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Background: Electrosurgery is fundamental to the precise, fast and bloodless preparation of internal thoracic artery grafts in cardiac surgery. The PEAK PlasmaBlade is a monopolar electrosurgical device that uses pulsed radiofrequency energy to generate a plasma-mediated discharge along an insulated electrode, creating a cutting edge while the blade stays near body temperature. The aim of this study is to compare the histological samples, cardiac computed-tomography of graft patency, and clinical outcomes of patients after off-pump coronary artery bypass grafting with preparation of the internal thoracic arteries by a conventional electrosurgical device and the PlasmaBlade.Methods: In twenty subjects one internal thoracic artery was prepared with PlasmaBlade and the other artery with a conventional electrosurgical device. Histological samples were evaluated for three factors for potential graft failure: endothelial damage, integrity of the vessel wall and adventitial hemorrhage. Five samples per artery were evaluated by a novel scoring method based on the exposed circumference of the histological sample ("0": 0%, "1": 1-25%, "2": 26-50%, "3": 51-75%, "4": ≥76% of the circumference). The Wilcoxon signed ranks test for mean scores within subjects was performed. Six-month-follow up by cardiac computed tomography for evaluation of graft patency was completed in 16 patients.Results: Histological results demonstrated significantly less endothelial damage after PlasmaBlade (83% vs 60%, absolute: 75/90 vs. 53/89 samples with score "0-1", p = 0.04). PlasmaBlade samples demonstrated a tendency to better wall integrity (72% vs. 54%, absolute: 64/89 vs. 47/87 samples with score "0-1", p = 0.32). There were no differences in endothelial bleeding (PlasmaBlade 46% vs. electrosurgery 53%, absolute: 41/88 vs. 48/90 samples with score "0-1", p = 0.63). Computed tomography confirmed non-inferiority of the PlasmaBlade to conventional electrosurgery with a patency rate of 94%.Conclusion: Histologically, internal thoracic arteries harvested with PlasmaBlade demonstrate a more intact endothelial layer and a tendency to better wall integrity. Computed tomography of graft patency speaks for non-inferiority to conventional electrosurgery. PlasmaBlade may be preferable to conventional electrosurgery, if further follow-up confirms patency of internal thoracic arteries.Trial Registration: NCT03510026 , registered 4th April 2018 (retrospectively registered). [ABSTRACT FROM AUTHOR]

Objective: To report first-hand narrative experience of autoimmune encephalitis and to briefly review currently available evidence of autoimmune encephalitis in cancer patients treated with immune checkpoint inhibitors. Setting: A case study is presented on the management of a patient who developed autoimmune encephalitis during nivolumab monotherapy occurring after 28 weeks on anti-PD-1 monotherapy (nivolumab 3 mg/kg every 2 weeks) for non-small cell lung cancer. Results: No substantial improvement was observed by antiepileptic treatment. After administration of 80 mg methylprednisolone, neurologic symptoms disappeared within 24 h and the patient fully recovered. Conclusions: Immune checkpoint inhibitor treatment can lead to autoimmune encephalitis. Clinical trial data indicate a frequency of autoimmune encephalitis of =0.1 to <1% with a higher probability during combined or sequential anti-CTLA-4/anti-PD-1 therapy than during anti-PD-1 or anti-PD-L1 monotherapy. Further collection of evidence and translational research is warranted. [ABSTRACT FROM AUTHOR]

Reports on developments in several aspects of endocrine pathology. Update on the pathology of the adrenal medulla and related paraganglia; Characteristics of multiple endocrine neoplasia type 1; Clinical features of familial paraganglioma-pheochromactoma syndrome; Pathogenesis of pituitary tumor.

Molecular diagnosis of autosomal dominant acute hepatic porphyrias (AHPs) plays an important role in the management of these disorders. To introduce next generation sequencing (NGS) to the porphyria diagnosis, we designed a panel that contained four genes, ALAS1, HMBS, CPOX and PPOX for mutational analysis of acute intermittent porphyria (AIP), hereditary coproporphyria (HCP) and variegate porphyria (VP). To validate the AHP panel, 30 samples with known pathogenic variants as determined by Sanger sequencing, were analyzed using the Ion PGM™. Among them, nine have so far not been reported. The pathogenic variants were identified and annotated manually in IGV by three individuals who were blinded to the Sanger results. The AHP panel consists of 95 amplicons that covers 92% of the coding region of the four genes. Of the 95 amplicons, 93 had an average read-depth of >500 reads. In 29 of the 30 tested samples, pathogenic variants were correctly identified and annotated. The number of reads from the mutated alleles were approximately 50% of the total. The annotation of a 22-bp duplication with NGS differed from that of Sanger by one nucleotide. NGS showed an advantage in allelic discrimination over Sanger sequencing and was also able to detect a known somatic variant in the HMBS gene. The AHP panel will be applied in the initial diagnosis of new patients. Any sequence variations with a frequency of ≥10% will be confirmed by Sanger sequencing. The cost-effectiveness of a NGS approach for AHP in a diagnostic laboratory needs to be further assessed. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a three-tier (WHO-AJCC 2010) to a four-tier system by introducing the novel category of NET G3 (WHO-AJCC 2017). Objectives: This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. Method: A total of 2,102 patients were enrolled; entry criteria were: (i) patient underwent surgery; (ii) at least 2 years of follow-up; (iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan-Meier method, Cox regression analysis, Harrell's C statistics, and Royston's explained variation in univariable and multivariable analyses. Results: In descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. In Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS; however, no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. In multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. Conclusions: The WHO-AJCC 2017 grading system is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for predicting patient survival. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) enables parallel analysis of multiple genomic targets. The increasing demand for NGS-based multiplexed molecular diagnostics requires standardized protocols and recommendations to ensure reproducibility and accuracy of test results for routine clinical decision making. However, the lack of clinical NGS data from multi-laboratory tests and the absence of inter-laboratory comparisons have hampered the establishment of instructive clinical NGS standards. To fill the gap, we set up Proficiency Testing (PT) for inter-laboratory comparison, in which formalin-fixed paraffin-embedded specimens from eight lung and eight colon cancers were analyzed by 15 European molecular diagnostic laboratories on three different platforms using multiple target enrichment systems. We first performed platform, test, and informatics pipeline validation and conducted sensitivity and specificity analysis by random in silico down-sampling. We then implemented a multi-level filtering strategy based on performance tests of base substitution, replicate runs, and Sanger sequencing verified variants. We finally applied the filter criteria to the NGS data from the respective PT participants and obtained high inter-laboratory agreement. We demonstrated accuracy, scalability, and robustness of NGS by means of PT, serving as a benchmark for detecting clinically actionable molecular alterations in research and diagnostic laboratories. In conclusion, this study strongly highlights the importance of establishing standards for NGS-based testing, particularly when the test results impact on clinical decisions, and systematically provides data sets from multiple different labs to infer such standards. [ABSTRACT FROM AUTHOR]

Background: Although the majority of solitary fibrous tumors of the pleura (SFTP) follow a benign course, 10-25% of patients suffer from recurrence or metastatic disease. Several scoring models have been proposed to predict the outcome. However, none of these included immunohistochemical (IHC) markers as possible prognosticators.Methods: In this multicenter study, we collected clinical data and formalin-fixed and paraffin-embedded (FFPE) tissue blocks of patients with histologically proven SFTP which had been surgically resected between 2000 und 2015. After systematic and extensive IHC staining on tissue microarrays, the results were analyzed and compared to histomorphological and clinical data for their possible prognostic value.Results: In total, 78 patients (mean age 61 ± 11 years) were included. Of these, 9 patients (11%) had an adverse outcome including SFTP recurrence (n = 6) or SFTP-related death (n = 3). Mean overall survival was 172 ± 13 months. 1 and 10-year event-free survival rates were 99% and 93%. In the multivariable analysis only MIB-1 proliferation index (Ki-67) ≥10% (HR 12.3, CI 1.1-139.5, p = 0.043), ≥4 mitoses per 10 high power fields (HR 36.5, CI 1.2-1103.7, p = 0.039) and tumor size larger than 10 cm (HR 81.8, CI 1.7-4016.8, p = 0.027) were independently associated with adverse outcome.Conclusion: A high proliferation rate by MIB-1 IHC was associated with impaired outcome. Upon this, we established a new score using mitosis, necrosis, size of the tumor and MIB-1, which performed better than the traditional scores in our data set. This prognostic score could help to better evaluate outcome of SFTP, but requires external validation. [ABSTRACT FROM AUTHOR]

The tall cell (TC) variant of papillary thyroid carcinoma (PTC) has an unfavorable prognosis. The diagnostic criteria remain inconsistent, and the role of a minor TC component is unclear. Molecular diagnostic markers are not available; however, there are two potential candidates: BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutations. Using a novel approach, we enriched a collective with PTCs that harbored an adverse outcome, which overcame the limited statistical power of most studies. This enabled us to review 125 PTC patients, 57 of which had an adverse outcome. The proportion of TCs that constituted a poor prognosis was assessed. All of the tumors underwent sequencing for TERT promoter and BRAF V600E mutational status and were stained with an antibody to detect the BRAF V600E mutation. A 10% cutoff for TCs was significantly associated with advanced tumor stage and lymph node metastasis. Multivariate analysis showed that TCs above 10% were the only significant factor for overall, tumor-specific, and relapse-free survival. Seven percent of the cases had a TERT promoter mutation, whereas 61% demonstrated a BRAF mutation. The presence of TC was significantly associated with TERT promoter and BRAF mutations. TERT predicted highly significant tumor relapse (P<0.001). PTCs comprised of at least 10% TCs are associated with an adverse clinical outcome and should be reported accordingly. BRAF did not influence patient outcome. Nevertheless, a positive status should encourage the search for TCs. TERT promoter mutations are a strong predictor of tumor relapse, but their role as a surrogate marker for TCs is limited. [ABSTRACT FROM AUTHOR]

Variegate porphyria (VP) and acute intermittent porphyria (AIP), the two most common types of acute porphyrias (AHPs), result from a partial deficiency of protoporphyrinogen oxidase (PPOX) and hydroxymethylbilane synthase (HMBS), respectively. A rare but serious complication in the AHPs is hepatocellular carcinoma (HCC). However, the underlying pathomechanisms are yet unknown. We performed DNA sequence analysis in cancerous and non-cancerous liver tissue of a VP and an AIP patient, both with HCC. In samples of both cancerous and non-cancerous liver tissues from the patients, we identified the underlying PPOX and HMBS germline mutations, c.1082dupC and p.G111R, respectively. Additionally, we detected a second somatic mutation, only in the cancer tissue i.e., p.L416X in the PPOX gene of the VP patient and p.L220X in the HMBS gene of the AIP patient, both located in trans to the respective germline mutations. Both somatic mutations were not detected in 10 non-porphyria-associated HCCs. Our data demonstrate that in the hepatic cancer tissue of AHP patients, somatic second-hit mutations result in nearly complete inactivation of the enzymes catalyzing major steps in the heme biosynthetic pathway. Both PPOX and HMBS, which might act as tumor suppressors, play a crucial role in the development of HCC in these individuals. [ABSTRACT FROM AUTHOR]

Background: The tumor suppressor phosphatase and tensin homolog (PTEN) is a pleiotropic enzyme, inhibiting phosphatidyl-inositol-3 kinase (PI3K) signaling in the cytosol and stabilizing the genome in the nucleus. Nucleo-cytosolic partitioning is dependent on the post-translational modifications ubiquitinylation and sumoylation. This cellular compartmentalization of PTEN was investigated in lung neuroendocrine tumors (lung NET). Methods: Tumor tissues from 192 lung NET patients (surgical specimens = 183, autopsies = 9) were investigated on tissue microarrays. PTEN was H-scored by two investigators in nucleus and cytosol using the monoclonal antibody 6H2.1. Results were correlated with immunoreactivity for USP7 (herpes virus-associated ubiquitin-specific protease 7) and SUMO2/3 (small ubiquitin-related modifier protein 2/3) as well as PTEN and p53 FISH gene status. Clinico-pathologic data including overall survival, proliferation rate and diagnostic markers (synaptophysin, chromogranin A, Mib-1, TTF-1) were recorded. Results: The multicentre cohort included 58 typical carcinoids (TC), 42 atypical carcinoids (AC), 32 large cell neuroendocrine carcinomas (LCNEC) and 60 small cell lung carcinomas (SCLC). Carcinoids were smaller in size and had higher synaptophysin and chromogranin A, but lower TTF-1 expressions. Patients with carcinoids were predominantly female and 10 years younger than patients with LCNEC/SCLC. In comparison to the carcinoids, LCNEC/SCLC tumors presented a stronger loss of nuclear and cytosolic PTEN associated with a loss of PTEN and p53. Concomitantly, a loss of nuclear USP7 but increase of nuclear and cytosolic SUMO2/3 was found. Loss of nuclear and cytosolic PTEN, loss of nuclear USP7 and increase of cytosolic SUMO2/3 thus correlated with poor survival. Among carcinoids, loss of cytosolic PTEN was predominantly found in TTF1-negative larger tumors of male patients. Among SCLC, loss of both cytosolic and nuclear PTEN but not proliferation rate or tumor size delineated a subgroup with poorer survival (all p-values <0.05). Conclusions: Cellular ubiquitinylation and sumoylation likely influence the functional PTEN loss in high grade lung NET. Both nuclear and cytosolic PTEN immunoreactivity should be considered for correlation with clinico-pathologic parameters. [ABSTRACT FROM AUTHOR]

Background/Aims: O6-methylguanine-methyltransferase (MGMT) is an important enzyme of DNA repair. MGMT promoter methylation is detectable in a subset of pancreatic neuroendocrine neoplasms (pNEN). A subset of pNEN responds to the alkylating agent temozolomide (TMZ). We wanted to correlate MGMT promoter methylation with MGMT protein loss in pNEN, correlate the findings with clinico-pathological data and determine the role of MGMT to predict response to TMZ chemotherapy. Methods: We analysed a well-characterized collective of 141 resected pNEN with median follow-up of 83 months for MGMT protein expression and promoter methylation using methylation-specific PCR (MSP). A second collective of 10 metastasized, pretreated and progressive patients receiving TMZ was used to examine the predictive role of MGMT by determining protein expression and promoter methylation using primer extension-based quantitative PCR. Results: In both collectives there was no correlation between MGMT protein expression and promoter methylation. Loss of MGMT protein was associated with an adverse outcome, this prognostic value, however, was not independent from grade and stage in multivariate analysis. Promoter hypermethylation was significantly associated with response to TMZ. Conclusion: Loss of MGMT protein expression is associated with adverse outcome in a surgical series of pNET. MGMT promoter methylation could be a predictive marker for TMZ chemotherapy in pNEN, but further, favourably prospective studies will be needed to confirm this result and before this observation can influence clinical routine. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The diagnosis of conventional and oncocytic poorly differentiated (oPD) thyroid carcinomas is difficult. The aimof this study is to characterise their largely unknownmiRNAexpression profile and to compare it withwell-differentiated thyroid tumours, aswell as to identify miRNAswhich could potentially serve as diagnostic and prognosticmarkers. A total of 14poorly differentiated (PD), 13 oPD, 72 well-differentiated thyroid carcinomas and eight normal thyroid specimens were studied for the expression of 768 miRNAs using PCR-Microarrays. MiRNA expression was different between PD and oPD thyroid carcinomas, demonstrating individual clusters on the clustering analysis. Both tumour types showed upregulation of miR-125a-5p, -15a-3p, -182, -183-3p, -222, -222-5p, and downregulation of miR-130b, -139-5p, -150, -193a-5p, -219-5p, -23b, -451, -455-3p and of miR-886-3p as compared with normal thyroid tissue. In addition, the oPD thyroid carcinomas demonstrated upregulation of miR-221 and miR-885-5p. The difference in expression was also observed between miRNA expression in PD and well-differentiated tumours. The CHAID algorithm allowed the separation of PD from well-differentiated thyroid carcinomas with 73-79% accuracy using miR-23b and miR-150 as a separator. Kaplan-Meier and multivariate analysis showed a significant association with tumour relapses (for miR-23b) and with tumour-specific death (for miR-150) in PD and oPD thyroid carcinomas. MiRNA expression is different in conventional and oPD thyroid carcinomas in comparison with welldifferentiated thyroid cancers and can be used for discrimination between these tumour types. The newly identified deregulatedmiRNAs (miR-150,miR-23b) bear the potential to be used in a clinical setting, delivering prognostic and diagnostic informations. [ABSTRACT FROM AUTHOR]

Background: Follicular variant of papillary thyroid carcinoma (FVPTC) shares features of papillary (PTC) and follicular (FTC) thyroid carcinomas on a clinical, morphological, and genetic level. MicroRNA (miRNA) deregulation was extensively studied in PTCs and FTCs. However, very limited information is available for FVPTC. The aim of this study was to assess miRNA expression in FVPTC with the most comprehensive miRNA array panel and to correlate it with the clinicopathological data. Methods: Forty-four papillary thyroid carcinomas (17 FVPTC, 27 classic PTC) and eight normal thyroid tissue samples were analyzed for expression of 748 miRNAs using Human Microarray Assays on the ABI 7900 platform (Life Technologies, Carlsbad, CA). In addition, an independent set of 61 tumor and normal samples was studied for expression of novel miRNA markers detected in this study. Results: Overall, the miRNA expression profile demonstrated similar trends between FVPTC and classic PTC. Fourteen miRNAs were deregulated in FVPTC with a fold change of more than five (up/down), including miRNAs known to be upregulated in PTC (miR-146b-3p, -146-5p, -221, -222 and miR-222-5p) and novel miRNAs (miR-375, -551b, 181-2-3p, 99b-3p). However, the levels of miRNA expression were different between these tumor types and some miRNAs were uniquely dysregulated in FVPTC allowing separation of these tumors on the unsupervised hierarchical clustering analysis. Upregulation of novel miR-375 was confirmed in a large independent set of follicular cell derived neoplasms and benign nodules and demonstrated specific upregulation for PTC. Two miRNAs (miR-181a-2-3p, miR-99b-3p) were associated with an adverse outcome in FVPTC patients by a Kaplan-Meier ( p<0.05) and multivariate Cox regression analysis ( p<0.05). Conclusions: Despite high similarity in miRNA expression between FVPTC and classic PTC, several miRNAs were uniquely expressed in each tumor type, supporting their histopathologic differences. Highly upregulated miRNA identified in this study (miR-375) can serve as a novel marker of papillary thyroid carcinoma, and miR-181a-2-3p and miR-99b-3p can predict relapse-free survival in patients with FVPTC thus potentially providing important diagnostic and predictive value. [ABSTRACT FROM AUTHOR]

Aims Follicular thyroid carcinoma ( FTC) has been a diagnostic challenge for decades. The PAX8- PPARγ rearrangement has been detected in FTC and classic papillary thyroid carcinomas ( PTCs). The aims of this study were to assess the presence of PAX8- PPARγ by using tissue microarrays in a large cohort of different thyroid neoplasms, and to assess its diagnostic and prognostic implications. Methods and results Fluorescence in-situ hybridization ( FISH) analysis for PAX8- PPARγ was performed on 226 thyroid tumours, comprising FTCs ( n = 59), PTCs ( n = 126), poorly differentiated thyroid carcinomas ( PDs; n = 34), follicular thyroid adenomas ( FTAs; n = 5), and follicular tumours of unknown malignant potential ( FTUMPs; n = 2). PAX8- PPARγ was detected in 12% of FTCs, 1% of PTCs, 7% of PDs, and in both cases of FTUMP. There was no correlation between the extent of capsular or vascular invasion and PAX8- PPARγ, or between lymph node or haematogenous metastasis and PAX8- PPARγ. Overall survival ( OS), tumour-specific survival ( TSS) and relapse-free-survival ( RFS) were not influenced by PAX8- PPARγ. Conclusions In this study, we demonstrate for the first time the presence of PAX8- PPARγ in PDs and FTUMPs, whereas in FTCs and PTCs the prevalence of PAX8- PPARγ is lower than previously reported. PAX8- PPARγ did not correlate with invasiveness or affect prognosis in any tumour type. [ABSTRACT FROM AUTHOR]

Objectives: To assess the diagnostic accuracy of 64-multidetector CT (MDCT) for restaging of patients with oesophageal cancer undergoing neoadjuvant therapy. Methods: Results of pathological staging were correlated with those from 64-MDCT before and after neoadjuvant treatment in 35 patients using the American Joint Committee on Cancer/TNM classification (7th edition). CT response was determined using the Response Evaluation Criteria in Solid Tumours (RECIST) method, modified for one-dimensional tumour diameter measurement. Results: 64-MDCT predicted T stage correctly in 34 % (12/35), overstaged in 49 % (17/35) and understaged in 17 % (6/35). Sensitivity/specificity values were as follows: T0, 20 %/92 %; T1-T2, 31 %/59 %; T3, 60 %/64 %; T4, 100 %/4 %. Negative predictive values for T3/T4 were 80 %/100 %. MDCT accurately predicted complete histopathological response in 20 % (accuracy 74 %) and overstaged in 80 %. Tumour regression grade was predicted correctly in only 8 % (2/25) and underestimated in 68 % (17/25). Accurate N stage was noted in 69 % (24/35). Conclusion: Although MDCT tends to be able to exclude advanced tumour stages (T3, T4) with a higher likelihood, the diagnostic accuracy of high resolution MDCT for restaging oesophageal cancer and assessing the response to neoadjuvant therapy has not improved in comparison to older-generation CT. Therefore, the future assessment of oesophageal tumour response should focus on combined morphologic and metabolic imaging. Key Points: • Multidetector CT (MDCT) has been beneficial for the evaluation of many tumours. • However diagnostic accuracy for restaging oesophageal cancer has not improved with MDCT. • MDCT tends to be able to exclude advanced tumour stages (T3/T4). • MDCT has a low accuracy for determining lymph node metastasis. • Oesophageal tumour response should be assessed by combined morphological and metabolic imaging. [ABSTRACT FROM AUTHOR]

Dettmer M, Schmitt A, Steinert H, Moch H, Komminoth P & Perren A (2012) Histopathology 60, 1045-1051 Poorly differentiated oncocytic thyroid carcinoma - diagnostic implications and outcome Aims: Poorly differentiated thyroid carcinomas (PDTC) are an ongoing diagnostic challenge. Although the Turin consensus criteria for PDTC excluded consideration of oncocytic tumours, the World Health Organization (WHO) classification does recognise an oncocytic variant of conventional PDTC. The aims of this study were to establish whether the Turin criteria can be applied to oncocytic PDTC, and to determine if there are prognostic differences between conventional and oncocytic PDTC. Methods and results: We applied the Turin criteria to 129 thyroid carcinomas. We identified 18 oncocytic PDTC and 16 conventional PDTC. Kaplan-Meier analysis revealed a significantly worse outcome for oncocytic PDTC with regard to overall and tumour-specific survival but no difference for relapse-free survival, all of which were confirmed by multivariate analysis. There was no association of survival with gender, age or tumour stage. Conclusions: The Turin criteria can be applied to oncocytic PDTC and patients with this variant have a decreased survival using conventional radioiodine treatment compared to conventional PDTC and might therefore be candidates for novel treatment modalities. [ABSTRACT FROM AUTHOR]

No abstract available Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article discusses guidelines for treatment of bone and lung metastases from neuroendocrine tumors (NETs) recommended by the European Neuroendocrine Tumor Society. The prevalence of gastroenteropancreatic neuroendocrine tumors are considered rare and often at an advance stage when detected in patients. Bone and lung metastases are frequent complications of the disease. Clinical presentations and prognosis of the disease are presented. A multimodal approach emphasizing quality of life and survival of patients in the treatment of NETs is recommended.

The purpose of this guideline is to assist physicians caring for patients with neuroendocrine tumors in considering eligibility criteria for peptide receptor radionuclide therapy (PRRT), and in defining the minimum requirements for PRRT. This guideline also makes recommendations on what minimal patient, tumor, and treatment outcome characteristics should be reported for PRRT in order to make comparisons between studies possible. It is not this guideline’s aim to give specific recommendations on the use of specific radiolabeled somatostatin analogs for PRRT because different analogs are being used, and their availability depends on national law and local permissions. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article presents guidelines formulated at the 2007 European Neuroendocrine Tumor Society (ENETS) Standards of Care Conference on the approach to the morphological diagnosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETS). The needs and options for the process include the use of tissue from GEP-NETS obtained from biopsy or the surgical removal of the tissue. A special challenge in the classification is posed by gastrointestinal and pancreatic adenocarcinomas with mixed differentiation.

Summary: Background: Phaeochromocytomas and paragangliomas are neuro-endocrine tumours that occur sporadically and in several hereditary tumour syndromes, including the phaeochromocytoma–paraganglioma syndrome. This syndrome is caused by germline mutations in succinate dehydrogenase B (SDHB), C (SDHC), or D (SDHD) genes. Clinically, the phaeochromocytoma–paraganglioma syndrome is often unrecognised, although 10–30% of apparently sporadic phaeochromocytomas and paragangliomas harbour germline SDH-gene mutations. Despite these figures, the screening of phaeochromocytomas and paragangliomas for mutations in the SDH genes to detect phaeochromocytoma–paraganglioma syndrome is rarely done because of time and financial constraints. We investigated whether SDHB immunohistochemistry could effectively discriminate between SDH-related and non-SDH-related phaeochromocytomas and paragangliomas in large retrospective and prospective tumour series. Methods: Immunohistochemistry for SDHB was done on 220 tumours. Two retrospective series of 175 phaeochromocytomas and paragangliomas with known germline mutation status for phaeochromocytoma-susceptibility or paraganglioma-susceptibility genes were investigated. Additionally, a prospective series of 45 phaeochromocytomas and paragangliomas was investigated for SDHB immunostaining followed by SDHB, SDHC, and SDHD mutation testing. Findings: SDHB protein expression was absent in all 102 phaeochromocytomas and paragangliomas with an SDHB, SDHC, or SDHD mutation, but was present in all 65 paraganglionic tumours related to multiple endocrine neoplasia type 2, von Hippel–Lindau disease, and neurofibromatosis type 1. 47 (89%) of the 53 phaeochromocytomas and paragangliomas with no syndromic germline mutation showed SDHB expression. The sensitivity and specificity of the SDHB immunohistochemistry to detect the presence of an SDH mutation in the prospective series were 100% (95% CI 87–100) and 84% (60–97), respectively. Interpretation: Phaeochromocytoma–paraganglioma syndrome can be diagnosed reliably by an immunohistochemical procedure. SDHB, SDHC, and SDHD germline mutation testing is indicated only in patients with SDHB-negative tumours. SDHB immunohistochemistry on phaeochromocytomas and paragangliomas could improve the diagnosis of phaeochromocytoma–paraganglioma syndrome. Funding: The Netherlands Organisation for Scientific Research, Dutch Cancer Society, Vanderes Foundation, Association pour la Recherche contre le Cancer, Institut National de la Santé et de la Recherche Médicale, and a PHRC grant COMETE 3 for the COMETE network. [Copyright &y& Elsevier]

The article presents consensus guidelines on the management of patients with well-differentiated colon and rectum carcinoma. It discusses the classification and epidemiology of colon tumours and rectal tumours as well as their clinical presentation and prognosis. It also outlines several diagnostic procedures such as endoscopy, endoanal/rectal ultrasound, and computed tomography.

The article discusses a study on gastric endocrine tumors (GET). It found that current incidence of GET is estimated at around 8 percent of digestive endocrine tumors. It emphasizes that the yearly age-adjusted incidence of gastric type 1 and 2 endocrine tumors is approximately 0.2 per population of 100,000. It stresses that pathological diagnosis is mandatory in all cases and is easily obtained from tumor biopsies performed during gastroscopy.

Determines whether tumor suppresor gene SDHD plays a role in the development of sporadic neuroendocrine tumors (NET). Description of the tumors of the diffuse neuroendocrine system; Inheritance pattern of the disease phenotype of familial PGL1 caused by SDHD mutations; Lack of somatic SDHD mutations in NET of the lung, gastrointestinal trace, pancreas and parathyroids.

Five percent of papillary thyroid carcinomas (PTC) show an adverse clinical outcome (ACO). The tall cell variant of papillary thyroid carcinomas (TCV) is a good predictor of an ACO, however, the identification of tall-cells is subjective. Micro RNAs are short non-coding ribonucleic acids (miRNA). Their expression in PTC could be a powerful, more objective predictor of prognosis. Methods: Forty-four PTC underwent miRNA profiling, twenty-four of them were TCV. The miRNA dataset was validated by analysis of expression of known target proteins (vascular endothelial growth factor (VEGF) and phosphatase and tensin homolog (PTEN)) in 125 patients including 48 TCV and 57 with an ACO. Results: One hundred and forty-nine miRNAs were significantly associated with an ACO, seventy-one of them with TC-morphology. Twenty-two miRNAs were identified as targets for VEGF and thirty-two as targets for PTEN. In univariate and multivariable analysis, reduced expression of PTEN and an increased expression of VEGF were associated with shorter relapse free survival. A classifier, including TC-morphology, pT-stage, VEGF, and PTEN, predicted relapse with an 80% accuracy. Conclusions: Some miRNAs predict outcome in PTC and are involved in TC-morphology in PTC. These miRNAs may serve as more objective indicators of an ACO than tall cell morphology. PTEN and VEGF protein expression are prognostically relevant and are at least partially regulated by miRNAs. [ABSTRACT FROM AUTHOR]

Background: The tumor suppressor phosphatase and tensin homolog (PTEN) is a pleiotropic enzyme, inhibiting phosphatidyl-inositol-3 kinase (PI3K) signaling in the cytosol and stabilizing the genome in the nucleus. Nucleo-cytosolic partitioning is dependent on the post-translational modifications ubiquitinylation and sumoylation. This cellular compartmentalization of PTEN was investigated in lung neuroendocrine tumors (lung NET).Methods: Tumor tissues from 192 lung NET patients (surgical specimens = 183, autopsies = 9) were investigated on tissue microarrays. PTEN was H-scored by two investigators in nucleus and cytosol using the monoclonal antibody 6H2.1. Results were correlated with immunoreactivity for USP7 (herpes virus-associated ubiquitin-specific protease 7) and SUMO2/3 (small ubiquitin-related modifier protein 2/3) as well as PTEN and p53 FISH gene status. Clinico-pathologic data including overall survival, proliferation rate and diagnostic markers (synaptophysin, chromogranin A, Mib-1, TTF-1) were recorded.Results: The multicentre cohort included 58 typical carcinoids (TC), 42 atypical carcinoids (AC), 32 large cell neuroendocrine carcinomas (LCNEC) and 60 small cell lung carcinomas (SCLC). Carcinoids were smaller in size and had higher synaptophysin and chromogranin A, but lower TTF-1 expressions. Patients with carcinoids were predominantly female and 10 years younger than patients with LCNEC/SCLC. In comparison to the carcinoids, LCNEC/SCLC tumors presented a stronger loss of nuclear and cytosolic PTEN associated with a loss of PTEN and p53. Concomitantly, a loss of nuclear USP7 but increase of nuclear and cytosolic SUMO2/3 was found. Loss of nuclear and cytosolic PTEN, loss of nuclear USP7 and increase of cytosolic SUMO2/3 thus correlated with poor survival. Among carcinoids, loss of cytosolic PTEN was predominantly found in TTF1-negative larger tumors of male patients. Among SCLC, loss of both cytosolic and nuclear PTEN but not proliferation rate or tumor size delineated a subgroup with poorer survival (all p-values <0.05).Conclusions: Cellular ubiquitinylation and sumoylation likely influence the functional PTEN loss in high grade lung NET. Both nuclear and cytosolic PTEN immunoreactivity should be considered for correlation with clinico-pathologic parameters. [ABSTRACT FROM AUTHOR]