PDF file - 110K, Supplemental Table 1. Analysis of Patient Stage vs MMP3 & Rac1b Staining Intensity.

PDF file - 95K, Supplemental Table 2. Analysis of Ra.c1b polarity vs MMP3 & Rac1b Staining Intensity

XLSX file - 14K, Supplemental Table 4. Gene Ontology categories enriched in transcriptional profiles of cells treated with MMP-3.

XLSX file - 364K, Supplemental Table 5. Overlap of genes between MMP-3-treated cells and TGFbeta-treated cells.

XLSX file - 59K, Supplemental Table 3. Gene expression changes in response to MMP-3 treatment.

XLSX file - 609K, Supplemental Table 6. Overlap of genes between MMP-3-treated cells and invasive/metastatic pancreatic cancer cells.

PDF file - 883K, Supplemental Figure 1. MMP3 and Rac1b expression are not correlated with collagen and smooth muscle actin in pancreatic adenocarcinoma cells. Supplemental Figure 2. Association of Rac1b subcellular localization with patient prognosis is not dependent upon patient stage or grade. Supplemental Figure 3. Induction of fibrosis and activation of metaplasia in response to MMP3. Supplemental Figure 4. Meta-analysis of datasets showing overlap of response of PaTu8988T to MMP3 with pancreas biosets. Supplemental Figure 5. Nuclear localization of pSMAD2 in response to MMP3.

Das Nebennierenrindenkarzinom ist ein seltener, maligner primärer Nebennierentumor, der von der Nebennierenrinde ausgeht. Typische Symptome sind durch Kompression benachbarter Organe oder durch einen Hormonexzess meist Kortisol-bedingt. Die Diagnostik sollten eine sorgfältige hormonelle Evaluation und ein schnittbildgebendes Verfahren bestimmen. Die einzige kurative Therapie ist die vollständige Resektion. Eine Eröffnung der Tumorkapsel bei der Resektion sollte unbedingt vermieden werden. Der Goldstandard ist die offene Adrenalektomie mit einer lokoregionären Lymphadenektomie. Das diffus metastasierte Nebennierenkarzinom sollte durch die Kombination einer Chemotherapie und dem Adrenolytikum Mitotane behandelt werden. Falls ein lokalbegrenztes Stadium vorliegt kann durch eine R0-Resektion ein 5-Jahres-Überleben von 60–80 % erreicht werden.

BACKGROUND AND AIMS:The purpose of this review is to provide updated recommendations for the surgical management of primary (pHPT) and renal (rHPT) hyperparathyroidism, formulating a new guideline of the German Association of Endocrine Surgeons (CAEK).METHODS:Evidence-based recommendations for the diagnosis and therapy of pHPT and rHPT were assessed by a multidisciplinary panel using PubMed for a comprehensive literature search together with a structured consensus dialogue (S2k guideline of the Association of the German Scientific Medical Societies, AWMF).RESULTS:During the last 20 years, a variety of new preoperative localization procedures, such as sestamibi-SPECT, 4D-CT, and various PET/CT procedures, were established for pHPT. High-resolution imaging, together with intraoperative parathyroid hormone (IOPTH) measurement, enabled focused or minimally invasive surgery to become the most favored surgical technique. Patients with pHPT and nonlocalizing imaging have a higher risk of multiglandular disease. Surgical therapy provides very high cure rates, with a clear relation to the surgeon's experience in parathyroid procedures. Reoperative parathyroidectomy, children with pHPT or familial forms, and parathyroid carcinoma are addressed and require special surgical expertise. A multidisciplinary team of experienced nephrologists, transplant, and endocrine surgeons should assess the diagnosis and treatment of renal HPT.CONCLUSION:Surgery is the only curative treatment for pHPT and should be considered for all patients with pHPT. For rHPT, a more selective approach is required, and parathyroidectomy is indicated only when conservative treatment options fail. In parathyroid carcinoma, the adequacy of local resection influences local disease control.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Background and aimsPrevious guidelines addressing surgery of adrenal tumors required actualization in adaption of developments in the area. The present guideline aims to provide practical and qualified recommendations on an evidence-based level reviewing the prevalent literature for the surgical therapy of adrenal tumors referring to patients of all age groups in operative medicine who require adrenal surgery. It primarily addresses general and visceral surgeons but offers information for all medical doctors related to conservative, ambulatory or inpatient care, rehabilitation, and general practice as well as pediatrics. It extends to interested patients to improve the knowledge and participation in the decision-making process regarding indications and methods of management of adrenal tumors. Furthermore, it provides effective medical options for the surgical treatment of adrenal lesions and balances positive and negative effects. Specific clinical questions addressed refer to indication, diagnostic procedures, effective therapeutic alternatives to surgery, type and extent of surgery, and postoperative management and follow-up regime.MethodsA PubMed research using specific key words identified literature to be considered and was evaluated for evidence previous to a formal Delphi decision process that finalized consented recommendations in a multidisciplinary setting.ResultsOverall, 12 general and 52 specific recommendations regarding surgery for adrenal tumors were generated and complementary comments provided.ConclusionEffective and balanced medical options for the surgical treatment of adrenal tumors are provided on evidence-base. Specific clinical questions regarding indication, diagnostic procedures, alternatives to and type as well as extent of surgery for adrenal tumors including postoperative management are addressed.

IMPORTANCE:The risk stratification of adrenocortical carcinoma (ACC) based on tumor proliferation index and stage is limited. Adjuvant therapy after surgery is recommended for most patients. Pan-genomic studies have identified distinct molecular groups closely associated with outcome. OBJECTIVE:To compare the molecular classification for prognostic assessment of ACC with other known prognostic factors. DESIGN, SETTING, AND PARTICIPANTS:In this retrospective biomarker analysis, ACC tumor samples from 368 patients who had undergone surgical tumor removal were collected from March 1, 2005, to September 30, 2015 (144 in the training cohort and 224 in the validation cohort) at 21 referral centers with a median follow-up of 35 months (interquartile range, 18-74 months). Data were analyzed from March 2016 to March 2018. EXPOSURES:Meta-analysis of pan-genomic studies (transcriptome, methylome, chromosome alteration, and mutational profiles) was performed on the training cohort. Targeted biomarker analysis, including targeted gene expression (BUB1B and PINK1), targeted methylation (PAX5, GSTP1, PYCARD, and PAX6), and targeted next-generation sequencing, was performed on the training and validation cohorts. MAIN OUTCOMES AND MEASURES:Disease-free survival. Cox proportional hazards regression and C indexes were used to assess the prognostic value of each model. RESULTS:Of the 368 patients (mean [SD] age, 49 [16] years), 144 were in the training cohort (100 [69.4%] female) and 224 were in the validation cohort (142 [63.4%] female). In the training cohort, pan-genomic measures classified ACC into 3 molecular groups (A1, A2, and A3-B), with 5-year survival of 9% for group A1, 45% for group A2, and 82% for group A3-B (log-rank P < .001). Molecular class was an independent prognostic factor of recurrence in stage I to III ACC after complete surgery (hazard ratio, 55.91; 95% CI, 8.55-365.40; P < .001). The combination of European Network for the Study of Adrenal Tumors (ENSAT) stage, tumor proliferation index, and molecular class provided the most discriminant prognostic model (C index, 0.88). In the validation cohort, the molecular classification, determined by targeted biomarker measures, was confirmed as an independent prognostic factor of recurrence (hazard ratio, 5.96 [95% CI, 1.81-19.58], P = .003 for the targeted classifier combining expression, methylation, and chromosome alterations; and 2.61 [95% CI, 1.31-5.19], P = .006 for the targeted classifier combining methylation, chromosome alterations, and mutational profile). The prognostic value of the molecular markers was limited for patients with stage IV ACC. CONCLUSIONS AND RELEVANCE:The findings suggest that in localized ACC, targeted classifiers may be used as independent markers of recurrence. The determination of molecular class may improve individual prognostic assessment and thus may spare unnecessary adjuvant treatment.

BACKGROUNDAdrenocortical 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.METHODSWe performed phenotyping of formalin-fixed, paraffin-embedded tissue samples from 72 ACC by MALDI-MSI at a metabolomics level.RESULTSTumoral steroid hormone metabolites- estradiol sulfate [hazard ratio (HR) 0.26; 95% CI, 0.10-0.69; P = 0.005] and estrone 3-sulfate (HR 0.22; 95% CI, 0.07-0.63; P = 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; P = 0.015 and HR 0.30; 95% CI, 0.10-0.91; P = 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.CONCLUSIONSMALDI-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.

Pancreatic cancer (PDAC) is one of the most dismal of human malignancies. Inhibiting or delaying the progression of precursor lesions of PDAC, pancreatic intraepthial neoplasia (PanINs), to invasive cancer, would be a major step. In the present study, we used a transgenic murine model of pancreatic cancer to evaluate the impact of a conditional knockout of the transcription factor Snail1, a major factor in epithelial-to-mesenchymal transition, on acinar-to-ductal formation and on PanIN progression. By interbreeding conditional LsL-Snail floxf/wt ; LsL-Kras G12D and Pdx1-Cre strains, we obtained LsL-Kras G12D ;Pdx1-Cre(KP) mice, Snail1 heterozygous knockout LsL-Kras G12D ; LsL-Snail flox/- ;Pdx1-Cre(KPShet) mice or Snail1 homozygous knockout LsL-Kras G12D ;LsL-Snail flox/flox ;Pdx1-Cre(KPS) mice. Mice were then followed in a longitudinal study for 2, 4, 6, 8, 10, and 12 months. Furthermore, in mice with a genetic or pharmacological inhibition of Snail1, using the Snail1 inhibitor GN25, a model of pancreatic injury by administration of cerulein was introduced to evaluate ADM formation in this setting. A translational approach with a tissue microarray (TMA) of human PanINs and an in vivo nude mouse platform to test GN25 in human pancreatic adenocarcinoma was then adopted. Quantification of PanINs showed delayed initiation and progression of PanIN lesions at all ages in both homozygous and heterozygous Snaildel1;Pdx-1-Cre;LSL-KrasG12D/+-Mice. PanINs at TMA revealed snail expression in the majority of cases. GN25 showed growth inhibition in 2/2 human pancreatic adenocarcinomas using a nude mice in vivo platform. Genetic and pharmacologic abrogation of Snail1 signaling in exocrine pancreas impairs development of acinar-to-ductal metaplasia following cerulein-mediated pancreatic injury. The present study suggests a fundamental new approach to delay the progression of PDAC.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Background: Pancreatic ductal adenocarcinoma (PDAC) is among the most dismal of human malignancies. Neuropeptides have shown to be implicated in angiogenesis, tumor growth, and formation of distant metastases in various solid tumors. In the present study, we used a genetically engineered mouse model of pancreatic cancer to evaluate the impact of neuropeptide Y (NPY) and its receptors 1 (Y1) and 2 (Y2) in preneoplastic lesions and pancreatic cancer as a potential target with antiproliferative properties. In addition, human PDAC tissue was analyzed. Materials and methods: By interbreeding conditional LsL-Trp53(R172H), LsL-Kras(G12D) and Pdx1-Cre strains, we obtained LsL-Kras(G12D); LsL-Trp53(R172H); Pdx1-Cre(KPC), LsL-Kras(G12D); Pdx1-Cre(KP) and control mice (n = 8 each). Mice were then followed in a longitudinal study for 3 to 6 mo. Pancreata were analyzed in regard to pancreatic intraepithelial neoplasia (PanIN) lesions and invasive carcinoma. Corresponding sections were then assessed by immunohistochemistry and quantitative polymerase chain reaction for NPY, Y1 and Y2 expression in murine and human samples. Results: NPY and Y1 expressions were detected inhuman and murine pancreatic samples, but expression levels were similar in neoplastic and non-neoplastic tissue. Y2 revealed a significant increase of expression in the transgenic mouse model in PanIN lesions and pancreatic cancer compared to control. This holds also true for human samples of pancreatic cancer. Immunohistochemistry of Y2 in murine and human samples of PanINs and pancreatic carcinoma revealed an increased expression in PanIN lesions and pancreatic cancer. Conclusions: Y2 is strongly overexpressed in pancreatic cancer and may modulate angiogenesis. (C) 2017 Elsevier Inc. All rights reserved.