Von Hippel Lindau tumor suppressor controls m6A-dependent gene expression in renal tumorigenesis.

N6-Methyladenosine (m6A) is the most abundant posttranscriptional modification, and its contribution to cancer evolution has recently been appreciated. Renal cancer is the most common adult genitourinary cancer, approximately 85% of which is accounted for by the clear cell renal cell carcinoma (ccRCC) subtype characterized by VHL loss. However, it is unclear whether VHL loss in ccRCC affects m6A patterns. In this study, we demonstrate that VHL binds and promotes METTL3/METTL14 complex formation while VHL depletion suppresses m6A modification, which is distinctive from its canonical E3 ligase role. m6A RNA immunoprecipitation sequencing (RIP-Seq) coupled with RNA-Seq allows us to identify a selection of genes whose expression may be regulated by VHL-m6A signaling. Specifically, PIK3R3 is identified to be a critical gene whose mRNA stability is regulated by VHL in a m6A-dependent but HIF-independent manner. Functionally, PIK3R3 depletion promotes renal cancer cell growth and orthotopic tumor growth while its overexpression leads to decreased tumorigenesis. Mechanistically, the VHL-m6A-regulated PIK3R3 suppresses tumor growth by restraining PI3K/AKT activity. Taken together, we propose a mechanism by which VHL regulates m6A through modulation of METTL3/METTL14 complex formation, thereby promoting PIK3R3 mRNA stability and protein levels that are critical for regulating ccRCC tumorigenesis.

Lung function trajectories in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease characterised by decline in lung function. We evaluated trajectories of forced vital capacity (FVC) and diffusing capacity (DLco) in a cohort of patients with IPF. METHODS: Patients with IPF that was diagnosed or confirmed at the enrolling centre in the previous 6 months were enrolled into the IPF-PRO Registry between June 2014 and October 2018. Patients were followed prospectively, with lung function data collected as part of routine clinical care. Mean trajectories of FVC and DLco % predicted in all patients and in subgroups by characteristics assessed at enrolment were estimated using a joint model that accounted for factors such as disease severity and visit patterns. RESULTS: Of 1002 patients in the registry, 941 had ≥ 1 FVC and/or DLco measurement after enrolment. The median (Q1, Q3) follow-up period was 35.1 (18.9, 47.2) months. Overall, mean estimated declines in FVC and DLco % predicted were 2.8% and 2.9% per year, respectively. There was no evidence that the mean trajectories of FVC or DLco had a non-linear relationship with time at the population level. Patients who were male, white, had a family history of ILD, were using oxygen, or had prior/current use of antifibrotic therapy at enrolment had greater rates of decline in FVC % predicted. Patients who were male or white had greater rates of decline in DLco % predicted. CONCLUSIONS: Data from the IPF-PRO Registry suggest a constant rate of decline in lung function over a prolonged period, supporting the inexorably progressive nature of IPF. A graphical abstract summarising the data in this manuscript is available at: https://www.usscicomms.com/respiratory/IPF-PRORegistry_LungFunctionTrajectories . TRIAL REGISTRATION: NCT01915511.

A double-blind, placebo-controlled, randomized withdrawal trial of sarilumab for the treatment of glucocorticoid-dependent sarcoidosis.

OBJECTIVES: Effective steroid-sparing therapies for the treatment of sarcoidosis are lacking; interleukin-6 (IL-6) antagonists may reduce sarcoidosis disease activity. This study assessed the safety and efficacy of the IL-6 receptor antagonist, sarilumab, in subjects with glucocorticoid-dependent sarcoidosis. METHODS: This phase II, double-blind, placebo-controlled, randomized withdrawal trial enrolled 15 subjects with biopsy-proven sarcoidosis at Stanford University from November 2019 to September 2022. In Period 1, subjects were treated with open-label sarilumab 200mg subcutaneously every two weeks for 16 weeks, with predefined tapering of prednisone. Subjects who completed Period 1 without a sarcoidosis flare entered Period 2 and were randomized to continue sarilumab or to receive matching placebo for 12 weeks. Endpoints included flare-free survival, as well as changes in pulmonary function tests, chest imaging, patient reported outcomes, and laboratory values. RESULTS: Fifteen subjects were enrolled in the study (median age 57 years, 80% male, 73.3% White), and 10 subjects successfully completed Period 1. During Period 1, 4 of 15 subjects (26.7%) discontinued due to worsening of their sarcoidosis, and CT chest imaging worsened in 5 of 15 subjects (35.7%). During Period 2, 0 of 2 subjects in the sarilumab group and 1 of 8 subjects (12.5%) in the placebo group had a flare. Treatment with sarilumab 200 mg was generally well tolerated in subjects with sarcoidosis. CONCLUSION: In this double-blind, placebo-controlled, randomized withdrawal trial, a meaningful signal for improvement in subjects with sarcoidosis treated with sarilumab was not observed. Given the small numbers in this study, no definitive conclusions can be drawn. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04008069.

AIMS65, Glasgow-Blatchford bleeding score and modified Glasgow-Blatchford bleeding score in predicting outcomes of upper gastrointestinal bleeding: An accuracy and calibration study.

BACKGROUND: Albumin, international normalized ratio (INR), mental status, systolic blood pressure, age >65 years (AIMS65), Glasgow-Blatchford bleeding score (GBS) and modified GBS (mGBS) are three pre-endoscopy scoring systems used in the risk stratification of upper gastrointestinal bleeding (UGIB). The utility of such scoring systems in a population is estimated by their accuracy and calibration in the population. We aimed at validating and comparing the accuracy of the three scoring systems in predicting clinical outcomes including in-hospital mortality, need for blood transfusion, endoscopic treatment and rebleeding risk. METHOD: We conducted a single-center, retrospective cohort study on patients with UGIB at a tertiary care center in India over 12 months. Clinical and laboratory data was collected from all patients admitted with UGIB. All patients were risk stratified using AIMS65, GBS and mGBS. The clinical outcome examined were: in-hospital mortality, requirement of blood transfusion, need for endoscopic treatment and rebleeding during hospital stay. The area under receiver-operating curve (AUROC) was calculated to assess the performance and calibration curves (Hosmer-Lemeshow goodness of fit curve) were plotted to examine how accurately the model describes the data of all three scoring systems. RESULTS: Total 260 patients were included in the study, of which 236 (90.8%) were males. As many as 144 (55.4%) patients required blood transfusion and 64 (30.8%) required endoscopic treatment. While the incidence of rebleeding was 7.7%, in hospital mortality was 15.4%. Of 208 who underwent endoscopy, the most common causes identified were varices (49%) and gastritis (18.2%), followed by ulcer (11%), Mallory-Weiss tear (8.1%), portal hypertensive gastropathy (6.7%), malignancy (4.8%) and esophageal candidiasis (1.9%). The median AIMS65 score was 1, GBS 7 and mGBS 6. The area under curve (AUROC) for AIMS65, GBS and mGBS was (0.77, 0.73,0.70), (0.75, 0.82,0.83), (0.56, 0.58,0.83), (0.81, 0.94,0.53) for in-hospital mortality, blood transfusion requirement, endoscopic treatment and rebleeding prediction, respectively. CONCLUSION: GBS and mGBS are superior to AIMS65 in predicting the requirement of blood transfusion and rebleeding risk, whereas in-hospital mortality was better predicted by AIMS 65. Both scores performed poorly in predicting the need of endoscopic treatment. An AIMS65 of 0,1 and a GBS of ≤ 1 are not associated with significant adverse events. A poor calibration of the scores in our population points to the lack of generalizability of these scoring systems.

Integrative multi-omics analysis reveals novel idiopathic pulmonary fibrosis endotypes associated with disease progression.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix in the pulmonary interstitium and progressive functional decline. We hypothesized that integration of multi-omics data would identify clinically meaningful molecular endotypes of IPF. METHODS: The IPF-PRO Registry is a prospective registry of patients with IPF. Proteomic and transcriptomic (including total RNA [toRNA] and microRNA [miRNA]) analyses were performed using blood collected at enrollment. Molecular data were integrated using Similarity Network Fusion, followed by unsupervised spectral clustering to identify molecular subtypes. Cox proportional hazards models tested the relationship between these subtypes and progression-free and transplant-free survival. The molecular subtypes were compared to risk groups based on a previously described 52-gene (toRNA expression) signature. Biological characteristics of the molecular subtypes were evaluated via linear regression differential expression and canonical pathways (Ingenuity Pathway Analysis [IPA]) over-representation analyses. RESULTS: Among 232 subjects, two molecular subtypes were identified. Subtype 1 (n = 105, 45.3%) and Subtype 2 (n = 127, 54.7%) had similar distributions of age (70.1 +/- 8.1 vs. 69.3 +/- 7.6 years; p = 0.31) and sex (79.1% vs. 70.1% males, p = 0.16). Subtype 1 had more severe disease based on composite physiologic index (CPI) (55.8 vs. 51.2; p = 0.002). After adjusting for CPI and antifibrotic treatment at enrollment, subtype 1 experienced shorter progression-free survival (HR 1.79, 95% CI 1.28,2.56; p = 0.0008) and similar transplant-free survival (HR 1.30, 95% CI 0.87,1.96; p = 0.20) as subtype 2. There was little agreement in the distribution of subjects to the molecular subtypes and the risk groups based on 52-gene signature (kappa = 0.04, 95% CI= -0.08, 0.17), and the 52-gene signature risk groups were associated with differences in transplant-free but not progression-free survival. Based on heatmaps and differential expression analyses, proteins and miRNAs (but not toRNA) contributed to classification of subjects to the molecular subtypes. The IPA showed enrichment in pulmonary fibrosis-relevant pathways, including mTOR, VEGF, PDGF, and B-cell receptor signaling. CONCLUSIONS: Integration of transcriptomic and proteomic data from blood enabled identification of clinically meaningful molecular endotypes of IPF. If validated, these endotypes could facilitate identification of individuals likely to experience disease progression and enrichment of clinical trials. TRIAL REGISTRATION: NCT01915511.

Structures and mechanisms of tRNA methylation by METTL1-WDR4.

Specific, regulated modification of RNAs is important for proper gene expression1,2. tRNAs are rich with various chemical modifications that affect their stability and function3,4. 7-Methylguanosine (m7G) at tRNA position 46 is a conserved modification that modulates steady-state tRNA levels to affect cell growth5,6. The METTL1-WDR4 complex generates m7G46 in humans, and dysregulation of METTL1-WDR4 has been linked to brain malformation and multiple cancers7-22. Here we show how METTL1 and WDR4 cooperate to recognize RNA substrates and catalyse methylation. A crystal structure of METTL1-WDR4 and cryo-electron microscopy structures of METTL1-WDR4-tRNA show that the composite protein surface recognizes the tRNA elbow through shape complementarity. The cryo-electron microscopy structures of METTL1-WDR4-tRNA with S-adenosylmethionine or S-adenosylhomocysteine along with METTL1 crystal structures provide additional insights into the catalytic mechanism by revealing the active site in multiple states. The METTL1 N terminus couples cofactor binding with conformational changes in the tRNA, the catalytic loop and the WDR4 C terminus, acting as the switch to activate m7G methylation. Thus, our structural models explain how post-translational modifications of the METTL1 N terminus can regulate methylation. Together, our work elucidates the core and regulatory mechanisms underlying m7G modification by METTL1, providing the framework to understand its contribution to biology and disease.

Case report: Uridine triacetate in the management of delayed onset 5-fluorouracil toxicity: A case report and review of literature.

5-fluorouracil (5FU) and capecitabine are fluoropyrimidine anti-neoplastic drugs commonly used in the treatment of different types of cancer. Hereditary dihydropyrimdine deaminase (DPD), thymidylate synthase mutations and drug overdose may lead to life-threatening toxicities. Uridine triacetate (UTA) is an emergency treatment for overdoses and early onset, severe or life-threatening toxicities from fluoropyrimidines. It is approved for use in adults and children within 96 h of last fluoropyrimidine administration. We present the case of a 64-year-old male treated with 5-FU and oxaliplatin as adjuvant systemic therapy for stage IIIA rectal cancer who developed delayed central nervous system toxicity 18 days after initiating chemotherapy. He had rapidly worsening encephalopathy and ataxia. Laboratory workups, MRI brain and EEG were negative. He was started on UTA with concerns of 5-FU toxicity due to the life-threatening nature of his condition even beyond the recommended 96-h time cut-off. He had rapid improvement in clinical status and resolution of encephalopathy. DPD deficiency testing later resulted as heterozygous for IVS14+1G>A allele indicating enzyme deficiency. This report demonstrates the importance of identifying delayed side effects with fluoropyrimidine therapy and potential treatment for reversing these effects. We also did an extensive literature review and obtained reports from the uridine triacetate clinical trials on patients receiving UTA after the 96-h cut-off. Based on our experience and previous published reports, a patient developing life-threatening delayed 5-FU toxicity should also be considered for UTA on a case-by-case basis.

A Case of Undiagnosed Functional Gonadotroph Adenoma Leading to Ovarian Hyperstimulation Syndrome.

A functional gonadotroph adenoma is a very rare endocrinopathy, and only a few cases have been reported in the literature. We present a case of a woman in her early 50s with a past medical history of recurrent ovarian cysts who developed bilateral hemianopsia and was referred to the endocrinology clinic after a magnetic resonance imaging (MRI) identified a pituitary mass. Anterior pituitary hormone workup confirmed hypersecretion of follicle-stimulating hormone (FSH), which suggested ovarian hyperstimulation syndrome (OHSS) as the etiology of recurrent ovarian cysts. The patient underwent transsphenoidal resection of the pituitary tumor with improvement in visual symptoms. Our case illustrates that functional gonadotroph adenoma can be a potential cause of OHSS apart from the setting of assisted reproductive technology and hence warranting a meticulous endocrine evaluation to rule out this rare disease.

Case Report: Vancomycin-Associated Tubulointerstitial Nephritis in Clinical Practice-Case Report and Review of Literature.

Nephrotoxicity is one of the major limiting factors for vancomycin use. The most common histological patterns of kidney injury are acute tubulointerstitial nephritis and acute tubular necrosis. Patients who develop acute tubulointerstitial nephritis are prone to develop acute kidney injury with vancomycin rechallenge and, in most cases, present alone or as a part of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). The purpose of the review study is to identify biopsy-proven vancomycin-associated-tubulointerstitial nephritis in literature, determine possible underlying pathophysiology and identify the consequences of vancomycin rechallenge in such patients.

Crossover based technique for data augmentation.

BACKGROUND AND OBJECTIVE: Medical image classification problems are frequently constrained by the availability of datasets. "Data augmentation" has come as a data enhancement and data enrichment solution to the challenge of limited data. Traditionally data augmentation techniques are based on linear and label preserving transformations; however, recent works have demonstrated that even non-linear, non-label preserving techniques can be unexpectedly effective. This paper proposes a non-linear data augmentation technique for the medical domain and explores its results. METHODS: This paper introduces "Crossover technique", a new data augmentation technique for Convolutional Neural Networks in Medical Image Classification problems. Our technique synthesizes a pair of samples by applying two-point crossover on the already available training dataset. By this technique, we create N new samples from N training samples. The proposed crossover based data augmentation technique, although non-label preserving, has performed significantly better in terms of increased accuracy and reduced loss for all the tested datasets over varied architectures. RESULTS: The proposed method was tested on three publicly available medical datasets with various network architectures. For the mini-MIAS database of mammograms, our method improved the accuracy by 1.47%, achieving 80.15% using VGG-16 architecture. Our method works fine for both gray-scale as well as RGB images, as on the PH2 database for Skin Cancer, it improved the accuracy by 3.57%, achieving 85.71% using VGG-19 architecture. In addition, our technique improved accuracy on the brain tumor dataset by 0.40%, achieving 97.97% using VGG-16 architecture. CONCLUSION: The proposed novel crossover technique for training the Convolutional Neural Network (CNN) is painless to implement by applying two-point crossover on two images to form new images. The method would go a long way in tackling the challenges of limited datasets and problems of class imbalances in medical image analysis. Our code is available at https://github.com/rishiraj-cs/Crossover-augmentation.

Polypharmacy in a Patient With Intellectual and Developmental Disabilities.

Prader-Willi syndrome (PWS) is an uncommon condition and its clinical manifestation in adulthood includes central obesity, hypogonadism, osteoporosis, cardiovascular disease, diabetes mellitus, and sleep apnea. These patients often have mild to moderate intellectual disability and are dependent upon their caregiver for healthcare needs. Hence, they may be at increased risk of polypharmacy-related complications, if there is poor communication between healthcare providers and caregivers. We present a case of a 26-year-old adult with PWS and mild to moderate intellectual disability, who was found to have acute kidney injury resulting from drug interaction between multiple nephrotoxic medications. Our case report highlights the importance of continuity of care with primary care providers, especially in patients with intellectual and developmental disabilities (IDD).

An Update on the Management of Mixed Neuroendocrine-Non-neuroendocrine Neoplasms (MiNEN).

OPINION STATEMENT: The classification of mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) is evolving, and no clear management guidelines are currently available. However, recent studies provide insight into factors affecting outcomes and could help develop treatment decisions for patients with these rare malignancies. The majority of MiNENs have a poorly differentiated neuroendocrine carcinoma (NEC) component which is associated with an aggressive clinical course and poor outcomes. Due to the paucity of clinical trials, strategies adopted in gastrointestinal cancers and NECs are used to manage MiNENs. It is also to be noted that the thoracic neuroendocrine neoplasm WHO 2021 classification does not recognize MiNEN terminology but suggests an equivalent terminology called "combined neuroendocrine non neuroendocrine neoplasm." Surgical management is appropriate in early-stage disease with a low threshold for addition of adjuvant chemotherapy. Multimodality treatment with chemotherapy offers a survival benefit in advanced disease or when surgical resection is not possible without significant morbidity. Chemotherapy should be directed at the more aggressive component which is often the NEC component. In addition, molecular testing should be employed to evaluate patients for enrollment in clinical trials and other targeted treatments. Being a rare disease with retrospective studies and case series providing the majority of data on treatment selection, it is essential to include more granular details of pathology (e.g., Ki-67, mitotic index, percentage of each component, staging information) and treatment modalities (e.g., type and duration, rationale, radiologic response, survival outcomes) in future studies to make systematic reviews possible and help derive meaningful conclusions.

Late onset of pituitary apoplexy following gonadotropin-releasing hormone agonist for prostate cancer treatment.

Pituitary apoplexy (PA) is a clinical condition characterised by a sudden increase in pituitary gland volume secondary to ischaemia and/or necrosis. Most cases occur in non-functioning pituitary adenoma but can also occur in functioning adenoma. Certain predisposing factors can result in PA and the use of gonadotropin-releasing hormone (GnRH) agonists for prostate cancer (PCa) is one such condition. Once diagnosed, both surgical and conservative management has been used for the treatment of PA. We present a case of a man in his late 50s who developed PA following treatment of PCa with leuprolide. His symptoms developed insidiously and he presented 6 months after symptom onset. Anterior pituitary hormone workup along with pituitary MRI confirmed the diagnosis of PA and patient was subsequently treated with adequate replacement of pituitary hormone with significant improvement in his symptoms. It is very important to keep a high index of suspicion for PA, especially among elderly patients receiving GnRH agonist treatment for PCa.

Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies.

Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR). These androgen-receptor signaling inhibitors (ARSI) include androgen synthesis inhibitor-abiraterone and androgen receptor antagonists-enzalutamide, apalutamide, and darolutamide. Although these medications provide significant improvement in survival among men with prostate cancer, drug resistance develops in nearly all patients with time. This could be through androgen-dependent or androgen-independent mechanisms. Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR. AR splice variant, AR-V7 is the most studied among these and is not targeted by available ARSIs. Non-androgen receptor dependent resistance mechanisms are mediated by activation of an alternative signaling pathway when AR is inhibited. DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins. Multiple clinical trials are underway exploring therapeutic strategies to overcome these resistance mechanisms.

A Rapidly Progressive Case of Ectopic Adrenocorticotropic Hormone (ACTH) Syndrome.

BACKGROUND Adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) secondary to an ectopic source is an uncommon condition, accounting for 4-5% of all cases of CS. Refractory hypokalemia can be the presenting feature in patients with ectopic ACTH syndrome (EAS), and is seen in up to 80% of cases. EAS can be rapidly progressive and life-threatening without timely diagnosis and intervention. CASE REPORT We present a case of a 74-year-old White woman who first presented with hypokalemia, refractory to treatment with potassium supplementation and spironolactone. She progressively developed generalized weakness, recurrent falls, bleeding peptic ulcer disease, worsening congestive heart failure, and osteoporotic fracture. A laboratory workup showed hypokalemia, hypernatremia, and primary metabolic alkalosis with respiratory acidosis. Hormonal evaluation showed elevated ACTH, DHEA-S, 24-h urinary free cortisol, and unsuppressed cortisol following an 8 mg dexamethasone suppression test, suggestive of ACTH-dependent CS. CT chest, abdomen, and pelvis, and FDG/PET CT scan showed a 1.4 cm right lung nodule and bilateral adrenal enlargement, confirming the diagnosis of EAS, with a 1.4-cm lung nodule being the likely source of ectopic ACTH secretion. Due to the patient's advanced age, comorbid conditions, and inability to attend to further evaluation and treatment, her family decided to pursue palliative and hospice care. CONCLUSIONS This case illustrates that EAS is a challenging condition and requires a multidisciplinary approach in diagnosis and management, which can be very difficult in resource-limited areas. In addition, a delay in diagnosis and management often results in rapid deterioration of clinical status.

Oncogenic osteomalacia secondary to glomus tumor.

SUMMARY: Oncogenic osteomalacia secondary to glomus tumor is extremely rare. Localization of causative tumors is critical as surgical resection can lead to a complete biochemical and clinical cure. We present a case of oncogenic osteomalacia treated with resection of glomus tumor. A 39-year-old woman with a history of chronic sinusitis presented with chronic body ache and muscle weakness. Biochemical evaluation revealed elevated alkaline phosphatase hypophosphatemia, increased urinary phosphate excretion, low calcitriol, and FGF23 was unsuppressed suggestive of oncogenic osteomalacia. Diagnostic studies showed increase uptake in multiple bones. Localization with MRI of paranasal sinuses revealed a sinonasal mass with concurrent uptake in the same area on the octreotide scan. Surgical resection of the sinonasal mass was consistent with the glomus tumor. The patient improved both clinically and biochemically postoperatively. Along with the case of oncogenic osteomalacia secondary to a glomus tumor, we have also discussed in detail the recent development in the diagnosis and management of oncogenic osteomalacia. LEARNING POINTS: Tumor-induced osteomalacia is a rare cause of osteomalacia caused by the secretion of FGF23 from mesenchymal tumors. Mesenchymal tumors causing TIO are often difficult to localize and treat. Resection of the tumor can result in complete resolution of biochemical and clinical manifestations in a very short span of time. Glomus tumor can lead to tumor induced osteomalacia and should be surgically treated.

Pituitary apoplexy induced by gonadotropin-releasing hormone (GnRH) agonist administration for treatment of prostate cancer: a systematic review.

OBJECTIVE: We aimed to review of literature on the clinical presentation, management and outcomes of pituitary apoplexy following gonadotrophic release hormone (GnRH) agonist administration for the treatment of prostate cancer. METHODS: We used PRISMA guidelines for our systematic review and included all English language original articles on pituitary apoplexy following GnRH agonist administration among prostate cancer patients from Jan 1, 1995 to Dec 31, 2020. Data on patient demographics, prostate cancer type, Gleason score at diagnosis, history of pituitary adenoma, clinical presentation, GnRH agonist, interval to pituitary apoplexy, laboratory evaluation at admission, radiologic findings, treatment of pituitary apoplexy, time to surgery if performed, pathology findings, and clinical/hormonal outcomes were collected and analyzed. RESULTS: Twenty-one patients with pituitary apoplexy met our inclusion criteria. The mean age of patients was 70 (60-83) years. Leuprolide was the most common used GnRH agonist, used in 61.9% of patients. Median duration to symptom onset was 5 h (few minutes to 6 months). Headache was reported by all patients followed by ophthalmoplegia (85.7%) and nausea/vomiting (71.4%). Three patients had blindness at presentation. Only 8 cases reported complete anterior pituitary hormone evaluation on presentation and the most common endocrine abnormality was FSH elevation. Tumor size was described only in 15 cases and the mean tumor size was 26.26 mm (18-48 mm). Suprasellar extension was the most common imaging finding seen in 7 patients. 71.4% of patients underwent pituitary surgery, while 23.8% were managed conservatively. Interval between symptoms onset to pituitary surgery was 7 days (1-90 days). Gonadotroph adenoma was most common histopathologic finding. Clinical resolution was comparable, while endocrine outcomes were variable among patients with conservative vs surgical management. CONCLUSION: Although the use of GnRH agonists is relatively safe, it can rarely lead to pituitary apoplexy especially in patients with pre-existing pituitary adenoma. Physicians should be aware of this complication as it can be life threatening. A multidisciplinary team approach is recommended in treating individuals with pituitary apoplexy.

The Role of Surgical Lung Biopsy in the Diagnosis of Fibrotic Interstitial Lung Disease: Perspective from the Pulmonary Fibrosis Foundation.

Diagnosis of interstitial lung disease (ILD) requires a multidisciplinary discussion approach that includes clinicians, radiologists, and pathologists. Surgical lung biopsy (SLB) is currently the recommended standard in obtaining pathologic specimens for patients with ILD requiring a tissue diagnosis. The increased diagnostic confidence and accuracy provided by microscopic pathology assessment of SLB specimens must be balanced with the associated risks in patients with ILD. This document was developed by the SLB Working Group of the Pulmonary Fibrosis Foundation, composed of a multidisciplinary group of ILD physicians, including pulmonologists, radiologists, pathologists, and thoracic surgeons. In this document, we present an up-to-date literature review of the indications, contraindications, risks, and alternatives to SLB in the diagnosis of fibrotic ILD; outline an integrated approach to the decision-making around SLB in the diagnosis of fibrotic ILD; and provide practical information to maximize the yield and safety of SLB.

Adrenal Vein Cortisol to Metanephrine Ratio for Localizing ACTH-Independent Cortisol-Producing Adenoma: A Case Report.

CONTEXT: Finding the source of adrenocorticotropic hormone (ACTH)-independent cortisol-producing adenoma in the patients with subclinical Cushing syndrome (SCS) and bilateral adrenal nodules is sometimes challenging. Computed tomography (CT) and positron emission tomography are helpful, but adrenal venous sampling (AVS) is the gold standard approach. However, interpretation of AVS is important to improve the accuracy of decision-making for surgery. We report a case and review of the literature to assess the benefit of using adrenal vein cortisol to metanephrine ratio to determine the source of cortisol production in SCS and bilateral nodules. EVIDENCE ACQUISITION: Three authors searched PubMed for data on patients with SCS who had AVS procedure and measurements of cortisol and catecholamines. CASE DESCRIPTION: A 51-year-old woman with SCS and hypertension crisis presented to our clinic. Paraclinical investigations revealed that she had an ACTH-independent cortisol-producing adenoma and her CT scan showed bilateral adrenal nodules. After AVS, cortisol (high to low) lateralization ratio could not determine the source of cortisol production but the cortisol to metanephrine ratio localized the source to the left side, which included the larger nodule according to CT measurements. Left adrenalectomy led to clinical and paraclinical improvement. CONCLUSION: There is a possibility of co-secretion of other steroids accompanied with cortisol in the setting of ACTH-independent SCS. Moreover, cortisol measurement alone and interpretation of AVS results based on cortisol values may not help lateralizing the source of cortisol production with bilateral adrenal nodules. Therefore, we suggest applying cortisol to metanephrine ratio with the same gradient (gradient > 2.3, highest to lowest concentration) when the source of cortisol production cannot be determined by cortisol lateralization ratio.