Types Of Epithelial Tumors Research Articles

Spectrum of epithelial ovarian tumors with HER2/neu expression by the carcinomas among patients admitted in a tertiary care hospital in Eastern India

Background: Women in India constitute a neglected part of the society and their sufferings are least highlighted. Ovarian cancer is a fatal disease that affects them silently. Its incidence is rising with progressively enlarging elderly population. Early diagnosis is challenging, since majority of the cases of ovarian carcinomas are detected in advanced stage with nonspecific symptoms. Neo-adjuvant chemotherapy, a useful therapeutic modality, is limited by toxicity and resistance. Hence, targeted therapy is now being proposed to overcome these hurdles. Objectives: 1. To study the histopathological spectrum of epithelial ovarian tumors. 2. To study the expression of HER2/neu among carcinomas on immunohistochemistry. Materials and Methods: It was an observational, descriptive, cross-sectional study carried out among 68 patients admitted in the hospital, who were newly diagnosed as having primary epithelial ovarian tumor. Postoperatively, the surgical specimens were processed accordingly. Histopathological sections were examined under Hematoxylin and Eosin stain. Histopathologically confirmed carcinomas were analyzed for HER2/neu expression status on immunohistochemistry. Statistical analysis was carried out using SPSS software, version 20. Results: Of the total cancer cases, 64.71% were benign, 5.88% borderline, 29.41% malignant. Serous type constituted majority for both benign and malignant variants (59.09% and 70% respectively). Overall, serous type constituted 58.82% of total population studied. Risk of malignancy index score was >200 for 95% of carcinomas in sharp contrast to benign tumors (15.91%). Grade 3+ HER2/neu expression was found in 35% of malignant cases, of which 85.71% were at advanced stage (FIGO III and IV). Conclusion: Serous type was the most common type of epithelial ovarian tumor. Risk of malignancy index score had strongly correlated with the malignant nature of tumor (p < 0.001). Grade 3+ HER2/neu expression was associated with advanced stage carcinomas.

Bone marrow as a reservoir for disseminated tumor cells: a special source for liquid biopsy in cancer patients.

Besides circulating tumor cells, disseminated tumor cells (DTCs) in bone marrow (BM) might be used as a 'liquid biopsy' to obtain information helpful to steer therapies in individual patients. Moreover, the molecular characterization of DTCs may provide important insight into the biology of cancer metastasis. BM is a frequent site of metastasis in breast, prostate and lung cancer, and it might represent a sanctuary site for DTCs derived from various additional types of epithelial tumors. Highly sensitive and specific immunocytological and molecular methods enable the detection of DTCs in BM of cancer patients at the single-cell level years before the occurrence of metastases. This information might be useful to assess individual prognosis and stratify patients at risk to systemic adjuvant anti-cancer therapies. Although most data on the prognostic value of DTCs are available for breast cancer, several single institution studies including patients with colon, lung, prostate, esophageal, gastric, pancreatic, ovarian and head and neck carcinomas have also documented an association between the presence of DTCs at primary surgery and subsequent metastatic relapse. Most DTCs are in a dormant (that is, non-proliferative) stage, frequently express HER2 and display a cancer stem cell and immune escape phenotype. Here, we summarize the current knowledge about specific biological properties of DTCs in BM, and discuss the clinical relevance of DTC detection in cancer patients with regard to an improved individualized therapeutic management. This will stimulate further technical developments that may make BM sampling more acceptable for the clinical management of patients with solid tumors.

DEAR1, a novel tumor suppressor that regulates cell polarity and epithelial plasticity.

Elucidation of the regulatory controls on epithelial plasticity is pivotal not only to better understand the nature of metastasis but also for the design of targeted therapies to prevent the earliest steps in migration and invasion from the primary tumor. This review will highlight the role of the novel TRIM protein DEAR1 (annotated as TRIM62) in the regulation of apical-basal polarity and acinar morphogenesis as well as its function as a chromosome 1p35 tumor suppressor and negative regulator of TGFβ-driven epithelial-mesenchymal transition (EMT). DEAR1 binds to and promotes the ubiquitination of SMAD3, the major effector of TGFβ-mediated EMT, as well as downregulates SMAD3 targets SNAIL1/2, master transcriptional regulators of EMT. Cumulative results suggest a novel paradigm for DEAR1 in the regulation of the breast tumor microenvironment, polarity, and EMT. Because DEAR1 undergoes loss-of-function mutations, homozygous deletion, as well as copy-number losses in multiple epithelial cancers, including breast cancer, DEAR1 has clinical use as a predictive and prognostic biomarker as well as for stratifying breast cancers and potentially other epithelial tumor types for targeted therapies aimed at the pathways regulated by DEAR1.

Seeing through the miRage of tissue complexity

Seeing through the miRage of tissue complexity

The mTOR signaling pathway as a treatment target for intracranial neoplasms.

Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway has become an attractive target for human cancer therapy. Hyperactivation of mTOR has been reported in both sporadic and syndromic (hereditary) brain tumors. In contrast to the large number of successful clinical trials employing mTOR inhibitors in different types of epithelial neoplasms, their use to treat intracranial neoplasms is more limited. In this review, we summarize the role of mTOR activation in brain tumor pathogenesis and growth relevant to new human brain tumor trials currently under way using mTOR inhibitors.

PDGF receptors in tumor biology: prognostic and predictive potential.

PDGF receptors (PDGFRs) exert cell type-specific effects in many different tumor types. They are emerging as key regulators of mesenchymal cells of the tumor microenvironment, and of many common malignancies, such as cancer of the breast, colon and prostate. In some tumor types PDGFRs are genetically activated and are thus directly involved in stimulation of malignant cell growth. Recent studies have uncovered clinically relevant variations in stromal PDGFR expression. High stromal PDGFRβ expression or activation is associated with poor prognosis in breast and prostate cancer. Indications of prognostic significance of stromal PDGFRβ expression in various GI tract tumor types also exist. The prognostic significance of PDGFRα and β in malignant cells of common epithelial tumor types should be further studied. Collectively data suggest that continued characterization of PDGFR expression in human tumors should present opportunities for improved accuracy in prognosis and also allow novel biomarker-based clinical studies exploring the efficacy of PDGFR-directed tumor therapies.

CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT.

Cluster of differentiation 166 (CD166) is a cell surface membrane protein, which is regarded as a valuable prognostic marker in several types of epithelial tumors. We previously reported that CD166 exerts its pro-carcinogenic role by enhancing YAP function in liver cancer cells. However, YAP cannot completely rescue the increased anti‑carcinogenic effects by gene silencing of CD166, whose downstream effectors require further investigation. Here, we found that knockdown of CD166 inhibits phosphorylation of anti-carcinogenic FOXO proteins. Overexpression of CD166 led, not only to a faster protein degradation rate, but also a more accumulated ubiquitination of FOXO compared to the control. Moreover, overexpression of CD166 facilitated FOXO protein localization from the nuclear fraction to the cytosolic fraction, suggesting that CD166 modulates FOXO protein stability through alteration of their subcellular localization. In addition, simultaneous overexpression of CD166 partially reversed the evoked anti-carcinogenic effects by overexpression of FOXO both in vitro and in vivo. Furthermore, CD166 knockdown‑induced anti‑carcinogenic effects and dephosphorylation of FOXO proteins were rescued by overexpression of AKT. In liver cancer tissues, we also observed that higher expression levels of CD166, phospho-AKT, total AKT and phospho‑FOXO were correlated with lower expression levels of total FOXO, suggesting that the upregulation of CD166 leads to the activation of AKT, which in turn facilitates phosphorylation and degradation of FOXO. Taken together, our data demonstrate that AKT is an inter-mediator between the upstream regulator, CD166, and downstream effector, FOXO, in liver cancer cells. Disrupting the relationship between CD166 and the AKT/FOXO axis may serve as a novel therapeutic target for liver cancer patients.

Invadopodia are essential in transurothelial invasion during the muscle invasion of bladder cancer cells

Muscle invasive bladder cancer is an aggressive type of epithelial tumor with a high rate of metastasis. For bladder cancer cells to reach the muscle layer, cells must invade through an urothelial cell monolayer (transurothelial invasion) and basement membrane. However, the process by which transurothelial invasion occurs has not been fully characterized. In this study we developed a novel method to evaluate the transurothelial invasion capacity and investigated its cellular and molecular processes using primary culture cells from bladder cancer patients. The analysis revealed that compared with the prognosis for patients with non‑muscle invasive bladder cancer that of patients with muscle invasive bladder cancer was particularly poor due to metastatic recurrence. Cancer cells from patients with muscle invasive bladder cancer exhibited a higher invasive capacity through the urothelial cell monolayer compared with those from non‑invasive bladder cancer patients. Furthermore, muscle invasive bladder cancer cells demonstrated a greater ability to form invadopodia, the filamentous actin‑based membrane protrusions required for matrix degradation and invasion compared with non‑invasive cells. Bladder cancer cell lines were established with reduced invadopodia formation by silencing the expression of cortactin, an essential component of invadopodia. The cortactin knockdown bladder cancer cells with reduced invadopodia formation demonstrated a markedly reduced ability to invade through the urothelial cell monolayer, indicating that invadopodia are essential for transurothelial invasion. The results indicate that invadopodia formation is required for muscle invasion of aggressive bladder cancer cells.

Papillary renal cell carcinoma revisited: a comprehensive histomorphologic study with outcome correlations.

Papillary renal cell carcinoma (P-RCC) is the second most common type of malignant renal epithelial tumor and can be subclassified into type 1, which demonstrates simple cuboidal low-grade epithelium and type 2, which demonstrates pseudostratified high-grade epithelium with abundant eosinophilic cytoplasm. Despite this clinically useful subclassification, P-RCCs exhibit considerable histomorphologic diversity, with many cases having features differing from classically described type 1 and type 2 tumors. To our knowledge, there has been no recent study that has methodically evaluated the histomorphologic features of a series of P-RCCs. To address this, we evaluated a cohort of P-RCCs diagnosed between 1997 and 2004 with long-term clinical follow-up data (n = 56). Histomorphologic features previously described in the spectrum of type 1 and type 2 P-RCCs were recorded for each tumor, including nuclear grade, complete tumor capsule, and cytoplasmic eosinophilia as well as several other features. The current TNM staging (American Joint Committee on Cancer, seventh edition) was assigned to all cases. Histomorphologic features were diverse, demonstrating classic type 1 P-RCC and classic type 2 P-RCC morphology and several tumors with nonclassic features. Four patients in this cohort had distant metastasis. The primary tumor was equally divided between type 1 (2 cases) and type 2 (2 cases) morphology in the cases with metastasis. All P-RCC cases with metastases demonstrated presence of high nuclear grade and high tumor stage in the primary tumor. Cluster analysis using staging parameters and histomorphologic features divided tumors into 2 primary clusters. All primary tumors associated with metastasis were in the same cluster.

Inhibition of type I insulin-like growth factor receptor tyrosine kinase by picropodophyllin induces apoptosis and cell cycle arrest in T lymphoblastic leukemia/lymphoma

It has been recently shown that the type I insulin-like growth factor receptor (IGF-IR) contributes significantly to the survival of T lymphoblastic leukemia/lymphoma (T-LBL) cells, and it was therefore suggested that IGF-IR could represent a legitimate therapeutic target in this aggressive disease. Picropodophyllin (PPP) is a potent, selective inhibitor of IGF-IR that is currently used with notable success in clinical trials that include patients with aggressive types of epithelial tumors. In the present study, we tested the effects of PPP on Jurkat and Molt-3 cells; two prototype T-LBL cell lines. Our results demonstrate that PPP efficiently induced apoptotic cell death and cell cycle arrest of these two cells. These effects were attributable to alterations of downstream target proteins. By using proteomic analysis, seven different proteins were found to be affected by PPP treatment of Jurkat cells. These proteins are involved in various aspects of cellular metabolism, cytoskeleton organization and signal transduction pathways. The results suggest that PPP affects multiple signaling molecules and inhibits fundamental pathways that control cell growth and survival. Our study also provides novel evidence that PPP could be potentially utilized for the treatment of aggressive T-LBL.

CSF1 Is a Novel p53 Target Gene Whose Protein Product Functions in a Feed-Forward Manner to Suppress Apoptosis and Enhance p53-Mediated Growth Arrest

The p53 tumor suppressor gene has a common polymorphism at codon 72 that alters its function. We previously reported that the proline 72 polymorphic variant of p53 (P72) demonstrates increased ability to transactivate a subset of genes, relative to arginine 72 (R72); one of these genes is macrophage colony stimulating factor (CSF1). At present, the mechanism(s) underlying the increased transcriptional activity of P72 toward genes like CSF1 have not been completely elucidated. Additionally, the consequences of increased transcription of genes like CSF1 by the P72 variant to the downstream p53 pathway are unknown. In this report, we address these issues. We show that the CSF1 gene contains a conserved binding site for p53, and interestingly that the P72 variant shows increased ability to bind to this site. Moreover, we show that increased CSF1/CSF1R signaling in P72 cells feeds back on the p53 pathway to enhance p53 phosphorylation, levels, and transactivation of target genes, particularly the cyclin-dependent kinase inhibitor p21 (CDKN1A). This leads to an increase in p53-mediated growth arrest, along with a concomitant decrease in apoptosis. Notably, the CSF1/CSF1R signaling axis is overexpressed in several epithelial cancers, and there is clinical evidence that this pathway plays a role in radio-resistance of some cancers. We show that cells expressing CSF1 and CSF1R are indeed radio-resistant, and further, that this effect requires p53. These combined data are the first to implicate the CSF1/CSF1R pathway in the decision between p53-mediated growth arrest and apoptosis. They are also the first to highlight a cytokine as influential in cell fate determined by p53 in epithelial cells. Finally, these data may explain the association of the P72 variant and the CSF1/CSF1R pathway with increased senescence and radio-resistance in some epithelial tumor types.

Transitional carcinoma with extensive invasion of the bony orbit in a dog

A 12-year-old male English Pointer was examined due to a soft-tissue swelling at the medial canthus of the right orbital region, which was causing facial deformity. The dog had epiphora, purulent nasal discharge, epistaxis, dyspnea, and progressive weight loss. An intraoral mass was observed near the right maxillary premolars. Neoplastic disease was diagnosed based on ancillary tests, which included blood work, skull and intraoral radiographs, ocular ultrasonography and computed tomography. Histopathology revealed transitional carcinoma involving the nasal and oral cavities, maxilla, bony orbit and retrobulbar space. Nasal tumors represent approximately 2% of all tumors diagnosed in this species. Transitional carcinoma is the second most common type of malignant epithelial tumor in the nasal sinuses. This case illustrates the extensive destruction of the soft and bony tissues of the face, including the bony orbit that this type of tumor can cause.

Current Thinking on Malignant Salivary Gland Neoplasms

Malignant salivary gland neoplasms are rare, representing approximately 3% to 7% of all head and neck cancers. Contrasting from the more common mucosal head and neck cancers, which, in general, are ascribed to excessive tobacco, alcohol use, and more recently to viral infection, specific carcinogenic factors for malignant salivary gland growths have not been as clearly identified. Histologically, they represent a heterogeneous group of tumors. Forty histologic types of epithelial tumors of the salivary glands have been reported; some are exceedingly rare and may be the topic of only a few case reports. Salivary tumors can arise in the major salivary glands or in one of the minor salivary glands (predominantly mucus secreting glands), which are distributed throughout the upper aerodigestive. Most patients who develop malignant salivary gland tumors are in the sixth or seventh decade of life. FNA should be considered as part of the diagnostic evaluation but due to its varying sensitivities and specificities imaging modalities such as ultrasound, CT scans, and MRI should also be used as diagnostic adjuncts. Surgery is the primary modality for management of these tumors, nontraditional surgical approaches and instrumentation, as well as facial nerve monitoring, can be selectively utilized to try and decrease the morbidity associated with these surgical procedures. Adjuvant treatment is primarily achieved with radiation therapy. Chemotherapy continues to have a palliative role in the management of salivary gland tumors; however, research in this field is trying to identify a therapeutic role for chemotherapy in order to improve overall survival.

Relationship Between Computed Tomography Manifestations of Thymic Epithelial Tumors and the WHO Pathological Classification

To explore the relationship between computed tomography (CT) manifestations of thymoma and its WHO pathological classification. One hundred and five histopathologically confirmed cases were collected for their pathological and CT characteristics and results were statistically compared between different pathological types of thymoma. Tumor size, shape, necrosis or cystic change, capsule integrity, invasion to the adjacent tissue, lymphadenopathy, and the presence of pleural effusion were significantly different between different pathological types of thymomas (P<0.05). Type B2, B3 tumors and thymic carcinomas were greater in size than other types. More than 50% of type B3 tumors and thymic carcinomas had a tumor size greater than 10 cm. The shape of types A, AB, and B1 tumors were mostly round or oval, whereas 75% of type B3 tumors and 85% of thymic carcinomas were irregular in shape. Necrosis or cystic change occurred in 67% of type B3 thymomas and 57% of thymic carcinomas, respectively. The respective figures for capsule destruction were 83% and 100%. Increases in the degree of malignancy were associated with increases in the incidence of surrounding tissue invasion: 33%, 75%, and 81% in type B2, type B3, and thymic carcinomas, respectively. Pleural effusion occurred in 48% of thymic carcinomas, while calcification was observed mostly in type B thymomas. Different pathological types of thymic epithelial tumors have different CT manifestations. Distinctive CT features of thymomas may reflect their pathological types.

P2-023 - Utility of 18F-Fluorodeoxyglucose Positron Emission Tomography for Distinguishing between the Histologic Types of Early Stage Thymic Epithelial Tumors

ABSTRACT Objectives Recent studies have shown the usefulness of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in differentiatingbetween World Health Organization (WHO) histological subgroups of thymic epithelial tumours. However, these reports may have includedmany advanced cases of these lesions (Masaoka stage III or IV) of high-risk subtypes. The objective of our present study was to assess the usefulnessof FDG-PET for distinguishing the histological subtypes of early stage thymic epithelial tumours (Masaoka stage I or II). Methods Twenty patients who had undergone an FDG-PET examination before treatment and had been diagnosed with an earlystage thymic epithelial tumour between July 2005 and July 2011 were enrolled in the present study. All patients underwent a total thymectomy.This cohort was divided into two groups according to the WHO histological classification of their lesion, i.e. low-risk tumours (types A, AB or B1) in one group and high-risk tumours (types B2, B3 or thymic carcinoma) in the other. Focal FDG accumulation was evaluated by determining the maximum standardized uptake value (SUV-max). Results The patient cohort for this study included 13 men and 7 women ranging in age from 26 to 70 years (mean 55 years). The low-risk group included seven cases (type A, 0; type AB, 7; type B1, 0), and the high-risk group comprised 13 cases (type B2, 7; type B3, 3; thymic carcinoma, 3). The SUV-max values of the low- and high-risk tumours were 3.09 ± 0.51 and 6.19 ± 3.13, respectively, and this was a significant difference. For the differential diagnosis of low- and high-risk tumours, sensitivity and specificity were 92.3 and 83.3%, respectively, when an SUV-max of 3.5 was used as a cutoff. Conclusions FDG-PET is a useful method for distinguishing histological types of early-stage thymic epithelial tumours.

EGFR Expression and Gene Copy Number in Malignant Pleural Mesothelioma in Turkey

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis. Standart chemotherapy regimens still remain palliative. There is urgent need for novel therapy options such as targeted therapies in order to improve the outcome of the patients. Epidermal growth factor receptor (EGFR) is a common target for cancer chemotherapy. There is relatively less data in the literature regarding EGFR expression status in MPMs. In this study we analysed EGFR expression immunohistochemically in 21 Turkish MPM cases. As gene amplificaiton is one of the mechanism responsible from receptor overexpression, we also studied EGFR gene copy number by fluorescent in situ hybridization (FISH) method. We found EGFR overexpression in 16/19 (84.2%) cases. EGFR overexpression was seen in all epithelial and most (66,6%) biphasic tumor types. There was, however, no association between EGFR expression and survival. Although we did not find gene amplification, we detected gene copy number increase (e.g., high polysomy) in two cases (9,5%). Gene copy number increase seems to be responsible from EGFR overexpression in only a small percentage of MPM cases. Further studies investigating other potential factors which might be associated with EGFR expression are needed, and more clinical trials are required to evaluate whether MPM patients are candidates for EGFR targeting therapies.

Development and characterization of a preclinical ovarian carcinoma model to investigate the mechanism of acquired resistance to trastuzumab

Trastuzumab (Herceptin®) is a humanized monoclonal antibody designed to bind and inhibit the function of the human epidermal growth factor receptor2 (HER2)/erbB2 receptor. Trastuzumab has demonstrated clinical activity in several types of HER2-overexpressing epithelial tumors, such as breast and metastatic gastric or gastroesophageal junction cancer. Relapse and therapeutic resistance, however, still occur in a subset of patients treated with regimens including trastuzumab, despite significant improvements in response rates, survival and quality of life. To investigate the potential mechanisms of acquired therapeutic resistance to trastuzumab, we developed a preclinical model of human ovarian cancer cells, SKOV-3 Herceptin-resistant (HR), and examined the corresponding changes in gene expression profiles. SKOV-3HR cells were developed by invivo serial passaging of parental trastuzumab-sensitive SKOV-3cells. Following four rounds of serial transplantation of 'break-through' xenograft tumors under trastuzumab treatment, significant and reproducible differences in the effects of trastuzumab treatment between SKOV-3HR and SKOV-3 cells invivo and invitro were revealed. SKOV-3HR cells retained HER2protein expression but were unaffected by the antiproliferative effects of trastuzumab. The trastuzumab binding affinity for SKOV-3HR cells was diminished, despite these cells having more binding sites for trastuzumab. Microarray expression profiling (MEP) was performed to determine the genes involved in the resistance mechanism. Functional analysis revealed the differential expression of genes potentially involved in angiogenesis, metastasis, differentiation and proliferation, such as mucin1(MUC1). Immunohistochemical staining of SKOV-3HR cells demonstrated a marked overexpression of MUC1. Based on these data, we hypothesize that the overexpression of MUC1 may hinder trastuzumab binding to HER2receptors, abrogating the antitumor effects of trastuzumab and thus could contribute to resistance to therapy. Moreover, the resultant MEP preclinical gene signature in this preclinical model system may provide the basis for further investigation of potential clinical mechanisms of resistance to trastuzumab.

Abstract 1738: Assay development for detecting cMET expression in circulating tumor cells (CTC), a potential patient tailoring marker for evaluation of cMET inhibitors

Abstract Hepatocyte growth factor and its receptor c-MET have been implicated in tumor formation and progression as well as drug treatment resistance to targeted agents such as EGFR inhibitors. cMET over-expression or gene amplification has been reported in a wide variety of human malignancies correlating with poor patient prognosis. A reasonable hypothesis for experimental agents targeting the cMET receptor is that patients with tumors expressing high levels of cMET may respond better. CTC counts are prognostic of survival in metastatic breast, colorectal, and prostate cancers (NEJM 2004;351:781-91; J Clin Oncol 2008;26:3213-21; Clin Can Res 2008;14:6302-9). CTCs are shed from tumors and are believed to be representative of cells migrating to form distal metastasis. The presence of these cells in blood provides an attractive and easy source for serial monitoring of tumors without the limitations of traditional solid tumor biopsy. We describe here the development of an assay that measures cMET expression in CTCs. The CTC assay was developed using the Veridex CellSearch® System, and RUO reagents for enumeration of CTCs and a Lilly proprietary cMET antibody (Ab) optD11. For assay development, cultured tumor cell lines with differing cMET expression levels representing solid epithelial tumor types were spiked into whole blood drawn into a CellSave tube. For initial assay development, mouse whole blood was used and results reproduced subsequently with human whole blood from healthy subjects. The spiked tumor cells in blood samples were recovered using the CellCapture™ Mouse/Rat CTC kit (for mouse blood) or CellSearch® CXC kit (for human blood), supplemented with the fluorescent dye (R- phycoerythrin) conjugated anti-cMET Ab. cMET in the recovered tumor cells was detected in the open/fourth channel on the CellTrack® Analyzer II®. Several proprietary and commercial cMET antibodies were screened for specificity and sensitivity. A commonly used commercially available cMET Ab (Santa Cruz Biotechnology C28) was not able to discriminate between cMET negative and positive cell lines. Results were confirmed by flow cytometry and by western blot analyses. optD11 was selected for CTC cMET expression assay development for the following reasons: a) ability to detect different cMET levels among positive cell lines (H441, MKN45, SNU5, SKOV3) while identifying SKBR3 as cMET negative; b) high affinity for cMET to allow for an image acquisition time of 0.02-0.04 second in the open channel; c) tolerance to the presence of LY2875358 (LA480), an experimental therapeutic anti-cMET Ab, allowing evaluation of cMET levels in CTCs post-treatment. The CTC assay for cMET expression, as well as a CTC assay measuring cMET gene amplification are currently being implemented in the early phase clinical studies for Lilly cMET inhibitors (JSBA, NCT01285037 &amp; JTBA, NCT01287546). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1738. doi:1538-7445.AM2012-1738

Expression of High Mobility GroupA2 is Associated with Poor Survival in Hepatocellular Carcinoma

Primary hepatocellular carcinoma (HCC) is one of the most common solid malignancies [1]. Despite recent improvements in surveillance, diagnosis and clinical treatment strategies, HCC prognosis remains dismal. Patients often experience high metastasis or recurrence rates, and postoperative 5-year survival ranges from 17 % to 53 % [2]. To date, many studies have reported aberrant gene expression in HCC, but molecular factors identified as potential therapeutic targets remain limited. Therefore, it is a challenging task to identify relevant biomarkers or potential pharmacological targets in clinical practice. The high mobility group A2 (HMGA2; also called HMGI-C) protein, a member of the high mobility group AT-hook (HMGA) family, is a small non-histone chromosomal protein that has no intrinsic transcriptional activity, but can modulate transcription by binding to DNA and altering chromatin architecture [3–5]. By interacting with many different transcription factors, HMGA2 is an important regulator of cell growth, differentiation, apoptosis, and transformation [5]. HMGA2 protein is expressed at a high level during embryogenesis, but is hardly detectable in adult human tissues [6, 7]. HMGA2 is frequently involved in chromosomal translocations that occur in benign human tumors, such as lipomas [8], uterine leiomyomas [9], and lung hamartomas [10]. Furthermore, increased HMGA2 expression has been detected in various human epithelialtype tumors, including breast cancers [11], lung cancers [12, 13], pancreatic carcinomas [14], thyroid carcinomas [15], and gastric cancers [16]. These studies suggest that HMGA2 protein overexpression may lead to neoplastic transformation. However, there have been no reports of HMGA2 expression in hepatocellular carcinoma. In this study, we investigated HMGA2 expression in HCC to determine its clinicopathologic and prognostic value.

Utility of 18F-fluorodeoxyglucose positron emission tomography for distinguishing between the histological types of early stage thymic epithelial tumours

Recent studies have shown the usefulness of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in differentiating between World Health Organization (WHO) histological subgroups of thymic epithelial tumours. However, these reports may have included many advanced cases of these lesions (Masaoka stage III or IV) of high-risk subtypes. The objective of our present study was to assess the usefulness of FDG-PET for distinguishing the histological subtypes of early stage thymic epithelial tumours (Masaoka stage I or II). Twenty patients who had undergone an FDG-PET examination prior to treatment and had been diagnosed with an early stage thymic epithelial tumour between July 2005 and July 2011 were enrolled in the present study. All patients underwent a total thymectomy. This cohort was divided into two groups according to the WHO histological classification of their lesion, i.e. low-risk tumours (types A, AB or B1) in one group and high-risk tumours (types B2, B3 or thymic carcinoma) in the other. Focal FDG accumulation was evaluated by determining the maximum standardized uptake value (SUV-max). The patient cohort for this study included 13 men and 7 women ranging in age from 26 to 70 years (mean 55 years). The low-risk group included seven cases (type A, 0; type AB, 7; type B1, 0), and the high-risk group comprised 13 cases (type B2, 7; type B3, 3; thymic carcinoma, 3). The SUV-max values of the low-risk and high-risk tumours were 3.09±0.51 and 6.19±3.13, respectively, and this was a significant difference. For the differential diagnosis of low-risk and high-risk tumours, sensitivity and specificity were 92.3% and 83.3%, respectively, when an SUV-max of 3.5 was used as a cutoff. FDG-PET is a useful method for distinguishing histological types of early stage thymic epithelial tumours.