Evaluation of histological dynamics, kidney function and diabetes in liver transplant patients after antiviral treatment with direct-acting antivirals: Therapy of HCV-recurrence.

BACKGROUND: Direct-acting antivirals allow efficient and safe treatment of hepatitis C (HCV) before and after liver transplantation (LT). However, the impact of sofosbuvir on the graft, diabetes, and on kidney function is not answered yet. Primary endpoint of this analysis was the evaluation of kidney function after antiviral treatment (AVT). Secondary endpoints were the assessment of extrahepatic manifestation of HCV-infection by diabetes mellitus and the histopathological changes in terms of inflammation, content of fat, and fibrosis stage. METHODS: From 2014 to 4/2015, 100 patients with HCV-recurrence after LT were successfully treated with AVT. Ninety-eight received a sofosbuvir-based regimen. Indication was based on genotype, transplant fibrosis stage, and urgency. Biopsies were evaluated before and after treatment. Renal function and diabetes were assessed before, during, and after AVT. RESULTS: All patients achieved sustained virological response. A significant improvement of inflammation (P = 0.001) and fibrosis stage (P = 0.031) were observed. Significantly less insulin was required in 32 patients with diabetes (P < 0.001) to keep Hb1Ac unchanged after AVT. Kidney function was stable during, 12 weeks after and 48 weeks after antiviral therapy. Stages of renal insufficiency were comparable before and after AVT. CONCLUSION: Successful sofosbuvir-based AVT leads to a variety of positive development in transplant patients including a significant improvement of inflammation, fat content and fibrosis, a significant decrease in daily insulin dose and no significant impairment of kidney function.

Calcified Liver Metastases from a Neuroendocrine Tumor of the Lung (Atypical Carcinoid) - A Case Report.

Pulmonary neuroendocrine tumors (NETs) are rare tumors with an incidence rate of 0.2-2/100 000 population/year in Western countries (M. E. Caplin et al. Ann Oncol 2015; 26:1604-20). They account for 1-2% of all neoplasms of the lung and constitute one-fourth to one-third of all NETs. Atypical carcinoids are far less common than typical carcinoids and predominantly occur in male smokers aged 50 -70 years. Most pulmonary NETs are asymptomatic due to their peripheral location. Surgical resection is the treatment of choice. Medical management should take hormone-related symptoms into account.

Inflammatory myofibroblastic tumor of the liver mimicking an infiltrative malignancy in computed tomography and magnetic resonance imaging with Gd-EOB.

Inflammatory myofibroblastic tumors (IMT) are a benign tumor entity, which rarely develop in the liver. Surgery is the most common treatment for these lesions as it is difficult to distinguish them from malignant liver tumors and local recurrent growth may occur. IMT is a diagnostic challenge for imaging. Only a limited number of reports of single cases or small number of patients described the imaging features on computed tomography. Reports on IMT appearance on magnetic resonance imaging are scarce. We present a case of IMT of the liver with infiltration of the abdominal wall treated with surgery and describe the imaging features with the use of the hepatobiliary contrast agent, gadoxetic acid (Gd-EOB).

A mathematical approach predicting the number of events in different tumors.

Supported by different investigations, multi-step models for tumorigenesis have been proposed for epithelial tumors. The age specific incidence of some cancers shows an exponential rise with increasing patient age. Yet, the onset and the slope of incidence curves varies between tumor types. One simple explanation for this disparity is that the number of mutations required for transformation differs in various tissues. We used a homogeneous Poisson process to estimate the number of events (N) and the intensity or event rate (lambda) that might be needed for cancer development in various tissues (colon, prostate, oralpharynx, larynx). Estimations were performed, including 95% confidence intervals, for the male and female population. The expected number of events needed was higher in adenocarcinomas (colorectal carcinoma: N approximately 10 for females and N approximately 11.0 for males; prostatic cancer: N approximately 23) than in squamous cell carcinomas (oropharynx: N approximately 5-6 for females and N approximately 6 for males; larynx: N approximately 7 for females and N approximately 8 males). Still, alternative models fixing N to values within the 95% confidence intervals determined, showed good coincidence with epidemiological data. Although the herein applied mathematical model neglects several biologic conditions, especially a presumed acceleration of mutation rates after tumor initiation it offers a plausible theory for the given epidemiologic data and matches with molecular biologic findings in the investigated cancers.

COX-2 upregulation in thymomas and thymic carcinomas.

The treatment of advanced stage thymomas and thymic carcinomas is a multimodal therapy. New therapeutic targets are currently under investigation, including the epidermal growth factor receptor (EGFR) as well as KIT. A number of studies have shown protumorigenic potential of Cyclooxygenase-2 (COX-2) in a variety of human malignancies, but so far it is unknown whether COX-2 is expressed in primary malignancies of the thymus. Using tissue microarrays, the expression of COX-2, microsomal-PGES-1 and -PGES-2 (mPGES-1 and mPGES-2), as well as EGFR was evaluated in different subtypes of thymoma and thymic carcinomas. COX-2 was expressed in all subtypes as determined by immunohistochemistry. Some cases of type B2 and thymic carcinomas had COX-2 staining levels classified as mild to moderate. However, when measuring the optical color intensity, no significant differences could be detected. Concerning the expression levels, a weak correlation between the expression of COX-2, mPGES-1 and mPGES-2 as well as EGFR was found. Furthermore, additional cases of thymomas and thymic carcinomas were analyzed by COX-2 Western immunoblot analysis and were compared to normal thymi. The analysis showed that thymomas and thymic carcinomas had a significantly stronger COX-2 expression than that of the normal thymi (p < 0.04). In summary, COX-2 is expressed in all subtypes of thymomas and thymic carcinomas and thus represents, in addition to EGFR and KIT, a potential therapeutic target. Further studies are needed in order to determine whether a combined therapy using COX-2 inhibitors in addition to the evolving anti-EGFR antibody therapy may be considered as a treatment option.

Chromosomal imbalances in sporadic neuroendocrine tumours of the thymus.

Neuroendocrine (carcinoid) tumours of the thymus are rare neoplasms characterized by a highly malignant clinical behavior. Some of these tumors are associated with MEN1. In this study we evaluated 10 cases of sporadic thymic neuroendocrine tumours using immunohistochemistry and comparative genomic hybridization (CGH). All tumours showed a diffuse expression of neuron specific enolase (NSE) and synaptophysin. Chromosomal imbalances were detected in 8/10 cases, the most frequent gains were seen on chromosome Xp (3/10 cases), 7p, 7q, 11q, 12q, and 20q (2/10 each), losses were most frequently detected at 6q (5/10 each), 6p (3/10 each), 4q (3/10 each), 3p, 10q, 11q and 13 q (2/10 each). These CGH data show a degree of overlap with chromosomal imbalances commonly observed in advanced thymomas.

Oncogenetic tree models based on cytogenetic data: new insights into the development of epithelial tumors of the thymus.

Epithelial tumors of the thymus are rare neoplasms typically arising in the anterior mediastinum. There is an ongoing discussion whether thymomas of different histological subtypes form a biological continuum or represent distinct biological entities. To further investigate this question, we performed a statistical analysis of CGH data of 65 previously published cases. Losses of 3p, 6p, 6q, 13q, 16q, and 17p, as well as gains on 1q, were found in at least 10% of the cases. Comparing the data from B2, B3, and C thymomas, we noted an increasing complexity of karyotypes that may be well explained by a sequential order of these types. The frequencies of losses on 16q and 17p show a significant trend with respect to the sequence from B2 to B3 and C thymomas, indicating that these aberrations may be important events in the transition between these tumor types. To identify pathways of genetic development and progression of thymomas, we used oncogenetic tree models representing the dependencies between recurrent chromosomal aberrations. This analysis suggests that gains on the long arm of chromosome 1 occur early in tumor development and are correlated with losses on 6p and 6q. There is a weak correlation with losses on 16q and 17p, which appear to be late events. An independent pathway leads to losses on 3p and 13q, which are closely correlated. Our results indicate that the development of thymomas seems to be in some part a multistep mechanism. Oncogenetic tree models are a helpful means to determine developmental pathways of tumors arising from the same progenitor cell, as shown here for thymomas.

Clusters of chromosomal imbalances in thymic epithelial tumours are associated with the WHO classification and the staging system according to Masaoka.

Using comparative genomic hybridisation, we investigated chromosomal imbalances in 28 cases of thymic epithelial neoplasms including type A, B2, B3, the A component of type AB and different subtypes of type C thymoma. To identify different patterns of chromosomal aberrations associated with the biological behaviour and the histological diversity of thymomas, a hierarchical cluster analysis of 65 cases was performed. The here-reported Comparative Genomic Hybridisation (CGH) data (28 cases) of partly uninvestigated tumour subtypes were pooled with previously published data of chromosomal imbalances of 37 thymomas (Zettl et al. [Am J Pathol 2000;157:257-66]). The analysis of 278 chromosomal subbands yielded 2 main clusters. The first main cluster was characterised by gains of the chromosomal arm 1q, consisted only of type C and B3 thymomas and was further subdivided into 2 subgroups. To the first subgroup only thymomas were attributed, which, in addition to gains of the chromosomal arm 1q, showed losses on 6q and 16q, whereas tumours belonging to the second subgroup exhibited no further recurrent chromosomal alterations. The second main cluster was formed by a heterogeneous group of thymoma types (types A, AB, B2, B3 and C), showing no specific pattern of chromosomal imbalances. In 19 thymomas, no chromosomal imbalances could be detected (3 type B2 and 5 type A thymomas of our study as well as 11 type A thymomas investigated by Zettl et al., Am J Pathol 2000;157:257-66). Chromosomal imbalances were more frequent in type C thymomas than in other subtypes. The distribution of tumour stages according to Masaoka (p = 0.003) and the World Health Organisation (WHO) classification (p < 0.0001) was significantly different in the clusters and subgroups obtained. The groups reflect the staging system and the WHO classification and show that type B3 and type C carcinomas have a strong relationship concerning their chromosomal imbalances. Furthermore, chromosomal imbalances detected in some type A thymomas might be responsible for the aggressive behaviour described in a few cases of this thymoma subtype.

Histologic classification of thymic epithelial tumors: comparison of established classification schemes.

The object of our multicenter retrospective study was to compare the new histologic World Health Organization (WHO) classification and the classical histologic Bernatz classification in terms of interobserver agreement and prognostic importance. The influence of coexisting diseases was also analyzed using the Charlson score. We evaluated 218 patients from 5 different hospitals who were treated between 1967 and 1998. The statistical methods of analysis included Kaplan-Meier estimates of survival curves and the application of Cox proportional hazards models to identify sets of prognostic factors for survival. Interobserver agreement was assessed by kappa coefficients. For both WHO and Bernatz classifications, interobserver agreement was good (weighted kappa > 0.87). However, the subdiversification of the "bioactive" WHO subgroup (B1, B2, B3) resulted in an interobserver agreement of only 0.49 within this group. In multivariable models, both the WHO classification and the Bernatz classification including carcinomas showed similar prognostic capabilities. The B3 type in the WHO classification and the predominantly epithelial type in the Bernatz classification had an intermediate prognostic ranking in comparison with the carcinomas and with the other subgroups. For both classifications, further simplification and subclassification into 3 subgroups led to classes with good discriminative power in respect to survival. In addition, very good interobserver agreement was observed in the simplified classifications. Comorbidity, sex, age of the patient and lymphofollicular hyperplasia had no major influence on overall survival. Both classifications showed similar prognostic power. Interobserver agreement of the type B subgroups was only moderate. By simplification of the classifications, subgroups with distinct survival could be identified.