bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating Biomarkers of Cell Death After Treatment with the BH-3 Mimetic ABT-737 in a Preclinical Model of Small-Cell Lung Cancer
Authors: Micha Dimitra , Cummings Jeff , Shoemaker Alex , Elmore Steven , Foster Kelly , Greaves Martin , Ward Tim , Rosenberg Saul , Dive Caroline , Simpson Kathryn
Published: November 2008

Purpose: This study evaluated epithelial cell death ELISAs that measure circulating cytokeratin 18 in mice bearing small-cell lung cancer xenografts treated with a proapoptotic dose of the BH-3 mimetic ABT-737.

Experimental Design: H146 tumor–bearing and non–H146 tumor-bearing severe combined immunodeficient (SCID)/bg mice were treated with ABT-737 or vehicle control. Plasma collected before and 2 to 360 hours after treatment was analyzed by M30 (caspase-cleaved cytokeratin 18) and M65 (intact and cleaved cytokeratin 18) ELISA. In parallel, tumors were interrogated for cleaved caspase-3 and cleaved cytokeratin 18 as biomarkers of apoptosis.

Results: ABT-737–treated tumors regressed by 48 hours (P < 0.01) compared with controls, correlating with increased cleaved cytokeratin 18 (P < 0.01; 6 and 24 hours) and increased intact cytokeratin 18 (P < 0.01; 24 hours). Cleaved cytokeratin 18 levels decreased below baseline between 72 and 360 hours for ABT-737–treated and control mice whereas intact cytokeratin 18 decreased below the level of detection at 8 and 15 days in ABT-737–treated mice only. Apoptosis in tumors reflected changes in circulating cytokeratin 18 (cleaved caspase-3, P < 0.05 at 2 hours and P < 0.001 at 6, 12, and 24 hours; caspase-cleaved cytokeratin 18, P < 0.05 at 15 days, for drug treated versus controls).

Conclusions: ABT-737 caused tumor regression by apoptosis in H146 xenografts that mapped to a drug-specific, early increase in circulating cleaved cytokeratin 18 that subsequently declined. Circulating, intact cytokeratin 18 levels correlated with tumor burden. Cleaved caspase-3 and caspase-cleaved cytokeratin 18 in tumor correlated with treatment (P < 0.05, 2 hours; P < 0.001, 6, 12, and 24 hours; cleaved caspase-3, P < 0.05, 15 days; caspase-cleaved cytokeratin 18), indicating that events in plasma were tumor derived. These circulating biomarker data will be translated to clinical trials wherein serial tumor biopsies are rarely obtained.
High Risk for Ovarian Cancer in a Prospective Series Is Restricted to BRCA1/2 Mutation Carriers
Authors: Mæhle Lovise , Apold Jaran , Paulsen Torbjørn , Hagen Bjørn , Løvslett Kjell , Fiane Bent , Van Ghelue Marijke , Clark Neal , Møller Pål
Published: November 2008

Purpose: Inherited ovarian cancer carries a serious prognosis. Prophylactic oophorectomy has been advocated. The degree to which inherited ovarian cancer is restricted to BRCA mutation carriers is not fully known. We wanted to determine the prevalence of BRCA mutation carriers in women at high risk from ovarian cancer.

Experimental Design: Healthy women who were found to be at increased risk judged by family history were followed prospectively. Full BRCA1/2 mutation analysis was conducted on all patients who contracted pelvic cancer.

Results: We identified 1,582 women at risk during 5,674 person-years. Forty infiltrating epithelial ovarian cancers, six peritoneal cancers, and one fallopian tube cancer were diagnosed. All but one of these patients (98%) had a BRCA mutation, a frequency that was significantly higher than for the 3 patients with borderline ovarian cancers, who were all mutation negative (P = 0.0002). Eighty-two percent of the detected mutations belonged to one of the 10 Norwegian founder mutations previously reported. At prophylactic bilateral salpingo-oophorectomy, cancer was found in 18 of 345 (5.2%) of mutation carriers compared with none in the 446 mutation negative (P = 0.0000).

Conclusions: In healthy women with a family history of ovarian cancer, high risk for ovarian cancer was restricted to BRCA1/2 mutation carriers. A woman at risk for ovarian cancer according to her family history should have access to full BRCA1/2 mutation testing before deciding on prophylactic bilateral salpingo-oophorectomy.
Phase I Study of Copper-Binding Agent ATN-224 in Patients with Advanced Solid Tumors
Authors: Lowndes Sarah A. , Adams Avril , Timms Anthony , Fisher Nita , Smythe Jon , Watt Suzanne M. , Joel Simon , Donate Fernando , Hayward Carolyn , Reich Steven , Middleton Mark , Mazar Andrew , Harris Adrian L.
Published: November 2008

Purpose: Copper chelation reduces the secretion of many angiogenic factors and reduces tumor growth and microvascular density in animal models. ATN-224 is a second-generation analogue of ammonium tetrathiomolybdate. The aim of our phase I study was to reduce serum copper levels, as measured by ceruloplasmin, to 5 to 15 mg/dL (normal 16-60) in 14 to 21 days, to determine the pharmacokinetic profile of ATN-224 and to evaluate dose-limiting toxicities.

Patients and Methods: Cohorts of patients were treated with escalating oral doses of ATN-224 until copper depletion followed by a titrated maintenance dose.

Results: Eighteen patients received 78 cycles of ATN-224. Mean baseline ceruloplasmin was 39.6 mg/dL. The maximum administered dose was 330 mg/d where grade 3 fatigue was dose-limiting. At the maximum tolerated dose of 300 mg/d, the median time to achieve target ceruloplasmin was 21 days, and toxicities included grade 3 anemia, grade 3 neutropenia, fatigue, and sulfur eructation. ATN-224 treatment caused a significant reduction (>90%) in RBC superoxide dismutase 1 activity and circulating endothelial cells. Pharmacokinetic data indicate greater absorption of ATN-224 and more rapid ceruloplasmin reduction when administered with a proton pump inhibitor. Stable disease of >6 months was observed in 2 patients.

Conclusions: Oral ATN-224 is a well-tolerated therapy and at a loading dose of 300 mg/d leads to a reduction of serum ceruloplasmin levels in 80% patients within 21 days. A loading dose of 300 mg/d for 2 weeks followed by a titrated maintenance dose will be the recommended starting dose for phase II study.
Methylation of Tip30 Promoter Is Associated with Poor Prognosis in Human Hepatocellular Carcinoma
Authors: Lu Bin , Ma Yunchao , Wu Guobin , Tong Xin , Guo Huaizu , Liang Anmin , Cong Wenming , Liu Chang , Wang Hao , Wu Mengchao , Zhao Jian , Guo Yajun
Published: November 2008

Purpose: To investigate Tip30 promoter methylation status in human hepatocellular carcinoma (HCC) and the correlation with clinicopathologic features and prognosis.

Experimental Design: The methylation status of CpG islands in Tip30 promoter was examined in 15 HCC cell lines as well as 59 paired HCC and adjacent nontumor tissues. The associations between Tip30 methylation status and the survival of patients were analyzed.

Results: Tip30 promoter was hypermethylated in 6 of 10 HCC cell lines with reduced Tip30 mRNA. DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, greatly enhanced TIP30 expression and sensitized HCC cells to cytotoxic drug-induced cell death. The promoter region of Tip30 was identified and the main promoter activity was located in the -135 to -45 region sited within a CpG island. The minimal promoter element contained four Sp1 binding sites, which were hypermethylated in HCC cell-derived promoters. Moreover, analyses of Tip30 promoter methylation status in 59 paired HCC tissues showed that 47% of the cases were hypermethylated. Recurrence rate (95% versus 67%; P = 0.011) and mortality (82% versus 53%; P = 0.033) were significantly higher in patients with methylated Tip30. Disease-free survival was significantly higher in patients with unmethylated Tip30 (33.3% versus 4.5%; P = 0.036).

Conclusions: Our results show that epigenetic silencing of Tip30 gene expression by CpG island DNA hypermethylation is associated with poor prognosis in patients with HCC.
Loss of Nuclear p27 Expression and Its Prognostic Role in Relation to Cyclin E and p53 Mutation in Gastroenteropancreatic Neuroendocrine Tumors
Authors: Grabowski Patricia , Schrader Jörg , Wagner Julia , Hörsch Dieter , Arnold Rudolf , Arnold Christian N. , Georgieva Inna , Stein Harald , Zeitz Martin , Daniel Peter T. , Sturm Isrid
Published: November 2008

Purpose: Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are classified by the WHO, yet its prognostic value needs to be confirmed. Therefore, we aimed to determine the prognostic role of cell cycle key regulatory genes p53, p27kip1 (p27), and cyclin E in this tumor entity.

Experimental Design: Tumor specimen from 89 patients with a complete follow-up were studied immunohistochemically for p27 and cyclin E expression and for p53 mutations. The functional relevance of p27 was evaluated in the neuroendocrine cell lines BON1 (human) and INS1 (rat) by the use of small interfering RNA.

Results: Twenty-six of 29 benign, well-differentiated endocrine tumors (WHO class 1) showed a high expression (>50%) of p27, whereas all 10 poorly differentiated endocrine carcinomas (WHO class 3) displayed a low expression of p27. Metastatic well-differentiated endocrine carcinomas (WHO class 2) showed a low p27 expression in 20 of 50 (40%) patients, which conferred a poor prognosis (median survival, 57 versus 140 months; P = 0.037). This prognostic dichotomy was improved by the use of a combination of p27 and cyclin E (high cyclin E/low p27 versus low cyclin E/high p27: median survival 53 months versus not reached; P = 0.0044). p53 mutations were rare (1 of 10 poorly differentiated endocrine carcinomas).

Conclusions: Loss of p27 and overexpression of cyclin E play a critical role in the aggressiveness of gastroenteropancreatic neuroendocrine tumors. This coincides with increased cell cycle progression. We propose a discussion whether to incorporate the immunohistochemical expression of p27 into a revised classification to individualize therapeutic strategies in this tumor entity.
Clonal Evolution in t(14;18)-Positive Follicular Lymphoma, Evidence for Multiple Common Pathways, and Frequent Parallel Clonal Evolution
Authors: d'Amore Francesco , Chan Eric , Iqbal Javeed , Geng Huimin , Young Ken , Xiao Li , Hess Michelle M. , Sanger Warren G. , Smith Lynette , Wiuf Carsten , Hagberg Oskar , Fu Kai , Chan Wing C. , Dave Bhavana J.
Published: November 2008

Purpose: Follicular lymphoma typically has acquired a t(14;18) translocation, but subsequent additional cytogenetic abnormalities contribute to disease progression. The main aims of the study are to (a) identify the frequency and temporal sequence of cytogenetic events in t(14;18)-positive follicular lymphoma, (b) determine if there are specific pathways in the evolution of follicular lymphoma, (c) determine the clonal divergence in cases with sequential biopsies or multiple clones from a single biopsy, and (d) determine the association of genetic imbalances with clinical outcome.

Experimental Design: All cases with a histologically confirmed diagnosis of follicular lymphoma and cytogenetic analysis showing t(14;18)(q32;q21) were included. The karyotypes were reviewed and cytogenetic data were entered into a relational database for further computational analysis; 418 biopsies from 360 follicular lymphoma patients including 43 sequential biopsies were analyzed.

Results: Of the cases with only one or two genomic imbalances, the most frequent chromosomal imbalances were +7, del(6q), +der(18)t(14;18), +18, and +X. These abnormalities were also among the most frequent ones encountered when all karyotypes were analyzed. Cytogenetically abnormal clones in the same (26%) and sequential biopsies (63%) often showed divergence of genetic alterations. Balanced translocations other than the t(14;18) were uncommon events, but chromosomal breaks involving 14q32, 18q21, 1p36, 1q21, 10q22, 10q24, and a large cluster at 6q occurred relatively frequently. del(6q), +5, +19, and +20 were associated with poorer overall survival, and del(17p) was associated with poorer event-free survival. Lower-grade tumors (1 and 2) were associated with fewer imbalances.

Conclusion: Our analysis suggested that +der(18)t(14;18) may be an entry point to a distinct pathway of genetic evolution in follicular lymphoma. The other common early events appeared to provide multiple entry points, and they might cooperate in the pathogenesis and progression of the follicular lymphoma. Cytogenetically abnormal clones from same patients often showed divergence of genetic alterations, suggesting that parallel evolution from precursor clones are frequent events. This study provides the framework for further analysis of genetic pathways of tumor progression.
Vascular Endothelial Growth Factor C Stimulates Progression of Human Gastric Cancer via Both Autocrine and Paracrine Mechanisms
Authors: Kodama Michiyo , Kitadai Yasuhiko , Tanaka Miwako , Kuwai Toshio , Tanaka Shinji , Oue Naohide , Yasui Wataru , Chayama Kazuaki
Published: November 2008

Purpose: Vascular endothelial growth factor (VEGF)-C induces lymphangiogenesis by activating the VEGF receptor (VEGFR)-3, which is expressed by lymphatic endothelial cells. VEGFR-3 has also been detected on several malignant cells, but the significance of VEGFR-3 expression on malignant cells remains unclear. In this study, we examined the expression and function of VEGFR-3 in gastric carcinoma cells.

Experimental Design: We examined the expression of VEGFR-3 by four human gastric carcinoma cell lines and in 36 surgical specimens of gastric carcinoma. We also used cDNA microarrays to examine the effect of VEGF-C on gene expression in VEGFR-3-expressing KKLS cells. To stimulate VEGF-C/VEGFR-3 signaling in an autocrine manner, the VEGF-C expression vector was transfected into KKLS cells, and stable transfectants were established. These cells were then transplanted into the gastric walls of nude mice.

Results: Two of the four gastric carcinoma cell lines expressed VEGFR-3 mRNA. In 17 of 36 gastric carcinoma specimens, VEGFR-3-specific immunoreactivity was detected on tumor cells. In vitro treatment of KKLS cells with VEGF-C stimulated cell proliferation and increased expression of mRNAs encoding cyclin D1, placental growth factor, and autocrine motility factor. Following inoculation of VEGF-C-transfected and control cells into the gastric walls of nude mice, tumor growth of the VEGF-C-transfected cells was greatly accelerated in comparison with that of control cells. Greater angiogenesis and lymphangiogenesis were also detected in VEGF-C-transfected tumors than in control tumors.

Conclusions: Gastric carcinoma cells express VEGF-C and VEGFR-3. VEGF-C may play a role in the progressive growth of human gastric carcinoma through both autocrine and paracrine mechanisms.
Preferential Tumor Targeting and Selective Tumor Cell Cytotoxicity of 5-[131/125I]Iodo-4′-Thio-2′-Deoxyuridine
Authors: Morgenroth Agnieszka , Deisenhofer Sandra , Glatting Gerhard , Kunkel Falk H-G. , Dinger Cornelia , Zlatopolskiy Boris , Vogg Andreas T.J. , Kull Thomas , Reske Sven N.
Published: November 2008

Purpose: Auger electron emitting radiopharmaceuticals are attractive for targeted nanoirradiation therapy, provided that DNA of malignant cells is selectively addressed. Here, we examine 5-[123/125/131I]iodo-4′-thio-2′-deoxyuridine (ITdU) for targeting DNA in tumor cells in a HL60 xenograft severe combined immunodeficient mouse model.

Experimental Design: Thymidine kinase and phosphorylase assays were done to determine phosphorylation and glycosidic bond cleavage of ITdU, respectively. The biodistribution and DNA incorporation of ITdU were determined in severe combined immunodeficient mice bearing HL60 xenografts receiving pretreatment with 5-fluoro-2′-deoxyuridine (FdUrd). Organ tissues were dissected 0.5, 4, and 24 h after radioinjection and uptake of [131I]ITdU (%ID/g tissue) was determined. Cellular distribution of [125I]ITdU was imaged by microautoradiography. Apoptosis and expression of the proliferation marker Ki-67 were determined by immunohistologic staining using corresponding paraffin tissue sections.

Results: ITdU is phosphorylated by thymidine kinase 1 and stable toward thymidylate phosphatase-mediated glycosidic bond cleavage. Thymidylate synthase-mediated deiodination of [123/125/131I]ITdU was inhibited with FdUrd. Pretreatment with FdUrd increased preferentially tumor uptake of ITdU resulting in favorable tumor-to-normal tissue ratios and tumor selectivity. ITdU was exclusively localized within the nucleus and incorporated into DNA. In FdUrd-pretreated animals, we found in more than 90% of tumor cells apoptosis induction 24 h postinjection of ITdU, indicating a highly radiotoxic effect in tumor cells but not in cells of major proliferating tissues.

Conclusion: ITdU preferentially targets DNA in proliferating tumor cells and leads to apoptosis provided that the thymidylate synthase is inhibited.
Surgery followed by Persistence of High-Grade Squamous Intraepithelial Lesions Is Associated with the Induction of a Dysfunctional HPV16-Specific T-Cell Response
Authors: de Vos van Steenwijk Peggy J. , Piersma Sytse J. , Welters Marij J.P. , van der Hulst Jeanette M. , Fleuren Gertjan , Hellebrekers Bart W.J. , Kenter Gemma G. , van der Burg Sjoerd H.
Published: November 2008

Purpose: To characterize HPV16 E6- and E7-specific T-cell immunity in patients with high-grade squamous intraepithelial lesions (HSIL).

Experimental Design: Peripheral blood mononuclear cells isolated from 38 patients with HPV16+ HSIL were used to determine the magnitude, breadth, and polarization of HPV16-specific T-cell responses by proliferation assays and cytokine assays. Furthermore, HSIL-infiltrating T cells isolated from 7 cases were analyzed for the presence of HPV16 E6- and/or E7-specific T cells, phenotyped, and tested for the specific production of IFN-γ and interleukin-10 as well as for their capacity to suppress immune responses.

Results: HPV16-specific T-cell responses were absent in the circulation of the majority (∼60%) of patients who visit the clinic for treatment of a HPV16+ HSIL lesion. Notably, HPV16-specific T-cell reactivity was predominantly detected in patients returning to the clinic for repetitive treatment of a persistent or recurrent HPV16+ HSIL lesion after initial destructive treatment. The majority (>70%) of these HPV16-specific T-cell responses did not secrete proinflammatory cytokines, indicating that most of the subjects, although in principle able to mount a HPV16-specific immune response, fail to develop protective cellular immunity. This notion is sustained by our observation that only three HSIL-infiltrating T-cell cultures contained HPV16-specific T cells, one of which clearly consisted of HPV16 E7-specific regulatory T cells.

Conclusions: The presence of HPV16-specific T cells with a non-Th1/Th2 cytokine and even suppressive signature in patients with HSIL may affect the outcome of vaccine approaches aiming at reinforcing human papillomavirus-specific immunity to attack human papillomavirus-induced lesions.
Enforced Expression of MCAM/MUC18 Increases In vitro Motility and Invasiveness and In vivo Metastasis of Two Mouse Melanoma K1735 Sublines in a Syngeneic Mouse Model
Authors: Wu Guang-Jer , Fu Pingping , Wang Shur-Wen , Wu Mei-Whey H.
Published: November 2008

Human MCAM/MUC18 has been shown to increase metastasis of human melanoma cells in xenograft mouse systems. To be more relevant to understanding the progression of clinical melanoma and for designing better preclinical therapeutic trials, it is highly desirable to establish a syngeneic mouse model for studying the mechanisms of MCAM/MUC18-mediated tumorigenesis and metastasis of melanoma cells. To reach this goal, we transfected the mouse MCAM/MUC18 (moMCAM/MUC18) cDNA into two MCAM/MUC18-minus, low-metastatic mouse melanoma K1735 sublines, K1735-10 (tumor−/metlow) and K1735-3 (tumor+/metlow), and selected for G418-resistant clones, which expressed different levels of moMCAM/MUC18, and used for testing the effect of MCAM/MUC18 overexpression on their in vitro growth rate, motility, and invasiveness and in vivo subcutaneous tumor growth and pulmonary metastasis in syngeneic mice. Enforced expression of moMCAM/MUC18 did not significantly affect in vitro growth rate, but it increased the in vitro motility and invasiveness of clones derived from both sublines. Ectopic expression of moMCAM/MUC18 did not alter the nontumorigenicity of the K1735-10 clones per cells nor significantly affect the subcutaneous tumor growth of the K1735-3 clones per cells. The moMCAM/MUC18-expressing K1735-10 clones were able to establish only microscopic lung modules in 86% of the mice. In contrast, the moMCAM/MUC18-expressing K1735-3 clones could induce numerous large lung nodules (3-4 mm in diameter) in all the mice. We concluded that increased moMCAM/MUC18 expression in the two K1735 sublines minimally affected their tumorigenicity, but it augmented their in vitro motility and invasiveness and increased their pulmonary metastasis in the syngeneic C3H mice. (Mol Cancer Res 2008;6(11):1666–77)
Inhibition of Src Family Kinases with Dasatinib Blocks Migration and Invasion of Human Melanoma Cells
Authors: Buettner Ralf , Mesa Tania , Vultur Adina , Lee Frank , Jove Richard
Published: November 2008

Src family kinases (SFK) are involved in regulating a multitude of biological processes, including cell adhesion, migration, proliferation, and survival, depending on the cellular context. Therefore, although SFKs are currently being investigated as potential targets for treatment strategies in various cancers, the biological responses to inhibition of SFK signaling in any given tumor type are not predictable. Dasatinib (BMS-354825) is a dual Src/Abl kinase inhibitor with potent antiproliferative activity against hematologic malignancies harboring activated BCR-ABL. In this study, we show that dasatinib blocks migration and invasion of human melanoma cells without affecting proliferation and survival. Moreover, dasatinib completely inhibits SFK kinase activity at low nanomolar concentrations in all eight human melanoma cell lines investigated. In addition, two known downstream targets of SFKs, focal adhesion kinase and Crk-associated substrate (p130CAS), are inhibited with similar concentrations and kinetics. Consistent with inhibition of these signaling pathways and invasion, dasatinib down-regulates expression of matrix metalloproteinase-9. We also provide evidence that dasatinib directly inhibits kinase activity of the EphA2 receptor tyrosine kinase, which is overexpressed and/or overactive in many solid tumors, including melanoma. Thus, SFKs and downstream signaling are implicated as having key roles in migration and invasion of melanoma cells. (Mol Cancer Res 2008;6(11):1766–74)
High-Throughput Hacking of the Methylation Patterns in Breast Cancer by In vitro Transcription and Thymidine-Specific Cleavage Mass Array on MALDI-TOF Silico-Chip
Authors: Radpour Ramin , Haghighi Mahdi Montazer , Fan Alex Xiu-Cheng , Torbati Peyman Mohammadi , Hahn Sinuhe , Holzgreve Wolfgang , Zhong Xiao Yan
Published: November 2008

Over the last decade, the rapidly expanding interest in the involvement of DNA methylation in developmental mechanisms, human diseases, and malignancies has highlighted the need for an accurate, quantitative, and high-throughput assay. Existing methods are limited and are often too laborious for high-throughput analysis or inadequate for quantitative analysis of methylation. Recently, a MassCLEAVE assay has been developed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to analyze base-specific methylation patterns after bisulfite conversion. To find an efficient and more cost-effective high-throughput method for analyzing the methylation profile in breast cancer, we developed a method that allows for the simultaneous detection of multiple target CpG residues by using thymidine-specific cleavage mass array on matrix-assisted laser desorption/ionization time-of-flight silicon chips. We used this novel quantitative approach for the analysis of DNA methylation patterns of four tumor suppressor genes in 96 breast tissue samples from 48 patients with breast cancer. Each individual contributed a breast cancer specimen and corresponding adjacent normal tissue. We evaluated the accuracy of the approach and implemented critical improvements in experimental design. (Mol Cancer Res 2008;6(11):1702–9)
Collision Tumor of the Stomach: A Case of an Adenocarcinoma and a Gastrointestinal Stromal Tumor
Authors: Idema D.L.M. , Daryanani D. , Sterk L.M.T. , Klaase J.M.
Published: November 2008

A collision tumor of the stomach is a rare event. We report the case of a collision tumor of the stomach consisting of an adenocarcinoma and a gastrointestinal stromal tumor (GIST). This is, to our knowledge, the second report in the literature of such a case. A 71-year-old man with abdominal discomfort underwent an esophagogastroduodenoscopy which revealed a tumor of the oesophagogastric junction. A total gastrectomy was performed. Histologic examination showed a mixed tumor consisting of a primary adenocarcinoma and multiple nodules of GIST. The adenocarcinoma showed both diffuse and intestinal growth, angio-invasion and metastasis to lymph nodes. The GIST tumor cells were strongly immunoreactive to CD117 and CD34. Based on mitotic index, size and cytonuclear details, the biological behavior of this GIST tumor was supposed to be benign. This case reports the rare finding of a collision tumor consisting of an adenocarcinoma and a GIST with an unknown etiology.
Medical Thoracoscopy
Authors: Rodríguez-Panadero Francisco
Published: November 2008

As opposed to ‘video-assisted thoracoscopic surgery’ which requires general anesthesia, double-lumen tracheal intubation and single lung ventilation, medical thoracoscopy (or ‘pleuroscopy’) is frequently performed in the respiratory endoscopy suite using local anesthesia. It can be done by well-trained physicians, either pulmonologists or thoracic surgeons, and its main indication is related to diagnosis and treatment of pleural effusions. Also, pneumothorax can be managed in most cases using medical thoracoscopy. This article focuses in particular on technical aspects of medical thoracoscopy, including the selection and preparation of the patient, the choice of equipment, specific details of the procedure itself, and other technical details aimed at preventing complications.
Leukocytoclastic Vasculitis as an Onset Symptom of Crohn’s Disease
Authors: Tsiamoulos Z. , Karamanolis G. , Polymeros D. , Triantafyllou K. , Oikonomopoulos T.
Published: November 2008

We report the case of an octagenerian who presented with leukocytoclastic vasculitis as the first symptom of Crohn’s disease. The patient was admitted with skin rash on the lower extremities and ankles and episodes of bloody diarrhea. Skin and colon biopsies revealed acute leukocytoclastic vasculitis and moderate Crohn’s disease, respectively. The patient was treated with intravenous corticosteroids in conjunction with antibiotics and per os mesalazine. Symptoms resolved rapidly within 5 days, and the patient was still asymptomatic on follow-up 3 months later.
Thirteen-Year Disease-Free Survival after Surgery for Cystic Duct Carcinoma: A Case Report
Authors: Benchellal Zine Abedine , Soro Kountélé Gona , Orain Isabelle , Poret Hélène , Ferhi Abd Hak , Darquies-Chevalley Julien
Published: November 2008

Cystic duct carcinoma is known to have a better prognosis compared to its location in other biliary ducts. Only one case with a survival over ten years has been previously published. The authors report a case of survival over 13 years without recurrence or metastasis. Preoperative diagnosis of cystic duct tumor was carried in a 66-year-old male. Under the diagnosis of carcinoma of the cystic duct, the patient underwent en bloc resection of the gallbladder, cystic duct, hepaticocholedochus and lymph node dissection. A Roux-en-Y hepaticojejunostomy was performed. Histological examination revealed a moderately differentiated adenocarcinoma of the cystic duct. Five months later the patient underwent second look surgery for benign obstruction of the hepaticojejunal anastomosis. The patient is still doing well 13 years later without any local recurrence or metastasis. To our knowledge, this is the longest disease-free survival ever published in the literature. This case sustains that better and longer survival is possible with a real chance of potential cure if radical surgery is performed.
Groove Pancreatitis with Several Cystic Lesions around the Pancreatic Head Treated Conservatively: Report of a Case
Authors: Ito Ryusuke , Shiba Hiroaki , Okamoto Tomoyoshi , Fujioka Shuichi , Gocho Takeshi , Yanaga Katsuhiko
Published: November 2008

A 61-year-old man was admitted to our hospital with epigastric pain and vomiting. Enhanced abdominal computed tomography revealed inflammatory change of the pancreatic groove and focal wall thickening of the second portion of the duodenum with several cystic lesions around the head of the pancreas. We diagnosed atypical type of groove pancreatitis. The patient made a satisfactory recovery by conservative medication treatment for acute on chronic pancreatitis and cystic lesions disappeared in parallel with pancreatitis. Groove pancreatitis is a rare form of chronic pancreatitis, and to the best of our knowledge, our patient is the first case in the English literature of groove pancreatitis with cystic lesions around the head of the pancreas, which disappeared after conservative treatment for pancreatitis.
Spontaneous Resolution of Brain Edema in Fulminant Hepatic Failure due to Hepatitis E
Authors: Spahr Laurent , Morard Isabelle , Mentha Gilles , Hadengue Antoine , Giostra Emiliano
Published: November 2008

Fulminant hepatic failure is characterized by the presence of hepatic encephalopathy in the setting of acute liver injury that occurs in a noncirrhotic organ. Brain edema is the ultimate complication of advanced hepatic encephalopathy as it often leads to cerebral herniation and death. Thus, the presence of fulminant hepatic failure indicates the need for urgent liver transplantation to prevent death or irreversible brain damage. We report a very unusual evolution of fulminant hepatic failure complicated by brain edema and hepatic coma in a 45-year-old woman admitted with acute viral hepatitis E infection.
Herpes simplex Virus Esophagitis in an Immunocompetent Patient with Ebstein-Barr Virus Infection
Authors: Tzouvala M. , Gaglia A. , Papantoniou N. , Triantafyllou K. , Karamanolis G.
Published: November 2008

Epstein-Barr virus infectious mononucleosis can cause transient immune deficiency which may predispose to reactivation of latent herpes simplex virus (HSV) infection in the immunocompetent host. We report the case of a 15-year-old male who presented with severe odynophagia and herpes labialis during the course of Epstein-Barr virus infectious mononucleosis that had been diagnosed ten days before. Esophagoscopy revealed extensive ulcerations with distinct borders and whitish exudates at the mid and distal esophagus. Polymerase chain reaction detected HSV-1 DNA in the biopsy specimens. The patient was treated with intravenous acyclovir. The symptoms resolved rapidly within 3 days, in accordance with improved endoscopic findings.
Effects of a Semioccluded Vocal Tract on Laryngeal Muscle Activity and Glottal Adduction in a Single Female Subject
Authors: Laukkanen Anne-Maria , Titze Ingo R. , Hoffman Henry , Finnegan Eileen
Published: November 2008

Voice training exploits semiocclusives, which increase vocal tract interaction with the source. Modeling results suggest that vocal economy (maximum flow declination rate divided by maximum area declination rate, MADR) is improved by matching the glottal and vocal tract impedances. Changes in MADR may be correlated with thyroarytenoid (TA) muscle activity. Here the effects of impedance matching are studied for laryngeal muscle activity and glottal resistance. One female repeated [pa:p:a] before and immediately after (a) phonation into different-sized tubes and (b) voiced bilabial fricative [β:]. To allow estimation of subglottic pressure from the oral pressure, [p] was inserted also in the repetitions of the semiocclusions. Airflow was registered using a flow mask. EMG was registered from TA, cricothyroid (CT) and lateral cricoarytenoid (LCA) muscles. Phonation was simulated using a 7 × 5 × 5 point-mass model of the vocal folds, allowing inputs of simulated laryngeal muscle activation. The variables were TA, CT and LCA activities. Increased vocal tract impedance caused the subject to raise TA activity compared to CT and LCA activities. Computer simulation showed that higher glottal economy and efficiency (oral radiated power divided by aerodynamic power) were obtained with a higher TA/CT ratio when LCA activity was tuned for ideal adduction.
Infliximab as a Rescue Therapy for Hospitalized Patients with Severe Ulcerative Colitis Refractory to Systemic Corticosteroids
Authors: Yamamoto-Furusho Jesús K. , Uzcanga Luis F.
Published: November 2008

Background: Infliximab therapy is effective for the induction and maintenance of clinical remission in patients with moderate to severe ulcerative colitis. However, it has not been studied extensively in hospitalized patients who require colectomy as a rescue therapy for severe ulcerative colitis refractory to intravenous corticosteroids. Aim: To evaluate the effectiveness of infliximab in hospitalized patients with severe ulcerative colitis refractory to intravenous corticoids as a rescue therapy before colectomy. Methods: 10 severe ulcerative colitis patients refractory to intravenous hydrocortisone administered for at least 7 days and candidate for colectomy were selected to receive a single infusion of infliximab (5 mg/kg). Results: 8 patients failed to respond to infliximab and required colectomy during the hospitalization period. The median time to operation after infliximab infusion was 21 days. Of 8 patients, 6 had a partial clinical response manifested by a decreasing number of bowel movements and rectal bleeding during 7–14 days after the infliximab infusion, and the remaining 2 patients showed a lack of response to infliximab infusion. Conclusion: These results suggest that a single infliximab infusion seems to be ineffective as a rescue therapy of colectomy in hospitalized patients with severe ulcerative colitis refractory to systemic corticosteroids.
Reasons for Hospital Admissions in Dementia Patients in Birmingham, UK, during 2002–2007
Authors: Natalwala Ammar , Potluri Rahul , Uppal Hardeep , Heun Reinhard
Published: November 2008

Background: There is a lack of evidence to explain why patients with dementia are admitted to a general hospital. Methods: Main reasons for hospitalisation were investigated in all patients admitted to a multi-ethnic general hospital during 2002–2007, by analysis of type of admission and primary diagnosis on admission. Anonymised data from the Hospital Activity Analysis Register was used to trace these patients; 505 were diagnosed with Alzheimer’s disease (AD), 283 with vascular dementia (VD) and 1,773 patients were classified as unspecified dementia (UnD). Logistic regression analysis was used to compare these groups to 53,123 age-matched controls. Statistical significance of p < 0.001 was accepted. Results: More dementia patients were admitted as emergency cases compared to controls (AD = 95.8%, VD = 95.4%, UnD = 96.7%, controls = 54.4%; p < 0.001 for all comparisons). The proportion of patients admitted for dementia as their primary diagnosis was small (AD = 5.9%, VD = 10.6%, UnD = 6.0%). Primary diagnoses such as syncope and collapse, bronchopneumonia, urinary tract infection and dehydration were more frequent in all dementia patients than controls. Conclusion: Dementia patients are frequently admitted as emergency cases, but dementia itself is often not the primary diagnosis. Earlier detection of the specific conditions mentioned above may reduce emergency hospital admissions amongst dementia patients.
Flat Threshold and Mid-Frequency Hearing Impairment in a Dutch DFNA8/12 Family with a Novel Mutation in TECTA
Authors: de Heer A.R. , Pauw R.J. , Huygen P.L.M. , Collin R.W.J. , Kremer H. , Cremers C.W.R.J.
Published: November 2008

A novel TECTA mutation (c.5331G>A) was identified affecting α-tectorin just N-terminally of the zona pellucida domain in a Dutch family with nonsyndromic autosomal dominant sensorineural hearing impairment. The present mutation is clearly associated with a flat-threshold type of hearing impairment. Intriguingly, our results demonstrated that the present TECTA mutation had a significant protective effect against presbyacusis. Substantial protection against presbyacusis is a novel finding in a family with autosomal dominant hearing impairment.
Binaural Hearing after Cochlear Implantation in Subjects with Unilateral Sensorineural Deafness and Tinnitus
Authors: Vermeire Katrien , Van de Heyning Paul
Published: November 2008

The aim of this clinical study was to assess speech recognition in noise after cochlear implantation in subjects with single-sided deafness and incapacitating tinnitus. 20 subjects complaining of severe intractable tinnitus unresponsive to treatment received a MED-EL cochlear implant (CI). 11 subjects had normal hearing (NH group) on the contralateral side, while 9 used a hearing aid (HA group). The subjects were tested in noise in two listening conditions, i.e. with their acoustic hearing only and with adding the CI to the acoustic hearing (binaural). Subjective improvement in daily life was evaluated using the Speech Spatial and Qualities Hearing Scale (SSQ). The summation effect (3.3 dB for the HA group and 0.6 dB for the NH group) is not significant in both groups. A significant squelch effect of adding the CI was seen for the HA users (3.8 dB), but not for the NH group (1.2 dB). Additionally, a significant effect of adding the CI was found for the spatial configuration where noise is presented in front and speech on the CI side for both the HA group (6.5 dB) and the NH group (1.7 dB). Results of the SSQ show a significant overall benefit of wearing the CI for both groups. The preliminary results of these 20 subjects suggest that cochlear implantation can improve hearing in people suffering from single-sided deafness combined with tinnitus.
Retrograde Blood Flow in the Aortic Arch Determined by Transesophageal Doppler Ultrasound
Authors: Svedlund S. , Wetterholm R. , Volkmann R. , Caidahl K.
Published: November 2008

Background: Aortic arch atheromas may be important sources of cerebral embolism. Aortic plaques are frequently found somewhat distal to the origin of the cerebral arteries, implying that cerebral embolization from such plaques depends on local retrograde blood flow components in this area. Therefore, we investigated the occurrence of blood flow reversal in this part of the aorta. Furthermore, since the presence and magnitude of retrograde flow might be influenced by aortic wall properties, we also studied the relationship between plaque size and distribution, aortic strain and degree of retrograde flow. Methods: We evaluated aortic arch ante- and retrograde blood flow velocities in 56 patients by transesophageal echocardiography using color-Doppler-guided pulsed-Doppler techniques. The velocity-time integrals (VTI) were measured and the diastolic/systolic VTI ratio was calculated. Results: Retrograde diastolic blood flow was noted in all subjects, and diastolic/systolic VTI ratios were higher (p < 0.05) in patients with plaque ≥4 mm (n = 17) compared to those (n = 39) without. Patients exhibiting plaques exclusively in the aortic arch showed the highest VTI ratios (p < 0.01) and tended to have the lowest strain values. Aortic strain was also reduced in patients >50 years of age (p < 0.01). Conclusions: Our findings demonstrate retrograde aortic flow in all subjects and its proportion increases in subjects with atherosclerosis, particularly in the aortic arch. Aortic plaques situated distally to the origin of the cerebral arteries are therefore possible sources of cerebral emboli.
Five-Year Survival after First-Ever Ischaemic Stroke Is Worse in Total Anterior Circulation Infarcts: The SINPAC Cohort
Authors: Reggiani M.
Published: November 2008

Background: Few studies have addressed predictors of long-term mortality after first-ever ischaemic stroke. Methods: We prospectively collected data on 361 consecutive patients admitted to 18 neurology departments in Italy for a first-ever ischaemic stroke in 1999, categorized according to the Oxfordshire Community Stroke Project (OCSP) classification. Age, gender, risk factors, previous vascular disease, in-hospital complications, stroke severity, functional status, therapy and living place at admission, discharge and after 6 months were recorded. Follow-up was available for 97% patients at 5 years. Results: Survival probability was 91% (95% CI = 88–94) at 1 month, 84% (80–88) at 6 months and 64% (58–69) at 5 years. Mortality was higher for the TACI (total anterior circulation infarct) group compared to the other categories (p < 0.0001). Hazard ratios for 5-year mortality in the final model were: 5.4 for age ≥65 years (p < 0.0001), 2.8 for TACI (p < 0.0001), 2.7 for previous vascular disease (p < 0.01) and 1.9 for cardio-embolic risk according to the TOAST risk stratification (p < 0.05). Conclusions: Our study extends the prognostic value of the OCSP classification to 5-year survival.
The Influence of Oseltamivir Treatment on the Risk of Stroke after Influenza Infection
Authors: Madjid Mohammad , Curkendall Suellen , Blumentals William A.
Published: November 2008

Objectives: It was the aim of this study to examine the influence of the antiviral medication oseltamivir on stroke and transient ischemic attack (TIA) in adults diagnosed with influenza. Methods: This retrospective cohort study used medical and pharmaceutical claims data from May 2000 to September 2006 from an administrative claims database. Episodes of stroke/TIA in the 6 months after influenza in adults (aged ≥18 years) prescribed oseltamivir within 1 day before or 2 days after influenza diagnosis (oseltamivir cohort), and adults prescribed no antivirals (comparison cohort) were compared using multivariate analyses adjusted for demographic and clinical risk factors. Results: The oseltamivir cohort comprised 49,238 patients and the comparison cohort 102,692 patients. Oseltamivir was associated with a 28% reduction in risk of stroke/TIA in the 6 months after influenza [hazard ratio (HR) 0.72; 95% CI 0.62–0.82] and with significant reductions after 1 and 3 months. In patients <65 years of age, there was a 34% risk reduction with oseltamivir after 6 months (HR 0.66; 95% CI 0.56–0.77) and also significant reductions after 1 and 3 months. In those aged ≥65 years, there was a 51% reduction in risk after 1 month (HR 0.49; 95% CI 0.27–0.91). Conclusions: Prescription of oseltamivir for influenza is associated with a reduced risk of stroke/TIA.
Change in Morphology and Oxytocin Receptor Expression in the Uterine Blood Vessels during the Involution Process
Authors: Wakasa Tomoko , Wakasa Kenichi , Nakayama Masahiro , Kuwae Yuko , Matsuoka Keiko , Takeuchi Makoto , Suehara Noriyuki , Kimura Tadashi
Published: November 2008

Background: The histological changes in uterine blood vessels during pregnancy have been well investigated, but there have been few reports focusing on the changes in blood vessels during the involution process, especially within the first 24 h. We observed the process of uterine involution, focusing on the vessels of the resected uterus. Methods: Paraffin-embedded uterine samples from 15 patients who underwent hysterectomy because of severe cervical laceration and uterine rupture were examined. The time between delivery and hysterectomy ranged from 15 min to 456 h. The specimens were stained with hematoxylin-eosin, elastica-van Gieson and an antioxytocin receptor antibody. Results: Changes in the uterine vessels varied substantially based on their location. The intima in arteries of the endometrial side thickened within 5 h after delivery. On the serosal side, phlebosclerosis was demonstrated 6 weeks postpartum. Immunoreactivity for the oxytocin receptor (OTR) appeared in the muscular medias of arteries 5 h after delivery although it was not expressed before this period. Conclusion: Remodeling of uterine vessels involved thickening of the arterial intima and OTR expression in vessel walls during the first 5 h postpartum; the parameters normalized within 6 weeks. However, phlebosclerosis persisted for a long time on the serosal side.
Molecular Analysis of the Adiponectin Gene in Severely Obese Patients from Southern Italy
Authors: Daniele A. , Cammarata R. , Pasanisi F. , Finelli C. , Salvatori G. , Calcagno G. , Bracale R. , Labruna G. , Nardelli C. , Buono P. , Sacchetti L. , Contaldo F. , Oriani G.
Published: November 2008

Background: Severe obesity is a major worldwide public health concern affecting 0.5–5% of the adult population. Adiponectin (Acpr30), an adipokine secreted from adipocytes, shows pleiotropic beneficial effects on obesity and related disorders. In this study, sequence analysis of Acpr30 gene (ACDC) was performed in a highly selected population of severely obese young adult patients from Southern Italy to investigate the associations between polymorphisms in the ACDC gene and the development of severe obesity concomitantly with other features of the metabolic syndrome. Methods: The ACDC gene was analyzed by direct sequencing in the severely obese patients (n = 220) and compared to healthy controls (n = 116). The associations between the ACDC gene single-nucleotide polymorphisms (SNPs) and the levels of serum Acpr30 as well as the correlation with the presence of severe obesity jointly associated with other features of the metabolic syndrome were also investigated. Total serum Acpr30 concentrations were measured by the ELISA method. Results: ACDC gene molecular screening revealed the presence of previously described SNPs and a new nucleotide alteration, c.355T>G, leading to a protein variant, p.L119V. Measurement of serum concentration of Acpr30 demonstrated lower levels of Acpr30 in the obese population compared to controls (30.5 ± 28.3 vs. 43.9 ± 35.7 μg/ml, p < 0.01); in particular, significantly lower Acpr30 concentrations were observed in obese patients bearing c.–11377C>G SNP CG+GG genotypes than in those with CC genotype (22.9 ± 20.5 vs. 33.1 ± 29.4 μg/ml, p < 0.05). Conclusions: Our results confirmed that low serum levels of Acpr30 are related to severe obesity and a difference in protein expression is associated with variants in ACDC gene promoter region.
Comparison of Body Mass Index and Waist/Height Ratio in Predicting Definite Coronary Artery Disease
Authors: Siavash M. , Sadeghi M. , Salarifar F. , Amini M. , Shojaee-Moradie F.
Published: November 2008

Background: Body mass index (BMI), waist circumference (WC), waist/hip ratio, waist/height ratio (WHtR) and skin fold thickness are clinical tools enabling the evaluation of obesity. WHtR is a recently introduced index to assess central fat distribution. This study was performed to compare the prognostic value of WHtR and BMI for definite coronary artery disease (CAD). Methods: A cross-sectional study was performed in the Shahid-Chamran Hospital, Isfahan, Iran. The study included 591 patients undergoing coronary angiography for suspected ischemia. We measured BMI, WC and coronary artery scores of the patients. Prevalence of CAD was compared between obese (BMI ≥30) and abdominal obese (WHtR ≥0.55) participants. Results: Prevalence of CAD was significantly higher in abdominal obese patients (WHtR ≥0.55) than in patients without abdominal obesity (odds ratio, OR = 1.63, p = 0.008). The difference in CAD prevalence between obese (BMI ≥30) and non-obese patients nearly reached significance (OR = 1.48, p = 0.058). There was a significant positive correlation between CAD score and age (p < 0.01), WC (p < 0.05), and WHtR (p < 0.01) in male participants. Conclusion: WHtR may be a better marker of central obesity and may better predict CAD than BMI and WC.