Jupiter's X-Ray and UV Dark Polar Region.

We present 14 simultaneous Chandra X-ray Observatory (CXO)-Hubble Space Telescope (HST) observations of Jupiter's Northern X-ray and ultraviolet (UV) aurorae from 2016 to 2019. Despite the variety of dynamic UV and X-ray auroral structures, one region is conspicuous by its persistent absence of emission: the dark polar region (DPR). Previous HST observations have shown that very little UV emission is produced by the DPR. We find that the DPR also produces very few X-ray photons. For all 14 observations, the low level of X-ray emission from the DPR is consistent (within 2-standard deviations) with scattered solar emission and/or photons spread by Chandra's Point Spread Function from known X-ray-bright regions. We therefore conclude that for these 14 observations the DPR produced no statistically significant detectable X-ray signature.

Real-World Data for Lenvatinib in Radioiodine-Refractory Differentiated Thyroid Cancer (RELEVANT): A Retrospective Multicentric Analysis of Clinical Practice in Austria.

BACKGROUND: Lenvatinib has proven efficacy in progressive, radioiodine- (RAI-) refractory thyroid cancer (TC). Dose reductions are commonly performed due to decreased tolerability and adverse effects. This retrospective multicenter study analyzed overall survival (OS) and progression-free survival (PFS) and tolerability in the Austrian patient population treated with lenvatinib. METHODS: Clinical data of 43 patients (25 males and 18 females) with a median age of 70 years (range: 39-91 years) and RAI-refractory TC with metastases to the lymph nodes (74%), lungs (86%), bone (35%), liver (16%), and brain (12%) were analyzed. The mean duration of treatment with lenvatinib was 26.6 ± 15.4 months with dosage reductions required in 39 patients (91%). RESULTS: PFS after 24 months was 71% (95% CI: 56-87), and overall survival (OS) was 74% (95% CI: 60-88), respectively. OS was significantly shorter (p=0.048) in patients with a daily maintenance dosage ≤ 10 mg (63%) (95% CI: 39-86) as compared to patients on ≥ 14 mg lenvatinib (82%) (95% CI: 66-98) daily. Dose reduction was noted in 39 patients (91%). Grade ≥3 toxicities (hypertension, diarrhea, weight loss, and palmar-plantar erythrodysesthesia syndrome) were most common leading to discontinuation of lenvatinib in 7 patients (16%). CONCLUSION: Lenvatinib showed sustained clinical efficacy in patients with metastatic RAI-refractory TC even with reduced maintenance dosages over years. The effects were comparable to the registration trial, although patients had a higher median age and, more commonly, dose reductions.

Determination of deamidated isoforms of human insulin using capillary electrophoresis.

The applicability of capillary zone electrophoresis (CZE) for the separation of the deamidated forms of insulin has been studied. 50 mM NH4Ac (pH=9) with 20 % v/v isopropylalcohol was found optimal for efficient separation of insulin from its even 10 deamidated forms. The developed method was efficiently applied for monitoring the degradation rate of insulin and the formation of different deamidation isoforms. Two months after the acidification more than thirty peaks can be observed in the electropherogram, because degradation products other than deamidated components were formed as well. The recorded mass spectra enabled us to assign the exact mass of the components, and thus the identification of insulin isoforms could be accomplished. We think that this study provides useful information on how the determination of several deamidation forms can be carried out with CE-MS, but the identification of the exact position of deamidation sites in the insulin molecule remains a challenge.

Prognostic relevance of topoisomerase II α and minichromosome maintenance protein 6 expression in colorectal cancer.

BACKGROUND: Despite rising incidence rates of colorectal malignancies, only a few prognostic tools have been implemented in proven clinical routine. Cell division and proliferation play a significant role in malignancies. In terms of colorectal cancer, the impact of proliferation associated proteins is controversially debated. The aim of our study was to examine the expression of topoisomerase II α and minichromosome maintenance protein 6 and to correlate these findings with the clinical data. METHODS: Tissue samples of 619 patients in total were stained using the antibodies Ki-S4 and Ki-MCM6 targeting topoisomerase II α as well as minichromosome maintenance protein 6. The median rate of proliferation was correlated with clinical and follow up data. RESULTS: The expression rate of minichromosome maintenance protein 6 is significantly higher than the proportion of topoisomerase II α in tumour cells (p < 0.001). A high expression of both proteins coincides with a beneficial outcome for the patient, indicating a favourable prognostic marker (p < 0.001 and p = 0.008). CONCLUSIONS: We have demonstrated that high expression rates of proliferative markers is linked to a beneficial patient outcome. According to the general opinion, a high expression rate correlates with a poor patient outcome. In this study, we were able to refute this assertion.

[Neuroendocrine neoplasms of the auditory, olfactory, and visual sensory organs]. / Neuroendokrine Neoplasien der Sinnesorgane Ohr, Riechorgan und Auge.

Neuroendocrine neoplasms (NENs) are infrequent in sensory organs. There are well-differentiated neuroendocrine neoplasms that should be classified as neuroendocrine tumors, in analogy to their gastrointestinal counterparts, however the nomenclature is inconsistent. The best defined entities are neuroendocrine tumors in the middle ear and ectopic pituitary adenoma in the sphenoid region. Poorly differentiated NENs most often arise in the olfactory organ and nasal cavity that are represented by olfactory neuroblastomas and poorly differentiated neuroendocrine carcinomas. They have several mimickers such as the sinonasal undifferentiated carcinoma, poorly differentiated squamous cell carcinoma, mucosal malignant melanoma, rhabdomyosarcoma, Ewing sarcoma/primitive neuroectodermal tumor and non-Hodgkin lymphoma.

[Formulation and special investigations of innovative intraoral solid dosage forms.] / Not available.

During our work, we summarized the types of solid dosage forms which were in the focus of attention in the last years because of their innovative pharmaceutical technology solution and simple use. The biopharmaceutics of solid dosage forms for intraoral use and the advantages of the use of these dosages forms were presented in general. However, these dosage forms cannot always be prepared with conventional pharmaceutical processes, therefore the special pharmaceutical solutions which can be applied for their preparation were presented. In addition to testing the European Pharmacopoeia dosage forms, the special tests which can be applied for the characterization of innovative solid dosage forms were highlighted.

Liver fluke-infested graft used for living-donor liver transplantation: case report and review of the literature.

Clonorchiasis is a cholangiopathy caused by foodborne trematode parasites, also known as liver flukes. Clonorchiasis is endemic in a wide geographical area extending from Eastern Europe to Southeast Asia. Infested hosts may remain asymptomatic for decades and consequently their liver can become available as a graft. To date, 20 liver transplantations with liver fluke-infested grafts have been reported in the literature. All of them occurred in Asian countries. We, here, report the first case to our knowledge in the Western world of living-donor liver transplantation (LDLT) with an Opisthorchis felineus-infested graft, and present a review of the literature. A 6-month-old girl with decompensated secondary biliary cirrhosis underwent an LDLT with a left lateral graft infested with O. felineus. After prompt diagnosis and adequate therapy, both donor and recipient had an uneventful postoperative course and long-term follow-up. Liver grafts infested with liver flukes do not pose a contraindication to liver donation from deceased or living donors, provided that a correct diagnosis and treatment are performed in a timely fashion.

[Primary perivascular epitheloid cell tumour (PEComa) of the liver - is a new entity of the liver tumors?]. / Das PECom der Leber - eine neue Entität der Lebertumoren?

Perivascular epitheloid cell tumor (PEComa) is a rare tumor, characterized by dual Expression of smooth muscle and melanocytic markers. Due to the development of diagnostic procedures, we now diagnose PEComa more often. We report about a case of PEComa of the liver as an accidental finding. We analyze the clinical and morphological characteristics of this tumor and compare it with the data of the literature. Management of patients with PEComa is not yet standardized; therefore biopsy with immunhistochemical staining is necessary for the diagnosis. In case of liver tumors which cannot be classified by their morphology on imaging modalities, it is important to think about this rare entity.

[Classification and malignant potential of pancreatic cystic tumors]. / Klassifikation und malignes Potenzial der zystischen Pankreastumoren.

Cystic lesions of the pancreas are increasingly diagnosed with a reported prevalence of 10 % in 70-year-old individuals. Despite their broad spectrum, most resected cystic lesions can be attributed to one of the following entities: intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), serous cystic neoplasms (SCN), neuroendocrine cystic tumors (NECT), and solid pseudopapillary neoplasms (SPN). Among them, IPMN and MCN represent precursors of ductal adenocarcinoma, NECT and SPN are low-grade, potentially malignant lesions, and SCN are usually benign. Due to the not negligible morbidity and mortality rates in pancreatic surgery, even in highly specialized centers, an interdisciplinary preoperative stratification of pancreatic cystic lesions into high- and low-risk tumors is necessary in order to accurately select those cases that need to undergo immediate resection. The role of the pathologist is fundamental in both the preoperative assessment and in the postoperative classification, which determines prognosis, further treatment, and follow-up.

c-Rel is a critical mediator of NF-κB-dependent TRAIL resistance of pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies with an overall life expectancy of 6 months despite current therapies. NF-κB signalling has been shown to be critical for this profound cell-autonomous resistance against chemotherapeutic drugs and death receptor-induced apoptosis, but little is known about the role of the c-Rel subunit in solid cancer and PDAC apoptosis control. In the present study, by analysis of genome-wide patterns of c-Rel-dependent gene expression, we were able to establish c-Rel as a critical regulator of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in PDAC. TRAIL-resistant cells exhibited a strong TRAIL-inducible NF-κB activity, whereas TRAIL-sensitive cells displayed only a small increase in NF-κB-binding activity. Transfection with siRNA against c-Rel sensitized the TRAIL-resistant cells in a manner comparable to siRNA targeting the p65/RelA subunit. Gel-shift analysis revealed that c-Rel is part of the TRAIL-inducible NF-κB complex in PDAC. Array analysis identified NFATc2 as a c-Rel target gene among the 12 strongest TRAIL-inducible genes in apoptosis-resistant cells. In line, siRNA targeting c-Rel strongly reduced TRAIL-induced NFATc2 activity in TRAIL-resistant PDAC cells. Furthermore, siRNA targeting NFATc2 sensitized these PDAC cells against TRAIL-induced apoptosis. Finally, TRAIL-induced expression of COX-2 was diminished through siRNA targeting c-Rel or NFATc2 and pharmacologic inhibition of COX-2 with celecoxib or siRNA targeting COX-2, enhanced TRAIL apoptosis. In conclusion, we were able to delineate a novel c-Rel-, NFATc2- and COX-2-dependent antiapoptotic signalling pathway in PDAC with broad clinical implications for pharmaceutical intervention strategies.

Accumulation of small hyaluronan oligosaccharides in tumour interstitial fluid correlates with lymphatic invasion and lymph node metastasis.

BACKGROUND: Association studies have implicated the glycosaminoglycan hyaluronan (hyaluronic acid, HA) and its degrading enzymes the hyaluronidases in tumour progression and metastasis. Oligosaccharides of degraded HA have been ascribed a number of biological functions that are not exerted by high-molecular-weight HA (HMW-HA). However, whether these small HA oligosaccharides (sHA) have a role in tumour progression currently remains uncertain due to an inability to analyse their concentration in tumours. METHODS: We report a novel method to determine the concentration of sHA ranging from 6 to 25 disaccharides in tumour interstitial fluid (TIF). Levels of sHA were measured in TIF from experimental rat tumours and human colorectal tumours. RESULTS: While the majority of HA in TIF is HMW-HA, concentrations of sHA up to 6 µg ml(-1) were detected in a subset of tumours, but not in interstitial fluid from healthy tissues. In a cohort of 72 colorectal cancer patients we found that increased sHA concentrations in TIF are associated with lymphatic vessel invasion by tumour cells and the formation of lymph node metastasis. CONCLUSIONS: These data document for the first time the pathophysiological concentration of sHA in tumours, and provide evidence of a role for sHA in tumour progression.

[Neuroendocrine neoplasms of the distal jejunum and ileum]. / Neuroendokrine Neoplasien des distalen Jejunums und Ileums.

Neuroendocrine neoplasms (NEN) of the distal jejunum and ileum derive from serotonin-producing enterochromaffin (EC) cells. Due to their low proliferation rate and their infiltrative growth, they are often discovered at an advanced disease stage when metastasis has already occurred. The biology of these tumours is different from other NEN of the digestive tract. In order to standardise and improve diagnosis and therapy, the guidelines for the diagnosis and clinical management of jejuno-ileal NEN as well as for the management of patients with liver and other distant metastases from NEN were revised by the European Neuroendocrine Tumour Society (ENETS) in 2012. This review focuses on aspects relevant for surgical pathology.

Establishment of robust controls for the normalization of miRNA expression in neuroendocrine tumors of the ileum and pancreas.

There is need to determine tissue-specific robust controls for normalization of microRNA expression to avoid false results and misinterpretation. The aim of this study was to evaluate the expression of different small RNAs in neuroendocrine tumors (NETs) and their suitability as normalizers in miRNA real-time PCR experiments. We investigated the expression of the nine small RNAs miR-93, miR-191, SNORD48, SNORD61, SNORD68, SNORD72, SNORD95, SNORD96a, and RNU6-2 in formalin-fixed, paraffin-embedded tissue samples of 25 ileal NETs by real-time PCR determining the most stable controls for expression normalization using four different algorithms. This analysis was expended to ten pancreatic NETs. Finally, five small RNAs were further tested as normalizers for miRNA-133a expression, which is known to be downregulated in metastases of ileal NETs, in ten matched pairs of ileal NETs and their metastases. Ranking of the expression results revealed the following order of stability from high to low: SNORD61 < SNORD95 < SNORD72 < SNORD96a < SNORD68 < miR-191 < miR-93 < RNU6-2 < SNORD48 for ileal NETs and SNORD95 < miR-93 < SNORD96a < SNORD61 < SNORD68 < SNORD72 < RNU6-2 < miR-191 < SNORD48 for pancreatic NETs. The determination of SNORD61 and SNORD95 for ileal NETs and SNORD95 and miR-93 for pancreatic NETs as good normalizers presents a useful tool for experiments involving the analysis of miRNA expression.

FOLFIRINOX as first-line treatment for unresectable acinar cell carcinoma of the pancreas: a case report.

Pancreatic acinar cell carcinoma (ACC) is a rare, aggressive variant of pancreatic ductal adenocarcinoma. Surgery is the only curative treatment option and protocols for palliative chemotherapies in this context are not standardized yet. We reported a 63-year-old white male patient who had painless jaundice, weight loss, elevated bilirubin, and a mass of the pancreatic head as well as liver metastasis. Core biopsy revealed the diagnosis of ACC. Therapy with FOLFIRINOX resulted in a significant decrease of the primary tumor and regressiveness of a liver metastasis after chemotherapy. Our report suggests that pancreatic ACC treated by FOLFIRINOX is well tolerated and might be superior to other single chemotherapies in this rare tumor disease.

[Mesothelial proliferation in rectal cancer]. / Mesotheliale Proliferate bei Rektumkarzinom.

In an epiphrenic lymph node of a 55 years old female patient who underwent surgical resection of a rectal adenocarcinoma epitheloid proliferations with papillary and solid growth pattern were seen additional to a metastasis of the carcinoma. Adjacent vessels contained similar infiltrates. Immunohistochemically a co-expression of pan-keratin, calretinin and WT1 was seen, suggestive for a diagnosis of a metastasis of a malignant mesothelioma. However, radiologic examination yielded no morphologic correlate to this suspicion. Further immunohistochemical work-up showed positivity for desmin, negativity for EMA, GLUT1, p53 and a low ki67-fraction of 2-3 %. Therefore, a final diagnosis of benign mesothelial proliferations disseminated into the lymph node and the adjacent vessels was made.

[Will molecular diagnostics become established in pancreatic pathology?]. / Findet die molekulare Diagnostik Einzug in die Pankreaspathologie?

Genetic alterations of solid and cystic tumors of the pancreas have been increasingly more characterized over the last few years. Pancreatic ductal adenocarcinoma (PDAC) carries numerous point mutations and, to a lesser extent, deletions and amplifications of genes that are associated with at least 13 tumor relevant signalling pathways and processes. Besides the four common driver mutations in the KRAS, p53, CDKN2a and SMAD4 genes there are a number of low frequency driver mutations. The classification of PDAC subtypes has benefited from recent analyses of transcriptional profiles that revealed a classical KRAS driven and a KRAS independent quasi-mesenchymal subtype. The analyses of mRNA and miRNA expression profiles of fine needle aspirates serve as a basis for reliable preoperative diagnosis of pancreatic masses.The four most common cystic pancreatic tumors bear tumor-specific genetic alterations, such as GNAS mutations in intraductal papillary mucinous neoplasms, ß-catenin mutations in solid pseudopapillary neoplasms and VHL mutations or loss of heterozygosity in serous cystadenoma. Recovery of DNA from aspirates of cyst fluids enables an improved preoperative management of cystic pancreatic tumors by mutational analysis. In addition to the analysis of DNA there are promising approaches in distinguishing benign and premalignant/malignant cystic tumors by evaluating miRNA profiles.In recent years much progress has been made in molecular genetic characterization and preoperative evaluation of pancreatic tumors. Hopefully these results will contribute to prognostic and therapeutic stratification of PDAC and to a reliable preoperative diagnostics of benign cystic pancreatic tumors in the future.

Dipeptidase 1 (DPEP1) is a marker for the transition from low-grade to high-grade intraepithelial neoplasia and an adverse prognostic factor in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Improvements in the understanding of its molecular mechanism and the characterisation of CRC-specific biomarkers facilitating early detection are considered to increase overall survival. METHODS: A meta-analysis of microarray and Serial Analysis of Gene Expression (SAGE) has been performed to identify differentially regulated genes in CRC. Dipeptidase 1 (DPEP1/MDP/RDP) and Syntenin-2 (SDCBP2/SITAC18) were found to be differentially expressed in tumour tissue compared with normal mucosa. Expression of DPEP1 was assessed in a validation set of 87 normal mucosa samples, 20 hyperplastic polyps, 46 CR adenomas with low- and high-grade intraepithelial neoplasia (IEN) and 217 well-documented CRCs by immunohistochemistry and partially by immunoblotting and real-time PCR. RESULTS: Expression of DPEP1 was specifically increased in human CRC tissue samples compared with normal mucosa (P<0.0001, Mann-Whitney U-test), showing a striking upregulation in high-grade compared with low-grade IEN. Furthermore, high DPEP1 expression was found to strongly correlate with histological stage (P<0.0001, chi-square test) as well as localisation (P<0.0001, chi-square test) and has been recognised as an independent adverse prognostic factor, showing significant prognostic values with an ROC (receiver operating characteristic)-AUC of 0.9230. CONCLUSION: Dipeptidase 1 has been identified as an excellent marker of high-grade IEN and CRC, and may thus be applied for screening of early neoplastic lesions and for prognostic stratification.

Limited disease of extra-pulmonary small cell carcinoma. Impact of local treatment and nodal status, role of cranial irradiation.

PURPOSE: As extra-pulmonary small cell carcinoma (EPSCC) is a rare entity of tumors, the available treatment recommendations are mainly based on retrospective analyses and deduction from treatment of small cell lung cancer. The aim of this study was to provide a detailed analysis concerning prognostic factors and treatment modalities. PATIENTS AND METHODS: A total of 20 patients with limited disease (LD) of EPSCC treated at our institution from 1999­2009 were retrospectively analyzed. Data were gathered from chart review. Localization, lymph node involvement, as well as local and systemic treatment were documented and their impact on pattern of failure and survival times statistically evaluated. RESULTS: With a median follow-up of 21 months, the estimated median overall- and disease-free survival were 59 and 25 months, respectively. Local control was excellent with 100% at 2 years. Nodal involvement was observed in 74% (n = 14/19) of evaluable patients. However, outcome was not altered by this parameter. Local treatment consisted of surgery in 10 cases, radiotherapy in 7 cases, and a combination of both in 3 cases. Only 3 patients (15%) developed hematogenous central nervous system metastases, while none of the patients received prophylactic cranial irradiation. CONCLUSION: Nodal involvement did not worsen prognosis. Local control was excellent irrespective of local treatment modality and the leading cause of failure was distant metastasis. Therefore, systemic treatment should not be omitted. Prophylactic cranial irradiation might be dispensable but discussed for head and neck malignancies.

Differentiation potential of pancreatic fibroblastoid cells/stellate cells: effects of peroxisome proliferator-activated receptor gamma ligands.

Pancreatic stellate cells have been investigated mostly for their activation process, supposed to support the development of pancreatic disease. Few studies have been presented on reversal of the activation process in vitro. Thiazolidinediones (TZDs) have been used as antidiabetics and have now been reported to exert antifibrotic activity. We tested effects of natural and synthetic ligands of peroxisome proliferator-activated receptor gamma (PPARγ) on human pancreatic fibroblastoid cells (hPFCs) in search for specificity of action. Ciglitazone, as a prototype of TZDs, was shown to have reversible growth inhibitory effects on human pancreatic fibroblastoid cells/stellate cells. Cells treated with ciglitazone for three days showed enhanced lipid content and induction of proteins involved in lipid metabolism. Collagen synthesis was reduced in hPFC. Interaction of PPARγ with DNA binding sites upon ligand binding was shown by gel shift analysis. These findings point toward a potential for adipocyte differentiation in human pancreatic fibroblastoid cells.

[Precursor lesions of pancreatobiliary cancer]. / Vorläuferläsionen pankreatobiliärer Karzinome.

Precursor lesions of pancreatobiliary cancer can be divided into cystic and flat lesions. Mucinous cystic neoplasm and intraductal papillary mucinous neoplasm (IPMN) comprise the cystic precursors in the pancreas, while intraductal papillary neoplasm (IPN) represents their counterpart in the bile duct system. There is an adenoma-carcinoma sequence in the cystic precursors arising from four different types of epithelia: pancreatobiliary, oncocytic, intestinal and gastric. These subtypes of IPMN/IPN are morphologically and immunohistochemically well characterised and show clinical and prognostic relevance: the gastric subtype is associated with the best prognosis, followed by the oncocytic and intestinal subtypes, while the pancreatobiliary subtype is characterized by adverse clinical behaviour. Pancreatic intraepithelial neoplasia (PanIN) and biliary intraepithelial neoplasia (BilIN) represent the flat precursors. PanIN are morphologically and biologically well defined. PanIN with lobulocentric atrophy has recently been described as a putative precursor of pancreatic cancer. Despite well defined morphological features in BilIN, the molecular alterations seen during early tumor progression in the biliary tract are poorly understood.