bluuebunny/crossref_metadata_2025 huggingface dataset:
A Review and Update on Cholangiocarcinoma
Authors: Olnes Matthew J. , Erlich Rodrigo
Published: June 2004

Cholangiocarcinoma is a malignant neoplasm arising from the biliary epithelium that was first described by Durand-Fardel in 1840. Today, it continues to defy diagnosis and treatment. It is difficult to diagnose in part because of its relative rarity, and because it is clinically silent until it becomes advanced disease with obstructive symptoms. The worldwide incidence of cholangiocarcinoma has risen over the past three decades. There is marked geographic variability in the prevalence of this disease, due in large part to regional environmental risk factors. Surgical resection remains the only curative treatment, and high priorities are improving diagnostic methods, and clinical staging for resection once the disease is suspected. A recent trend towards aggressive surgical management has improved outcomes. Chemotherapy, palliative stenting, and radiation are reserved for patients who are not resectable, those with recurrence after surgery, and those who decline surgical intervention. Recent trials using combination systemic chemotherapy and neoadjuvant chemoradiation are promising, but require further study. Over the past five years, several important studies have yielded new insights into the molecular mechanisms of cholangiocarcinoma tumorigenesis. In this review we discuss epidemiology, etiologic factors, molecular pathogenesis, diagnosis, staging, and treatment of cholangiocarcinoma. Particular focus is on recent studies into the cellular and molecular pathogenesis of the disease, recent chemotherapy trials, and newer methods of staging and screening for this devastating malignancy.
Relationship between Urokinase-Type Plasminogen Receptor, Interleukin-8 Gene Expression and Clinicopathological Features in Gastric Cancer
Authors: Lee Kyung Hee , Bae Sung Hwa , Lee Jae Lyun , Hyun Myung Soo , Kim Sang Hoon , Song Sun Kyo , Kim Hee Sun
Published: June 2004

Objective: The serine protease urokinase-type plasminogen (uPA) and its receptor (uPAR) appear to have a major function in tumor invasion and metastasis. Interleukin-8 (IL-8) acts as an angiogenic factor in solid cancer. The purpose of this study was to determine whether the expression of IL-8 and the uPAR gene correlates with clinicopathological parameters in human gastric carcinoma. Methods: We examined the expression of uPAR mRNA and IL-8 mRNA using Northern blot analysis and RT-PCR in 35 gastric carcinomas and the surrounding normal mucosa. Macroscopic and histopathological tumor findings and survival rates were obtained from the patient records. Results: uPAR and IL-8 mRNA expression levels were higher in most neoplasms compared to the corresponding normal mucosal tissue. A correlation between uPAR and IL-8 expression in tumors was observed (r = 0.447, p < 0.01). uPAR mRNA expression in the tumors correlated well with lymph node metastasis (p < 0.02), and its stage (p < 0.01). The IL-8 MRNA expression in the tumors correlated with diffuse-type gastric cancer (p < 0.05). The survival rates of patients with tumors displaying high uPAR expression levels were significantly lower (p < 0.04) than those of patients without uPAR expression, but patients with IL-8 expression only showed a tendency to a lower survival rate. Conclusion: These results suggest that uPAR and IL-8 may be important prognostic factors in human gastric carcinomas.
Adenosquamous Carcinoma of the Esophagus
Authors: Yachida Shinichi , Nakanishi Yukihiro , Shimoda Tadakazu , Nimura Satoshi , Igaki Hiroyasu , Tachimori Yuji , Kato Hoichi
Published: June 2004

Objectives: Adenosquamous carcinoma (ASC) of the esophagus is an uncommon form of esophageal cancer. Despite isolated case reports on this tumor type, no large clinicopathologic series appears to have been studied at a single institution. Methods: At our institution, 20 cases of ASC were diagnosed pathologically between 1970 and 2001 (20/2,056 total esophageal cancers; 1.0%). Excluding 2 patients who received preoperative radiation therapy, 18 were selected for review of their clinicopathologic features, including survival time, in comparison with those of patients with conventional squamous cell carcinomas (SCCs; n = 850) and adenocarcinomas (ACs; n = 40) of the esophagus. Results: The location and macroscopic type of the ASCs were similar to those of the SCCs. ASC tumors were significantly smaller than SCC (p = 0.004) and AC (p = 0.012) tumors, and the depth of invasion of ASCs was significantly less than that of SCCs (p = 0.028). Lymphatic permeation and blood vessel invasion were seen in 14 (77.8%) and 7 (38.9%) of the 18 patients with ASCs, respectively, and intraepithelial carcinoma contiguous to the main lesion was evident in 10 cases (56.6%). The cumulative postoperative survival rates of patients with ASC at 3, 5 and 10 years were 71.5, 63.6 and 47.7%, respectively, the outcome being significantly better than for patients with either SCC (p = 0.027) or AC (p = 0.013). Conclusion: In the esophagus, ASCs have better prognosis than conventional SCCs or ACs, probably due to their smaller size and lower stage.
Low Thymidylate Synthase Expression in the Primary Tumor Predicts Favorable Clinical Outcome in Resected Gastric Cancer Patients Treated with Adjuvant Tegafur
Authors: Grau Juan J. , Domingo-Domenech Josep , Morente Vanesa , Pera Manuel , Garcia-Valdecasas Juan C. , Fuster Josep , Bombí Antoni , Mellado Begoña , Albanell Joan , Gascón Pere
Published: June 2004

Objective: To assess the thymidylate synthase protein (TS) in tumor cells of resected gastric cancer patients treated with adjuvant tegafur (TG), we reviewed the outcome of 94 randomized patients treated either with adjuvant TG plus mitomycin C (MMC) or MMC alone. Methods: TS was determined in 76 out of 94 patients, previously randomized to receive adjuvant TG, 500 mg/m2/day p.o. for 6 months plus four courses of MMC, 10– 20 mg/m2 i.v. every 6 weeks or MMC alone. An immunohistochemical assessment with the monoclonal antibody TS-106 was performed. Results: Low TS was observed in 38 patients (20 treated with TG-MMC and 18 with MMC) and high TS in the other 38 patients (21 treated with TG-MMC and 17 with MMC). After 10 years’ median follow-up time, 61% of adjuvant TG-MMC patients and 43% of MMC patients were alive and disease-free. Disease-free survival and overall survival were significantly better for patients treated with TG-MMC compared to MMC adjuvant (p = 0.0277 and p = 0.05), and low-TS compared to high-TS patients (p = 0.0184 and p = 0.0198). In 38 low-TS patients we observed an 83% chance to be disease-free in TG-MMC-treated patients and 55% in MMC-treated patients (p = 0.04). Conclusions: A low TS level determines a subset of patients that may benefit from adjuvant oral TG when added to MMC showing a 5-year cure rate of more than 80%.
Public Attitudes to Human Gene Therapy: A Pilot Study in Wales
Authors: Iredale Rachel , Dolan Gina , McDonald Kevin , Kirk Maggie
Published: June 2004

Objective: This study aimed to explore some factors influencing perceptions of human gene therapy. Method: A small qualitative study using two semi-structured interviews per participant (n = 22). The groups comprised (1) people with cystic fibrosis and members of their family (n = 9), and (2) students from a science evening class as well as lay members of the public selected from the practice list of a local general practitioner (n = 13). Results: This pilot study demonstrates support for somatic gene therapy and ambivalence about germline gene therapy. A clear distinction is drawn between therapy and enhancement, with the majority opposing gene enhancement. Conclusions: Attitudes towards the acceptability of gene therapy are not necessarily determined by experience of, or exposure to, a genetic condition. More research is needed with the general public to determine what is perceived to be acceptable public policy in this field.
Awareness of Genetic Testing for Increased Cancer Risk in the Year 2000 National Health Interview Survey
Authors: Wideroff Louise , Thomas Vadaparampil Susan , Breen Nancy , Croyle Robert T. , Freedman Andrew N.
Published: June 2004

Objectives: This study explores factors associated with differential awareness of genetic tests for increased cancer risk in the US. Methods: 27,405 respondents from the 2000 National Health Interview Survey, ages 25+, were asked if they had heard of these tests. Results: 44.4% said ‘yes’, including 49.9% of whites, 32.9% of African-Americans, 32.3% of American Indians/Alaskan Natives, 28.0% of Asian/Pacific Islanders, and 20.6% of Hispanics. In multivariate analysis, test awareness was significantly associated with higher education, white race, age <60 years, female gender, private health insurance, personal or parent’s history of certain cancers, physical activity, and vitamin/supplement use, among other factors. Conclusions: The survey showed which population subgroups may lack access to cancer genetics information and may therefore benefit from targeted strategies to ensure risk-appropriate utilization of genetic counseling and testing.
The Cancer Genetics Network: Recruitment Results and Pilot Studies
Authors: Anton-Culver Hoda , Ziogas Argyrios , Bowen Deborah , Finkelstein Dianne , Griffin Constance , Hanson James , Isaacs Claudine , Kasten-Sportes Carol , Mineau Geraldine , Nadkarni Prakash , Rimer Barbara , Schildkraut Joellen , Strong Louise , Weber Barbara , Winn Deborah , Hiatt Robert , Nayfield Susan
Published: June 2004

Objective: The National Cancer Institute established the Cancer Genetics Network (CGN) to support collaborative investigations into the genetic basis of cancer susceptibility, explore mechanisms to integrate this new knowledge into medical practice, and identify ways of addressing the associated psychosocial, ethical, legal, and public health issues. Subjects and Methods: The CGN has developed the complex infrastructure required to support the projects, including the establishment of guidelines and policies, uniform methods, standard questionnaires to be used by all of the centers, and a standard format for submission of data to the Informatics Center. Cancer patients and their family members have been invited to enroll and be included in a pool of potential study participants. The Information Technology Group is responsible for support of the design, implementation, and maintenance of the multicenter Network-wide research protocols. Results: As of January 2004, the CGN contained data on 23,995 probands (participants) and 425,798 family members. As a resource for cancer genetic studies, the CGN has a large number of probands and first-degree relatives with and without cancer and with multiple ethnicities. Different study designs can be used including case-control, case-case, and family studies. Conclusions: The unique resources of the CGN are available for studies on cancer genetic susceptibility, translational research, and behavioral research. The CGN is now at a point where approved collaborators may have access to enrolled patients and their families for special studies, as well as to the clinical, environmental and family cancer history data banked in the Informatics Center.
Benefit Sharing in Smaller Markets: The Case of Newfoundland and Labrador
Authors: Pullman Daryl , Latus Andrew
Published: June 2004

This case report describes recent efforts in the Canadian province of Newfoundland and Labrador to establish an appropriate benefit-sharing model for human genetic research conducted there. The relatively homogeneous population of this island province has proven to be attractive to the drug development industry. However, unlike large-scale national projects that include broad benefit-sharing arrangements from the outset such as those proposed for places like Iceland and Estonia, there are no plans in Newfoundland and Labrador to establish a large gene bank. Hence a benefit-sharing protocol that will assess individual genetic studies on a case by case basis has been proposed. The province is moving toward legislation to establish a Provincial Health Research Ethics Board (PHREB) that will ensure that all human health research conducted in the province receives local ethics review. The proposed benefit-sharing protocol calls for the establishment of a Standing Committee on Human Genetic Research (SCHGR) that will operate in concert with the PHREB and will ensure that research sponsors enter into appropriate benefit-sharing arrangements with the province.
Dose Escalation Study on Oxaliplatin and Capecitabine (Xeloda) in Patients with Advanced Solid Tumors
Authors: Kakolyris S. , Souglakos J. , Kouroussis C. , Androulakis N. , Samonis G. , Vardakis N. , Amarantidis K. , Agelaki S. , Mavroudis D. , Xenidis N. , Georgoulias V.
Published: June 2004

Objectives: Capecitabine (CAP) and oxaliplatin (OX) have shown interesting activity in a wide range of solid tumors. A phase I study was conducted in order to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of their combination in patients with refractory solid tumors. Patients and Methods: Thirty-three pretreated patients with histologically confirmed inoperable neoplasms were enrolled. The patients’ median age was 64 years, 21 were males, and 27 had a WHO performance status of 0–1. OX was administered on days 1 and 8, as a 3-hour intravenous infusion, at escalated doses ranging from 50 to 70 mg/m2. CAP was administered orally for 14 consecutive days, at escalated doses ranging from 1,200 to 2,100 mg/m2/day. Treatment was repeated every 3 weeks. Results: At the dose of 2,100 mg/m2 (Xeloda) and 70 mg/m2 (OX), all 3 enrolled patients presented DLT (grade 3 diarrhea, grade 3 asthenia and grade 3 neurotoxicity, respectively), and, thus, the recommended MTD for future phase II studies are 2,000 mg/m2 for CAP and 70 mg/m2 for OX. A total of 145 treatment cycles were administered. Toxicity was very mild. Grade 2/3 neutropenia was observed in 4 (3%) treatment cycles. The main nonhematologic toxicities were grade 2/3 nausea/vomiting (7 cycles; 5%), grade 2/3 neurotoxicity (10 cycles; 7%), grade 2/3 asthenia (8 cycles; 5.5%) and grade 2/3 diarrhea (6 cycles; 4%). There was no treatment-related death. One (4%) complete remission, 2 (8%) partial remissions, and 9 (36%) cases of stable disease were observed among 25 evaluable patients. Conclusions: The results demonstrate that CAP and OX can be safely combined at clinically relevant doses and that this regimen merits further evaluation.
Patterns of Relapse and Modalities of Treatment of Breast Cancer: The ‘IRIS’ Project, a Multicenter Observational Study
Authors: Cazzaniga M. , Pronzato P. , Leto di Priolo S.L. , De Matteis A. , Di Costanzo F. , Passalacqua R. , Rosso R. , Torri V.
Published: June 2004

Objectives: The aim of this study was to describe the patterns of breast cancer relapse and the factors influencing therapeutic choices in an unselected postmenopausal population. Methods: Five hundred and thirty-nine patients were enrolled between October 1999 and March 2001. The majority (92.6%) underwent surgery for the primary tumor: there was no difference between general and university hospitals in terms of the type of mastectomy, but a slight difference was found between Southern and Northern Centers. Results: At the time of first relapse, 61.6% of the patients had a good Karnofsky performance status. The median disease-free interval (DFI) was 34 months. More than half of the patients (62.3%) presented a single metastasis. Metastatic disease was treated with chemotherapy in 64.8% of cases (alone in 44.1%, and in combination with hormone therapy in 20.1%), hormone therapy alone was given in 30.8% of cases. The main reasons for choosing chemotherapy were age (31%), standard guidelines (19.4%) and the site of metastatic disease (14.3%), and those for selecting hormone therapy were age (26.6%), site of relapse (19.3%), standard guidelines (19.2%), biological tumor characteristics (14.3%) and the DFI (11.1%). Taxane-containing treatments accounted for 46.1% of the chemotherapies, whereas letrozole was the preferred hormone (41.2%). Conclusion: The first relapse of breast cancer is often single, at bone or viscera, and mainly diagnosed by instrumental screening examinations. The preferred chemo- and hormone therapies are taxane-containing regimens and letrozole, respectively.
Cyclooxygenase-2 Expression in Chondrosarcoma
Authors: Sutton Karen M. , Wright Marianne , Fondren Gertrud , Towle Christine A. , Mankin Henry J.
Published: June 2004

Objective: In recent years it has become evident that tissue cyclooxygenase-2 (COX-2) may play a role in carcinogenesis and tumor malignancy. There is now a mounting body of information that strongly implies that COX-2 inhibitors may be of some value in the management of patients with carcinomas, and most recently several similar reports have appeared relating to sarcomas. Methods: The authors studied 32 samples of cartilage tumors from our tumor tissue bank for the presence of COX-2 by a Western blot technique. There were 29 patients from whom the samples were obtained, including 8 with enchondromas and 21 with chondrosarcomas. Results: Thirteen of the 24 chondrosarcoma samples and none of the 8 enchondromas were positive for COX-2. An attempt was made to correlate these results with clinical data including age, gender, staging according to the Musculoskeletal Tumor Society, anatomical site, ploidic pattern, presence of metastases and death rate but no statistically valid correlation could be found. Conclusion: It is evident that COX-2 may play some role in chondrosarcoma but not in the benign enchondroma and that further studies with COX-2 inhibitors are warranted.
A Weekly Schedule of Docetaxel for Metastatic Hormone-Refractory Prostate Cancer
Authors: Ferrero J.M. , Foa C. , Thezenas S. , Ronchin P. , Peyrade F. , Valenza B. , Lesbats G. , Garnier G. , Boublil J.L. , Tchiknavorian X. , Chevallier D. , Amiel J.
Published: June 2004

Rationale: Docetaxel has proven its efficacy in the management of hormone-refractory prostate cancer (HRPC). Schedules of docetaxel administration differ. This prospective phase II study was designed to reevaluate the activity and toxicity of docetaxel administered weekly at an optimal dose to a large cohort of HRPC patients. Patients and Methods: Sixty-four patients were treated with docetaxel 40 mg/m2 i.v., administered weekly for 6 consecutive weeks followed by a 2-week recovery period. Three treatment cycles were planned in the absence of progression or toxicity. The principal end point was the biochemical response based on the prostate-specific antigen (PSA) level (a decline of more than 50% for at least 4 weeks). Secondary end points were objective response to measurable disease, survival and toxicity. Results: Toxicity was assessed in 64 patients. Toxicity was acceptable, with no toxicity-related deaths. Twenty-one percent of the patients developed grade 3–4 hematological toxicity. Sixty-four patients were evaluable for the PSA response. Forty-one patients (64%) achieved a decrease in PSA of >50%, 13 of whom had a PSA <4 ng/ml. Two out of 12 patients with measurable disease exhibited an objective response. With respect to PSA, the median progression-free survival was 29 weeks (95% confidence interval: 18–46 weeks). The global 1-year survival rate was 58%. Conclusion: Weekly docetaxel at a dosage of 40 mg/m2 is a well-tolerated treatment, which has very promising activity on the reduction of PSA in metastatic HRPC. A large phase III study is underway.
Expression of Placental Leucine Aminopeptidase Is Associated with a Poor Outcome in Endometrial Endometrioid Adenocarcinoma
Authors: Shibata Kiyosumi , Kikkawa Fumitaka , Suzuki Yuka , Mizokami Yayoi , Kajiyama Hiroaki , Ino Kazuhiko , Nomura Seiji , Nagasaka Tetsuro , Mizutani Shigehiko
Published: June 2004

Objective: Placental leucine aminopeptidase (P-LAP) is a cell surface aminopeptidase (oxytocinase). We cloned P-LAP cDNA and found a widespread tissue distribution of P-LAP. Since P-LAP can degrade several small peptide hormones such as oxytocin, this enzyme may affect many cellular functions of carcinoma cells as well as normal cells. This study investigated whether the expression of P-LAP correlates with clinicopathologic factors and prognosis in patients with endometrial endometrioid adenocarcinoma. Methods: Histologic sections of formalin-fixed, paraffin-embedded specimens from 99 primary endometrial carcinomas were stained for P-LAP using polyclonal P-LAP antibody. Disease-free survival and other clinicopathologic characteristics were analyzed according to the intensity of P-LAP staining. Results: Of 99 cases, 69 (69.7%) showed specific P-LAP immunostaining. We found a positive correlation between the expression of P-LAP and histological grade (p < 0.01), surgical stage of the disease (p = 0.02), myometrial invasion (p = 0.01), lymph node involvement (p < 0.01), and vascular infiltration (p < 0.01). In patients who had strongly positive P-LAP staining, the disease-free interval was significantly lower than in patients who had negative or weakly positive P-LAP staining (p < 0.01). Multivariate analysis demonstrated that strongly immunoreactive P-LAP (odds ratio, 12.8; 95% confidence interval, 2.84–58.8; p < 0.01) and surgical stage (odds ratio, 8.78; 95% confidence interval, 2.77–27.8; p < 0.01) are independent prognostic factors. Conclusions: This study suggests P-LAP as an independent prognosticator of clinical outcome in patients with endometrial carcinoma. Therefore, assessment of the P-LAP status provides clinically useful prognostic information in patients with endometrial carcinoma.
Phase II Study of Gemcitabine in Combination with Docetaxel in Patients with Advanced Pancreatic Carcinoma (E1298)
Authors: Shepard Robert C. , Levy Donna E. , Berlin Jordan D. , Stuart Keith , Harris Jules E. , Aviles Victor , Thomas James P. , Benson, III Al Bowen
Published: June 2004

Background: Responses have been observed in several studies of docetaxel as treatment for advanced pancreatic carcinoma. This trial was designed to determine if the addition of docetaxel to gemcitabine therapy produced responses in ≧25% of patients with chemonaive advanced pancreatic cancer. Patients and Methods: This trial involved patients with biopsy-proven, advanced carcinoma of the pancreas not amenable to surgical resection. Patients received docetaxel 75 mg/m2 i.v. over 1 h followed by gemcitabine 2,000 mg/m2 biweekly until progression or intolerable toxicity. The primary endpoint of the trial was to determine the objective response rate with secondary endpoints of progression-free survival and overall survival. Results: Out of the 32 eligible patients, 2 patients had a complete response and 2 patients had a partial response for an observed objective response rate of 12.5% (90% CI: 4.4, 26.4%). Median survival was 4.7 months. Most toxicities were hematologic, with 48% of patients experiencing grade 4 toxicity. Conclusions: The confirmed complete response rate of 6% and partial response rate of 6% is encouraging, but the toxicity of this regimen appears significant. Based upon these results, this combination of gemcitabine and docetaxel is not worthy of further study. Different schedules and dosages may be more promising.
Overexpression of Cyclin D1 Is Associated with Poor Survival in Epithelial Ovarian Cancer
Authors: Barbieri Federica , Lorenzi Paola , Ragni Nicola , Schettini Gennaro , Bruzzo Cristina , Pedullà Francesco , Alama Angela
Published: June 2004

Objective: In order to assess the prognostic role of the cell-cycle regulator cyclin D1 in epithelial ovarian cancer, 70 patients have been studied during an observation period of 8 years. Methods: The cyclin D1 protein content was analyzed by Western blotting, and classed as negative, positive and highly positive by densitometric scanning. The relationship between cyclin D1 expression and clinicopathological variables was determined. Univariate and multivariate survival analyses were also carried out. Results: Patients with highly positive cyclin D1 tumors had shorter overall survival than patients with positive cyclin D1 (median survival 31 vs. 49 months; p = 0.058). Furthermore, in patients with stage III/IV tumors and residual disease greater than 2 cm, cyclin D1 expression significantly influenced clinical outcome (p = 0.047 and 0.040, respectively). In the Cox’s regression model, cyclin D1 expression and residual disease were identified as the most important predictors of survival (p = 0.016 and 0.002, respectively). In patients with high cyclin D1 expression and residual disease after debulking surgery greater than 2 cm, the relative risks of death were to 2.48 and 3.7, respectively, compared to their correspondent counterparts. Conclusion: The overexpression of cyclin D1 is significantly related to a more aggressive tumor phenotype and poor prognosis in ovarian carcinoma.
Growth-Regulated Oncogene-1 Expression Is Associated with Angiogenesis and Lymph Node Metastasis in Human Oral Cancer
Authors: Shintani Satoru , Ishikawa Tohru , Nonaka Tomoko , Li Chunnan , Nakashiro Koh-ichi , Wong David T.W. , Hamakawa Hiroyuki
Published: June 2004

Growth-regulated oncogene-1 (GRO-1) is an autocrine growth factor in melanoma and is a member of the CXC family of chemokines which promote chemotaxis of granulocytes and endothelia through binding to CXC receptor 2. A previous article noted that GRO-1 was upregulated in oral cancer using a genome-wide microarray approach. We have examined the expression of GRO-1 in 9 oral squamous cell carcinoma (OSCC) cell lines and 94 OSCC specimens. Using real-time quantitative polymerase chain reaction analyses, GRO-1 expressions were varied in OSCC cell lines. Of the 94 OSCC specimens, 37 (39.4%) showed GRO-1 cytoplasmic immunostaining, and microvessel density revealed a correlation between GRO-1 expression and tumor angiogenesis. GRO-1 expression was also associated with leukocyte infiltration, and lymph node metastasis. These findings suggest a possible relationship between the expression level of GRO-1 and tumor progression.
Suppression of Hepatocellular Carcinoma Growth via Oral Immune Regulation towards Tumor-Associated Antigens Is Associated with Increased NKT and CD8+ Lymphocytes
Authors: Shibolet Oren , Alper Ruslana , Zlotogarov Lydia , Thalenfeld Barbara , Engelhardt Dean , Rabbani Elazar , Ilan Yaron
Published: June 2004

Background: Oral immune regulation towards viral proteins was previously shown to modulate the anti-HBV immune response. Adoptive transfer of orally immunomodulated lymphocytes suppressed the growth of hepatocellular carcinoma (HCC) expressing HBsAg in athymic mice. NKT lymphocytes play a role in the defense against tumor growth. Aim: To evaluate the effect of oral immune regulation towards HCC-associated antigens or HBV proteins on growth of HBsAg-expressing HCC, and to determine the role of NKT lymphocytes in immune modulation. Methods: Sublethally irradiated athymic Balb/c mice were injected with 107 human hepatoma cells followed 10 days later by transplantation of 2 × 106 splenocytes from naive donor mice. Immune modulation was performed via feeding of HCC-extracted proteins or HBV antigens (HBsAg + Pre S1 + Pre S2). The control group was fed with bovine serum albumin (BSA). Mice were followed for survival, tumor volume, and serum α-fetoprotein levels. To determine the role of NKT cells in tumor suppression, cytokine expression and FACS analysis for CD4+, CD8+, and NK1.1+ T lymphocyte subsets were performed. Results: Oral immune regulation towards HCC-extracted proteins induced complete tumor suppression in recipient mice. Mortality rates were 0% in HCC-immune-regulated mice, compared with an 80% mortality rate using HBV antigens and a 100% mortality rate in control mice. Oral immune regulation towards HCC prevented weight loss. No visible tumor mass was observed in orally immune-regulated mice as compared with 112 mm3 in controls. Serum αFP levels were 0.9, 378 and 1,358 ng/ml in HCC, HBV immune-regulated and controls, respectively. Immune regulation towards HCC antigens significantly increased the NK1.1+ T lymphocytes/CD4+ and CD8+/CD4+ ratios. IFNγ production increased two-fold. Conclusion: Oral immune regulation towards HCC antigens effectively enhanced the anti-tumor immune response, thus suppressing the growth of HCC in mice. This effect was associated with an increased NKT,CD8+/CD4+ lymphocyte ratio and may be mediated via enhancement of IFNγ production.
Toxic Encephalopathy Induced by Capecitabine
Authors: Niemann B. , Rochlitz C. , Herrmann R. , Pless M.
Published: June 2004

Toxic encephalopathy is a rarely described side effect of 5-fluorouracil which usually presents with cerebellar, neuropsychiatric, and focal neurological symptoms. Magnetic resonance imaging findings are described as patchy white matter alterations. We report the 1st case of capecitabine-induced toxic encephalopathy with epilepsy-like symptoms and diffuse white matter alterations on magnetic resonance imaging.
False-Positive Human Serum Chorionic Gonadotropin in a Patient with a History of Germ Cell Cancer
Authors: Trojan Andreas , Joller-Jemelka Helen , Stahel Rolf A. , Jacky Emanuel , Hersberger Martin
Published: June 2004

Tumor markers, including the β-subunit of human chorionic gonadotropin (β-hCG), and radiological imaging methods are commonly used for the diagnosis and monitoring of testicular cancer. We report of a patient with a history of classical seminoma stage I who had elevated serum levels of β-hCG suggesting relapse 5 years after initial treatment. Radiological evaluation revealed a pericardial cyst, which was surgically removed. Histological evaluation did not demonstrate malignant tissue, suggesting a false-postive β-hCG. Further workup confirmed this suspicion as we could demonstrate false-positive test results due to heterophilic antibodies detectable in the patient’s serum. This case stresses the need for verification of β-hCG levels in patients where clinical results are not in line with laboratory results.
A Numerical Scale Comparison of Renal Transplant Recipient Experience with and Opinions about Calcineurin Inhibitors
Authors: Prasad G.V. Ramesh , Nash Michelle M. , McFarlane Philip A. , Zaltzman Jeffrey S.
Published: June 2004

Background: Many studies compare the relative benefits of cyclosporine and tacrolimus with respect to graft and patient outcomes, but comparative renal transplant recipient opinion on calcineurin inhibitor (CI) use has not been directly sought. Methods: We administered a confidential clinic-distributed written questionnaire to adult single-organ recipients pertaining to CI use and related physical side effects experienced. Sixteen common immunosuppressive therapy-related side effects were rated on a 1–10 Likert numerical scale, with 1 meaning complete disagreement and 10 complete agreement with their own CI experience. Comparisons were made among recipients on cyclosporine, tacrolimus, and those with a dual drug experience. Results: The questionnaire was filled by 316 patients. The efficacy of cyclosporine and tacrolimus was considered equivalent (p = 0.99), while the overall side effect profile reported was greater for cyclosporine (p = 0.001). The side effect profile for cyclosporine was greater in the dual group than the cyclosporine-only group (p = 0.01). Cyclosporine was perceived as more difficult to swallow (p = 0.001), nephrotoxic (p = 0.005), and to cause more hypertension (p = 0.04) and hyperlipidemia (p = 0.001), while tacrolimus was perceived to be more neurotoxic (p < 0.0001), but not causing more diabetes (p = 0.64). Conclusions: Renal transplant recipients experience fewer and less severe side effects with tacrolimus. Further contemporaneous study of CI preferences in this population is warranted. Transplant centers should consider patient opinion in tailoring their own immunosuppressive strategies and regimens.
Antihypertensive Effects of Long-Acting Calcium Channel Blockers on Hemodialysis Days – A Randomized Crossover Trial between Benidipine and Nifedipine CR
Authors: Kojima Masayoshi , Taniguchi Masahito , Sato Koichi , Ueda Ryuzo , Dohi Yasuaki
Published: June 2004

Background/Aims: Since antihypertensive effects of most calcium channel blockers largely depend on their plasma concentrations, a rapid increase in blood pressure may occur as circulating levels of such blockers decrease after hemodialysis. Thus, the effects of benidipine and nifedipine CR (extended-release coated tablets, Adalat CR®), which are long-acting calcium channel blockers, on post-hemodialytic blood pressures were investigated. Methods: A randomized crossover trial was carried out with 10 hypertensive patients on chronic maintenance hemodialysis. Patients were assigned to receive benidipine (4–8 mg/day) or nifedipine CR (20–40 mg/day), and after 4 weeks, 24-hour ambulatory blood pressure monitoring was performed on the day of hemodialysis and blood samples were obtained before and after hemodialysis to measure plasma concentrations of the blockers. The calcium channel blockers were then exchanged in each patient and the same protocol was repeated. Results: The pattern of fluctuation of blood pressure differed markedly between the treatment with benidipine and nifedipine CR. Under treatment with nifedipine CR, rapid increase in blood pressure was observed after hemodialysis, while blood pressure remained at favorable levels with benidipine. Plasma concentrations of the blockers were significantly decreased by hemodialysis. Conclusion: Benidipine exerts more sustained antihypertensive effects than expected from its disposition in plasma. The stable depressor effects of benidipine even after hemodialysis may contribute to favorable control of blood pressure in this population.
Improved Immunogenicity of a Novel Third-Generation Recombinant Hepatitis B Vaccine in Patients with End-Stage Renal Disease
Authors: Weinstein Talia , Chagnac Avry , Boaz Mona , Ori Yaacov , Herman Michal , Zevin Dina , Schmilovitz-Weiss Hemda , Gafter Uzi
Published: June 2004

Hepatitis B (HBV) infection remains a significant epidemiological problem in the end-stage renal disease (ESRD) population. Vaccination programs using second-generation vaccines lead to effective seroprotection in only 50–60% of these patients. The purpose of this case series was to describe our experience with a novel third-generation vaccine, Bio-Hep-B®, in ESRD patients who had not developed protective anti-HBs titers following a second-generation HBV vaccination protocol. Twenty-nine ESRD patients who had not responded in the past to a standard second-generation HBV vaccination protocol were included in this series. Each patient received 10 µg of Bio-Hep-B® intramuscularly at 0, 1 and 6 months. A month after completion of the vaccination protocol, anti-HBs antibody levels were measured. Following immunization, 25 of 29 patients (86%) developed seroprotective anti-HBs levels ≧10 mIU/ml. There was a significant difference in the titers of anti-HBs antibodies prior to and following vaccination (p < 0.0001). Statistical analysis of the variables age, gender, diagnosis, dialysis mode, weight, hemoglobin, albumin, and KT/V failed to detect predictors of antibody response. A retrospective analysis of the results of a second-generation vaccination program for the years 1999–2001 in our department showed that 19 of 36 (56.4%) ESRD patients developed seroprotection. In conclusion, the results of this study show that the third-generation HBV vaccine Bio-Hep-B® is highly immunogenic in the population of ESRD patients who did not respond in the past to a second-generation vaccine. This enhanced seroprotection offers hope that the new vaccine will reduce the rate of non-responders and help to eliminate HBV infection from dialysis centers.
Oxidative Stress Status in Kidney Tissue after Losartan and Atenolol Treatment in Experimental Renal Failure
Authors: Pechter Ülle , Aunapuu Marina , Riispere Zivile , Vihalemm Tiiu , Kullissaar Tiiu , Zilmer Kersti , Zilmer Mihkel , Ots Mai
Published: June 2004

Background/Aims: Rats with subtotal nephrectomy (5/6NPX) rapidly develop systemic hypertension and proteinuria. The aim of our study was to evaluate the changes in oxidative stress parameters after 2 and 4 weeks of treatment with renin-angiotensin system (RAS)-blocking agent losartan and beta-blocking agent atenolol in experimental chronic renal failure (CRF). Methods: After 5/6NPX, rats were immediately treated with losartan or atenolol. The lipid peroxidation (LPO) products malondialdehyde and 4-hydroxyalkenals and oxidized and reduced glutathione values were measured in the renal cortex tissue and in blood; isoprostanes in urine. Results: There were no differences in the blood pressure values, serum creatinine levels or in daily proteinuria using both antihypertensive treatments. Losartan treatment lowered significantly LPO in kidney tissue after 2 and 4 weeks of treatment compared with untreated and atenolol-treated animals and induced the decrease of excretion of isoprostanes in urine at the end of the study. There was no ameliorating impact of losartan or atenolol observed in the blood status of oxidative stress in this period of time. Conclusion: In the early period of experimental CRF, losartan treatment but not atenolol treatment induces significant decline in LPO grade in the kidney tissue of nephrectomized rats. RAS blockade in the kidney influences local tissue LPO in a much greater extent than in blood.
A Study on the Effects to Diabetic Nephropathy of Hachimi-jio-gan in Rats
Authors: Yokozawa Takako , Yamabe Noriko , Cho Eun Ju , Nakagawa Takako , Oowada Shigeru
Published: June 2004

To investigate the effects of Hachimi-jio-gan on diabetic nephropathy, we employed an animal model, rats subjected to sub-total nephrectomy followed by streptozotocin injection, and administered Hachimi-jio-gan orally at a dose of 50, 100 or 200 mg/kg body weight/day for 15 weeks. The administration of Hachimi-jio-gan reduced dose-dependently the elevated blood glucose and urinary protein excretion levels in rats with diabetic nephropathy over the experimental period, whereas it increased creatinine clearance significantly, suggesting that Hachimi-jio-gan would prevent or delay the progression of diabetic nephropathy. In addition, the serum glycosylated protein and urea nitrogen levels were markedly elevated in rats with diabetic nephropathy compared with normal rats, and were significantly reduced by the administration of Hachimi-jio-gan, whereas Hachimi-jio-gan reversed the decrease in the serum albumin level. The serum triglyceride and total cholesterol concentrations were reduced by Hachimi-jio-gan, implying that Hachimi-jio-gan would improve the metabolic disorder of lipids caused by diabetic nephropathy. Moreover, Hachimi-jio-gan inhibited lipid peroxidation in the serum and kidney, which suggests that Hachimi-jio-gan would ameliorate oxidative stress associated with diabetic nephropathy. Furthermore, the disorders of the glucose-dependent metabolic pathway due to this pathological condition were also normalized by the administration of Hachimi-jio-gan through decreases in advanced glycation end-product formation and sorbitol levels in the kidney. Hachimi-jio-gan protected against the development of renal lesions, glomerular sclerosis, tubulointerstitial lesions, mesangial matrix expansion and arteriolar sclerosis, estimated by histopathological evaluation and scoring. This study suggests that Hachimi-jio-gan may be a novel therapeutic approach to improving diabetic nephropathy.
Rho-ROCK Signal Pathway Regulates Microtubule-Based Process Formation of Cultured Podocytes – Inhibition of ROCK Promoted Process Elongation
Authors: Gao Shuang-Yan , Li Chun-Yu , Chen Jie , Pan Lei , Saito Shouichiro , Terashita Takehiro , Saito Kyoko , Miyawaki Kyojy , Shigemoto Kazuhiro , Mominoki Katsumi , Matsuda Seiji , Kobayashi Naoto
Published: June 2004

Background: Podocytes, renal glomerular visceral epithelial cells, have two kinds of processes, namely major processes containing microtubules (MTs) and foot processes with actin filaments (AFs). The present study investigated how MTs are organized by the Rho-ROCK signal transduction pathway during process formation of podocytes. Method: After induction of differentiation, podocytes of the conditionally immortalized mouse cell line were treated with Y-27632, a specific inhibitor of ROCK, and exoenzyme C3, an inhibitor of RhoA, as well as with forskolin whose effects include inhibition of RhoA, in order to inhibit the Rho-ROCK pathway. Results: Inhibition of ROCK significantly enhanced the formation of thick processes containing MT bundles. Y-27632 promoted process formation even in the presence of latrunculin A which disrupts AFs, strongly suggesting that ROCK directly regulates MT assembly. Treatment with Y-27632 increased MT stability, and stabilized MTs preferentially localized in podocyte processes. Moreover, when treated with a combination of Y-27632 and forskolin, and with Y-27632 and C3 as well, podocytes developed not only MT-based thick processes but also AF-based thin projections. Conclusions: These data indicate a contribution of ROCK in MT organization to promote podocyte process formation, although it was originally thought to regulate AF assembly. AF-based thin projections seem to be induced mainly by inhibition of RhoA and ROCK. The present study reveals a significant role of the Rho-ROCK signal pathway in the reorganization of both MTs and AFs during process formation of podocytes.
Adrenal Aldosterone Biosynthesis Is Elevated in a Model of Chronic Renal Failure – Role of Local Adrenal Renin-Angiotensin System
Authors: Endemann Dierk H. , Wolf Konrad , Boeger Carsten A. , Riegger Günter A.J. , Krämer Bernhard K.
Published: June 2004

Background: Aldosterone seems to play a role in the development of chronic renal failure and proteinuria. We investigated the adrenal aldosterone production and the adrenal renin-angiotensin system (RAS) in rats with 5/6 nephrectomy with and without spironolactone treatment. Methods: Sprague-Dawley rats underwent 5/6, 4/6 nephrectomy, heminephrectomy and sham operation. After 1 and 4 weeks creatinine clearance, urinary protein excretion, plasma aldosterone concentration, and plasma renin activity were measured. In adrenals mRNA expression of aldosterone synthase (CYP11B2) and genes of the RAS were measured. Results: Creatinine clearance was significantly decreased and proteinuria significantly elevated in 5/6 nephrectomy. Treatment with spironolactone significantly reduced proteinuria after 8 but not after 30 days. With reduction of renal mass, renal renin mRNA and plasma renin activity were reduced significantly. In early 5/6 nephrectomy plasma aldosterone concentration was increased and in parallel adrenal CYP11B2 mRNA was increased significantly. Both were further augmented by spironolactone. Adrenal renin was up-regulated in 5/6 nephrectomy and further stimulated with spironolactone, possibly serving as a stimulus for the adrenal aldosterone synthesis. Conclusion: In early chronic renal failure after 5/6 nephrectomy adrenal aldosterone production is elevated despite a marked decrease of plasma renin activity. An up-regulated adrenal RAS may contribute to the observed increase in aldosterone.
Development of Thyroid-Stimulating Hormone Beta Subunit-Producing Cells in the Chicken Embryonic Pituitary Gland
Authors: Nakamura Kazuaki , Iwasawa Atushi , Kidokoro Hinako , Komoda Masazumi , Zheng Jun , Maseki Yoko , Inoue Kinji , Sakai Takafumi
Published: June 2004

In previous studies, the distribution of thyrotropes in the chicken pituitary gland has been analyzed by immunohistochemistry using heterologous antibodies. In this study, we examined the distribution of thyroid-stimulating hormone beta subunit-immunopositive (TSHbeta-ip) cells and the expression of TSHbeta mRNA in the pituitary glands of chicken embryos by immunohistochemistry using a specific antiserum to the chicken TSHbeta, in situ hybridization and RT-PCR. Immunohistochemical and morphometric analyses revealed that the TSHbeta-ip cells first appeared on embryonic day 10 (E10) in the pituitary gland and were mainly distributed in the cephalic lobe and that the cell density on E20 was almost 4 times greater than that on E10. The chicken TSHbeta-ip cells could be classified into two types based on morphological characteristics: round-shaped cells and club-shaped cells, which have long cytoplasmic processes. In situ hybridization analysis revealed that TSHbeta mRNA-expressing cells were expressed from E9 in the cephalic lobe and that the extent of TSHbeta mRNA-expressing cells coincided with that of TSHbeta-ip cells. RT-PCR also showed that TSHbeta mRNA was expressed from E9 and that Pit-1 mRNA was expressed from E5. These results clearly demonstrated that the expression of chicken TSHbeta mRNA starts on E9, that TSHbeta-ip cells appear on E10, mainly in the cephalic lobe, and that TSHbeta-ip cells can be classified into two cell types (round- and club-shaped cells).
Collagen Type I Prevents Glyoxal-Induced Apoptosis in Osteoblastic Cells Cultured on Titanium Alloy
Authors: Tippelt S. , Ma C. , Witt M. , Bierbaum S. , Funk R.H.W.
Published: June 2004

Advanced glycation end products (AGEs) irreversibly cross-link proteins with sugars and accumulate at a higher age and in diabetes, processes which can interfere with the integration of implants into the tissue. Glyoxal is a highly reactive glycating agent involved in the formation of AGEs and is known to induce apoptosis, as revealed by the upregulation of caspase-3 and fractin (caspase-3 being a key enzyme activated during the late stage of apoptosis and fractin being a caspase-cleaved actin fragment). In this study, we investigated the influence of collagen type I coating on the cytotoxic effect of glyoxal on rat calvarial osteoblastic cells and on human osteosarcoma cells (Saos-2) grown on titanium alloy, Ti6Al4V. Activation of caspase-3 and fractin was measured by counting immunohistochemically stained cells and by flow cytometry with propidium iodide (detection of the apoptosis indicating a sub-G1 peak). Our results showed an increased number of apoptotic osteoblasts after incubation with glyoxal on Ti6Al4V discs. However, the number of apoptotic cells on collagen-coated titanium was significantly smaller than on uncoated titanium after the same treatment. The present findings demonstrate that osteoblasts treated with glyoxal undergo apoptosis, whereas collagen type I coating of titanium alloys (used for implants) has an antiapoptotic function.
Establishment and Characterization of a Human Gastric Carcinoma Cell Line TMC-1
Authors: Shyu Rong-Yaun , Jiang Shun-Yuan , Jong Yiin-Jeng , Cheng Kuo-Chen , Lin Chi-Hung , Yu Jyh-Cherng , Wu Ming-Fang , Chang Tzu-Ming
Published: June 2004

Established cancer cell lines are useful in the study of various cancers. We established a human gastric carcinoma cell line TMC-1 derived from the lymph node of a moderately differentiated adenocarcinoma of the stomach. TMC-1 cells grew in vitro as a mixture of attached and suspension cells, and exhibited spindle or ovoid morphology. They had a population doubling time of 15 h, a plating efficiency of 61%, formed colonies in semisolid agar, secreted the tumor marker CA 19-9, and were tumorigenic in athymic nude mice. The cells expressed E-cadherin and β-catenin. The karyotypic analysis demonstrated hyperdiploid features with a modal chromosome of 53. The cell had the deletion at chromosome 18q and gains at chromosome 2p13–25, 5p15, 5q21–35, 7, 8q24, 9q, 11, 12p, 14q24–32 and 20. Analysis by fluorescence in situ hybridization showed the deletion at 7qtel and duplication at 7q11.2 at the rearranged chromosome 7. Growth of TMC-1 cells was inhibited by 27–32% by interferon-α (2,000 U/ml) and by interferon-γ with an IC50 of 125 U/ml. The cell line is tumorigenic in vivo, and its growth is moderately inhibited by interferon-α and interferon-γ. It can be used to develop new modalities of human gastric cancer treatment.