bluuebunny/crossref_metadata_2025_split huggingface dataset:
Appropriate Systemic Therapy Dosing for Obese Adult Patients With Cancer: ASCO Guideline Update
Authors: Griggs Jennifer J. , Bohlke Kari , Balaban Edward P. , Dignam James J. , Hall Evan T. , Harvey R. Donald , Hecht Diane P. , Klute Kelsey A. , Morrison Vicki A. , Pini T. May , Rosner Gary L. , Runowicz Carolyn D. , Shayne Michelle , Sparreboom Alex , Turner Sophia , Zarwan Corrine , Lyman Gary H. 
Published: May 2021

PURPOSE To provide recommendations for appropriate dosing of systemic antineoplastic agents in obese adults with cancer. METHODS A systematic review of the literature collected evidence regarding dosing of chemotherapy, immunotherapy, and targeted therapies in obese adults with cancer. PubMed and the Cochrane Library were searched for randomized controlled trials, meta-analyses, or cohort studies published from November 1, 2010, through March 27, 2020. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS Sixty studies, primarily retrospective, were included in the review. Overall, the evidence supported previous findings that obese adult patients tolerate full, body-size–based dosing of chemotherapy as well as nonobese patients. Fewer studies have addressed the dosing of targeted therapies and immunotherapies in relation to safety and efficacy in obese patients. RECOMMENDATIONS The Panel continues to recommend that full, weight-based cytotoxic chemotherapy doses be used to treat obese adults with cancer. New to this version of the guideline, the Panel also recommends that full, approved doses of immunotherapy and targeted therapies be offered to obese adults with cancer. In the event of toxicity, the consensus of the Panel is that dose modifications of systemic antineoplastic therapies should be handled similarly for obese and nonobese patients. Important areas for future research include the impact of sarcopenia and other measures of body composition on optimal antineoplastic dosing, and more customized dosing based on pharmacokinetic or pharmacogenetic factors. Additional information is available at www.asco.org/supportive-care-guidelines .
GLP1 Receptor Agonists Reduce Fluid Intake in Primary Polydipsia
Authors: Winzeler Bettina Felicitas , Sailer Clara Odilia , Coynel David , Deborah Vogt , Davide Zanchi , Urwyler Sandrine , Refardt Julie , Christ-Crain Mirjam 
Published: May 2021

Abstract
Background Primary polydipsia, characterized by excessive fluid intake, carries the risk of water intoxication and hyponatremia, but treatment options are scarce. Glucagon-like peptide-1 (GLP-1) reduces appetite and food intake. In experimental models, they also play a role in thirst and drinking behavior in. The aim of this trial was to investigate whether GLP-1 receptor agonists reduce fluid intake in patients with primary polydipsia. Methods: In this randomized, double-blind, placebo-controlled, 3-week crossover-trial, 34 patients with primary polydipsia received weekly dulaglutide (Trulicity®) 1.5mg and placebo (0.9% sodium chloride). During the last treatment week, patients attended an 8-hour evaluation visit with free water access. The primary endpoint was total fluid intake during the evaluation visits. The treatment effect was estimated using a linear mixed-effects model. In a subset of 15 patients and matched controls, thirst perception and neuronal activity in response to beverage pictures were assessed by functional MRI. Results Median [IQR] total fluid intake was 2250ml [1600-2600] on dulaglutide versus 2400ml [1850-3400] on placebo. Patients on dulaglutide reduced fluid intake by 490ml [95%-CI -780, -199], p=0.002, corresponding to a relative reduction of 17%. 24-hour urinary output was reduced by -943ml [95%-CI -1473, -413]. Thirst perception in response to beverage pictures was higher in patients with primary polydipsia versus controls and lower on dulaglutide versus placebo, but functional neuronal activity was similar between groups and treatments. Conclusion: GLP-1 receptor agonists reduce fluid intake and thirst perception in patients with primary polydipsia and could therefore be a novel treatment option for these patients.
Clinical Correlation to E-cadherin and Granulation Patterns in Corticotroph Tumors
Authors: Lipe Kristin A , Fishbein Lauren Michelle , Kerr Janice M , Youssef Samy A , Lillehei Kevin O , Wierman Margaret E , Kleinschmidt-Demasters B K , Kiseljak-Vassiliades Katja 
Published: May 2021

Abstract
Corticotroph adenomas, either secretory or silent, are associated with significant disease persistence and/or recurrence. Surgical resection is the first line treatment; however, recurrence rates range from 30 to 60%. Although several clinical parameters (i.e. postoperative cortisol level, tumor invasion) have been reported to predict tumor recurrence, none have high diagnostic accuracy. Granulation pattern classifies corticotroph tumors as densely granulated (DG) or sparsely granulated (SG) types, with the latter usually larger and more aggressively behaving. E-cadherin, a calcium-dependent adhesion molecule strongly expressed in normal pituitary cells, plays a role in epithelial cell behavior, tissue development, and suppresses epithelial-mesenchymal transition. Since loss of E-cadherin expression in sparsely granulated somatotroph pituitary tumors correlates with a more aggressive disease course, we sought to examine correlation between E-cadherin expression and behavior in densely versus sparsely granulated corticotroph tumors. A retrospective chart review of adult patients with corticotroph adenomas, seen at our institution between January 2012 - 2020 yielded 62 patients: 18 (29%) male and 44 female (71%), with median age at diagnosis of 49 years (range 25-82). Inclusion criteria required sufficient tissue for E- cadherin immunostaining (IHC). Microadenomas were identified in 19/62 (31%) patients, and 38/62 (52%) patients had clinical and biochemical findings consistent with excess cortisol secretion. Pre-operative imaging showed that 22/62 (35%) tumors were invasive into surrounding structures. After further classification as to densely granulated (DG) or sparsely granulated (SG) types by ACTH granulation pattern on IHC, 19/56 (34%) adenomas were SG, 37/56 (66%) were DG and 6 were not classified. E-cadherin staining was absent in 7/62 tumors (11%) and diminished in 5/62 (8%) tumors and staining did not correlate with dense versus sparse corticotroph types. Chi-squared analysis found a significant association between tumor size (greater than or less than 1cm) and secretion, with hormonally active more likely tumors to be microadenomas (p=0.004). Microadenomas were exclusively DG tumors (p&lt;0.001). Further analysis did not find correlation between presence or absence of E-cadherin expression and tumor invasion into adjacent structures, or recurrence. In summary, the data suggests that, unlike somatotroph corticotroph adenomas for recurrence or invasion, nor does it correlate strongly with granulation status.
Activation of Norepinephrine Neurons in the NTS (A2 population) is Sufficient to Suppress Pulsatile LH Secretion in Female Mice
Authors: McCosh Richard B , Kreisman Michael J , Tian Katherine , Thomas Steven A , Breen Kellie M 
Published: May 2021

Abstract
The overarching goal of this work is to identify neural pathways underlying inhibition of pulsatile luteinizing hormone (LH) secretion during stress. Stress-induced suppression of LH secretion is mediated, at least in part, by suppression of arcuate kisspeptin (ARCKiss1) neurons. The mechanisms by which acute stress suppresses ARCKiss1 cell activity are largely unknown; however, several lines of evidence support the hypothesis that A2 neurons (norepinephrine [NE] neurons in the nucleus of the solitary tract [NTS] of the brainstem) are involved. First, A2 cells are activated during several reactive stress paradigms. Second, NE administered into the paraventricular nucleus, which is innervated by A2 neurons, suppressed pulsatile LH secretion. Finally, ablation of brainstem NE neurons restored estrous cyclicity following chronic glucoprivation (chronic metabolic stress model). The present study employed chemogenetics to test the hypothesis that A2 neurons are sufficient to suppress pulsatile LH secretion in ovariectomized female dopamine beta-hydroxylase (DBH) Cre positive and negative (wild type) mice. Mice received bilateral injections of either a Cre-dependent stimulatory Designer Receptor Exclusively Activated by Designer Drugs (DREADD) virus (AAV1-DIO-hM3Dq-mCherry) or a control virus (AAV1-DIO-mCherry) into the NTS. Mice were randomly assigned to receive either clozapine N-oxide (CNO, specific DREADD agonist; 1mg/kg, i.p.) or saline and blood samples were collected at 6-min intervals for 60 min before and 90 min after injection. Two weeks later, mice received the alternate treatment in a cross-over design (n= 5-10/grp). During the pre-injection period, all mice had clear LH pulses (mean: 6.0 ± 0.2 ng/mL, pulses/60 min: 3.4 ± 1.5). In DBH Cre- (wild type) mice with hM3D virus and DBH Cre+ with mCherry virus (both control groups), neither CNO nor saline altered mean LH or LH pulse frequency. However, DBH Cre+ mice with hM3D virus had a 54% reduction in mean LH (p &lt; 0.05) and 59% reduction in pulse frequency (p &lt; 0.05) following CNO; neither LH metric was altered in response to saline. To assess transduction efficiency, fixed neural tissue was collected. In tissue analyzed thus far, DBH Cre+ mice have mCherry labeling in ~70% of DBH-immunoreactive neurons in the NTS and &gt;90% of mCherry neurons contained DBH immunoreactivity. Three DBH Cre+ mice with hM3D virus mice had no LH response to CNO and may represent missed viral injections, which will be determined when tissue is analyzed. These data demonstrate that activation of A2 neurons is sufficient to impair pulsatile LH secretion in female mice. Moreover, these data support the broad hypothesis that the A2 population of neurons is critical for modulating neuroendocrine function during stress and raises the possibility that A2 neurons directly or indirectly influence ARCKiss1 cell activity.
An Unusual Case of Transient Diabetes Insipidus After Prolonged Vasopressin Infusion
Authors: Chang Albert , Arudkumaran Dharscika , Umadat Deviani , Cocks Eschler Deirdre A 
Published: May 2021

Abstract
Background: Vasopressin is a hormone produced in the hypothalamus and secreted by the posterior pituitary. Underproduction or resistance to vasopressin can lead to diabetes insipidus (DI) resulting in the imbalance of fluid status and serum sodium levels. Synthetic vasopressin is a common second line agent used in the critical care setting for its vasopressor effects with an added clinical benefit by increasing cerebral perfusion pressure. There have been reported cases of transient DI after discontinuation of vasopressin in neurosurgical patients, however only few cases have been reported in septic shock patients without neurological involvement. We present a case of transient DI during treatment for septic shock after attempts to wean off vasopressin infusion. Presentation: A 41-year-old female with history of type 2 diabetes mellitus, quadriplegia following a motor vehicle accident at age 11 was admitted to the surgical intensive care unit for urosepsis after placement of right ureteral stent. The patient was started on broad spectrum intravenous (IV) antibiotics and vasopressors norepinephrine and vasopressin. After 8 days of vasopressin treatment, with each effort to wean IV vasopressin, the patient was noted to have significant polyuria with urine output reaching as much as 800 mL/hr and increase in her serum sodium to a maximum of 148 mmol/L (n 145 mmol/L). During episodes of excessive diuresis, urine sodium reached 87 mmol/L, urine osmolality was 72 mOsm/kg (50-1400 mOsm/kg), and serum osmolality was 288 mOsm/kg (n 300 mOsm/kg). The patient received three doses of 1 microgram of desmopressin 24 hours apart while weaning off vasopressin. This helped slow excessive diuresis while also maintaining normal serum sodium levels. Urine output decreased to approximately 150 mL/hr after each administration of desmopressin. The serum sodium levels eventually stabilized between 135-140 mmol/L and urine output held steady around 200 cc/hr. The patient did not require additional desmopressin and was hemodynamically stable off all vasopressors. Discussion: The pathophysiology behind transient diabetes insipidus following vasopressin infusion is still unclear. It is known that in septic shock, there is depletion of vasopressin stores which suggests central DI. Yet, pharmacologic doses of vasopressin are speculated to downregulate V2 receptors in the renal distal convoluted tubules and collecting ducts which suggests nephrogenic DI. Our patient responded to desmopressin which indicates that she at least had a central component of DI. There is no consensus on the duration of vasopressin required to precipitate transient DI, but vasopressin infusion was administered for at least 24 hours in other cases prior to onset. We present a rare case of transient diabetes insipidus after prolonged vasopressin infusion that clinicians should be aware of in the critical care setting.
Idiopathic Hypophysitis
Authors: Amjed Hafsa , Sadiq Sobia 
Published: May 2021

Abstract
Introduction: Hypophysitis is a heterogeneous condition that leads to inflammation of the sella / suprasellar region, potentially resulting in hormonal deficiencies or mass effects. Prevalence of hypophysitis ranges from 0.2% to 0.88%. Annual incidence of hypophysitis is 1 case per 9 million individuals. We present an interesting case of idiopathic hypophysitis. Clinical Case: A 52-year-old female was evaluated for secondary hypothyroidism. Patient complained of excess fatigue, weight gain, headaches, polyuria with nocturia and vision changes. She was seen by ophthalmology for formal visual field testing revealing right superior quadrantanopia. Labs significant for TSH 4 uIU/mL (ref range 0.27-4.2uIU/mL), FT4 0.72ng/dL (ref range 0.93-1.7 ng/dL), Anti TPO ab negative, AM cortisol 8.9UG/dL, ACTH 18pg/mL, IGF1 127ng/mL, prolactin 7ng/mL, FSH 102MIU/mL, LH 41 MIU/mL. MRI sella revealed homogenous enhancement of the pituitary with convex superior margin - 0.8*1*0.9cm concerning for hyperplasia. Due to the concern for hypophysitis, an extensive inflammatory workup was pursued which was negative. She was started on thyroid hormone replacement and DDAVP. An empiric trial of high dose steroids failed to provide any relief. During workup, patient complained of transient right sided face and arm tingling, diagnosed with TIA and started on aspirin. Due to worsening headaches, a pituitary biopsy was pursued. Pathology significant for glandular tissue ruling out inflammatory, neoplastic, and infectious etiologies. Neurology diagnosed the patient with hemicrania continua. Patient is currently maintained on thyroid hormone replacement and DDAVP with close follow-up. Discussion: The incidence of hypophysitis has recently increased due to increased awareness and also due to the use of medications like ICI. Primary hypophysitis is mostly due to autoimmune etiology. Secondary hypophysitis could result from infections, neoplastic conditions or an adverse effect of medications. Clinical presentations ranges from being asymptomatic to having features of hypopituitarism. Usually presents with mass effect, visual symptoms due to the upward expansion of the pituitary gland impinging the dura mater and optic chiasm. This is followed by symptoms of hormone deficiency, central DI and hyperprolactinemia. Central AI has been reported in 20%-75%, central hypogonadism in 15%-60%, central hypothyroidism in 25%-58%, GH deficiency in 5%-41%, and prolactin deficiency in 13%-25%. Typical MRI findings include, homogeneous pituitary contrast enhancement, pituitary stalk thickening and loss of posterior pituitary bright spot, ‘figure of 8’ appearance, ‘dural tail’. Treatment consists of surgery, anti-inflammatory medications, and radiotherapy. Glucocorticoid treatment is the cornerstone for medical management; however, the overall recurrence rate is high.
Pleurihormonal Pituitary Adenomas Presenting as Acromegaly
Authors: Schwehr Megan , Endo Mayumi 
Published: May 2021

Abstract
Background: Pleurihormonal pituitary adenomas represent 10-15% of all functioning pituitary adenomas1. One of the rarest combinations is ACTH-GH co-secretion with concomitant acromegaly and Cushing’s disease. Clinical Case: 30-year-old female with type 2 diabetes (A1c 11.4%) developed rapidly progressive peripheral neuropathy. Labs revealed a transaminitis. Hepatic ultrasound revealed fatty infiltration of the liver consistent with steatosis. Patient endorsed life-long “chicken legs”, buffalo hump, and easy bruising. She continued to have worsening paresthesias and stated her teeth were “more translucent”. At an endocrinology visit peripheral muscle wasting, atraumatic bruising at the ankles and toes,and striae on the abdomen, shoulders, breasts, and armpits were noted. She had also noted teeth separation and thinning over time and worsening diffuse joint aches. Lab results showed elevated cortisol value of 8.4 mcg/dl after 1 mg dexamethasone suppression test. 24-hour urine cortisol was elevated (87 ug/24 hrs, nl &lt; 45 ug/24 hrs), confirming the diagnosis of Cushing’s syndrome. ACTH was inappropriately normal (56 pg/mL, nl 7.2 – 63 pg/mL), suggesting ACTH dependency. IGF-1 was elevated twice (328 ng/dL and 391 ng/dL, nl &lt;303 ng/dL), and a GH suppression test was abnormal (GH 1.14 ng/mL at 90 minutes) confirming the diagnosis of acromegaly. Brain MRI revealed a cystic pituitary microadenoma (0.5 x 0.5 x 0.6 cm), and the patient underwent surgical resection via transnasal transsphenoidal pituitary surgery with total tumor removal. Immunostaining was positive for only synaptophysin and ACTH. Postoperative diagnosis of Cushing’s disease was made, with formal diagnosis of acromegaly pending improvement in follow-up IGF-1 levels. Literature reviews have revealed very few cases of pleurihormonal pituitary adenomas presenting with concomitant Cushing’s Syndrome and acromegaly. Roca et. al examined 17 studies which described 20 patients with this condition; only 4 presented with symptoms of both acromegaly and Cushing’s disease. In many cases previously reported, the clinical presentation of Cushing’s syndrome was subtle, often with subclinical Cushing’s syndrome, while patients had florid symptoms of acromegaly.1. Conclusion: This Cushing’s predominant case of a GH-ACTH co-secreting tumor is an incredibly rare presentation for this pleurihormonal pituitary adenoma, which is already a rare diagnosis.
References: 1.Roca E, Mattogno PP, Porcelli T, Poliani L, Belotti F, Schreiber A, Maffezzoni F, Fontanella MM, Doglietto F. Plurihormonal ACTH-GH Pituitary Adenoma: Case Report and Systematic Literature Review. World Neurosurg. 2018 Jun;114:e158-e164. PMID: 29501516.
Specificity for the Epiphyseal Round Cell Layer is Significantly Associated With Height GWAS​
Authors: Renthal Nora Edwards , Nakka Priyanka , Baronas John , Kronenberg Henry M , Hirschhorn Joel N 
Published: May 2021

Abstract
Human height is a model polygenic trait with thousands of height-related SNPs identified in GWAS to date. An important determinant of height is the proliferation and hypertrophy of growth plate chondrocytes during childhood long bone elongation. Connecting the expression of specific genes that affect skeletal biology to associated variants in GWAS remains a difficult challenge. To connect the genetics of height and growth plate gene expression, we studied the relationship between gene expression in the murine growth plate and common-variant associations from GWAS of height. To obtain gene expression data from the growth plate, we dissected three layers of murine tibial growth plates, extracted RNA from each layer, and measured expression using the Affymetrix GeneChip 430 3.0. For each gene, we derived a specificity score for each growth plate layer, and SNP-level p-values from a published GWAS of height (N~700000) were combined into gene-level p-values using MAGMA. We then used MAGMA to test for association between specificity of expression for each growth plate layer and the GWAS gene level p-values for height. We found that specificity for the round cell layer is significantly associated with height GWAS p-values (p = 8.5x10-9). This association remains when we condition on each of the other cell layers and on membership in a set of genes from OMIM that cause skeletal growth disorders (3.3x10-8 &lt; p &lt; 4.1x10-6). We replicated this result in a RNA-seq dataset of maturing chondrocytes sampled at three time points during development in vitro (days 3, 5, and 10): we found that z-scores for expression in the earliest two days of development are significantly associated with gene-level p-values from height GWAS (pDay3 = 1.2x10-21 and pDay5 = 2.0x10-20) and that this association remains after conditioning on the other timepoints and on the OMIM gene set (3.1x10-20 &lt; pDay3 &lt; 8.3x10-5; 3.7x10-19 &lt; pDay5 &lt; 0.002). We then performed pathway analysis of genes that are both highly specific to the round layer and highly significant in GWAS using Enrichr. Together, our results suggest that genes expressed in early chondrocyte development (the round cell layer) are particularly relevant to the contribution of growth plate-expressed genes to height. This conclusion both sheds light on the regulation of human skeletal growth and also helps prioritize relevant genes implicated from the height GWAS in skeletal biology.
Racial/Ethnic Disparities in the Investigation and Treatment of Pediatric Growth Hormone Deficiency
Authors: Hawkes Colin Patrick , Gunturi Hareesh , Dauber Andrew Nahum , Hirschhorn Joel N , Grimberg Adda 
Published: May 2021

Abstract
Introduction : In the United States, non-Hispanic white (NHW) children are disproportionately over-represented relative to children of racial and ethnic minorities in pediatric growth hormone (GH) treatment registries. This study sought to determine if this racial inequity is due to differences in GH stimulation testing and/or GH prescribing patterns in children referred for endocrine evaluation of short stature.
Methods : Retrospective chart review was performed including children aged 2-16 years, with height z-score ≤ -1.5, and of NHW, non-Hispanic black (NHB) or Hispanic race/ethnicity, referred for endocrine growth evaluation between January 1, 2012 and December 31, 2019. Age, sex, anthropometry, GH stimulation test results and GH treatment data were extracted. Comparisons between NHB, NHW and Hispanic children were performed using analysis of variance, chi-squared tests, Mann Whitney U and logistic regression tests.
Results : This study included 7,425 patients (5,905 NHW, 800 NHB, and 720 Hispanic). GH stimulation testing was performed in 992, and 576 were prescribed GH. NHW children were 1.4 (95% CI 1.04 - 1.8) times more likely than NHB children and 1.7 (95% CI 1.2 - 2.2) times more likely than Hispanic children to undergo GH stimulation testing. NHB children treated with GH had: 1) lower median peak GH concentration when compared with NHW (p=0.02) and Hispanic (p=0.08) children (NHB 4.7 [1.2, 8.3] ng/ml, NHW 7.2 [4.9, 9.7] ng/ml, Hispanic 7.1 [4.3, 11.9] ng/ml); 2) lower median height z-scores than NHW (p=0.01) but not Hispanic children (p=0.5); and 3) a greater height deficit from mid-parental height when compared with NHW (p=0.01) and Hispanic (p=0.002) children
Discussion: Racial and ethnic disparities are present in the evaluation and treatment of children with disordered growth. This likely results from both over-investigation of NHW children as well as under-investigation and under-treatment of children from minority communities. The evaluation and treatment of children with short stature should be determined by clinical concern alone, but this is unfortunately not current practice.