Publications by authors named "Stefan Kircher"

72 Publications

Mass spectrometry imaging identifies metabolic patterns associated with malignant potential in pheochromocytoma and paraganglioma.

Eur J Endocrinol 2021 Jun 5;185(1):179-191. Epub 2021 Jun 5.

Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany.

Objective: Within the past decade, important genetic drivers of pheochromocytoma and paraganglioma (PPGLs) development have been identified. The pathophysiological mechanism that translates these alterations into functional autonomy and potentially malignant behavior has not been elucidated in detail. Here we used MALDI-mass spectrometry imaging (MALDI-MSI) of formalin-fixed paraffin-embedded tissue specimens to comprehensively characterize the metabolic profiles of PPGLs.

Design And Methods: MALDI-MSI was conducted in 344 PPGLs and results correlated with genetic and phenotypic information. We experimentally silenced genetic drivers by siRNA in PC12 cells to confirm their metabolic impact in vitro.

Results: Tissue abundance of kynurenine pathway metabolites such as xanthurenic acid was significantly lower (P = 2.35E-09) in the pseudohypoxia pathway cluster 1 compared to PPGLs of the kinase-driven PPGLs cluster 2. Lower abundance of xanthurenic acid was associated with shorter metastasis-free survival (log-rank tests P = 7.96E-06) and identified as a risk factor for metastasis independent of the genetic status (hazard ratio, 32.6, P = 0.002). Knockdown of Sdhb and Vhl in an in vitro model demonstrated that inositol metabolism and sialic acids were similarly modulated as in tumors of the respective cluster.

Conclusions: The present study has identified distinct tissue metabolomic profiles of PPGLs in relation to tumor genotypes. In addition, we revealed significantly altered metabolites in the kynurenine pathway in metastatic PPGLs, which can aid in the prediction of its malignant potential. However, further validation studies will be required to confirm our findings.
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http://dx.doi.org/10.1530/EJE-20-1407DOI Listing
June 2021

Epithelial and Mesenchymal Markers in Adrenocortical Tissues: How Mesenchymal Are Adrenocortical Tissues?

Cancers (Basel) 2021 Apr 6;13(7). Epub 2021 Apr 6.

Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, 97080 Würzburg, Germany.

A clinically relevant proportion of adrenocortical carcinoma (ACC) cases shows a tendency to metastatic spread. The objective was to determine whether the epithelial to mesenchymal transition (EMT), a mechanism associated with metastasizing in several epithelial cancers, might play a crucial role in ACC. 138 ACC, 29 adrenocortical adenomas (ACA), three normal adrenal glands (NAG), and control tissue samples were assessed for the expression of epithelial (E-cadherin and EpCAM) and mesenchymal (N-cadherin, SLUG and SNAIL) markers by immunohistochemistry. Using real-time RT-PCR we quantified the alternative isoform splicing of FGFR 2 and 3, another known indicator of EMT. We also assessed the impact of these markers on clinical outcome. Results show that both normal and neoplastic adrenocortical tissues lacked expression of epithelial markers but strongly expressed mesenchymal markers N-cadherin and SLUG. FGFR isoform splicing confirmed higher similarity of adrenocortical tissues to mesenchymal compared to epithelial tissues. In ACC, higher SLUG expression was associated with clinical markers indicating aggressiveness, while N-cadherin expression inversely associated with these markers. In conclusion, we could not find any indication of EMT as all adrenocortical tissues lacked expression of epithelial markers and exhibited closer similarity to mesenchymal tissues. However, while N-cadherin might play a positive role in tissue structure upkeep, SLUG seems to be associated with a more aggressive phenotype.
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http://dx.doi.org/10.3390/cancers13071736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038668PMC
April 2021

Case Report: Abdominal Lymph Node Metastases of Parathyroid Carcinoma: Diagnostic Workup, Molecular Diagnosis, and Clinical Management.

Front Endocrinol (Lausanne) 2021 23;12:643328. Epub 2021 Mar 23.

Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany.

Parathyroid carcinoma (PC) is an orphan malignancy accounting for only ~1% of all cases with primary hyperparathyroidism. The localization of recurrent PC is of critical importance and can be exceedingly difficult to diagnose and sometimes futile when common sites of recurrence in the neck and chest cannot be confirmed. Here, we present the diagnostic workup, molecular analysis and multimodal therapy of a 46-year old woman with the extraordinary manifestation of abdominal lymph node metastases 12 years after primary diagnosis of PC. The patient was referred to our endocrine tumor center in 2016 with the aim to localize the tumor causative of symptomatic biochemical recurrence. In view of the extensive previous workup we decided to perform [18F]FDG-PET-CT. A pathological lymph node in the liver hilus showed slightly increased FDG-uptake and hence was suspected as site of recurrence. Selective venous sampling confirmed increased parathyroid hormone concentration in liver veins. Abdominal lymph node metastasis was resected and histopathological examination confirmed PC. Within four months, the patient experienced biochemical recurrence and based on high tumor mutational burden detected in the surgical specimen by whole exome sequencing the patient received immunotherapy with pembrolizumab that led to a biochemical response. Subsequent to disease progression repeated abdominal lymph node resection was performed in 10/2018, 01/2019 and in 01/2020. Up to now (12/2020) the patient is biochemically free of disease. In conclusion, a multimodal diagnostic approach and therapy in an interdisciplinary setting is needed for patients with rare endocrine tumors. Molecular analyses may inform additional treatment options including checkpoint inhibitors such as pembrolizumab.
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http://dx.doi.org/10.3389/fendo.2021.643328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021949PMC
March 2021

A novel patient-derived cell line of adrenocortical carcinoma shows a pathogenic role of germline MUTYH mutation and high tumour mutational burden.

Eur J Endocrinol 2021 May 4;184(6):823-835. Epub 2021 May 4.

Division of Endocrinology and Diabetology Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany.

Background: The response of advanced adrenocortical carcinoma (ACC) to current chemotherapies is unsatisfactory and a limited rate of response to immunotherapy was observed in clinical trials. High tumour mutational burden (TMB) and the presence of a specific DNA signature are characteristic features of tumours with mutations in the gene MUTYH encoding the mutY DNA glycosylase. Both have been shown to potentially predict the response to immunotherapy. High TMB in an ACC cell line model has not been reported yet.

Design And Methods: The JIL-2266 cell line was established from a primary ACC tumour, comprehensively characterised and oxidative damage, caused by a dysfunctional mutY DNA glycosylase, confirmed.

Results: Here, we characterise the novel patient-derived ACC cell line JIL-2266, which is deficient in mutY-dependent DNA repair. JIL-2266 cells have a consistent STR marker profile that confirmed congruousness with primary ACC tumour. Cells proliferate with a doubling time of 41 ± 13 h. Immunohistochemistry revealed positivity for steroidogenic factor-1. Mass spectrometry did not demonstrate significant steroid hormone synthesis. JIL-2266 have hemizygous mutations in the tumour suppressor gene TP53 (c.859G>T:p.E287X) and MUTYH (c.316C>T:p.R106W). Exome sequencing showed 683 single nucleotide variants and 4 insertions/deletions. We found increased oxidative DNA damage in the cell line and the corresponding primary tumour caused by impaired mutY DNA glycosylase function and accumulation of 8-oxoguanine.

Conclusion: This model will be valuable as a pre-clinical ACC cell model with high TMB and a tool to study oxidative DNA damage in the adrenal gland.
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http://dx.doi.org/10.1530/EJE-20-1423DOI Listing
May 2021

CXCR4-Directed PET/CT in Patients with Newly Diagnosed Neuroendocrine Carcinomas.

Diagnostics (Basel) 2021 Mar 29;11(4). Epub 2021 Mar 29.

European Neuroendocrine Tumor Society (ENETS) Center of Excellence, NET Zentrum, University Hospital Würzburg, 97080 Würzburg, Germany.

We aimed to elucidate the diagnostic potential of the C-X-C motif chemokine receptor 4 (CXCR4)-directed positron emission tomography (PET) tracer Ga-Pentixafor in patients with poorly differentiated neuroendocrine carcinomas (NEC), relative to the established reference standard F-FDG PET/computed tomography (CT). In our database, we retrospectively identified 11 treatment-naïve patients with histologically proven NEC, who underwent F-FDG and CXCR4-directed PET/CT for staging and therapy planning. The images were analyzed on a per-patient and per-lesion basis and compared to immunohistochemical staining (IHC) of CXCR4 from PET-guided biopsies. Ga-Pentixafor visualized tumor lesions in 10/11 subjects, whileF-FDG revealed sites of disease in all 11 patients. Although weak to moderate CXCR4 expression could be corroborated by IHC in 10/11 cases, F-FDG PET/CT detected significantly more tumor lesions (102 vs. 42; total lesions, = 107; < 0.001). Semi-quantitative analysis revealed markedly higher F-FDG uptake as compared to Ga-Pentixafor (maximum and mean standardized uptake values (SUV) and tumor-to-background ratios (TBR) of cancerous lesions, SUV: 12.8 ± 9.8 vs. 5.2 ± 3.7; SUV: 7.4 ± 5.4 vs. 3.1 ± 3.2, < 0.001; and, TBR 7.2 ± 7.9 vs. 3.4 ± 3.0, < 0.001). Non-invasive imaging of CXCR4 expression in NEC is inferior to the reference standard F-FDG PET/CT.
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http://dx.doi.org/10.3390/diagnostics11040605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067200PMC
March 2021

Low dose stereotactic irradiation and dexamethasone in primary cerebral light chain deposition disease (LCDD).

Leuk Lymphoma 2021 Mar 31:1-5. Epub 2021 Mar 31.

Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany.

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http://dx.doi.org/10.1080/10428194.2021.1907380DOI Listing
March 2021

Ephrin receptor A2, the epithelial receptor for Epstein-Barr virus entry, is not available for efficient infection in human gastric organoids.

PLoS Pathog 2021 02 17;17(2):e1009210. Epub 2021 Feb 17.

Research Centre for Infectious Diseases, Institute for Molecular Infection Biology, Julius Maximilian University of Wuerzburg, Wuerzburg, Germany.

Epstein-Barr virus (EBV) is best known for infection of B cells, in which it usually establishes an asymptomatic lifelong infection, but is also associated with the development of multiple B cell lymphomas. EBV also infects epithelial cells and is associated with all cases of undifferentiated nasopharyngeal carcinoma (NPC). EBV is etiologically linked with at least 8% of gastric cancer (EBVaGC) that comprises a genetically and epigenetically distinct subset of GC. Although we have a very good understanding of B cell entry and lymphomagenesis, the sequence of events leading to EBVaGC remains poorly understood. Recently, ephrin receptor A2 (EPHA2) was proposed as the epithelial cell receptor on human cancer cell lines. Although we confirm some of these results, we demonstrate that EBV does not infect healthy adult stem cell-derived gastric organoids. In matched pairs of normal and cancer-derived organoids from the same patient, EBV only reproducibly infected the cancer organoids. While there was no clear pattern of differential expression between normal and cancer organoids for EPHA2 at the RNA and protein level, the subcellular location of the protein differed markedly. Confocal microscopy showed EPHA2 localization at the cell-cell junctions in primary cells, but not in cancer cell lines. Furthermore, histologic analysis of patient tissue revealed the absence of EBV in healthy epithelium and presence of EBV in epithelial cells from inflamed tissue. These data suggest that the EPHA2 receptor is not accessible to EBV on healthy gastric epithelial cells with intact cell-cell contacts, but either this or another, yet to be identified receptor may become accessible following cellular changes induced by inflammation or transformation, rendering changes in the cellular architecture an essential prerequisite to EBV infection.
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http://dx.doi.org/10.1371/journal.ppat.1009210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935236PMC
February 2021

HIF1α is a direct regulator of steroidogenesis in the adrenal gland.

Cell Mol Life Sci 2021 Apr 19;78(7):3577-3590. Epub 2021 Jan 19.

Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.

Endogenous steroid hormones, especially glucocorticoids and mineralocorticoids, derive from the adrenal cortex, and drastic or sustained changes in their circulatory levels affect multiple organ systems. Although hypoxia signaling in steroidogenesis has been suggested, knowledge on the true impact of the HIFs (Hypoxia-Inducible Factors) in the adrenocortical cells of vertebrates is scant. By creating a unique set of transgenic mouse lines, we reveal a prominent role for HIF1α in the synthesis of virtually all steroids in vivo. Specifically, mice deficient in HIF1α in adrenocortical cells displayed enhanced levels of enzymes responsible for steroidogenesis and a cognate increase in circulatory steroid levels. These changes resulted in cytokine alterations and changes in the profile of circulatory mature hematopoietic cells. Conversely, HIF1α overexpression resulted in the opposite phenotype of insufficient steroid production due to impaired transcription of necessary enzymes. Based on these results, we propose HIF1α to be a vital regulator of steroidogenesis as its modulation in adrenocortical cells dramatically impacts hormone synthesis with systemic consequences. In addition, these mice can have potential clinical significances as they may serve as essential tools to understand the pathophysiology of hormone modulations in a number of diseases associated with metabolic syndrome, auto-immunity or even cancer.
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http://dx.doi.org/10.1007/s00018-020-03750-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038963PMC
April 2021

Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma.

Front Endocrinol (Lausanne) 2020 13;11:597878. Epub 2020 Nov 13.

Division of Endocrinology and Diabetes, Department of Medicine I, University Hospital of Wuerzburg, University of Wuerzburg, Wuerzburg, Germany.

Chemokine receptors have a negative impact on tumor progression in several human cancers and have therefore been of interest for molecular imaging and targeted therapy. However, their clinical and prognostic significance in adrenocortical carcinoma (ACC) is unknown. The aim of this study was to evaluate the chemokine receptor profile in ACC and to analyse its association with clinicopathological characteristics and clinical outcome. A chemokine receptor profile was initially evaluated by quantitative PCR in 4 normal adrenals, 18 ACC samples and human ACC cell line NCI-H295. High expression of CXCR4 and CXCR7 in both healthy and malignant adrenal tissue and ACC cells was confirmed. In the next step, we analyzed the expression and cellular localization of CXCR4 and CXCR7 in ACC by immunohistochemistry in 187 and 84 samples, respectively. These results were correlated with clinicopathological parameters and survival outcome. We detected strong membrane expression of CXCR4 and CXCR7 in 50% of ACC samples. Strong cytoplasmic CXCR4 staining was more frequent among samples derived from metastases compared to primaries (0.01) and local recurrences (0.04). CXCR4 membrane staining positively correlated with proliferation index Ki67 (r=0.17, 0.028). CXCR7 membrane staining negatively correlated with Ki67 (r=-0.254, 0.03) but positively with tumor size (r=0.3, 0.02). No differences in progression-free or overall survival were observed between patients with strong and weak staining intensities for CXCR4 or CXCR7. Taken together, high expression of CXCR4 and CXCR7 in both local tumors and metastases suggests that some ACC patients might benefit from CXCR4/CXCR7-targeted therapy.
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http://dx.doi.org/10.3389/fendo.2020.597878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691376PMC
June 2021

Clinical Presentation, Treatment, and Outcome of Parathyroid Carcinoma: Results of the NEKAR Retrospective International Multicenter Study.

Ann Surg 2020 Jul 7. Epub 2020 Jul 7.

Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Würzburg, Würzburg, Germany.

Objective: In this retrospective cohort study, we describe the clinical presentation and workup of parathyroid carcinoma (PC) and determine its clinical prognostic parameters. Primary outcome was recurrence free survival.

Summary Background Data: PC is an orphan malignancy for which diagnostic workup and treatment is not established.

Methods: Eighty-three patients were diagnosed with PC between 1986 and 2018. Disease-specific and recurrence-free survivals were estimated with the Kaplan-Meier method. Risk factors for recurrence were identified by binary logistic regression with adjustment for age and sex. Thirty-nine tumors underwent central histopathological review.

Results: Renal (39.8%), gastrointestinal (24.1%), bone (22.9%), and psychiatric (19.3%) symptoms were the most common symptoms. Surgical treatment was heterogeneous [parathyroidectomy [PTx)] alone: 22.9%; PTx and hemithyroidectomy: 24.1%; en bloc resection 15.7%; others 37.3%] and complications of surgery were frequent (recurrent laryngeal nerve palsy 25.3%; hypoparathyroidism 6%). Recurrence of PC was observed in 32 of 83 cases. In univariate analysis, rate of recurrence was reduced when extended initial surgery had been performed (P = 0.04). In multivariate analysis low T status [odds ratio (OR) = 2.65, 95% confidence interval (CI) 1.02-6.88, P = 0.045], N0 stage at initial diagnosis (OR = 6.32, 95% CI 1.33-30.01, P = 0.02), Ki-67 <10% (OR = 14.07, 95% CI 2.09-94.9, P = 0.007), and postoperative biochemical remission (OR = 0.023, 95% CI 0.001-0.52, P = 0.018) were beneficial prognostic parameters for recurrence-free survival.

Conclusion: Despite a favorable overall prognosis, PC shows high rates of recurrence leading to repeated surgery and postoperative recurrent laryngeal nerve palsy and hypoparathyroidism. In view of the reduced recurrence rate in cases of extended surgery, ipsilateral completion surgery may be considered when PC is confirmed.
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http://dx.doi.org/10.1097/SLA.0000000000004144DOI Listing
July 2020

Expression of SOAT1 in Adrenocortical Carcinoma and Response to Mitotane Monotherapy: An ENSAT Multicenter Study.

J Clin Endocrinol Metab 2020 08;105(8)

Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany.

Context: Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approximately 20%, and adverse drug effects are frequent. To date, there is no marker established that predicts treatment response. Mitotane has been shown to inhibit sterol-O-acyl transferase 1 (SOAT1), which leads to endoplasmic reticulum stress and cell death in ACC cells.

Objective: To investigate SOAT1 protein expression as a marker of treatment response to mitotane.

Patients: A total of 231 ACC patients treated with single-agent mitotane as adjuvant (n = 158) or advanced disease therapy (n = 73) from 12 ENSAT centers were included. SOAT1 protein expression was determined by immunohistochemistry on formalin-fixed paraffin-embedded specimens.

Setting: Retrospective study at 12 ACC referral centers.

Main Outcome Measure: Recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS).

Results: Sixty-one of 135 patients (45%) with adjuvant mitotane treatment had recurrences and 45/68 patients (66%) with mitotane treatment for advanced disease had progressive disease. After multivariate adjustment for sex, age, hormone secretion, tumor stage, and Ki67 index, RFS (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 0.61-1.85; P = 0.82), and DSS (HR = 1.30; 95% CI, 0.58-2.93; P = 0.53) in adjuvantly treated ACC patients did not differ significantly between tumors with high and low SOAT1 expression. Similarly, in the advanced stage setting, PFS (HR = 1.34; 95% CI, 0.63-2.84; P = 0.45) and DSS (HR = 0.72; 95% CI, 0.31-1.70; P = 0.45) were comparable and response rates not significantly different.

Conclusions: SOAT1 expression was not correlated with clinical endpoints RFS, PFS, and DSS in ACC patients with mitotane monotherapy. Other factors appear to be relevant for mitotane treatment response and ACC patient survival.
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http://dx.doi.org/10.1210/clinem/dgaa293DOI Listing
August 2020

Targeted Gene Expression Profile Reveals CDK4 as Therapeutic Target for Selected Patients With Adrenocortical Carcinoma.

Front Endocrinol (Lausanne) 2020 16;11:219. Epub 2020 Apr 16.

Division of Endocrinology and Diabetology, Department of Internal Medicine, University Hospital of Wuerzburg, Würzburg, Germany.

Adrenocortical carcinomas (ACC) are aggressive tumors with a heterogeneous prognosis and limited therapeutic options for advanced stages. This study aims to identify novel drug targets for a personalized treatment in ACC. RNA was isolated from 40 formalin-fixed paraffin-embedded ACC samples. We evaluated gene expression of 84 known cancer drug targets by reverse transcriptase quantitative real time-PCR and calculated fold change using 5 normal adrenal glands as reference (overexpression by fold change >2.0). The most promising candidate cyclin-dependent kinase 4 (CDK4) was investigated at protein level in 104 ACC samples and tested by experiments in two ACC cell lines (NCI-H295R and MUC1). The most frequently overexpressed genes were (100% of cases, median fold change = 16.5), (95%, fold change = 52.9), (80%, fold change = 6.7) (62%, fold change = 2.6) (60%, fold change = 2.8), and (52%, fold change = 2.3). CDK4 was chosen for functional validation, as it is actionable by approved CDK4/6-inhibitors (e.g., palbociclib). Nuclear immunostaining of CDK4 significantly correlated with mRNA expression (R = 0.52, < 0.005). We exposed both NCI-H295R and MUC1 cell lines to palbociclib and found a concentration- and time-dependent reduction of cell viability, which was more pronounced in the NCI-H295R cells in line with higher CDK4 expression. Furthermore, we tested palbociclib in combination with insulin-like growth factor 1/insulin receptor inhibitor linsitinib showing an additive effect. In conclusion, we demonstrate that RNA profiling is useful to discover potential drug targets and that CDK4/6 inhibitors are promising candidates for treatment of selected patients with ACC.
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http://dx.doi.org/10.3389/fendo.2020.00219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176906PMC
May 2021

The local immune phenotype influences prognosis in patients with nodal-positive rectal cancer after neoadjuvant chemoradiation.

Int J Colorectal Dis 2020 Feb 11;35(2):365-370. Epub 2019 Dec 11.

Department of General, Visceral, Transplantation, Vascular and Paediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany.

Indrocution: The local immune contexture in patients with locally advanced rectal cancer (LARC) has important prognostic value after neoadjuvant chemoradiation and surgical resection. In this study, we examined the prognostic role of Indoleamine-2,3-Dioxygenase (IDO1) and infiltrating cytotoxic T lymphocytes (CD8+) according to the nodal stage of LARC patients.

Masterial And Methods: Expression of IDO1 and CD8 was evaluated through immunohistochemistry in 106 archival tumour tissue samples from patients following neoadjuvant chemoradiation and radical resection. The average infiltration of IDO1+ and CD8+ cells was calculated and expressed as total scores as previously described. Kaplan-Meier curves were used to describe overall and disease-free survival.

Results: In nodal-positive tumours (N+), IDO-positivity was associated with a reduced disease-free survival (DFS) (p = 0.063) and CD8-positivity with an impaired OS (p = 0.024). Patients with a N+ LARC and a high total IDO1 score showed a clear advantage regarding five-year disease-free survival rates compared with patients with a low total IDO1 score (N+ 5y-DFS IDO1 high: 66.7% vs IDO low: 19%). We also detected better 5-years-OS rates in N+ LARC with a high total CD8 score (N+ 5y-OS CD8 high: 83.3% vs CD8 low: 32.3%). These survival benefits were not evident in patients with N-tumours.

Conclusion: Analysis of the local CD8 and IDO1 expression influences prognosis in nodal-positive LARC patients after multimodal therapy and may be a helpful tool in specifying individual adjuvant treatment strategies according to different immune profiles.
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http://dx.doi.org/10.1007/s00384-019-03466-0DOI Listing
February 2020

Ga-PSMA I&T PET/CT for primary staging of prostate cancer.

Eur J Nucl Med Mol Imaging 2020 01 16;47(1):168-177. Epub 2019 Sep 16.

Department of Nuclear Medicine, University Hospital Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Germany.

Purpose: The present study is based on a retrospective analysis of Gallium-68 (Ga)-labelled prostate-specific membrane antigen (Ga-PSMA I&T) PET/CT performed in newly diagnosed, treatment-naïve prostate cancer (PCa) patients prior to definitive treatment.

Methods: A total of 82 men were included in the study and were imaged with Ga-PSMA I&T PET/CT to assess the distribution of PSMA-avid disease for staging purposes (11 with low-risk, 32 with intermediate-risk, and 39 with high-risk PCa). Forty patients (20 with intermediate- and 20 with high-risk disease) underwent subsequent radical prostatectomy with extended pelvic lymph node dissection which allowed for correlation of imaging findings with histopathologic data.

Results: PSMA-positive disease was detected in 83% of patients with 66/82 (80.5%) primary tumours being visualized. PSMA-avid lymph nodes were recorded in 17/82 patients (20.7%, 3 with intermediate-risk and 14 with high-risk PCa); distant disease was found in 14/82 subjects (17.1%, 2 with intermediate-risk and 12 with high-risk PCa). No extraprostatic disease was found in low-risk PCa. SUV of primary tumours showed a weak but significant correlation with serum PSA values (r = 0.51, p < 0.001) and Gleason scores (GSC; r = 0.35, p = 0.001), respectively. In correlation with histopathology, calculated per-region sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for detection of lymph node metastases were 35.0%, 98.4%, 63.6%, 95.0%, and 93.0%, respectively.

Conclusions: In patients with initial diagnosis of intermediate- and high-risk prostate cancer, Ga-PSMA I&T PET/CT emerges as a relevant staging procedure by identifying nodal and/or distant metastases. Due to the low prevalence of extraprostatic disease, its value seems to be limited in low-risk disease.
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http://dx.doi.org/10.1007/s00259-019-04524-zDOI Listing
January 2020

Prognostic Relevance of Steroid Sulfation in Adrenocortical Carcinoma Revealed by Molecular Phenotyping Using High-Resolution Mass Spectrometry Imaging.

Clin Chem 2019 10 6;65(10):1276-1286. Epub 2019 Sep 6.

Department of Internal Medicine, Division of Endocrinology and Diabetology, University Hospital Würzburg, Würzburg, Germany;

Background: Adrenocortical carcinoma (ACC) is a rare tumor with variable prognosis even within the same tumor stage. Cancer-related sex hormones and their sulfated metabolites in body fluids can be used as tumor markers. The role of steroid sulfation in ACC has not yet been studied. MALDI mass spectrometry imaging (MALDI-MSI) is a novel tool for tissue-based chemical phenotyping.

Methods: We performed phenotyping of formalin-fixed, paraffin-embedded tissue samples from 72 ACC by MALDI-MSI at a metabolomics level.

Results: Tumoral steroid hormone metabolites-estradiol sulfate [hazard ratio (HR) 0.26; 95% CI, 0.10-0.69; = 0.005] and estrone 3-sulfate (HR 0.22; 95% CI, 0.07-0.63; = 0.003)-were significantly associated with prognosis in Kaplan-Meier analyses and after multivariable adjustment for age, tumor stage, and sex (HR 0.29; 95% CI, 0.11-0.79; = 0.015 and HR 0.30; 95% CI, 0.10-0.91; = 0.033, respectively). Expression of sulfotransferase SULT2A1 was associated with prognosis to a similar extent and was validated to be a prognostic factor in two published data sets. We discovered the presence of estradiol-17β 3,17-disulfate (E2S2) in a subset of tumors with particularly poor overall survival. Electron microscopy revealed novel membrane-delimited organelles in only these tumors. By applying cluster analyses of metabolomic data, 3 sulfation-related phenotypes exhibited specific metabolic features unrelated to steroid metabolism.

Conclusions: MALDI-MSI provides novel insights into the pathophysiology of ACC. Steroid hormone sulfation may be used for prognostication and treatment stratification. Sulfation-related metabolic reprogramming may be of relevance also in conditions beyond the rare ACC and can be directly investigated by the use of MALDI-MSI.
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http://dx.doi.org/10.1373/clinchem.2019.306043DOI Listing
October 2019

CXCR4-Directed Imaging in Solid Tumors.

Front Oncol 2019 14;9:770. Epub 2019 Aug 14.

Department of Nuclear Medicine, University of Wuerzburg, Wuerzburg, Germany.

Despite histological evidence in various solid tumor entities, available experience with CXCR4-directed diagnostics and endoradiotherapy mainly focuses on hematologic diseases. With the goal of expanding the application of CXCR4 theranostics to solid tumors, we aimed to elucidate the feasibility of CXCR4-targeted imaging in a variety of such neoplasms. Nineteen patients with newly diagnosed, treatment-naïve solid tumors including pancreatic adenocarcinoma or neuroendocrine tumor, cholangiocarcinoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, and prostate cancer underwent [Ga]Pentixafor PET/CT. CXCR4-mediated uptake was assessed both visually and semi-quantitatively by evaluation of maximum standardized uptake values (SUV) of both primary tumors and metastases. With physiologic liver uptake as reference, tumor-to-background ratios (TBR) were calculated. [Ga]Pentixafor findings were further compared to immunohistochemistry and [F]FDG PET/CT. On [Ga]Pentixafor PET/CT, 10/19 (52.6%) primary tumors were visually detectable with a median SUV of 5.4 (range, 1.7-16.0) and a median TBR of 2.6 (range, 0.8-7.4), respectively. The highest level of radiotracer uptake was identified in a patient with cholangiocarcinoma (SUV, 16.0; TBR, 7.4). The relatively low uptake on [Ga]Pentixafor was also noted in metastases, exhibiting a median SUV of 4.5 (range, 2.3-8.8; TBR, 1.7; range, 1.0-4.1). A good correlation between uptake on [Ga]Pentixafor and histological derived CXCR4 expression was noted ( = 0.62, < 0.05). In the 3 patients in whom [F]FDG PET/CT was available, [Ga]Pentixafor exhibited lower uptake in all lesions. In this cohort of newly diagnosed, treatment-naïve patients with solid malignancies, CXCR4 expression as detected by [Ga]Pentixafor-PET/CT and immunohistochemistry was rather moderate. Thus, CXCR4-directed imaging may not play a major role in the management of solid tumors in the majority of patients.
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http://dx.doi.org/10.3389/fonc.2019.00770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702266PMC
August 2019

Establishing Pure Cancer Organoid Cultures: Identification, Selection and Verification of Cancer Phenotypes and Genotypes.

J Mol Biol 2019 07 29;431(15):2884-2893. Epub 2019 May 29.

Research Centre for Infectious Diseases, Institute for Molecular Infection Biology, Julius-Maximilians-Universität Würzburg, Würzburg, Germany. Electronic address:

Precision medicine requires in vitro models which will both faithfully recapitulate the features of an individual's disease and enable drug testing on a wide variety of samples covering the greatest range of phenotypes possible for a particular disease. Organoid technology has immense potential to fulfill this demand, but it will be necessary to develop robust protocols that enable the generation of organoids in a dependable manner from nearly every patient. Here we provide a user's guide, including detailed step-by-step protocols, to the establishment, isolation and verification of gastric cancer organoids. Selection strategies include omission of growth factors, addition of drugs, isolation of distinct phenotypes and generation of monoclonal lines. For confirmation of cancer identity, we use sequencing, drug selection, karyotyping and histology. While we specify these protocols for human gastric cancer organoids here, the methods described are applicable to organoids derived from other tissues as well.
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http://dx.doi.org/10.1016/j.jmb.2019.05.031DOI Listing
July 2019

[99mTc]Tilmanocept Lymphscintigraphy after inconclusive [99mTc]Nanocolloid Scan in Breast Cancer.

Nuklearmedizin 2019 Jun 7;58(3):282-284. Epub 2019 May 7.

Lymphatic mapping for identification and subsequent removal of the sentinel lymph node (SLN) is an established procedure in breast cancer and cutaneous melanoma to minimize the extent of surgery (and thus, associated morbidity), simplify histopathological processing and subsequently provide prognostic information and help choose the optimal patient management. Established methods for SLN mapping include visual identification of nodal staining after peritumoral injection of a (blue) dye or the use of lymphoscintigraphy with technetium-labelled nanocolloid. In experienced hands, success rates for both methods exceed 95 %, nonetheless in some patients they fail despite correct application and imaging techniques. Potential reasons for false-negative SLN detection rates -beyond poor tracer injection technique or imaging of the wrong nodal basin- include inadequate pathologic examination of the SLN or complete replacement of the SLN with neoplastic disease, causing the injected tracer to completely bypass the infiltrated node 1.Beyond colloid particles, the more specific receptor-targeting small molecule [Tc]Tilmanocept has recently been approved for scintigraphic SLN detection. Tilmanocept, or mannosyl diethylene-triamine-pentaacetate (DTPA) dextran, has a small molecular size of approximately 7 nm and works via specific binding to the mannose receptor (CD206) 2. The mannose receptor is particularly overexpressed on macrophages and dendritic precursor cells within lymph nodes, thus uptake in lymph nodes is not dependent on particle size 2, 3. In pilot studies scintigraphic SLN detection with [Tc]Tilmanocept was superior to dye staining 4. Given its beneficial properties, [Tc]Tilmanocept might offer advantages over the alternatively used radiocolloids. We present four cases of [Tc]Tilmanocept application after inconclusive or unsuccessful attempts of SLN detection using [Tc]nanocolloid lymphoscintigraphy.
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http://dx.doi.org/10.1055/a-0891-7686DOI Listing
June 2019

Prognostic value of tumour-infiltrating CD8+ lymphocytes in rectal cancer after neoadjuvant chemoradiation: is indoleamine-2,3-dioxygenase (IDO1) a friend or foe?

Cancer Immunol Immunother 2019 Apr 22;68(4):563-575. Epub 2019 Jan 22.

Department of General-, Visceral-, Transplant-, Vascular- and Paediatric Surgery, University Hospital of Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany.

The prognostic value of the local immune phenotype in patients with colorectal cancer has been extensively studied. Neoadjuvant radiotherapy and/or chemotherapy may potentially influence these immune responses. In this study, we examined the prognostic role of indoleamine-2,3-Dioxygenase (IDO1) and infiltrating cytotoxic T lymphocytes (CD8+) in locally advanced rectal carcinomas after neoadjuvant treatment. Expression of IDO1 and CD8 was evaluated by immunohistochemistry in 106 archival tumour tissue samples from patients following neoadjuvant chemoradiation and radical resection. The average infiltration of IDO1+ and CD8+ cells was calculated along the tumour invasive front, in the tumour centre and within the neoplastic cells and expressed as total scores. Of the tumour specimens evaluable for immunohistochemistry, 100% showed CD8+ lymphocyte infiltration and 93.4% stained positive for IDO1. Total IDO1 score positively correlated with total CD8 score for all three subsites (p = 0.002, Kendall-tau-b 0.357). A high total CD8 score was positively correlated with lower ypUICC-stages (p = 0.047) and lower ypT-categories (p = 0.032). Total IDO1 expression showed a clear trend towards a lower risk of recurrence (p = 0.078). A high total IDO1 score was an independent prognostic marker for prolonged disease-free survival (HR 0.38, p = 0.046) and a high total CD8 score for favourable overall survival (HR 0.16, p = 0.029). Analysis of the local CD8 and IDO1 expression profile may be a helpful tool in predicting prognosis for patients with locally advanced rectal cancer following neoadjuvant chemoradiation.
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http://dx.doi.org/10.1007/s00262-019-02306-yDOI Listing
April 2019

Beneficial Effects of Vitamin D Treatment in an Obese Mouse Model of Non-Alcoholic Steatohepatitis.

Nutrients 2019 Jan 3;11(1). Epub 2019 Jan 3.

Division of Hepatology, University Hospital Würzburg, 97080 Würzburg, Germany.

Serum vitamin D levels negatively correlate with obesity and associated disorders such as non-alcoholic steatohepatitis (NASH). However, the mechanisms linking low vitamin D (VD) status to disease progression are not completely understood. In this study, we analyzed the effect of VD treatment on NASH in mice. C57BL6/J mice were fed a high-fat/high-sugar diet (HFSD) containing low amounts of VD for 16 weeks to induce obesity, NASH and liver fibrosis. The effects of preventive and interventional VD treatment were studied on the level of liver histology and hepatic/intestinal gene expression. Interestingly, preventive and to a lesser extent also interventional VD treatment resulted in improvements of liver histology. This included a significant decrease of steatosis, a trend towards lower non-alcoholic fatty liver disease (NAFLD) activity score and a slight non-significant decrease of fibrosis in the preventive treatment group. In line with these changes, preventive VD treatment reduced the hepatic expression of lipogenic, inflammatory and pro-fibrotic genes. Notably, these beneficial effects occurred in conjunction with a reduction of intestinal inflammation. Together, our observations suggest that timely initiation of VD supplementation (preventive vs. interventional) is a critical determinant of treatment outcome in NASH. In the applied animal model, the improvements of liver histology occurred in conjunction with reduced inflammation in the gut, suggesting a potential relevance of vitamin D as a therapeutic agent acting on the gut⁻liver axis.
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http://dx.doi.org/10.3390/nu11010077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356425PMC
January 2019

The plant hormone auxin beats the time for oscillating light-regulated lateral root induction.

Development 2018 11 26;145(23). Epub 2018 Nov 26.

Department of Molecular Plant Physiology, Faculty of Biology, Albert-Ludwigs-University, Schänzlestr. 1, D-79104 Freiburg, Germany.

The molecular mechanism underlying the periodic induction of lateral roots, a paradigmatic example of clock-driven organ formation in plant development, is a matter of ongoing, controversial debate. Here, we provide experimental evidence that this clock is frequency modulated by light and that auxin serves as a mediator for translating continuous light signals into discontinuous gene activation signals preceding the initiation of lateral roots in seedlings. Based on this evidence, we propose a molecular model of an ultradian biological clock involving auxin-dependent degradation of an AUX/IAA-type transcription repressor as a flexible, frequency-controlling delay element. This model widens the bandwidth of biological clocks by adding a new type that allows the pace of organ formation to adapt to the changing environmental demands of the growing plant.
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http://dx.doi.org/10.1242/dev.169839DOI Listing
November 2018

Hexokinase-2 Expression in C-Methionine-Positive, F-FDG-Negative Multiple Myeloma.

J Nucl Med 2019 03 2;60(3):348-352. Epub 2018 Nov 2.

Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany; and

PET with F-FDG is the standard modality in nuclear medicine for imaging multiple myeloma (MM). However, viable MM as detected by MRI or PET with other metabolic tracers, including C-methionine, may be missed-for example, because of low hexokinase 2 (HK2) expression of tumor cells. The aim of this study was to further investigate potential reasons for PET false negativity. A cohort of 15 mainly pretreated patients with relapsed or refractory biopsy-proven, serologically active MM who underwent both F-FDG and C-methionine PET/CT was retrospectively analyzed. In 9 of the 15 patients, F-FDG PET was negative in the presence of viable disease. In the remaining 6 patients, both F-FDG and C-methionine PET/CT revealed the same number of MM lesions. At immunohistochemistry, F-FDG-negative myeloma did not exhibit significant differences in HK2 or glucose-6-phosphatase expression from F-FDG-positive disease ( = 0.57 and = 0.44, respectively). Beyond HK2 expression, F-FDG negativity in (mainly pretreated) MM patients seems to be associated with additional causes not yet known.
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http://dx.doi.org/10.2967/jnumed.118.217539DOI Listing
March 2019

Chemokine Receptor 4 Expression in Primary Sjögren's Syndrome.

Clin Nucl Med 2018 Nov;43(11):835-836

Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany.

Ga-pentixafor is a novel radioligand of C-X-C motif chemokine receptor 4. A 55-year-old woman with a history of primary Sjögren's syndrome underwent Ga-pentixafor PET/CT for staging of lymphoma originating from mucosa-associated lymphoid tissue. Whereas no lymphoma manifestation could be detected, imaging revealed bilateral intense radiotracer uptake in both parotid and submandibular salivary glands, consistent with inflammatory cell infiltration.
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http://dx.doi.org/10.1097/RLU.0000000000002258DOI Listing
November 2018

Targeted Molecular Analysis in Adrenocortical Carcinomas: A Strategy Toward Improved Personalized Prognostication.

J Clin Endocrinol Metab 2018 12;103(12):4511-4523

Department of Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany.

Context: Adrenocortical carcinoma (ACC) has a heterogeneous prognosis, and current medical therapies have limited efficacy in its advanced stages. Genome-wide multiomics studies identified molecular patterns associated with clinical outcome.

Objective: Here, we aimed at identifying a molecular signature useful for both personalized prognostic stratification and druggable targets, using methods applicable in clinical routine.

Design: In total, 117 tumor samples from 107 patients with ACC were analyzed. Targeted next-generation sequencing of 160 genes and pyrosequencing of 4 genes were applied to formalin-fixed, paraffin-embedded (FFPE) specimens to detect point mutations, copy number alterations, and promoter region methylation. Molecular results were combined with clinical/histopathological parameters (tumor stage, age, symptoms, resection status, and Ki-67) to predict progression-free survival (PFS).

Results: In addition to known driver mutations, we detected recurrent alterations in genes not previously associated with ACC (e.g., NOTCH1, CIC, KDM6A, BRCA1, BRCA2). Best prediction of PFS was obtained integrating molecular results (more than one somatic mutation, alterations in Wnt/β-catenin and p53 pathways, high methylation pattern) and clinical/histopathological parameters into a combined score (P < 0.0001, χ2 = 68.6). Accuracy of prediction for early disease progress was 83.3% (area under the receiver operating characteristic curve: 0.872, 95% confidence interval 0.80 to 0.94). Furthermore, 17 potentially targetable alterations were found in 64 patients (e.g., in CDK4, NOTCH1, NF1, MDM2, and EGFR and in DNA repair system).

Conclusions: This study demonstrates that molecular profiling of FFPE tumor samples improves prognostication of ACC beyond clinical/histopathological parameters and identifies new potential drug targets. These findings pave the way to precision medicine in this rare disease.
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http://dx.doi.org/10.1210/jc.2018-01348DOI Listing
December 2018

Animal models of NAFLD from a hepatologist's point of view.

Biochim Biophys Acta Mol Basis Dis 2019 05 7;1865(5):943-953. Epub 2018 Jul 7.

University Hospital Würzburg, Division of Hepatology, Würzburg, Germany.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disorder closely linked to obesity, hyperlipidemia and type 2 diabetes and is increasingly recognized as a major health problem in many parts of the world. While early stages of NAFLD are characterized by a bland accumulation of fat (steatosis) in hepatocytes, the disease can progress to non-alcoholic steatohepatitis (NASH) which involves chronic liver inflammation, tissue damage and fibrosis and can ultimately lead to end-stage liver disease including cirrhosis and cancer. As no approved pharmacological treatment for NAFLD exists today, there is an urgent need to identify promising pharmacological targets and develop future therapies. For this purpose, basic and translational research in NAFLD animal models is indispensable. While a large number of diverse animal models are currently used in the field, there is an ongoing challenge to identify those models that mirror human pathology the closest to allow good translation of obtained results into further clinical development. This review is meant to provide a concise overview of the most relevant NAFLD animal models currently available and will discuss the strengths and weaknesses of these models with regard to their comparability to human disease conditions.
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http://dx.doi.org/10.1016/j.bbadis.2018.06.023DOI Listing
May 2019

Insight into nuclear body formation of phytochromes through stochastic modelling and experiment.

Phys Biol 2018 05 18;15(5):056003. Epub 2018 May 18.

Centre for Synthetic and Systems Biology (SynthSys), University of Edinburgh, United Kingdom. School of Biological Sciences, University of Edinburgh, United Kingdom. Freiburg Institute for Advanced Studies, University of Freiburg, Germany.

Spatial relocalization of proteins is crucial for the correct functioning of living cells. An interesting example of spatial ordering is the light-induced clustering of plant photoreceptor proteins. Upon irradiation by white or red light, the red light-active phytochrome, phytochrome B, enters the nucleus and accumulates in large nuclear bodies (NBs). The underlying physical process of nuclear body formation remains unclear, but phytochrome B is thought to coagulate via a simple protein-protein binding process. We measure, for the first time, the distribution of the number of phytochrome B-containing NBs as well as their volume distribution. We show that the experimental data cannot be explained by a stochastic model of nuclear body formation via simple protein-protein binding processes using physically meaningful parameter values. Rather modelling suggests that the data is consistent with a two step process: a fast nucleation step leading to macroparticles followed by a subsequent slow step in which the macroparticles bind to form the nuclear body. An alternative explanation for the observed nuclear body distribution is that the phytochromes bind to a so far unknown molecular structure. We believe it is likely this result holds more generally for other nuclear body-forming plant photoreceptors and proteins.
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http://dx.doi.org/10.1088/1478-3975/aac193DOI Listing
May 2018

Testicular Inflammatory Myofibroblastic Tumor: A Known Entity at a Very Rare Site.

Case Rep Urol 2017 21;2017:1410843. Epub 2017 Dec 21.

Institute of Pathology, University of Wuerzburg, 97080 Wuerzburg, Germany.

Inflammatory myofibroblastic tumors (IMT) are distinctive lesions of unknown etiology, composed of myofibroblastic spindle cells with an associated inflammatory background. They can occur in a wide age range and at all anatomic sites, but most frequently they can be observed in the lung (especially in pediatric cases), abdomen, or retroperitoneum. The urinary bladder is one of the most common sites in urological cases. We present a very rare case of IMT of the testis. Clinically, a 40-year-old patient showed a palpable painless lesion of the right testis. Ultrasound examination showed two solid intratesticular foci. During surgical intervention, the intraoperative frozen section revealed mesenchymal tumors admixed with an uncommon inflammatory infiltrate, consistent with a reorganized abscess. Despite the benign result, orchiectomy was performed due to the multifocal presentation and the large size of 3 cm. The final diagnosis was IMT without ALK-rearrangement. Incomplete resection increases the risk of local relapses to 30%. In this case, a complete resection could be achieved and the patient is free of tumor 15 months later.
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http://dx.doi.org/10.1155/2017/1410843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753005PMC
December 2017

High-Resolution Tissue Mass Spectrometry Imaging Reveals a Refined Functional Anatomy of the Human Adult Adrenal Gland.

Endocrinology 2018 03;159(3):1511-1524

Department of Internal Medicine, Division of Endocrinology and Diabetology, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.

In the adrenal gland, neuroendocrine cells that synthesize catecholamines and epithelial cells that produce steroid hormones are united beneath a common organ capsule to function as a single stress-responsive organ. The functional anatomy of the steroid hormone-producing adrenal cortex and the catecholamine-producing medulla is ill defined at the level of small molecules. Here, we report a comprehensive high-resolution mass spectrometry imaging (MSI) map of the normal human adrenal gland. A large variety of biomolecules was accessible by matrix-assisted laser desorption/ionization-Fourier transform-ion cyclotron resonance MSI, including nucleoside phosphates indicative of oxidative phosphorylation, sterol and steroid metabolites, intermediates of glycolysis and the tricarboxylic acid cycle, lipids, and fatty acids. Statistical clustering analyses yielded a molecularly defined adrenal anatomy of 10 distinct molecular zones including a highly structured corticomedullary interface. By incorporating pathway information, activities of carbohydrate, amino acid, and lipid metabolism as well as endocrine bioactivity were revealed to be highly spatially organized, which could be visualized as different molecularly defined zones. Together, these findings provide a molecular definition of human adult adrenal gland structure beyond classical histological anatomy.
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http://dx.doi.org/10.1210/en.2018-00064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839739PMC
March 2018