KDM5C is overexpressed in prostate cancer and is a prognostic marker for prostate-specific antigen-relapse following radical prostatectomy.

Currently, few prognostic factors are available to predict the emergence of castration-resistant prostate cancer and no curative options are available. Epigenetic gene regulation has been shown to trigger prostate cancer metastasis and androgen independence. Histone lysine demethylases (KDMs) are epigenetic enzymes that can remove both repressive and activating histone marks. KDM5 family members are capable of removing the histone H3 lysine 4 dimethylation-activating mark, rendering them potential players in the down-regulation of tumor suppressors and suggesting that their activity could repress oncogenes. Here, we systematically investigated KDM5C expression patterns in two independent radical prostatectomy cohorts (822 prostate tumors in total) by immunohistochemistry. Positive nuclear KDM5C staining was significantly associated with a reduced prostate-specific antigen relapse-free survival. Our study confirmed that nuclear KDM5C expression is an independent prognostic parameter. Most strikingly, the prognostic value of nuclear KDM5C expression for progression-free survival was exclusively pronounced for the Gleason group 7. In addition, KDM5C knockdown resulted in growth retardation of prostate cancer cells in vitro and induced regulation of several proliferation-associated genes. Our data indicate that KDM5C is functionally involved in proliferation control of prostate cancer cells and might represent a novel attractive therapy target. Moreover, overexpression of KDM5C is an independent new predictive marker for therapy failure as determined by biochemical recurrence in patients after prostatectomy.

Membranous CD24 expression as detected by the monoclonal antibody SWA11 is a prognostic marker in non-small cell lung cancer patients.

BACKGROUND: Lung cancer is one of the most common malignant neoplasms worldwide and has a high mortality rate. To enable individualized therapy regimens, a better understanding of the molecular tumor biology has still to be elucidated. The expression of the cell surface protein CD24 has already been claimed to be associated with shorter patient survival in non-small cell lung cancer (NSCLC), however, the prognostic value and applicability of CD24 immunostaining in paraffin embedded tissue specimens has been questioned due to the recent acknowledgement of restricted epitope specificity of the commonly used antibody SN3b. METHODS: A cohort of 137 primary NSCLC cases was immunostained with a novel CD24 antibody (clone SWA11), which specifically recognizes the CD24 protein core and the resulting expression data were compared with expression profiles based on the monoclonal antibody SN3b. Furthermore, expression data were correlated to clinico-pathological parameters. Univariate and multivariate survival analyses were conducted with Kaplan Meier estimates and Cox regression, respectively. RESULTS: CD24 positivity was found in 34 % resp. 21 % (SN3b) of NSCLC with a membranous and/or cytoplasmic staining pattern. Kaplan-Meier analyses revealed that membranous, but not cytoplasmic CD24 expression (clone SWA11) was associated with lympho-nodular spread and shorter overall survival times (both p < 0.05). CD24 expression established by SN3b antibodies did not reveal significant clinicopathological correlations with overall survival, neither for cytoplasmic nor membranous CD24 staining. CONCLUSIONS: Membranous CD24 immunoreactivity, as detected with antibody clone SWA11 may serve as a prognostic factor for lymphonodular spread and poorer overall survival. Furthermore, these results corroborate the importance of a careful distinction between membranous and cytoplasmic localisation, if CD24 is to be considered as a potential prognostic biomarker.

Expression of the microtubule-associated protein 2 (MAP2) as a potential independent prognostic marker in prostate cancer.

PURPOSE: Investigation of Microtubuli-associated Protein 2 (MAP2) expression and its clinical relevance in prostate cancer. MATERIAL AND METHODS: MAP2 expression was immunohistochemically analysed on radical prostatectomy specimens using whole block sections (n = 107) and tissue microarrays (TMA; n = 310). The staining intensity was evaluated for carcinoma, benign tissue and prostatic intraepithelial neoplasia. Expression data were correlated with clinicopathological parameters and biochemical recurrence-free survival. Additionally, MAP2 protein expression was quantitatively analysed in the serum of histologically confirmed prostate carcinoma patients and the control group using a commercial enzyme-linked immunosorbent assay. RESULTS: MAP2 staining was significantly stronger in neoplastic tissue than in non-neoplastic prostatic glands, both in whole block sections (p < 0.01) and in TMA sections (p < 0.05). TMA data revealed significantly stronger MAP2 staining in high-grade tumors. Survival analysis showed a significant correlation between strong MAP2 staining in carcinoma and shortened biochemical recurrence-free survival after prostatectomy (p < 0.001). Multivariate Cox regression analysis confirmed MAP2 as an independent predictor for an unfavourable course. Mean MAP2 serum levels for non-PCA vs. PCA patients differed significantly (non-PCA = 164.7 pg/ml vs. PCA = 242.5 pg/ml, p < 0.001). CONCLUSION: The present data support MAP2 as a novel biomarker in PCA specimens. MAP2 is correlated with tumor grade and MAP2 high-expressing PCA is associated with an increased risk of biochemical recurrence after radical prostatectomy. Future studies are necessary to evaluate MAP2 as a valuable immunohistochemical biomarker in preoperative PCA diagnostic procedures, in particular with regard to treatment modalities.

Mucosal atrophy in collagenous colitis: a case report.

BACKGROUND: Mucosal atrophy as a potential cause of impaired colonic compliance has not yet been described as a complication in Collagenous Colitis (CC). CASE PRESENTATION: We present a 51-year-old female patient with a 20-year history of diarrhea and diagnosed with CC ten years prior to her presentation. We reviewed reports from three colonoscopies performed after the diagnosis. Overall 12 biopsies obtained in the last two colonoscopies were re-analyzed by two pathologists blinded to the aim of the study. Besides the typical histological findings of CC, the endoscopic appearance was normal, and no histological signs of atrophy were found during the first colonoscopy. Surprisingly, the second and third colonoscopy revealed a region of advanced segmental mucosal atrophy in the cecum with the mucosal height normalizing toward the transverse colon. This pattern of atrophy was inversely related to the pattern of sub-epithelial collagen deposition, which increased toward the rectum. CONCLUSION: If no chance occurrence, our observation supports the idea that additional factors, probably luminal in nature, may be co-responsible for the mucosal atrophy in this case. Thus, mucosal atrophy in the proximal colon appears to be a new candidate among the growing list of rare complications associated with long standing CC.

Array analysis of epilepsy-associated gangliogliomas reveals expression patterns related to aberrant development of neuronal precursors.

Gangliogliomas, the most frequent neoplasms in patients with pharmacoresistant focal epilepsies, are characterized by histological combinations of glial and dysplastic neuronal elements, a highly differentiated phenotype and rare gene mutations. Their molecular basis and relationship to other low-grade brain tumours are not completely understood. Systematic investigations of altered gene expression in gangliogliomas have been hampered by their cellular complexity, the lack of suitable control tissue and of sensitive expression profiling approaches. Here, we have used discrete microdissected ganglioglioma and adjacent control brain tissue obtained from the neurosurgical access to the tumour of identical patients (n = 6) carefully matched for equivalent glial and neuronal elements in an amount sufficient for oligonucleotide microarray hybridization without repetitive amplification. Multivariate statistical analysis identified a rich profile of genes with altered expression in gangliogliomas. Many differentially expressed transcripts related to intra- and intercellular signalling including protein kinase C and its target NELL2 in identical ganglioglioma cell components as determined by real-time quantitative RT-PCR (qRT-PCR) and in situ hybridization. We observed the LIM-domain-binding 2 (LDB2) transcript, critical for brain development during embryogenesis, as one of the strongest reduced mRNAs in gangliogliomas. Subsequent qRT-PCR in dysembryoplastic neuroepithelial tumours (n = 7) revealed partial expression similarities as well as marked differences from gangliogliomas. The demonstrated gene expression profile differentiates gangliogliomas from other low-grade primary brain tumours. shRNA-mediated silencing of LDB2 resulted in substantially aberrant dendritic arborization in cultured developing primary hippocampal neurons. The present data characterize novel molecular mechanisms operating in gangliogliomas that contribute to the development of dysplastic neurons and an aberrant neuronal network.

Genetic alterations of protein-o-mannosyltransferase-1 in glioneuronal and glial brain tumors with subarachnoid spread.

Leptomeningeal spread is a casual but conspicuous finding in both low- and high-grade gliomas. We hypothesized a compromised integrity of the glia limitans-basal lamina complex due to glycosylation defects by loss of protein-o-mannosyltransferase-1 (POMT1) activity, also a well-known feature in developmental brain disorders with leptomeningeal heterotopia. Hypothesizing it as analogous in gliomas, we have performed a comprehensive polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis of the POMT1 gene in 41 brain tumor specimens. Each specimen was subjected to laser capture microdissection analyses to dissect: (i) subarachnoid tumor components; (ii) deeply localized tumor areas; and (iii) histologically unaffected CNS fragments. In addition, leukocyte DNA of healthy Caucasians served as controls (n = 100). Sequence alterations were found in exons 7, 9, 15 and 18. Exon 7 bore two sequence alterations, one 751C > T transition with amino acid exchange of arginine by tryptophane (Arg251Trp) (n = 12/41 in Tu vs n = 7/82 in Co) and a 752G > A transition with replacement of arginine by glutamine (Arg251Gln) (n = 3/41 in Tu vs n = 0/82 in Co) that were significantly increased in the tumor specimens compared to controls (P < 0.05). A 979G > A transition in exon 9 resulted in a valine to isoleucine switch (Val327Ile) (n = 6/40 in Tu vs n = 4/84 in Co). Individual specimens revealed a 1565G > A (Arg522Lys) transition in exon 15 and a 1922C > T (Ala641Val) transition in exon 18. Two gangliogliomas only revealed sequence alterations in the superficial area but not in intraparenchymal and adjacent control specimens. We conclude that a significant increase of POMT1 missense mutations may indicate a functional role in neoplastic conditions in individual tumors. Future studies will be important to evaluate a functional impact of POMT1 alterations in human brain tumors.

Increased frequency of distinct TSC2 allelic variants in focal cortical dysplasias with balloon cells and mineralization.

Focal cortical dysplasias with balloon cells (FCD(IIb)) usually present with characteristic imaging and molecular features, that is, a transmantle sign on fluid-attenuated inversion recovery MRI and abundance of allelic variants of the tuberous sclerosis gene 1 (TSC1). Recently, we observed several mineralized lesions (n = 5) lacking this MRI pattern and which surprisingly turned out as FCD(IIb) upon neuropathological examination. These mineralized FCD(IIb) revealed an increased frequency of TSC2 allelic variants but not TSC1 (intron 31: 60% vs. 11% in controls; P = 0.0164, exon 41: 40% vs. 6.5% in controls; P = 0.0441). Mineralized FCD(IIb) have a favorable postsurgical outcome and need consideration in the presurgical differential diagnosis of calcified lesions associated with pharmacoresistant focal epilepsies.

Differential Pi3K-pathway activation in cortical tubers and focal cortical dysplasias with balloon cells.

Balloon cells of distinct focal cortical dysplasias type IIb (FCD(IIb)) and giant cells of cortical tubers in tuberous sclerosis (TSC) constitute neuropathological hallmarks and cytological similarities. In TSC, frequent mutations in the TSC1 or TSC2 genes result in mTOR-signaling activity. Here, we addressed whether Pi3K-pathway activation differentiates balloon cells from giant cells. We used immunohistochemistry with antibodies against p-PDK1 (S241), p-Akt (S473), p-tuberin (T1462), p-p70(S6K) (T389), p-p70(S6K) (T229) and phalloidin-staining to analyze stress fiber formation in balloon cells of FCD(IIb) (n = 23) compared with cortical tuber giant cells (n = 5) and adjacent normal CNS tissue as control. We have further established an in vitro assay to assess potential phosphorylation between Akt and S6. We observed phosphorylated (p-)PDK1, p-Akt, p-tuberin, and p-p70-kDa S6-kinase (p-p70(S6K); residue T229) in balloon cells, whereas giant cells showed only equivalent levels of p-tuberin, p-p70(S6K) and stress fibers. Furthermore, Pi3K-cascade activity in balloon cells may reflect pathway "cross-talk". An in vitro assay revealed S6, a major target of p70(S6K), to increase phosphorylation of Akt. Our data suggest recruitment of different Pi3K-cascade factors in the molecular pathogenesis of giant cells in cortical tubers vs. balloon cells in FCD(IIb) and provides new implications for the development of treatment strategies for these cortical malformations.

PITX2 DNA Methylation as Biomarker for Individualized Risk Assessment of Prostate Cancer in Core Biopsies.

Hypermethylation of the paired-like homeodomain transcription factor 2 (PITX2) gene is a strong predictor of the risk of biochemical recurrence in patients with prostate cancer (PCa) after radical prostatectomy. We investigate whether PITX2 methylation is feasible for individualized risk assessment in prostate core biopsies before surgery. A quantitative, methylation-specific real-time PCR was used to measure PITX2 in three cohorts: i) matched samples of neoplastic and nonneoplastic tissue from 24 patients with PCa, ii) a well-characterized cohort of 300 patients with PCa after radical prostatectomy, and iii) core biopsy specimens from 32 patients with PCa and 31 patients with benign prostatic disease. PITX2 methylation discriminated between neoplastic and nonneoplastic tissue in patients with PCa (P < 0.001). In the second cohort, PITX2 methylation significantly correlated with clinicopathologic parameters, and PITX2 hypermethylation predicted an increased risk of biochemical recurrence in univariate Cox proportional hazards regression analysis (hazard ratio, 1.77; P = 0.046) and Kaplan-Meier analysis (P = 0.043). In 753 prostate biopsies, 720 (95.6%) were applicable for analysis, rendering the assay feasible for diagnostic biopsies. PITX2 methylation was furthermore significantly increased in tumor-positive biopsies and strongly correlated with International Society of Urological Pathology (ISUP) grade groups. This study indicates that the PITX2 methylation assay is feasible in prostate biopsies and might add valuable prognostic information for risk assessment in a presurgical diagnostic setting.

Molecular neuropathology of epilepsy-associated glioneuronal malformations.

Glioneuronal malformations (malformations of cortical development [MCD]) include focal cortical dysplasias (FCD) as well as highly differentiated glioneuronal tumors (i.e. gangliogliomas) and constitute frequent findings in patients with pharmacoresistent focal epilepsies. Tailored resection strategies evolved as promising treatment options and allow a systematic neuropathologic and molecular biologic examination of the epileptogenic area in these patients. The histopathologic appearance and immunophenotype of glioneuronal lesions are, however, characterized by numerous similarities and suggest impaired proliferation, migration, and differentiation of neural precursor cells to play a pathogenetic role. Recent studies point toward molecular alterations within a variety of genes and pathways involved in development of the central nervous system, neuronal growth, and maturation. Compromised signaling within insulin- or reelin-transduction cascades are common findings and were associated with specific MCD entities. Unraveling pathogenic mechanisms may advance refined classification systems for epilepsy-associated malformations and open new avenues for the development of targeted treatment strategies in pharmacoresistent focal epilepsies associated with cortical malformations.

CDO1 promoter methylation is associated with gene silencing and is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients.

Molecular biomarkers may facilitate the distinction between aggressive and clinically insignificant prostate cancer (PCa), thereby potentially aiding individualized treatment. We analyzed cysteine dioxygenase 1 (CDO1) promoter methylation and mRNA expression in order to evaluate its potential as prognostic biomarker. CDO1 methylation and mRNA expression were determined in cell lines and formalin-fixed paraffin-embedded prostatectomy specimens from a first cohort of 300 PCa patients using methylation-specific qPCR and qRT-PCR. Univariate and multivariate Cox proportional hazards and Kaplan-Meier analyses were performed to evaluate biochemical recurrence (BCR)-free survival. Results were confirmed in an independent second cohort comprising 498 PCa cases. Methylation and mRNA expression data from the second cohort were generated by The Cancer Genome Atlas (TCGA) Research Network by means of Infinium HumanMethylation450 BeadChip and RNASeq. CDO1 was hypermethylated in PCa compared to normal adjacent tissues and benign prostatic hyperplasia (P < 0.001) and was associated with reduced gene expression (ρ = -0.91, P = 0.005). Using two different methodologies for methylation quantification, high CDO1 methylation as continuous variable was associated with BCR in univariate analysis (first cohort: HR = 1.02, P = 0.002, 95% CI [1.01-1.03]; second cohort: HR = 1.02, P = 0.032, 95% CI [1.00-1.03]) but failed to reach statistical significance in multivariate analysis. CDO1 promoter methylation is involved in gene regulation and is a potential prognostic biomarker for BCR-free survival in PCa patients following radical prostatectomy. Further studies are needed to validate CDO1 methylation assays and to evaluate the clinical utility of CDO1 methylation for the management of PCa.

The Immune Checkpoint Regulator PD-L1 Is Highly Expressed in Aggressive Primary Prostate Cancer.

PURPOSE: Therapies targeting the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway promote anti-tumor immunity and have shown promising results in various tumors. Preliminary data further indicate that immunohistochemically detected PD-L1 may be predictive for anti-PD-1 therapy. So far, no data are available on PD-L1 expression in primary prostate cancer. EXPERIMENTAL DESIGN: Following validation of a monoclonal antibody, immunohistochemical analysis of PD-L1 expression was performed in two independent, well-characterized cohorts of primary prostate cancer patients following radical prostatectomy (RP), and resulting data were correlated to clinicopathological parameters and outcome. RESULTS: In the training cohort (n= 209), 52.2% of cases expressed moderate to high PD-L1 levels, which positively correlated with proliferation (Ki-67,P< 0.001), Gleason score (P= 0.004), and androgen receptor (AR) expression (P< 0.001). Furthermore, PD-L1 positivity was prognostic for biochemical recurrence [BCR;P= 0.004; HR, 2.37; 95% confidence interval (CI), 1.32-4.25]. In the test cohort (n= 611), moderate to high PD-L1 expression was detected in 61.7% and remained prognostic for BCR in univariate Cox analysis (P= 0.011; HR, 1.49; 95% CI, 1.10-2.02). The correlation of Ki-67 and AR with PD-L1 expression was confirmed in the test cohort (P< 0.001). In multivariate Cox analysis of all patients, PD-L1 was corroborated as independently prognostic for BCR (P= 0.007; HR, 1.46; 95% CI, 1.11-1.92). CONCLUSIONS: We provide first evidence that expression of the therapy target PD-L1 is not only highly prevalent in primary prostate cancer cells but is also an independent indicator of BCR, suggesting a biologic relevance in primary tumors. Further studies need to ascertain if PD-1/PD-L1-targeted therapy might be a treatment option for hormone-naïve prostate cancers.

Comprehensive analysis of the transcriptional profile of the Mediator complex across human cancer types.

The Mediator complex is a key regulator of gene transcription and several studies demonstrated altered expressions of particular subunits in diverse human diseases, especially cancer. However a systematic study deciphering the transcriptional expression of the Mediator across different cancer entities is still lacking.We therefore performed a comprehensive in silico cancer vs. benign analysis of the Mediator complex subunits (MEDs) for 20 tumor entities using Oncomine datasets. The transcriptional expression profiles across almost all cancer entities showed differentially expressed MEDs as compared to benign tissue. Differential expression of MED8 in renal cell carcinoma (RCC) and MED12 in lung cancer (LCa) were validated and further investigated by immunohistochemical staining on tissue microarrays containing large numbers of specimen. MED8 in clear cell RCC (ccRCC) associated with shorter survival and advanced TNM stage and showed higher expression in metastatic than primary tumors. In vitro, siRNA mediated MED8 knockdown significantly impaired proliferation and motility in ccRCC cell lines, hinting at a role for MED8 to serve as a novel therapeutic target in ccRCC. Taken together, our Mediator complex transcriptome proved to be a valid tool for identifying cancer-related shifts in Mediator complex composition, revealing that MEDs do exhibit cancer specific transcriptional expression profiles.

Distinct allelic variants of TSC1 and TSC2 in epilepsy-associated cortical malformations without balloon cells.

Epilepsy-associated malformations of cortical development (MCDs) comprise a variety of dysplastic and neoplastic lesions of yet undetermined molecular pathology. Histopathologic similarities between MCDs and dysplastic brain lesions in the autosomal inherited neurocutaneous phacomatosis tuberous sclerosis (TSC), which affects the TSC1 and/or TSC2 genes, suggest common pathogenetic mechanisms. Previous studies revealed different alterations of TSC1 and TSC2 in epilepsy-associated malformations and glio-neuronal tumors despite histopathologic similarities. In order to examine current clinico-pathologic classification systems of cortical malformations on the molecular level, we carried out a mutational analysis of TSC1 and TSC2 in a series of surgical specimens obtained from patients with FCD without Taylor type balloon cells (FCDIIa; n = 20), architectural dysplasias (FCDI; n = 15), nodular cortical heterotopias (NCH; n = 4), and heterotopic white matter neurons (WMNH; n = 19). In FCDIIa, abundant genomic polymorphisms were detected in TSC2 (intron 4) but no allelic variants observed in exon 17 of TSC1. This allelic distribution pattern is in contrast to findings in FCDI and WMNH but also to those previously reported in FCDIIb (Taylor's balloon cell type). The latter revealed increased frequencies of specific alleles only in TSC1. The determination of characteristic molecular genetic alterations in specific epilepsy-associated malformations will support a comprehensive clinico-pathologic classification system and help to identify molecular pathways with potential pathogenetic relevance. Our work is supported by DFG (SFB TR3 [AJB], DFG Bl 421/1-1 [IB]), BONFOR, and Deutsche Krebshilfe.

Putative association of polymorphism in the mannose 6-phosphate receptor gene with major depression and Alzheimer's disease.

The endosomal lysosomal system might play a role in Alzheimer's disease, but its impact in major depression is unknown. The expression of the cation-dependent mannose 6-phosphate receptor (CD-MPR) is increased in Alzheimer's disease and the CD-MPR gene is located next to a region on chromosome 12 possibly linked to Alzheimer's disease. We investigated a C/T polymorphism in the CD-MPR gene in 188 Alzheimer's disease patients, in a control sample of 193 patients with major depression, as hospitalized controls, and in 259 healthy controls. We examined the interaction of the CD-MPR polymorphism with the putative risk factor for Alzheimer's disease, the cathepsin D T-allele. No significant association of the CD-MPR C-allele with Alzheimer's disease was observed. However, exploratory data analysis revealed an increased frequency of the CD-MPR C-allele in patients with major depression; thus, the C-allele may be a risk factor for depression. Gene location and function of the CD-MPR suggest an involvement in Alzheimer's disease; however, we could not find an association of the CD-MPR polymorphism with Alzheimer's disease. Since exploratory data suggest an involvement of the endosomal lysosomal system in major depression, further studies are warranted to investigate the biological role of the CD-MPR in major depression.

Molecular profiling of temporal lobe epilepsy: comparison of data from human tissue samples and animal models.

The advent of gene chip technology and the era of functional genomics have initially been accompanied by huge anticipations to quickly unravel the molecular pathogenesis of multifactorial diseases. Expectations have, today, given way to some concerns about this non-hypothesis driven approach. However, the careful and controlled application of expression microarrays in concert with refined bioinformatic tools may provide novel insights in major disorders particularly of highly complex organs such as the central nervous system (CNS). Epilepsies are among the most frequent CNS disorders affecting approximately 1.5% of the population worldwide. In temporal lobe epilepsy (TLE), the seizure origin typically involves the hippocampal formation, a structure located in the mesial temporal lobe. Many TLE patients develop pharmacoresistance, i.e. seizures can no more be controlled by antiepileptic drugs. In order to achieve seizure control, surgical removal of the epileptogenic focus has been established as successful therapeutic strategy. Hippocampal biopsy tissue of pharmacoresistant TLE patients represents an excellent substrate to analyze molecular mechanisms related to structural and cellular reorganization in epilepsy. The complexity of alterations in TLE hippocampi suggests numerous genes and signaling cascades to be involved in the pathogenesis. By microarrays, genome wide expression profiles can be constituted from TLE tissues. However, hippocampi of pharmacoresistant TLE patients represent an advanced stage of the disease. Early stages of epilepsy development are not available for functional genome analysis in humans. Animal models of TLE appear particularly helpful to study molecular mechanisms of highly dynamic processes such as the development of hyperexcitability and pharmacoresistance. In this review, we summarize recent data of gene expression profiles in human and experimental TLE and discuss the relevance of novel tools for bioinformatic analysis and data mining.

Tuberous-sclerosis complex-related cell signaling in the pathogenesis of lung cancer.

BACKGROUND: Hamartin (TSC1) and tuberin (TSC2), encoded by the tuberous sclerosis complex (TSC) genes, form a tumor-suppressor heterodimer which is implicated in PI3K-Akt signaling and acts as a functional inhibitor of the mammalian target of rapamycin (mTOR). Dysregulation of mTOR has been assigned to carcinogenesis and thus may be involved in cancer development. We have addressed the role of hamartin, phospho-tuberin (p-TSC2) and phospho-mTOR (p-mTOR) in a series of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) samples. METHODS: We collected 166 NSCLC and SCLC samples for immunohistochemical studies and performed western blot analyses in NSCLC and SCLC cell lines as well as comparative analyses with EGFR phosphorylation and downstream effectors. RESULTS: In cell lines we found an inverse correlation between hamartin and p-mTOR expression. In surgical specimens cytoplasmic hamartin expression was observed in more than 50% of adenocarcinoma (AC) and squamous cell carcinoma (SCC) compared to 14% of SCLC. P-mTOR and p-TSC2 staining was found in a minority of cases.There was a significant correlation between p-EGFR Tyr-1068, p-EGFR Tyr-992 and hamartin, and also between p-mTOR and p-EGFR Tyr-1173 in AC. In SCC an inverse correlation between hamartin and p-EGFR Tyr-992 was detected. Phosphorylation of TSC2 was associated with expression of MAP-Kinase. Hamartin, p-TSC2 and p-mTOR expression was not dependant of the EGFR mutation status. Hamartin expression is associated with poorer survival in SCC and SCLC. CONCLUSIONS: Our findings confirm the inhibitory role of the tuberous sclerosis complex for mTOR activation in lung cancer cell lines. These results reveal hamartin expression in a substantial subset of NSCLC and SCLC specimens, which may be due to EGFR signaling but is not dependant on EGFR mutations. Our data provide evidence for a functional role of the tuberous sclerosis complex in lung cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9274845161175223.

Filariasis of the axilla in a patient returning from travel abroad: a case report.

BACKGROUND: The term filariasis comprises a group of parasitic infections caused by helminths belonging to different genera in the superfamily Filaroidea. The human parasites occur mainly in tropical and subtropical regions, but filariae are also found in temperate climates, where they can infect wild and domestic animals. Humans are rarely infected by these zoonotic parasites. PATIENTS AND METHODS: A 55-year-old patient presented with a new-onset, subcutaneous, non-tender palpable mass in the right axilla. Ultrasonography showed a 1.3-cm, solid, singular encapsulated node. Sonography of the breast on both sides, axilla and lymphatic drainage on the left side, lymphatic drainage on the right side, and mammography on both sides were without pathological findings. The node was excised under local anesthesia as the patient refused minimal invasive biopsy. RESULTS: On histopathological examination, the tail of a parasite of the group of filariae was found. The patient revealed that she had stayed in Africa and Malaysia for professional reasons. 6 months before the time of diagnosis, she had also suffered from a fever and poor general condition after a trip abroad. The patient was referred for further treatment to the Institute for Tropical Medicine at the University of Dusseldorf, where a treatment with ivermectin was conducted on the basis of positive staining with antibodies against filariae. CONCLUSION: Our case demonstrates the importance of interdisciplinary collaboration between breast center, pathology, and other specialties such as microbiology and tropical medicine.

Presence of temporal gray-white matter abnormalities does not influence epilepsy surgery outcome in temporal lobe epilepsy with hippocampal sclerosis.

BACKGROUND: Temporal lobe gray-white matter abnormalities (GWMA) are frequent morphological aberrances observed on MRI in patients with temporal lobe epilepsy (TLE) in addition to hippocampal sclerosis (HS). OBJECTIVE: To study the influence of temporal pole GWMA on clinical characteristics and seizure outcome in patients with HS operated on for TLE. METHODS: A cohort of 370 patients undergoing surgery for intractable TLE was prospectively collected in an epilepsy surgery data base. Clinical characteristics and seizure outcome of all 58 TLE patients with identified HS and GWMA (group 1) were compared with those of a matched control group of 58 HS patients without GWMA (group 2). Both groups were further subdivided into patients undergoing transsylvian selective amygdalohippocampectomy (sAH) and anterior temporal lobectomy with amygdalohippocampectomy (ATL). RESULTS: The HS plus GWMA patients were significantly younger at epilepsy onset than those without GWMA. In the HS plus GWMA group, 41% of patients were younger than 2 years when they experienced their first seizure in contrast to only 17% of patients with pure HS (P = .004). Seizure outcome was not statistically different between the 2 groups: 75.9% of the patients in group 1 were seizure free (Engel class I) compared with 81% of patients in group 2. Seizure outcome in both groups was about equally successful with selective amygdalohippocampectomy and anterior temporal lobectomy (ns). CONCLUSION: Limited and standard resections in TLE patients with HS are equally successful regardless of the presence of GWMA.