allow cancer cells to maintain their ability to respond to insulin. Significant progress has been made in the past decade in understanding the insulin receptor and its signalling pathways in cancer, and a number of lessons have been learnt from therapeutic failures. These discoveries have led to numerous clinical trials that have aimed to reduce the levels of circulating insulin and to abrogate insulin signalling in cancer cells. With the rising prevalence of obesity and diabetes worldwide, and the realization that hyperinsulinaemia may contribute to therapeutic failures, it is essential to understand how insulin and insulin receptor signalling promote cancer progression.
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http://dx.doi.org/10.1038/s41568-020-0295-5DOI Listing
November 2020

A COMMON PITUITARY AUTOANTIBODY IN TWO PATIENTS WITH IMMUNE CHECKPOINT INHIBITOR-MEDIATED HYPOPHYSITIS: ZCCHC8.

AACE Clin Case Rep 2020 Jul-Aug;6(4):e151-e160. Epub 2020 Apr 3.

Objective: Hypophysitis is an increasingly recognized adverse effect of immune checkpoint inhibitor (ICI) therapy for malignancy. However, the mechanisms through which ICIs induce hypophysitis are largely unknown. We aim to describe 2 cases of ICI-mediated hypophysitis and perform autoantibody profiling on serial samples from these patients to determine if common autoantibodies could be identified.

Methods: We describe 2 cases of patients with metastatic urothelial cancer who received ICI therapy and subsequently developed severe fatigue, prompting a hormonal workup consistent with hypopituitarism. Patient 1 received the ICI ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4) and patient 2 received the ICI pembrolizumab (anti-programmed cell death protein 1). Both patients had serial seromic immune biomarker profiling using high-density protein arrays before and after developing hypophysitis. Once a common autoantibody was found, zinc finger CCHC-type containing 8 (ZCCHC8), we used immunohistochemistry to assess its presence in pituitary tissue.

Results: Of a limited number of increased autoantibodies detected, those to ZCCHC8 were the only common antibodies to increase at least 3-fold post-hypophysitis in both patients. Using immunohistochemistry staining, we show for the first time that ZCCHC8 is expressed in pituitary gland tissue.

Conclusion: Seromic profiling identified a common autoantibody, ZCCHC8, in 2 patients who developed hypophysitis on ICI therapy, and other serial autoantibody increases in each patient. These findings warrant validation in other cohorts to determine if the response is to self or tumor antigen, and may reveal novel insights into pituitary gland physiology and the pathogenesis of ICI-mediated hypophysitis.
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http://dx.doi.org/10.4158/ACCR-2019-0585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357610PMC
April 2020

The midlife transition and the risk of cardiovascular disease and cancer Part I: magnitude and mechanisms.

Am J Obstet Gynecol 2020 12 1;223(6):820-833. Epub 2020 Jun 1.

Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

Heart disease and cancer are the leading causes of death in the United States. In women, the clinical appearance of both entities-coronary heart disease and cancer (breast, endometrium, and ovary)-escalate during the decades of the midlife transition encompassing the menopause. In addition to the impact of aging, during the interval between the age of 40 and 65 years, the pathophysiologic components of metabolic syndrome also emerge and accelerate. These include visceral adiposity (measured as waist circumference), hypertension, diabetes, and dyslipidemia. Osteoporosis, osteoarthritis, sarcopenia, depression, and even cognitive decline and dementia appear, and most, if not all, are considered functionally related. Two clinical reports confirm the interaction linking the emergence of disease: endometrial cancer and metabolic syndrome. One describes the discovery of unsuspected endometrial cancer in a large series of elective hysterectomies performed in aged and metabolically susceptible populations. The other is from the Women's Health Initiative Observational Study, which found a positive interaction between endometrial cancer and metabolic syndrome regardless of the presence or absence of visceral adiposity. Both provide additional statistical support for the long-suspected causal interaction among the parallel but variable occurrence of these common entities-visceral obesity, heart disease, diabetes, cancer, and the prevalence of metabolic syndrome. Therefore, 2 critical clinical questions require analysis and answers: 1: Why do chronic diseases of adulthood-metabolic, cardiovascular, endocrine-and, in women, cancers of the breast and endometrium (tissues and tumors replete with estrogen receptors) emerge and their incidence trajectories accelerate during the postmenopausal period when little or no endogenous estradiol is available, and yet the therapeutic application of estrogen stimulates their appearance? 2: To what extent should identification of these etiologic driving forces require modification of the gynecologist's responsibilities in the care of our patients in the postreproductive decades of the female life cycle? Part l of this 2-part set of "expert reviews" defines the dimensions, gravity, and interactive synergy of each clinical challenge gynecologists face while caring for their midlife (primarily postmenopausal) patients. It describes the clinically identifiable, potentially treatable, pathogenic mechanisms driving these threats to quality of life and longevity. Part 2 (accepted, American Journal of Obstetrics & Gynecology) identifies 7 objectives of successful clinical care, offers "triage" prioritization targets, and provides feasible opportunities for insertion of primary preventive care initiatives. To implement these goals, a reprogrammed, repurposed office visit is described.
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http://dx.doi.org/10.1016/j.ajog.2020.05.051DOI Listing
December 2020

Insulin resistance contributes to racial disparities in breast cancer prognosis in US women.

Breast Cancer Res 2020 05 12;22(1):40. Epub 2020 May 12.

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Racial disparities in breast cancer survival between Black and White women persist across all stages of breast cancer. The metabolic syndrome (MetS) of insulin resistance disproportionately affects more Black than White women. It has not been discerned if insulin resistance mediates the link between race and poor prognosis in breast cancer. We aimed to determine whether insulin resistance mediates in part the association between race and breast cancer prognosis, and if insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R) expression differs between tumors from Black and White women.

Methods: We conducted a cross-sectional, multi-center study across ten hospitals. Self-identified Black women and White women with newly diagnosed invasive breast cancer were recruited. The primary outcome was to determine if insulin resistance, which was calculated using the homeostatic model assessment of insulin resistance (HOMA-IR), mediated the effect of race on prognosis using the multivariate linear mediation model. Demographic data, anthropometric measurements, and fasting blood were collected. Poor prognosis was defined as a Nottingham Prognostic Index (NPI) > 4.4. Breast cancer pathology specimens were evaluated for IR and IGF-1R expression by immunohistochemistry (IHC).

Results: Five hundred fifteen women were recruited (83% White, 17% Black). The MetS was more prevalent in Black women than in White women (40% vs 20%, p < 0.0001). HOMA-IR was higher in Black women than in White women (1.9 ± 1.2 vs 1.3 ± 1.4, p = 0.0005). Poor breast cancer prognosis was more prevalent in Black women than in White women (28% vs 15%. p = 0.004). HOMA-IR was positively associated with NPI score (r = 0.1, p = 0.02). The mediation model, adjusted for age, revealed that HOMA-IR significantly mediated the association between Black race and poor prognosis (β = 0.04, 95% CI 0.005-0.009, p = 0.002). IR expression was higher in tumors from Black women than in those from White women (79% vs 52%, p = 0.004), and greater IR/IGF-1R ratio was also associated with higher NPI score (IR/IGF-1R >  1: 4.2 ± 0.8 vs IR/IGF-1R = 1: 3.9 ± 0.8 vs IR/IGF-1R < 1: 3.5 ± 1.0, p < 0.0001).

Conclusions: In this multi-center, cross-sectional study of US women with newly diagnosed invasive breast cancer, insulin resistance is one factor mediating part of the association between race and poor prognosis in breast cancer.
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http://dx.doi.org/10.1186/s13058-020-01281-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216707PMC
May 2020

Metabolic Effects of JAK1/2 Inhibition in Patients with Myeloproliferative Neoplasms.

Sci Rep 2019 11 12;9(1):16609. Epub 2019 Nov 12.

Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Ruxolitinib is an FDA approved janus kinase (JAK)1/2 inhibitor used to treat myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera. We aimed to determine the metabolic consequences of ruxolitinib treatment in patients with MPNs. We performed a retrospective single-center cohort study utilizing an electronic medical record based database of patients who began treatment with ruxolitinib for MPNs from January 2010 to March 2017. We also examined the effects of ruxolitinib on adipose tissue JAK/STAT signaling in a mouse model. 127 patients were identified, of which 69 had data available for weight, and at least one other parameter of interest before, and 72 weeks after starting ruxolitinib. Mean baseline weight was 73.9 ± 17.0 kg, and 78.54 ± 19.1 kg at 72 weeks (p < 0.001). 50% of patients gained >5% body weight. Baseline body mass index (BMI) was 25.8 ± 4.8 kg/m, and 27.5 ± 5.5 kg/m at 72 weeks (p < 0.001). Patients treated with ruxolitinib had a higher systolic blood pressure, serum AST, and ALT at 72 weeks, compared with baseline (p = 0.03, p = 0.01, p = 0.04, respectively). In mice, ruxolitinib decreased basal and GH-stimulated STAT5 phosphorylation in adipose tissue. As pharmacological JAK1/2 inhibitors are being developed and used in clinical practice, it is important to understand their long-term metabolic consequences.
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http://dx.doi.org/10.1038/s41598-019-53056-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851362PMC
November 2019

Recovery from secondary adrenal insufficiency in a patient with immune checkpoint inhibitor therapy induced hypophysitis.

J Immunother Cancer 2019 09 12;7(1):248. Epub 2019 Sep 12.

Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1055, New York, NY, 10029, USA.

Background: Hypophysitis is a well-recognized immune-related adverse event in patients treated with immune checkpoint inhibitors for cancer. Some anterior pituitary hormones may recover; however, secondary adrenal insufficiency is usually permanent.

Case Presentation: A 26-year old male with metastatic clear cell renal cell carcinoma was started on treatment with the anti-programmed cell death-1 monoclonal antibody (anti-PD-1 mAb) nivolumab, followed by combined nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) mAb, ipilimumab. After starting nivolumab monotherapy the patient developed thyroiditis, which resolved without treatment. Prior to commencing combined ICI therapy, a random serum cortisol drawn at 1:30 pm and was 15.0 μg/dL (414 nmol/L). Three weeks after starting combined ICI therapy he developed sudden onset of severe fatigue and 1 pm serum cortisol was 2.0 μg/dL (55.2 nmol/L), adrenocorticotropic hormone (ACTH) was 16 pg/mL (3.52 pmol/L). A diagnosis of hypophysitis was made, and he was immediately started on prednisone 1 mg/kg. His symptoms resolved rapidly, and he continued immune checkpoint inhibitor therapy. He was noted to also have low gonadotropic hormones and testosterone (nadir testosterone 81.19 ng/dL). The prednisone was tapered slowly over the next six weeks to a maintenance dose of 5 mg daily. Four months after the initial presentation his cortisol remained low, but his testosterone level had increased to 973.43 ng/dL. After five months his random serum cortisol (1 pm) increased to 11.0 μg/dL (303.6 nmol/L). The prednisone was cautiously discontinued with close monitoring. Two months off glucocorticoid replacement he remained asymptomatic with an ACTH of 24.1 pg/mL (5.3 pmol/L), and cortisol of 13.0 μg/dL (358.8 nmol/L).

Conclusions: This case documents the unusual recovery from secondary adrenal insufficiency in a patient who developed hypophysitis from immune checkpoint inhibitor therapy. Repeated pituitary hormone testing every three months for the first year after the development of hypophysitis may identify more patients with hypothalamic-pituitary-adrenal axis recovery.
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http://dx.doi.org/10.1186/s40425-019-0729-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739970PMC
September 2019

Dietary Intake Regulates the Circulating Inflammatory Monocyte Pool.

Cell 2019 08;178(5):1102-1114.e17

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA. Electronic address:

Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5'-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, we show that fasting improves chronic inflammatory diseases without compromising monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.
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http://dx.doi.org/10.1016/j.cell.2019.07.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357241PMC
August 2019

The effect of modifiable risk factors on breast cancer aggressiveness among black and white women.

Am J Surg 2019 10 18;218(4):689-694. Epub 2019 Jul 18.

Icahn School of Medicine at Mt. Sinai, Department of Internal Medicine, New York, NY 10029, USA.

Introduction: Although breast cancer incidence is higher among white women, black women are more likely to have aggressive tumors with less favorable histology, and to have a worse prognosis. Obesity and alcohol consumption have been identified as two modifiable risk factors for breast cancer, while physical activity may offer protection. Little however is known about the association of these factors with race on the severity of breast cancer.

Methods: Data collected as part of a large prospective study looking at insulin resistance and race among women with breast cancer was queried for patient characteristics, lifestyle factors and tumor characteristics. The association with Nottingham Prognostic Index (NPI) was assessed with different models using univariate and multivariate linear regression.

Results: Among 746 women in our cohort, 82% (n = 615) were white and 18% (n = 131) were black, mean age 58 years. Black patients were more likely to have high BMI (31.0 vs. 26.7, p < 0.0001), comorbidities (69% vs 55%, p = 0.01), self-reported poor diet (70% vs 42%, p < 0.001), be sedentary (56% vs 46%, p = 0.03) and were less likely to consume alcohol (8% vs 32%, p < 0.0001) compared to white patients. Overall, 137 (18%) of the patients had poorer prognosis (NPI > 4.4), which was significantly associated with younger age (55.6 vs 58.5 years, p = 0.02), black race (27% vs 15%, p = 0.001), triple negative cancer (15% vs 6%, p = 0.003), and poor diet (54% vs 45%, p = 0.046) compared to patients with better prognosis (NPI ≤ 4.4). On multivariate analysis, (model R = 0.12; p < 0.001), age (β = -0.011 per year, p = 0.002), healthy diet (β = -0.195, p = 0.02), and exercise (β = -0.004, p = 0.02) were associated with better prognosis, while black race (β = 0.247, p = 0.02) and triple negative cancer (β = 0.908, p < 0.0001) were associated with poor prognosis. Neither alcohol use nor BMI was significantly associated with NPI.

Conclusion: Among modifiable risk factors, diet and exercise are associated with NPI. Unmodifiable factors including race and biologic subtype remain the most important determinants of prognosis.
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http://dx.doi.org/10.1016/j.amjsurg.2019.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029579PMC
October 2019

Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer.

Epigenetics Chromatin 2019 07 17;12(1):44. Epub 2019 Jul 17.

Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA.

Background: Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC.

Results: MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells.

Conclusions: These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC.
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http://dx.doi.org/10.1186/s13072-019-0290-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636093PMC
July 2019

Diabetes, Obesity, and Breast Cancer.

Endocrinology 2018 11;159(11):3801-3812

Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York.

The rates of obesity and diabetes are increasing worldwide, whereas the age of onset for both obesity and diabetes are decreasing steadily. Obesity and diabetes are associated with multiple factors that contribute to the increased risk of a number of different cancers, including breast cancer. These factors are hyperinsulinemia, elevated IGFs, hyperglycemia, dyslipidemia, adipokines, inflammatory cytokines, and the gut microbiome. In this review, we discuss the current understanding of the complex signaling pathways underlying these multiple factors involved in the obesity/diabetes-breast cancer link, with a focus particularly on the roles of the insulin/IGF system and dyslipidemia in preclinical breast cancer models. We review some of the therapeutic strategies to target these metabolic derangements in cancer. Future research directions and potential therapeutic strategies are also discussed.
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http://dx.doi.org/10.1210/en.2018-00574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202853PMC
November 2018

Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model.

Int J Mol Sci 2018 Apr 14;19(4). Epub 2018 Apr 14.

Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, via Gattamelata, 64, 35128 Padua, Italy.

Hyperinsulinemia could have a role in the growing incidence of esophageal adenocarcinoma (EAC) and its pre-cancerous lesion, Barrett's Esophagus, a possible consequence of Gastro-Esophageal Reflux Disease. Obesity is known to mediate esophageal carcinogenesis through different mechanisms including insulin-resistance leading to hyperinsulinemia, which may mediate cancer progression via the insulin/insulin-like growth factor axis. We used the hyperinsulinemic non-obese FVB/N (Friend leukemia virus B strain) MKR (muscle (M)-IGF1R-lysine (K)-arginine (R) mouse model to evaluate the exclusive role of hyperinsulinemia in the pathogenesis of EAC related to duodeno-esophageal reflux. FVB/N wild-type (WT) and MKR mice underwent jejunum-esophageal anastomosis side-to end with the exclusion of the stomach. Thirty weeks after surgery, the esophagus was processed for histological, immunological and insulin/Insulin-like growth factor 1 (IGF1) signal transduction analyses. Most of the WT mice (63.1%) developed dysplasia, whereas most of the MKR mice (74.3%) developed squamous cell and adenosquamous carcinomas, both expressing Human Epidermal growth factor receptor 2 (HER2). Hyperinsulinemia significantly increased esophageal cancer incidence in the presence of duodenal-reflux. Insulin receptor (IR) and IGF1 receptor (IGF1R) were overexpressed in the hyperinsulinemic condition. IGF1R, through ERK1/2 mitogenic pattern activation, seems to be involved in cancer onset. Hyperinsulinemia-induced IGF1R and HER2 up-regulation could also increase the possibility of forming of IGF1R/HER2 heterodimers to support cell growth/proliferation/progression in esophageal carcinogenesis.
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http://dx.doi.org/10.3390/ijms19041198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979452PMC
April 2018

Statin Use and Breast Cancer Prognosis in Black and White Women.

Horm Cancer 2018 02 19;9(1):55-61. Epub 2017 Oct 19.

Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Studies show decreased risk of breast cancer recurrence and improved survival with statin use, but data on racial disparities regarding breast cancer prognosis and statin use are lacking. Our objective was to investigate if racial disparities in breast cancer prognosis can be partially explained by differences in pre-diagnosis statin use. Patients were identified from a prospective, multicenter study examining the effects of metabolic factors on breast cancer prognosis in Black and White women. Statin use, prognosis (as measured by Nottingham Prognostic Index), anthropometric, tumor, and socio-demographic characteristics were examined. Five hundred eighty-seven women (487 White, 100 Black) with newly diagnosed primary invasive breast cancer were recruited. Obesity was more prevalent in Black women than White women (47 vs 19%, p < 0.01); both groups had similar low-density lipoprotein (LDL) cholesterol levels (113 ± 41 vs 113 ± 36 mg/dl, p = 0.90). More Black women used statins than White women (18 vs 11%, p = 0.06). Black women had a worse prognosis in an adjusted model than White women (OR 2.13 95% CI 1.23-3.67). Statin use was not associated with prognosis in unadjusted (OR 1.03, 95% CI 0.53-2.0) and adjusted models (OR 1.14, 95% CI 0.56-2.31). In women with newly diagnosed breast cancer, Black women were more likely to be treated with statins than White women, contrary to previous studies. Black women had worse prognosis than White women, but this difference was not explained by differences in pre-diagnosis statin use. Our study suggests that differences in pre-diagnosis statin use do not contribute to racial disparities in breast cancer prognosis.
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http://dx.doi.org/10.1007/s12672-017-0312-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873288PMC
February 2018

RAPID EVOLUTION OF THYROID DYSFUNCTION IN PATIENTS TREATED WITH NIVOLUMAB.

Endocr Pract 2017 Oct;23(10):1223-1231

Objective: To describe the evolution of thyroid dysfunction in a series of patients with cancer treated with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) monoclonal antibody, nivolumab.

Methods: Cases of thyroid dysfunction after initiation of checkpoint inhibitor treatment were identified from the Division of Endocrinology clinical practice at Mount Sinai Hospital, New York from April 2016 to February 2017. Charts were reviewed to identify patients treated with nivolumab with new onset of thyroid dysfunction.

Results: Nine cases of thyroid function in patients who were treated with nivolumab were identified. There were 4 male and 5 female patients, with a mean age of 66 years (range 50-76 years). Seven patients ultimately developed hypothyroidism. Five of the 7 patients developed abnormal thyroid function tests within the first 90 days of starting therapy (range 21-84 days), 3 of whom had transient hyperthyroidism. Transient hyperthyroidism evolved rapidly to hypothyroidism; elevated thyroid-stimulating hormone (TSH) levels were detected within 16 to 32 days of the last documented low TSH. In the 2 patients without a hyperthyroid phase, TSH levels >50 were found 18 to 28 days after the last normal TSH value.

Conclusion: As the use of immune checkpoint inhibitor therapy increases, the need for prompt diagnosis and treatment of drug-induced thyroid disease will become more important. As illustrated in this case series, in contrast to other causes of auto-immune thyroiditis, hypothyroidism can develop rapidly within 3 months of treatment. Close monitoring is necessary to detect the development of thyroid dysfunction and avoid preventable morbidity.

Abbreviations: Anti-TPO Abs = anti-thyroglobulin antibodies; CT = computed tomography; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; FDA = U.S. Food & Drug Administration; FDG-PET = fluorodeoxyglucose-positron emission tomography; PD-1 = programmed cell death protein-1; PD-L1 = programmed death-ligand 1; T3 = triiodothyronine; T4 = thyroxine; TG = thyroglobulin; TPO = thyroperoxidase; TSH = thyroid-stimulating hormone.
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http://dx.doi.org/10.4158/EP171832.ORDOI Listing
October 2017

Erratum to: Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes.

Diabetologia 2017 04;60(4):758-759

Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1055, New York, NY, 10029, USA.

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http://dx.doi.org/10.1007/s00125-017-4225-3DOI Listing
April 2017

Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes.

Diabetologia 2016 09 30;59(9):2018-25. Epub 2016 May 30.

Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1055, New York, NY, 10029, USA.

Aims/hypothesis: Previous epidemiological studies have reported a potential link between insulin analogues and breast cancer; however, a prospective randomised controlled trial showed neutral effects of insulin glargine on cancer risk. Insulin glargine is metabolised in vivo to an M1 metabolite. A question remains whether a subset of individuals with slower rates of glargine metabolism or who are on high doses could, theoretically, have an increased risk of cancer progression if a tumour is already present. In this study, we aimed to determine whether a non-metabolisable form of insulin glargine induced murine breast cancer growth.

Methods: A mouse model of type 2 diabetes (MKR) was used for these studies. MKR mice were injected with two murine mammary cancer cell lines: Mvt-1 cells (derived from MMTV-c-Myc/Vegf tumours) and Met1 cells (derived from MMTV-polyoma virus middle T antigen tumours). Mice were treated with 25 U/kg per day of the long-acting insulin analogues, insulin glargine, insulin detemir, insulin degludec or non-metabolisable glargine, or vehicle.

Results: No difference in tumour growth was seen in terms of tumour size after insulin glargine, detemir, degludec or vehicle injections. Non-metabolisable glargine did not increase tumour growth compared with insulin glargine or vehicle. Insulin glargine and non-metabolisable glargine led to insulin receptor phosphorylation in vivo rather than IGF-1 receptor phosphorylation.

Conclusions/interpretation: These results demonstrate that in a mouse model of type 2 diabetes, at high concentrations, basal insulin analogues and a non-metabolisable glargine analogue do not promote the progression of breast tumours.
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http://dx.doi.org/10.1007/s00125-016-4000-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970885PMC
September 2016

Polyol accumulation in muscle and liver in a mouse model of type 2 diabetes.

J Diabetes Complications 2016 08 27;30(6):999-1007. Epub 2016 Apr 27.

Biotechnology Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg 14A, Bethesda, MD, 20892, USA.

Aims: Type 2 diabetes (T2D) is a complex metabolic disease leading to complications in multiple organs. Diabetic myopathy and liver disease are common complications of T2D, but are incompletely understood. To gain insight into the pathogenesis of these conditions we performed metabolomic analysis of skeletal muscle and liver in a mouse model of T2D.

Methods: Tissue metabolomics were performed by GC/MS and LC/MS of the skeletal muscle and liver in the MKR mouse model of T2D, compared with control mice. MKR mice were treated with the β-3 adrenergic receptor agonist, CL-316,243 to determine metabolite changes after correcting hyperglycemia.

Results: Blood glucose was higher in MKR vs WT mice, and normalized with CL-316,243 treatment. Compared with WT mice, MKR mice had 2.5 fold higher concentrations of sorbitol and 1.7 fold lower concentrations of reduced glutathione in skeletal muscle. In liver, MKR mice had 2 fold higher concentrations of the pentitol ribitol. CL-316,243 treatment normalized sorbitol and ribitol concentrations in MKR skeletal muscle and liver, respectively to the levels of the WT mice.

Conclusions: These results demonstrate tissue-specific accumulation of polyols in a mouse model of T2D and provide novel insights into the pathogenesis of myopathy and liver disease in T2D.
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http://dx.doi.org/10.1016/j.jdiacomp.2016.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949127PMC
August 2016

Metabolic syndrome and pre-diabetes contribute to racial disparities in breast cancer outcomes: hypothesis and proposed pathways.

Diabetes Metab Res Rev 2016 10 21;32(7):745-753. Epub 2016 Apr 21.

Icahn School of Medicine at Mount Sinai, Department of Population Health Science and Policy, Department of Medicine, New York, NY, USA.

Background: Women with obesity and type 2 diabetes (T2D) are at greater risk of dying from breast cancer than women without these conditions. Obesity and T2D are associated with insulin resistance and endogenous hyperinsulinemia and are more common in Black women. There is increasing disparity in breast cancer mortality between Black and White women in the USA. We hypothesize that insulin resistance and endogenous hyperinsulinemia in Black women with breast cancer contribute to their greater breast cancer mortality and are associated with increased insulin receptor signalling in tumours.

Methods: We will recruit 350 Black women and 936 White women with newly diagnosed breast cancer. We will determine the presence or absence of the metabolic syndrome/pre-diabetes and insulin resistance by measuring body mass index, waist circumference, lipids, blood pressure, glucose, insulin-like growth factor binding protein 1 and insulin. Breast cancer prognosis will be determined by a Nottingham Prognostic Index (NPI), with poor prognosis being defined as NPI >4.4. Tumour insulin receptor signalling will be determined by immunohistochemistry. Insulin receptor subtype expression will be measured using Nanostring. Analysis of these factors will determine whether endogenous hyperinsulinemia is associated with a worse prognosis in Black women than White women and increased tumour insulin receptor signalling.

Conclusions: The results of this study will determine if the metabolic syndrome and pre-diabetes contribute to racial disparities in breast cancer mortality. It may provide the basis for targeting systemic insulin resistance and/or tumour insulin receptor signalling to reduce racial disparities in breast cancer mortality. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/dmrr.2795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991957PMC
October 2016

Ovariectomy is associated with metabolic impairments and enhanced mammary tumor growth in MKR mice.

J Endocrinol 2015 Dec 17;227(3):143-151. Epub 2015 Sep 17.

Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Reseasch Institute at Rambam (CRIR), Rambam Medical Center, P.O.B 9602, Haifa 31096, Israel.

Obesity and type 2 diabetes (T2D) are associated with an increased risk of breast cancer incidence and mortality. Common features of obesity and T2D are insulin resistance and hyperinsulinemia. A mammary tumor promoting effect of insulin resistance and hyperinsulinemia was demonstrated in the transgenic female MKR mouse model of pre-diabetes inoculated with mammary cancer cells. Interestingly, in MKR mice, as well as in other diabetic mouse models, males exhibit severe hyperglycemia, while females display insulin resistance and hyperinsulinemia with only a mild increase in blood glucose levels. This gender-specific protection from hyperglycemia may be attributed to estradiol, a key player in the regulation of the metabolic state, including obesity, glucose homeostasis, insulin resistance, and lipid profile. The aim of this study was to investigate the effects of ovariectomy (including the removal of endogenous estradiol) on the metabolic state of MKR female mice and subsequently on the growth of Mvt-1 mammary cancer cells, inoculated into the mammary fat pad of ovariectomized mice, compared with sham-operated mice. The results showed an increase in body weight, accompanied by increased fat mass, elevated blood glucose levels, and hypercholesterolemia, in ovariectomized MKR mice. In addition, mammary tumor growth was significantly higher in these mice. The results suggest that ovarian hormone deficiency may promote impaired metabolic homeostasis in the hyperinsulinemic MKR female mice, which in turn is associated with an increased growth of mammary tumors.
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http://dx.doi.org/10.1530/JOE-15-0310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618719PMC
December 2015

The beta-3 adrenergic agonist (CL-316,243) restores the expression of down-regulated fatty acid oxidation genes in type 2 diabetic mice.

Nutr Metab (Lond) 2015 8;12. Epub 2015 Mar 8.

Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1055, New York, NY 10029 USA.

Background: The hallmark of Type 2 diabetes (T2D) is hyperglycemia, although there are multiple other metabolic abnormalities that occur with T2D, including insulin resistance and dyslipidemia. To advance T2D prevention and develop targeted therapies for its treatment, a greater understanding of the alterations in metabolic tissues associated with T2D is necessary. The aim of this study was to use microarray analysis of gene expression in metabolic tissues from a mouse model of pre-diabetes and T2D to further understand the metabolic abnormalities that may contribute to T2D. We also aimed to uncover the novel genes and pathways regulated by the insulin sensitizing agent (CL-316,243) to identify key pathways and target genes in metabolic tissues that can reverse the diabetic phenotype.

Methods: Male MKR mice on an FVB/n background and age matched wild-type (WT) FVB/n mice were used in all experiments. Skeletal muscle, liver and fat were isolated from prediabetic (3 week old) and diabetic (8 week old) MKR mice. Male MKR mice were treated with CL-316,243. Skeletal muscle, liver and fat were isolated after the treatment period. RNA was isolated from the metabolic tissues and subjected to microarray and KEGG database analysis.

Results: Significant decreases in the expression of mitochondrial and peroxisomal fatty acid oxidation genes were found in the skeletal muscle and adipose tissue of adult MKR mice, and the liver of pre-diabetic MKR mice, compared to WT controls. After treatment with CL-316,243, the circulating glucose and insulin concentrations in the MKR mice improved, an increase in the expression of peroxisomal fatty acid oxidation genes was observed in addition to a decrease in the expression of retinaldehyde dehydrogenases. These genes were not previously known to be regulated by CL-316,243 treatment.

Conclusions: This study uncovers novel genes that may contribute to pharmacological reversal of insulin resistance and T2D and may be targets for treatment. In addition, it explains the lower free fatty acid levels in MKR mice after treatment with CL-316,243 and furthermore, it provides biomarker genes such as ACAA1 and HSD17b4 which could be further probed in a future study.
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http://dx.doi.org/10.1186/s12986-015-0003-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362840PMC
March 2015

Survival of patients with stage IV lung cancer with diabetes treated with metformin.

Am J Respir Crit Care Med 2015 Feb;191(4):448-54

1 Division of General Internal Medicine.

Rationale: Prior studies have shown an anticancer effect of metformin in patients with breast and colorectal cancer. It is unclear, however, whether metformin has a mortality benefit in lung cancer.

Objectives: To compare overall survival of patients with diabetes with stage IV non-small cell lung cancer (NSCLC) taking metformin versus those not on metformin.

Methods: Using data from the Surveillance, Epidemiology, and End Results registry linked to Medicare claims, we identified 750 patients with diabetes 65-80 years of age diagnosed with stage IV NSCLC between 2007 and 2009. We used propensity score methods to assess the association of metformin use with overall survival while controlling for potential confounders.

Measurements And Main Results: Overall, 61% of patients were on metformin at the time of lung cancer diagnosis. Median survival in the metformin group was 5 months, compared with 3 months in patients not treated with metformin (P < 0.001). Propensity score analyses showed that metformin use was associated with a statistically significant improvement in survival (hazard ratio, 0.80; 95% confidence interval, 0.71-0.89), after controlling for sociodemographics, diabetes severity, other diabetes medications, cancer characteristics, and treatment.

Conclusions: Metformin is associated with improved survival among patients with diabetes with stage IV NSCLC, suggesting a potential anticancer effect. Further research should evaluate plausible biologic mechanisms and test the effect of metformin in prospective clinical trials.
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http://dx.doi.org/10.1164/rccm.201407-1395OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351595PMC
February 2015

Growth hormone receptor signaling is dispensable for HSC function and aging.

Blood 2014 Nov 1;124(20):3076-80. Epub 2014 Oct 1.

Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA; Department of Stem Cell and Regenerative Medicine, Harvard University, Cambridge, MA; and.

Growth hormone receptor (Ghr) signaling is important in a wide variety of cellular processes including aging; however, the role of Ghr signaling in hematopoietic stem cell (HSC) biology remains unexplored. Within the hematopoietic system, Ghr is expressed in a highly HSC-specific manner and is significantly upregulated during aging. Exposure of young and old HSCs to recombinant growth hormone ex vivo led to diminished short-term reconstitution and restored B-cell output from old HSCs. Hematopoietic-specific genetic deletion of Ghr neither impacted steady-state hematopoiesis nor serial transplantation potential. Repeat challenge with 5-fluorouracil showed that Ghr was dispensable for HSC activation and homeostatic recovery in vivo and, after challenge, Ghr-deficient HSCs functioned normally through serial transplantation. Although exogenous Gh induces age-dependent HSC effects, these results indicate that Ghr signaling appears largely dispensable for HSC function and aging.
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http://dx.doi.org/10.1182/blood-2014-05-575308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231418PMC
November 2014

IGF1R inhibition in mammary epithelia promotes canonical Wnt signaling and Wnt1-driven tumors.

Cancer Res 2014 Oct 4;74(19):5668-79. Epub 2014 Aug 4.

Department of Neurology and Neuroscience, New Jersey Medical School Cancer Center, Rutgers Biomedical and Health Sciences, Newark, New Jersey.

Triple-negative breast cancer (TNBC) is an aggressive disease subtype that, unlike other subtypes, lacks an effective targeted therapy. Inhibitors of the insulin-like growth factor receptor (IGF1R) have been considered for use in treating TNBC. Here, we provide genetic evidence that IGF1R inhibition promotes development of Wnt1-mediated murine mammary tumors that offer a model of TNBC. We found that in a double transgenic mouse model carrying activated Wnt1 and mutant Igf1r, a reduction in IGF1R signaling reduced tumor latency and promoted more aggressive phenotypes. These tumors displayed a squamous phenotype with increased expression of keratins 5/6 and β-catenin. Notably, cell lineage analyses revealed an increase in basal (CD29(hi)/CD24(+)) and luminal (CD24(+)/CD61+/CD29(lo)) progenitor cell populations, along with increased Nanog expression and decreased Elf5 expression. In these doubly transgenic mice, lung metastases developed with characteristics of the primary tumors, unlike MMTV-Wnt1 mice. Mechanistic investigations showed that pharmacologic inhibition of the IGF1R in vitro was sufficient to increase the tumorsphere-forming efficiency ofMMTV-Wnt1 tumor cells. Tumors from doubly transgenic mice also exhibited an increase in the expression ratio of the IGF-II-sensitive, A isoform of the insulin receptor versus the IR-B isoform, which when stimulated in vitro resulted in enhanced expression of β-catenin. Overall, our results revealed that in Wnt-driven tumors, an attenuation of IGF1R signaling accelerates tumorigenesis and promotes more aggressive phenotypes with potential implications for understanding TNBC pathobiology and treatment.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-0970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782979PMC
October 2014