ARX, PDX1, ISL1, and CDX2 Expression Distinguishes 5 Subgroups of Pancreatic Neuroendocrine Tumors With Correlations to Histology, Hormone Expression, and Outcome.

Many pancreatic neuroendocrine tumors (PanNETs) fall into 2 major prognostic subtypes based on DAXX/ATRX-induced alternative lengthening of telomerase phenotype and alpha- and beta-cell-like epigenomic profiles. However, these PanNETs are still flanked by other PanNETs that do not fit into either subtype. Furthermore, despite advanced genotyping, PanNETs are generally not well-characterized in terms of their histologic and hormonal phenotypes.

Spleen Volume Reduction Is a Reliable and Independent Biomarker for Long-Term Risk of Leukopenia Development in Peptide Receptor Radionuclide Therapy.

Lu-DOTATATE therapy is an effective treatment for advanced neuroendocrine tumors, despite its dose-limiting hematotoxicity. Herein, the significance of off-target splenic irradiation is unknown. Our study aims to identify predictive markers of peptide receptor radionuclide therapy-induced leukopenia.

Renal neuroendocrine tumors: clinical and molecular pathology with an emphasis on frequent association with ectopic Cushing syndrome.

Renal neuroendocrine tumors (RenNETs) are rare malignancies with largely unknown biology, hormone expression, and genetic abnormalities. This study aims to improve our understanding of the RenNETs with emphasis of functional, hormonal, and genetic features. Surgically resected RenNETs (N = 13) were retrieved, and immunohistochemistry and next-generation sequencing (NGS) were performed in all cases.

Gene fusions are frequent in ACTH-secreting neuroendocrine neoplasms of the pancreas, but not in their non-pancreatic counterparts.

Ectopic Cushing syndrome is a rare clinical disorder resulting from excessive adrenocorticotrophic hormone (ACTH) produced by non-pituitary neoplasms, mainly neuroendocrine neoplasms (NENs) of the lung, pancreas, and gastrointestinal tract, and other less common sites. The genetic background of ACTH-producing NENs has not been well studied. Inspired by an index case of ACTH-producing pancreatic NEN carrying a gene fusion, we postulated that ACTH-producing NENs might be enriched for gene fusions.

Anterior Pituitary Hormones in Blood and Cerebrospinal Fluid of Patients in Neurocritical Care.

Background: Anterior pituitary hormones in blood follow a circadian rhythm, which may be influenced by various factors such as intracranial pathologies. In cerebrospinal fluid (CSF), pituitary hormones have been collected only selectively and circadian rhythm has not yet been investigated. This pilot study analysed diurnal variations of anterior pituitary hormones in patients in neurocritical care to determine whether circadian rhythmicity exists in these patients.

Obesity and Impaired Metabolic Health Increase Risk of COVID-19-Related Mortality in Young and Middle-Aged Adults to the Level Observed in Older People: The LEOSS Registry.

Advanced age, followed by male sex, by far poses the greatest risk for severe COVID-19. An unresolved question is the extent to which modifiable comorbidities increase the risk of COVID-19-related mortality among younger patients, in whom COVID-19-related hospitalization strongly increased in 2021. A total of 3,163 patients with SARS-COV-2 diagnosis in the Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort were studied.

Neuroendocrine Differentiation in Conventional Colorectal Adenocarcinomas: Incidental Finding or Prognostic Biomarker?

Background: Colorectal mixed adenoneuroendocrine carcinomas (MANECs) are clinically highly aggressive neoplasms. MANECs are composed of variable adenocarcinoma components combined with morphologically distinct neuroendocrine carcinoma components, which are confirmed by synaptophysin immunohistochemistry, the gold standard marker of a neuroendocrine differentiation. However, the biological behavior of adenocarcinomas that express synaptophysin but do not show a typical neuroendocrine morphology remains unclear.

Transsphenoidal pituitary adenoma resection: do early post-operative cortisol levels predict permanent long-term hypocortisolism?

Transsphenoidal surgery provides a minimal invasive treatment for pituitary adenoma. Our aim is to evaluate the endocrinological outcomes after adenoma resection focusing on the corticotroph function, and to identify prognostic factors for an impaired hypothalamic-pituitary-adrenal-axis function (HPA) and the reliability of postoperative early morning serum cortisol measurements. We performed a retrospective analysis of all patients treated for pituitary adenoma from April 2006 to January 2019 in our neurosurgical department.

Visual acuity and its postoperative outcome after transsphenoidal adenoma resection.

Transsphenoidal surgery (TSS) represents the gold standard of pituitary adenoma resection, providing a safe and minimal invasive treatment for patients suffering from symptoms of mass effect. The aim of this study is to analyze the postoperative improvement of visual function after adenoma resection and to identify prognostic factors for the postoperative clinical recovery. We performed a retrospective analysis of all consecutive patients treated via a transsphenoidal approach for pituitary adenomas from April 2006 to December 2019 in a high-volume neurosurgical department.

First Experience Using F-Flubrobenguane PET Imaging in Patients with Suspected Pheochromocytoma or Paraganglioma.

Pheochromocytomas and paragangliomas are a rare tumor entity originating from adrenomedullary chromaffin cells in the adrenal medulla or in sympathetic, paravertebral ganglia outside the medulla. Small lesions are especially difficult to detect by conventional CT or MRI and even by SPECT with the currently available radiotracers (e.g.

MRI criteria of subtypes of adenomas and epithelial cysts of the pituitary gland.

This study aimed to assess the clinical applicability of MRI criteria for differentiation of pituitary adenomas and cystic pituitary lesions. One hundred ninety-eight consecutive patients with surgical resection of a pituitary adenoma/cystic pituitary lesion were retrospectively analyzed, blinded to clinical data and histopathological diagnosis. Different morphologic criteria were assessed: signal intensity in T2/T1w images, pattern of contrast enhancement, size, super-/infrasellar extension, and invasion of the cavernous sinus.

Effects of antiretroviral combination therapies F/TAF, E/C/F/TAF and R/F/TAF on insulin resistance in healthy volunteers: the TAF-IR Study.

Background: Increased insulin resistance (IR), associated with specific antiretroviral drugs or drug classes, is an established risk factor for type 2 diabetes in HIV patients, ultimately increasing morbidity and mortality. To date, data on the risk of IR in tenofovir alafenamide (TAF)-based protocols are unavailable.

Methods: This prospective randomized, open-label study evaluated the effects of IR on 30 healthy volunteers receiving fixed-dose combinations (FDCs) of emtricitabine/tenofovir alafenamide (F/TAF), elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or rilpivirine/emtricitabine/tenofovir alafenamide (R/F/TAF).

Dynamics of Adrenocorticotropin after Application of Metyrapone.

To investigate the kinetics of adrenocorticotropin (ACTH) following oral metyrapone administration and describe differences between ACTH-deficient and non-ACTH-deficient subjects. Patients from a tertiary endocrine center at a University Hospital in Munich, Germany, were tested for secondary adrenal insufficiency in a regular patient care setting. Metyrapone (Metopirone, HRA Pharma, France) was administered with a dosage of 40 mg/kg bodyweight at 8 a.

Neither boosted elvitegravir nor darunavir with emtricitabine/tenofovir disoproxil fumarate increase insulin resistance in healthy volunteers: results from the STRIBILD-IR study.

Background: Insulin resistance (IR) was one of the first reported complications in HIV-positive patients who were receiving antiretroviral therapy (ART). However, the metabolic effects of newer fixed-dose ART combinations are unclear.

Methods: This Phase I prospective randomized open-label study evaluated the effects on IR in 30 healthy volunteers who were receiving newer fixed-dose combinations of tenofovir disoproxil fumarate, emtricitabine, elvitegravir and cobicistat (E/C/F/TDF, 10 patients) or the established ART regimens, such as tenofovir disoproxil fumarate/emtricitabine with lopinavir/ritonavir (F/TDF+LPV/r, 9 patients) or darunavir/ritonavir (F/TDF+DRV/r, 9 patients).

Inhibition of telomerase induces alternative lengthening of telomeres during human esophageal carcinogenesis.

Immortalization is an important step toward the malignant transformation of human cells and is critically dependent upon telomere maintenance. Two mechanisms are known to maintain human telomeres. The process of telomere maintenance is either mediated through activation of the enzyme telomerase or through an alternative mechanism of telomere lengthening called alternative lengthening of telomeres (ALT).

Serum eosinophil cationic protein is superior to mast cell tryptase as marker for response to topical corticosteroid therapy in eosinophilic esophagitis.

Goals: We evaluated the serum levels of eosinophil cationic protein (ECP) and mast cell tryptase (MCT) as surrogate markers for response to treatment in adults with eosinophilic esophagitis (EoE) under topical steroid therapy with fluticasone.

Background: EoE is a chronic disease characterized histologically by eosinophilic inflammation of the esophagus. Esophageal mastocytosis and mast cell activation have been implicated in EoE pathogenesis.

Production of avian retroviruses and tissue-specific somatic retroviral gene transfer in vivo using the RCAS/TVA system.

Spatiotemporal retroviral gene transfer into specific somatic mammalian cells using the avian RCAS (replication-competent avian sarcoma-leukosis virus long terminal repeat with splice acceptor)/tumor virus A (TVA) system is a versatile tool for performing lineage tracing and gene function analysis in vivo. RCAS retroviruses carrying the subgroup A envelope transduce only genetically engineered mammalian cells that express the cognate avian retroviral receptor TVA. The RCAS/TVA gene delivery system has been successfully used in various different mouse TVA-expression models.

Prediction of extubation failure in medical intensive care unit patients.

Purpose: The purpose of this study was to evaluate prediction factors for extubation failure (need for reintubation within 48 hours) in medical intensive care unit patients.

Materials And Methods: Sixty-one patients extubated after mechanical ventilation for more than 48 hours were included in the study. A retrospective analysis of medical records and a prospectively maintained database on respiratory parameters was conducted.

Truncated IRAG variants modulate cGMP-mediated inhibition of human colonic smooth muscle cell contraction.

Nitric oxide (NO) induces relaxation of colonic smooth muscle cells predominantly by cGMP/cGMP-dependent protein kinase I (cGKI)-induced phosphorylation of the inositol 1,4,5-trisphosphate receptor (IP(3)R)-associated cGMP kinase substrate (IRAG), to block store-dependent calcium signaling. In the present study we analyzed the structure and function of the human IRAG/MRVI1 gene. We describe four unique first exon variants transcribed from individual promoters in diverse human tissues.

In vivo diagnosis of murine pancreatic intraepithelial neoplasia and early-stage pancreatic cancer by molecular imaging.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor patient outcome often resulting from late diagnosis in advanced stages. To date methods to diagnose early-stage PDAC are limited and in vivo detection of pancreatic intraepithelial neoplasia (PanIN), a preinvasive precursor of PDAC, is impossible. Using a cathepsin-activatable near-infrared probe in combination with flexible confocal fluorescence lasermicroscopy (CFL) in a genetically defined mouse model of PDAC we were able to detect and grade murine PanIN lesions in real time in vivo.

EGFR overexpression induces activation of telomerase via PI3K/AKT-mediated phosphorylation and transcriptional regulation through Hif1-alpha in a cellular model of oral-esophageal carcinogenesis.

Telomerase plays an important role during immortalization and malignant transformation as crucial steps in the development of human cancer. In a cellular model of oral-esophageal carcinogenesis, recapitulating the human disease, immortalization occurred independent of the activation of telomerase but through the recombination-based alternative lengthening of telomeres (ALT). In this stepwise model, additional overexpression of EGFR led to in vitro transformation and activation of telomerase with homogeneous telomere elongation in already immortalized oral squamous epithelial cells (OKF6-D1_dnp53).

Relapsing polychondritis: An autoimmune disease with many faces.

Relapsing polychondritis (RPC) is a rare immune mediated disease which is associated with inflammation in cartilaginous tissue throughout the body. Especially the cartilaginous structures of ear, nose, joints and respiratory tract are affected. In around 30% of the cases an association with other diseases especially systemic vasculitis or myelodysplatic syndrome can be detected.

E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex.

Background & Aims: Early metastasis is a hallmark of pancreatic ductal adenocarcinoma and responsible for >90% of pancreatic cancer death. Because little is known about the biology and genetics of the metastatic process, we desired to elucidate molecular pathways mediating pancreatic cancer metastasis in vivo by an unbiased forward genetic approach.

Methods: Highly metastatic pancreatic cancer cell populations were selected by serial in vivo passaging of parental cells with low metastatic potential and characterized by global gene expression profiling, chromatin immunoprecipitation, and in vivo metastatic assay.

RCAS-mediated retroviral gene delivery: a versatile tool for the study of gene function in a mouse model of pancreatic cancer.

Pancreatic cancer is one of the most common causes of cancer death in Western civilization and the 5-year survival rate is below 5%. To improve the prognosis of pancreatic cancer, there is the need to develop effective nonsurgical treatment options for the disease. In particular, in vivo models to validate potential targets at the genetic level are required.