Aneuploidy, TP53 mutation, and amplification of MYC correlate with increased intratumor heterogeneity and poor prognosis of breast cancer patients.

The clinical course of breast cancer varies from one patient to another. Currently, the choice of therapy relies on clinical parameters and histological and molecular tumor features. Alas, these markers are informative in only a subset of patients. Therefore, additional predictors of disease outcome would be valuable for treatment stratification. Extensive studies showed that the degree of variation of the nuclear DNA content, i.e., aneuploidy, determines prognosis. Our aim was to further elucidate the molecular basis of aneuploidy. We analyzed five diploid and six aneuploid tumors with more than 20 years of follow-up. By performing FISH with a multiplexed panel of 10 probes to enumerate copy numbers in individual cells, and by sequencing 563 cancer-related genes, we analyzed how aneuploidy is linked to intratumor heterogeneity. In our cohort, none of the patients with diploid tumors died of breast cancer during follow-up in contrast to four of six patients with aneuploid tumors (mean survival 86.4 months). The FISH analysis showed markedly increased genomic instability and intratumor heterogeneity in aneuploid tumors. MYC gain was observed in only 20% of the diploid cancers, while all aneuploid cases showed a gain. The mutation burden was similar in diploid and aneuploid tumors, however, TP53 mutations were not observed in diploid tumors, but in all aneuploid tumors in our collective. We conclude that quantitative measurements of intratumor heterogeneity by multiplex FISH, detection of MYC amplification and TP53 mutation could augment prognostication in breast cancer patients.

Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS.

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.

Combining aneuploidy and dysplasia for colitis' cancer risk assessment outperforms current surveillance efficiency: a meta-analysis.

PURPOSE: Cancer risk assessment for ulcerative colitis patients by evaluating histological changes through colonoscopy surveillance is still challenging. Thus, additional parameters of high prognostic impact for the development of colitis-associated carcinoma are necessary. This meta-analysis was conducted to clarify the value of aneuploidy as predictor for individual cancer risk compared with current surveillance parameters. METHODS: A systematic web-based search identified studies published in English that addressed the relevance of the ploidy status for individual cancer risk during surveillance in comparison to neoplastic mucosal changes. The resulting data were included into a meta-analysis, and odds ratios (OR) were calculated for aneuploidy or dysplasia or aneuploidy plus dysplasia. RESULTS: Twelve studies addressing the relevance of aneuploidy compared to dyplasia were comprehensively evaluated and further used for meta-analysis. The meta-analysis revealed that aneuploidy (OR 5.31 [95 % CI 2.03, 13.93]) is an equally effective parameter for cancer risk assessment in ulcerative colitis patients as dysplasia (OR 4.93 [1.61, 15.11]). Strikingly, the combined assessment of dysplasia and aneuploidy is superior compared to applying each parameter alone (OR 8.99 [3.08, 26.26]). CONCLUSIONS: This meta-analysis reveals that aneuploidy is an equally effective parameter for individual cancer risk assessment in ulcerative colitis as the detection of dysplasia. More important, the combined assessment of dysplasia and aneuploidy outperforms the use of each parameter alone. We suggest image cytometry for ploidy assessment to become an additional feature of consensus criteria to individually assess cancer risk in UC.

Applying Genomics and Proteomics in Translational Surgical Oncology Research.

BACKGROUND: Translational surgical research can range from investigating clinically oriented basic pathophysiological research via the correlation of molecular findings with a patient's clinical outcome to conducting treatment response studies. Herein, the specialist's opinion as a 'surgeon scientist' plays a pivotal role, e.g. in planning experimental setups focusing on the clinically most relevant needs. SUMMARY AND KEY MESSAGES: This review provides a survey of genomic and proteomic technologies and gives an up-to-date overview of those studies applying these technologies exemplarily in colorectal cancer-based biomarker research. Although current results are promising, future validation studies within multicenter networks are required to promote the translation of 'omics' from bench to bedside. In this endeavor, departments of surgery and institutes of experimental surgery together should play a fundamental role. The program for 'clinician scientists' recently launched by the German Research Society (DFG) could be one tool to promote interdisciplinary networks and surgeons' impact on translational research.

Is laparoscopic treatment of incisional and recurrent hernias associated with an increased risk for complications?

INTRODUCTION: Hernias of the ventral abdominal wall can be treated with an intraperitoneal onlay mesh (IPOM). The aim of this cohort study was to analyze the complications and recurrence rates after laparoscopic ventral hernia repair focusing especially on incisional and recurrent hernias. METHODS: The study population comprised 149 patients with a hernia of the abdominal wall, which was treated with an IPOM between January 2006 and January 2011. RESULTS: Fifty-one patients had a primary hernia (group I) and 98 patients had preceding abdominal surgery (group II). In group II 64 patients had an incisional hernia and 34 patients had a recurrent hernia. The median body mass index was 30.3 kg/m(2) (14.8-69.1) without any significance in sub-group comparison. The mean duration of surgery and the length of stay were significantly longer in group II (p < 0.05). The overall rate of minor complications was 18.1%. There were significantly more minor complications in group II (7.8% vs. 23.5%, p = 0.02). Notably, there were also significantly more major complications in group II (14.3% vs. 2.0%; p = 0.02). The recurrence rate was significantly higher in group II (group I: 3.9% vs. group II: 16.3%, p < 0.05). There were no early recurrences in group I, but 5 early recurrences in group II. CONCLUSION: Laparoscopic treatment of complex hernias as incisional hernias, recurrent hernias and hernias with interenteric and enteroperitoneal adhesions is associated with high rates of minor and major complications. A high level of expertise of the surgeon and the camera-guiding assistant is therefore needed.

Colorectal neoplasia in IBD--a single-center analysis of patients undergoing proctocolectomy.

PURPOSE: The risk, prevention, and treatment of colorectal neoplasia in inflammatory bowel disease (IBD) are still a matter of debate. The aim of this study was to analyze the occurrence of colorectal neoplasia in IBD patients who underwent proctocolectomy. METHODS: The study population comprised of 123 IBD patients who underwent proctocolectomy because of neoplasia, therapy refractivity, or complications between January 2000 and July 2011. RESULTS: One hundred fourteen (92.7%) patients were pre-operatively diagnosed with ulcerative colitis, 5 (4.1%) with colitis indeterminata, and 4 (3.3%) with colonic Crohn's disease. Colectomy was indicated in 39 (31.7%) patients because of a neoplasia, in 68 (55.3%) because of a refractory course of the disease, and in 16 (13.0%) because of complications. Neoplasia was found in 36 patients on a histopathologic evaluation of the colectomy specimens. Ten (8.1%) patients post-operatively showed a pre-operatively not described advanced neoplasia. In three (2.4%) of these patients, the detection of advanced neoplasia (two high-grade intraepithelial neoplasias (IENs), one carcinoma) was a complete de novo finding. Carcinoma had not been diagnosed pre-operatively in six (4.9%) patients. A multifocal distribution of neoplasia was seen in 66.7% of patients with neoplasia. The median duration of disease was 15.5 years in case of neoplasia opposed to 6.0 years in those without neoplasia detection. CONCLUSION: Our data demonstrate a high rate of pre-operatively undetected high-grade IENs and carcinoma and a frequent multifocal occurrence in IBD patients with long-standing inflammation of the colon. This should be kept in mind for treatment decisions particularly in patients with a chronic refractory course of the disease.

Spontaneous and non-spontaneous bleeding complications in patients with oral vitamin K antagonist therapy.

PURPOSE: The aim of the study was to evaluate potential differences between patients with spontaneous and non-spontaneous bleeding episodes during treatment with vitamin K antagonists which mainly resulted in compartment syndromes. METHODS: The population in this study comprised 116 patients who suffered at least one bleeding complication which required surgical treatment during therapy with an oral vitamin K antagonist. The patients were treated between September 2001 and July 2008. RESULTS: Significant differences were observed between the two patient groups with regard to the presence of renal failure, arterial hypertension, and diabetes mellitus, which occurred more frequently in patients with spontaneous bleeding. Also, significantly more patients with spontaneous bleedings developed compartment syndrome that needed emergency operation. Overall mortality was 9.6 %, was associated with multiorgan failure in all patients, and was not different between the two patient groups. CONCLUSIONS: The identification of high-risk patients before treatment with an oral vitamin K antagonist is of major importance. The existence of over-anticoagulation syndrome and compartment syndrome is associated with significant mortality and morbidity and should not be underestimated.

Nucleocytoplasmic shuttling of human inositol phosphate multikinase is influenced by CK2 phosphorylation.

Human inositol phosphate multikinase (IPMK) is a multifunctional protein in cellular signal transduction, namely, a multispecific inositol phosphate kinase, phosphatidylinositol 3-kinase, and a scaffold within the mTOR-raptor complex. To fulfill these nuclear and cytoplasmic functions, intracellular targeting of IPMK needs to be regulated. We show here that IPMK, which has been considered to be a preferentially nuclear protein, is a nucleocytoplasmic shuttling protein, whose nuclear export is mediated by classical nuclear export receptor CRM1. We identified a functional nuclear export signal (NES) additionally to its previously described nuclear import signal (NLS). Furthermore, we describe a mechanism by which the activity of the IPMK-NLS is controlled. Protein kinase CK2 binds endogenous IPMK and phosphorylates it at serine 284. Interestingly, this phosphorylation can decrease nuclear localization of IPMK cell type specifically. A controlled nuclear import of IPMK may direct its actions either toward nuclear inositol phosphate (InsPx) metabolism or cytoplasmic actions on InsPx, phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2], as well as mTOR-raptor.

Selectivity of calixarene-bonded silica-phases in HPLC: description of special characteristics with a multiple term linear equation at two different pH-values.

Six different calixarene-bonded phases were characterized by analyzing 36 and 26 solutes at pH 3 and 7, respectively. Dolan and Snyder's multiple term linear equation was used to correlate retention factors k' to parameters of the solutes and columns. The column parameters have been related to molecular properties of the stationary phases and new suggestions were made for the interpretation of steric selectivity. Ionic and polar interactions have been found dependent on pH value, while steric interactions are less dependent and hydrophobic interactions remain unchanged. Distinct differences of the supported interactions were confirmed between the calixarene-bonded and the common alkyl-bonded silicas. By use of the parameters, values of k' can be estimated with an average deviation of 2.50 and 7.92% at low and neutral pH-value, respectively.

Correlation of structural and electronic properties in a new low-dimensional form of mercury telluride.

Using high resolution electron microscopy and first principles quantum mechanical calculations we have explored the fundamental physics and chemistry of the semiconductor, HgTe grown inside single wall carbon nanotubes. This material forms a low-dimensional structure based on a repeating Hg2Te2 motif in which both atom species adopt new coordination geometries not seen in the bulk. Density-functional theory calculations confirm the stability of this structure and demonstrate conclusively that it arises solely as a consequence of constrained low dimensionality. This change is directly correlated with a modified electronic structure in which the low-dimensional form of HgTe is transformed from a bulk semimetal to a semiconductor.

Local measurement and computational refinement of aberrations for HRTEM.

Methods for accurate and automated determination of the coefficients of the wave aberration function are compared with particular emphasis on measurements of higher order coefficients in corrected instruments. Experimental applications of aberration measurement to the determination of illumination isoplanicity and high precision local refinement of restored exit waves are also described.

Structure determination of atomically controlled crystal architectures grown within single wall carbon nanotubes.

Indirect high resolution electron microscopy using one of several possible data-set geometries offers advantages over conventional high-resolution imaging in enabling the recovery of the complex wavefunction at the specimen exit plane and simultaneously eliminating the aberrations present in the objective lens. This article discusses results obtained using this method from structures formed by inorganic materials confined within the bores of carbon nanotubes. Such materials are shown to be atomically regulated due to their confinement, leading to integral layer architectures that we have termed "Feynman crystals." These one-dimensional (1D) crystals also show a wide range of structural deviations from the bulk, including unexpected lattice distortions, and in some cases entirely new forms have been observed.