bluuebunny/crossref_metadata_2025_split huggingface dataset:
PMON30 Low-dose Infigratinib, an Oral Selective Fibroblast Growth Factor Receptor Tyrosine Kinase Inhibitor, Demonstrates Activity in a Preclinical Model of Hypochondroplasia
Authors: Dambkowski Carl , Demuynck Benoit , Legeai-Mallet Laurence , Loisay Léa 
Published: November 2022

Abstract

Background
Fibroblast growth factor receptor 3 (FGFR3) gain-of-function mutations play a crucial role in achondroplasia (ACH), thanatophoric dysplasia (TD), and hypochondroplasia (HCH). HCH is a less severe form of dwarfism than ACH, but similarly is caused by gain-of-function mutations in the FGFR3 gene. HCH is characterized by a disproportionate short stature and a growth deficit affecting both endochondral and intramembranous ossification. While multiple therapeutic strategies are being tested for ACH, currently there are no approved therapeutic options for individuals with HCH. We tested the hypothesis that the oral, selective FGFR tyrosine kinase inhibitor (TKI) infigratinib (BGJ398) could improve the HCH phenotype and improve endochondral and intramembranous ossification in a preclinical mouse model of HCH Fgfr3N534K/+.

Methods
The first Hch mouse model studied expresses the most frequent human mutation p.Asn540Lys (Fgfr3Asn534Lys/+), and exhibits a mild dwarfism and most of the hallmarks of the human pathology. Fgfr3N534K/+ mice received subcutaneous injections of infigratinib or vehicle control every 3 days (1 mg/kg) or daily (1 mg/kg) for 15 days (post-natal day [PND] 4–19) or 21 days (PND 3–24), respectively.

Results
Fgfr3N534K/+ mice treated with 1 mg/kg infigratinib every 3 days did not show obvious and significant modification of the dwarf phenotype. In contrast, Fgfr3N534K/+ mice treated with 1 mg/kg infigratinib daily for a total of 21 days showed a statistically significant increase in appendicular and axial skeletal measures. Length of the long bones was statistically significantly increased in Fgfr3N534K/+ mice compared with Fgfr3+/+ mice (tibia +3.18%, femur +3.16%, humerus +3.04%, ulna +2.94%, radius +3.01%). Treatment also modified the skull shape (skull width, skull height, nasal bone length and naso-occipital length), the length of the mandible and skull base, as demonstrated by measurement of the foramen magnum (foramen magnum length +3.72%). Infigratinib treatment modified the cartilage growth plate organization, in particular the hypertrophic chondrocyte area. Finally, the high activation of the MAP kinase pathway due to the HCH missense FGFR3 mutation was reduced by treatment, as revealed by the immunolabelling of phosphorylated Erk1/2 proteins.

Conclusions
Treatment with daily 1 mg/kg infigratinib improved the length and weight of Fgfr3N534K/+ mice and significantly modified the skull and the axial and appendicular skeleton. We demonstrated in Fgfr3N534K/+ mice that infigratinib is able to counteract the constitutive activation of FGFR3 due to the heterozygous N540K mutation localized in the tyrosine kinase 1 domain of the protein. These results provide a rationale for targeting FGFR3 with a specific TKI for the treatment of children with HCH.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
RF17 | P715 Contribution of Low Muscle Mass and Genetic Factors in NAFLD and Liver Cirrhosis
Authors: Choe Hun Jee , Koo Bo Kyung , Kwak Soo-Heon , Lee DongHo , Lee Hyunsuk 
Published: November 2022

Abstract

Introduction
Both sarcopenia and genetic risk factors are important risk factors for non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the independent effects of low muscle mass and genetic risk factors in the development of NAFLD and liver cirrhosis (LC) in the Korean population.
Method: A prospective community-based cohort consisted of adults with age 40–70 years were followed-up biennially from 2001–2002 to 2017–2018. NAFLD was defined as hepatic steatosis index of ≥36, and liver cirrhosis (LC) was defined as a fibrosis-4 index score of ≥1.3. The subjects were divided into four groups according to body mass index (BMI)-adjusted muscle mass. Cox proportional hazards models incorporating age, sex, BMI≥ 25 kg/m2, metabolic syndrome, and PNPLA3, and TM6SF2 risk alleles were used to assess the independent determinants for the incident NAFLD and development of LC among individuals with NAFLD at baseline.

Results
Among the 4,038 participants without NAFLD at baseline, 920 (22.8%) developed NAFLD during the follow-up. Both the TM6SF2 risk alleles (hazard ratio [HR]. 1.19, [95% confidence interval (CI), 1.00–1.40], P=0.044) and muscle mass index quartiles (Q) (HR per 1 Q, 1.18, 95% CI, 1.11–1.27, P&lt;0.001) were associated with development of NAFLD in the fully adjusted model.
Of the 1,442 patients with NAFLD at baseline, LC was eventually confirmed in 552 (38.3%) patients. Only the PNPLA3 risk variant, but not the TM6SF2 genotype nor muscle mass index, was an independent risk factor for developing LC among NAFLD subjects (HR 1.22, 95% CI 1.08–1.38, P=0.001)

Conclusion
Both the lower muscle mass index and genetic risk variants are important contributors in the development of NAFLD. In patients already diagnosed with NALFD however, PNPLA3 conferred a greater risk for the progression to LC than lower muscle mass.
Presentation: No date and time listed
LBMON135 Diffuse Large B-cell Lymphoma Affecting The Pituitary Gland: A Case Report
Authors: Masumy Misha , Aschemeyer Jayme 
Published: November 2022

Abstract

Introduction
Diffuse large B-cell lymphoma is a common manifestation of non-Hodgkin lymphoma, representing approximately 25% of non-Hodgkin lymphoma cases. Patients typically present with an enlarging lymph node that is painless and associated with constitutional symptoms. For the pituitary to be involved is extremely uncommon with approximately 10 previously reported cases. We present a 51-year-old Caucasian female who initially presented with nausea, vomiting, polyuria, and polydipsia and was found to have a pituitary mass diagnosed as diffuse large B-cell lymphoma upon surgical resection.

Case Presentation
A 51-year-old female presented with nausea, vomiting, polydipsia, and polyuria. She had no history of lithium use. She was found to have an initial serum osmolarity of 324 mOsm/kg (280-300mOsm/kg), urine sodium of &lt;20mmol/L, and urine osmolality of 191 mOsm/kg (390-1,090 mOsm/kg). She was initially diagnosed with primary polydipsia, however, her symptoms did not improve with appropriate treatment. An MRI was performed demonstrating a 13mm lobulated, homogeneously enhancing hypothalamic mass with adjacent thickening of the pituitary stalk and pituitary. Subsequent lab work demonstrated deficiencies in ACTH, TSH, cortisol, FSH, LH, and GH. She was initiated on DDAVP, levothyroxine, and hydrocortisone. A repeat MRI several months later revealed that the pituitary mass had enlarged to 2.4cm×2.3cm×1.5cm. She underwent surgical removal of the mass via right frontal craniotomy, and histopathology demonstrated diffuse large B-cell lymphoma. She underwent chemotherapy with high dose methotrexate and cytarabine for 3 cycles. Subsequent MRIs demonstrated stable intracranial findings. Her pituitary function did not recover, and she remains on hormonal replacement with levothyroxine, hydrocortisone, and desmopressin. The patient continues to follow with endocrinology and oncology in the outpatient setting.

Conclusion
This is a rare instance of diffuse large B-cell lymphoma affecting the pituitary gland. In a patient presenting with symptoms of diabetes insipidus, it is prudent to evaluate for other signs of pituitary involvement. This patient was found to have a pituitary mass on MRI that did not have an appropriate response to medical therapy. Thus, surgical management was performed, and histopathology elucidated the etiology of her symptoms. Reference: Kenchaiah, M., Hyer, S. L. Diffuse large B-cell non Hodgkin's lymphoma in a 65-year-old woman presenting with hypopituitarism and recovering after chemotherapy: a case report. J Med Case Reports 5, 498 (2011). https://doi.org/10.1186/1752-1947-5-498
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
LBMON138 Leg Tumeo: Is It Neuroendocrine Tumor?
Authors: Priyadarshini Shista , Lamichhane Bikal , Manas F N U 
Published: November 2022

Abstract

Introduction
Neuroendocrine tumors (NETs) are heterogenous group of epithelial neoplasms often known to produce and secrete peptides and bioamines. The presentation varies from symptomatic functional to non-functional tumors. The functional tumors cause symptoms based on the substance secreted: corticotropin, gastrin, glucagon, insulin, norepinephrine, serotonin, somatostatin, etc. The prognosis ranges from well-differentiated tumors being indolent while the poorly differentiated forms are aggressive. We present a case with an atypical presentation of NET which was noted to secrete an atypical hormone, cortisol.

Case Presentation
A 55-year-old Caucasian man presented with bilateral lower extremity grade 3 pitting edema for past 2 weeks. His past medical history was significant for hypertension. Lower extremity doppler showed no evidence of deep vein thrombosis. Serum potassium was critically low at 1.9mmol/L. Computed tomography of abdomen and pelvis showed a large mass involving the right hepatic lobe, upper pole of right kidney and hypoattenuated lesions in left hepatic lobe. The intrahepatic inferior vena cava appeared to be severely compressed by the mass. MRI abdomen was suggestive of hepatocellular cancer but alfaprotein levels was normal. Biochemical testing for evaluation of hormonal hypersecretion showed elevated cortisol levels (57.2mcg/dl) and markedly elevated dehydroepiandrosterone sulfate (2641mcg/dl). Serum adrenocorticotrophic hormone and aldosterone levels were within normal limits. Low dose dexamethasone suppression test showed no decline in serum cortisol level reflecting adrenal origin. Urinary evaluation showed elevated cortisol but normal metanephrine and catecholamine levels. With concerns for adrenal carcinoma, right adrenal mass biopsy was performed. The biopsy showed poorly differentiated malignant neoplasm with neuroendocrine features. Tumor cells were positive for synaptophysin (a marker for neuroendocrine differentiation) and CD 138. Soon after, he progressed to multisystem organ failure, tumor lysis syndrome and resorted to comfort care. The patient passed away within a week of diagnosis.

Conclusion
NETs usually originate in gastrointestinal tract, pancreas, adrenal, lung and rarely genitourinary tract. The incidence of NETs is on the rise with increased detection by imaging. Adrenal NETs, well-known as pheochromocytoma are mostly benign but small cell adrenal neuroendocrine carcinomas are rare and have a grave prognosis. Flushing, diarrhea are the commonest presentations (75-85%) for gastrointestinal NETs and symptoms are based on the substance secreted. This case highlights a case of adrenal neuroendocrine cancer presenting with lower extremity swelling and secreting an uncommon hormone, cortisol. Increasing awareness among the medical fraternity will help with early diagnosis and better outcomes.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
LBMON140 Central Diabetes Insipidus Manifesting After Vasopressin Withdrawal In A Critically Ill Patient
Authors: Patel Toral , Arora Gunjan 
Published: November 2022

Abstract

Introduction
Central diabetes insipidus is a rare clinical entity characterized by a lack of vasopressin secretion from the posterior pituitary. We present a case of central diabetes insipidus manifesting after the withdrawal of vasopressin in a critically ill patient.

Case presentation
A 19 year old female with a history of Hodgkin's Lymphoma treated with chemotherapy was transferred from another medical facility while intubated and sedated for management of severe ARDS. She had undergone extensive infectious workup and the etiology was attributed to COVID-19 pneumonia and or bleomycin toxicity. She was started on Methylprednisolone for management of bleomycin toxicity and suspected organizing pneumonia. During her hospitalization, she developed septic shock for which she received broad spectrum antibiotics and pressor support. On day 12 of her hospitalization, vasopressin was discontinued and within 12 hours, there was a rise in serum sodium from 134 to 146 along with polyuria with dilute urine (daily urine output of ∼6-7 liters, urine osmolality decreased from 771 to 279 and urine specific gravity decreased from 1. 037 to 1. 026). No diuretics were administered and serum glucose was without excursions. With administration of 2 mcg DDAVP, urine osmolality increased by more than 50% from 279 to 497, serum sodium decreased from 146 to 141 and urine specific gravity increased from 1. 004 to 1. 026 confirming the diagnosis of central DI. CT head was negative. MRI brain could not be done due to hemodynamic instability. Endocrinology was consulted and concomitant adrenal insufficiency testing was not sought due to chronic steroid therapy. The dose of DDAVP was titrated to ∼1-2 mcg per day based on serum sodium levels and daily urine output. Approximately 10 days later, Vasopressin was restarted due to hemodynamic instability and with ongoing DDAVP therapy, hyponatremia was noted. Thus, DDAVP was discontinued while on vasopressin. She was continued on vasopressin for the remainder of her hospitalization ∼ 11 more days until she unfortunately passed away.

Discussion
Our patient developed central diabetes insipidus after withdrawal of vasopressin. She continued to require DDAVP for ∼10 days before Vasopressin had to be restarted due to hemodynamic instability, after which DDAVP had to be discontinued due to concern of SIADH. Central diabetes has been linked to critical illness in a transient state driven by depletion of endogenous stores, negative feedback repression and posterior pituitary hypoperfusion. However, our patient continued to require exogenous supplementation. More research is needed in this regard to elucidate the differing etiologies and characteristics of transient versus permanent DI. Critical illness is a rare but extremely important cause of central DI and can quickly prove to be life threatening without timely diagnosis and treatment.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
LBMON178 2nd Year Outcomes Of The Open-label Extension Of Chiasma Optimal, A Phase 3 Study Of Oral Octreotide Capsules In Acromegaly
Authors: Samson Susan , Nachtigall Lisa , Fleseriu Maria , Molitch Mark E , Giustina Andrea , Haviv Asi , Biermasz Nienke , Kennedy Laurence , Jensterle Mojca , Manning Patrick , Elenkova Atanaska , Melmed Shlomo , Strasburger Christian J 
Published: November 2022

Abstract

Background
Oral octreotide capsules (OOC) are an approved treatment option in the United States for patients with acromegaly who have previously responded to injectable somatostatin receptor ligands (iSRLs). Safety and efficacy of OOC was demonstrated in the CHIASMA OPTIMAL trial (NCT03252353), showing maintenance of response and a safety profile consistent with iSRLs. Results from the first 48 weeks of the open-label extension (OLE) of this trial suggested that this effect was durable for the long-term.

Objective
Report efficacy and safety through the second year of the OLE.

Methods
Eligible patients had the option to enroll in the OLE of CHIASMA OPTIMAL following the double-blind placebo-controlled (DPC) period. Endpoints in the second year of the OLE were exploratory, including: the proportion of patients completing week 96 of the OLE, the proportion of responders entering year 2 who remained responders of those with evaluable data (response defined as average Insulin-like growth factor I [IGF-I] ≤1. 0 × upper limit of normal [ULN] at last 2 visits between weeks 84-96), and changes in IGF-I and growth hormone (GH) from OLE baseline to OLE week 96 in those completing the DPC period on study drug.

Results
Thirty-two patients from the core period (DPC groups: n=14, placebo; n=18, OOC) entered year 2 of the OLE and 31 (97%) completed. OOC dose at the start of year 2 was 40 mg/d, n=3; 60 mg/d, n=8; and 80 mg/d, n=21. For patients who had non-missing data response rate at 96 weeks was 100% (17/17) for patients who entered year 2 as responders, and 93% (27/29) for patients overall. Mean IGF-I for patients from the OOC group who completed the DPC period on study drug (n=14) was 0.81 × ULN at baseline of OLE and 0.78 × ULN at week 96, (change, −0. 03 × ULN). Mean GH (n=12) was 0.43 ng/mL and 0.44 ng/mL at baseline and week 96, respectively (change, 0. 01 ng/mL). For patients who completed the DPC period on placebo (n=8), mean IGF-I was 1. 05 and 0.77 × ULN at OLE baseline and week 96, respectively (change, −0.28); mean GH (n=5) was 1. 06 and 0.34 ng/mL at OLE baseline and week 96, respectively (change, −0.72 ng/mL). Median exposure to OOC was 2.1 years, with exposure &gt;3 years for 5 patients. Throughout the OLE period, 50% of patients experienced adverse events (AEs), with no serious AEs. One patient discontinued treatment due to an AE (headache). The safety profile was consistent with that reported for OOC; no new patterns were observed with increased exposure.

Conclusion
Maintenance of biochemical response with OOC was durable up to 96 weeks. The safety profile of OOC was consistent with that of iSRLs. No new safety signals were observed with increased exposure duration.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
LBODP074 Autoimmune Hypophysitis: Diagnosis Beyond Imaging
Authors: Gonzalez Juanita , Monsalve Claudia , Aguilar Carolina , Aristizabal Natalia , Torres Jose Luis , Pompey Nestor Alfonso Lopez , Vargas Laura Valentina Estupiñan , Ramos Andres Felipe Garcia , Buenaventura Daisy , Ramirez Alex , Vargas Hernando , Herrera Sebastian 
Published: November 2022

Abstract

Background
Lymphocytic (LH) or autoimmune hypophysitis (AH) is a rare inflammatory disorder of the hypophyseal gland, often miss-diagnosed. LH is predominant in females, occasionally related with other rheumatic disorders (1-20%). The disease can lead to pituitary dysfunction and symptoms of hypopituitarism, the most affected axes are the ACTH and TSH. Definitive diagnosis of AH can be based only on pathological examination of a pituitary biopsy sample but such invasive procedure is seldom needed. Different imaging modalities, especially MRI, can be useful but up to 30% can be unremarkable, thus clinical manifestations and biochemical evaluation is of great importance in guiding the diagnosis. Hormonal replacement therapy is the main treatment strategy. Immunosuppressive drugs are indicated by the severity of the symptoms and the underlying autoimmune disease.

Clinical Case
A 36 year old patient with active lupus and Sjogren disease presented to the emergency department with syncope and hypotension preceded by a 6 month history of intense fatigue. She did not take any steroids in the 6 months prior. Initial tests were consistent with secondary adrenal insufficiency; low plasma cortisol (&lt;1ug/dl n 5-23 ug/dl) and ACTH-concentrations below detection (&lt; 4 ng/l), central hypothyroidism; abnormal low TSH (0. 04uU/ml n 0.4-4.5 uU/ml) and low free T4 (0.56 ng/dl n 0.8-2 ng/dl), and growth hormone deficiency (IGF1 below age and sex normal values). Craneal CT and pituitary MRI didn't show any anomaly. Based on symptoms, clinical context and test results the pressumtive diagnosis was AH related to her lupus. The patient was treated with hydrocortisone and levothyroxine with excellent response and complete resolution of her symptoms. Clinical Lesson: This case demonstrates that hypophysitis is a clinical entity that can be suspected and treated based on clinical and past medical history even in the context of normal imaging were an invasive procedure such as a biopsy would likely not change the final outcome.
Presentation: No date and time listed
As Wages Increase, Do People Work More or Less? A Wage Frame Effect
Authors: Shen Luxi , Hirshman Samuel D. 
Published: November 2022

In jobs in which workers have the flexibility to decide how much work to supply, such as in the gig economy, the effect of a wage change on work supply can be hard to predict. A wage increase offers workers the opportunity to make more money. At the same time, it allows them to make money faster, so they can enjoy more leisure and do not need to work as much. Economic theory alone does not predict which outcome is more likely to occur, and the empirical evidence is also mixed. This paper provides some psychological insights into this economic problem by showing that the short-term effect of a wage change on work supply depends on how the change is framed. Given a current wage of “work l hours to earn $m,” a pay-change frame (“work the same l hours and earn $M”) facilitates a change in work supply in the same direction as the wage change, whereas a load-change frame (“work L hours and earn the same $m”) facilitates the opposite change. Hence, if strategically framed, a wage decrease can elicit the same increase in work supply as a wage increase. A set of studies demonstrate this wage frame effect on both actual work performance and expressed willingness to work. The findings from these studies offer a behavioral perspective on a classic labor economics problem, document a novel framing effect for the judgment and decision-making literature, and suggest a nudge strategy that managers and policy makers can use in incentive designs. This paper was accepted by Yuval Rottenstreich, behavioral economics and decision analysis. Funding: The research of L. Shen was supported by the Research Grants Council, University Grants Committee of Hong Kong [Grant GRF 14501317]. The research of S. D. Hirshman was supported by the Center for Research on Consumer Financial Decision Making, the University of Colorado Leeds School of Business, and The Research Council of Norway (FAIR, project 262675). Supplemental Material: The online appendix and data are available at https://doi.org/10.1287/mnsc.2022.4591 .
Closed midshaft clavicle fractures
Authors: Khoriati Al-Achraf , Fozo Zien A. , Al-Hilfi Lena , Tennent Duncan 
Published: November 2022

Aims The management of mid-shaft clavicle fractures (MSCFs) has evolved over the last three decades. Controversy exists over which specific fracture patterns to treat and when. This review aims to synthesize the literature in order to formulate an appropriate management algorithm for these injuries in both adolescents and adults. Methods This is a systematic review of clinical studies comparing the outcomes of operative and nonoperative treatments for MSCFs in the past 15 years. The literature was searched using, PubMed, Google scholar, OVID Medline, and Embase. All databases were searched with identical search terms: mid-shaft clavicle fractures (± fixation) (± nonoperative). Results Using the search criteria identified, 247 studies were deemed eligible. Following initial screening, 220 studies were excluded on the basis that they were duplicates and/or irrelevant to the research question being posed. A total of 27 full-text articles remained and were included in the final review. The majority of the meta-analyses draw the same conclusions, which are that operatively treated fractures have lower nonunion and malunion rates but that, in those fractures which unite (either operative or nonoperative), the functional outcomes are the same at six months. Conclusion With regard to the adolescent population, the existing body of evidence is insufficient to support the use of routine operative management. Regarding adult fractures, the key to identifying patients who benefit from operative management lies in the identification of risk factors for nonunion. We present an algorithm that can be used to guide both the patient and the surgeon in a joint decision-making process, in order to optimize patient satisfaction and outcomes. Cite this article: Bone Jt Open 2022;3(11):850–858.