bluuebunny/crossref_metadata_2025_split huggingface dataset:
Performance of Immuno–Positron Emission Tomography with Zirconium-89-Labeled Chimeric Monoclonal Antibody U36 in the Detection of Lymph Node Metastases in Head and Neck Cancer Patients
Authors: Börjesson Pontus K.E. , Jauw Yvonne W.S. , Boellaard Ronald , de Bree Remco , Comans Emile F.I. , Roos Jan C. , Castelijns Jonas A. , Vosjan Maria J.W.D. , Kummer J. Alain , Leemans C. René , Lammertsma Adriaan A. , van Dongen Guus A.M.S. 
Published: April 2006

Abstract
Purpose: Immuno–positron emission tomography (PET), the combination of PET with monoclonal antibodies (mAb), is an attractive option to improve tumor detection and to guide mAb-based therapy. The long-lived positron emitter zirconium-89 (89Zr) has ideal physical characteristics for immuno-PET with intact mAbs but has never been used in a clinical setting. In the present feasibility study, we aimed to evaluate the diagnostic imaging performance of immuno-PET with 89Zr-labeled-chimeric mAb (cmAb) U36 in patients with squamous cell carcinoma of the head and neck (HNSCC), who were at high risk of having neck lymph node metastases.
Experimental Design: Twenty HNSCC patients, scheduled to undergo neck dissection with or without resection of the primary tumor, received 75 MBq 89Zr coupled to the anti-CD44v6 cmAb U36 (10 mg). All patients were examined by computed tomography (CT) and/or magnetic resonance imaging (MRI) and immuno-PET before surgery. Six patients also underwent PET with 18F-fluoro-2-deoxy-d-glucose. Immuno-PET scans were acquired up to 144 hours after injection. Diagnostic findings were recorded per neck side (left or right) as well as per lymph node level (six levels per side), and compared with histopathologic outcome. For this purpose, the CT/MRI scores were combined and the best of both scores was used for analysis.
Results: Immuno-PET detected all primary tumors (n = 17) as well as lymph node metastases in 18 of 25 positive levels (sensitivity 72%) and in 11 of 15 positive sides (sensitivity 73%). Interpretation of immuno-PET was correct in 112 of 121 operated levels (accuracy 93%) and in 19 of 25 operated sides (accuracy 76%). For CT/MRI, sensitivities of 60% and 73% and accuracies of 90% and 80% were found per level and side, respectively. In the six patients with seven tumor-involved neck levels and sides, immuno-PET and 18F-fluoro-2-deoxy-d-glucose PET gave comparable diagnostic results.
Conclusion: In this study, immuno-PET with 89Zr-cmAb U36 performed at least as good as CT/MRI for detection of HNSCC lymph node metastases.
Population Pharmacokinetics of Troxacitabine, a Novel Dioxolane Nucleoside Analogue
Authors: Lee Carlton K. K. , Rowinsky Eric K. , Li Jing , Giles Francis , Moore Malcolm J. , Hidalgo Manuel , Capparelli Edmund , Jolivet Jacques , Baker Sharyn D. 
Published: April 2006

Abstract
Purpose: To develop and validate a population pharmacokinetic model for troxacitabine, a novel l-nucleoside analogue, administered by short infusion; to characterize clinical covariates that influence pharmacokinetic variability; and to design a dosage rate for continuous infusion administration to achieve low micromolar concentrations, which may be more efficacious than shorter infusions.
Experimental Design: Plasma samples from 111 cancer patients receiving troxacitabine (0.12-12.5 mg/m2) as a 30-minute infusion in phase I trials were used to develop the model with NONMEM. Clinical covariates evaluated included creatinine clearance, body surface area, age, and sex. From the model, a troxacitabine dosage rate of 2.0 to 3.0 mg/m2/d was expected to achieve a target concentration of 0.1 μmol/L; plasma samples were obtained during the infusion from eight patients receiving troxacitabine as a 3-day infusion.
Results: Troxacitabine pharmacokinetics were characterized by a three-compartment linear model. The mean value for systemic clearance [interindividual variability (CV%)] from the covariate-free model was 9.1 L/h (28%). Creatinine clearance and body surface area accounted for 36% of intersubject variation in clearance. Troxacitabine 2.0 mg/m2/d (n = 3) and 3.0 mg/m2/d (n = 5) for 3 days produced mean ± SD end of infusion concentrations of 0.12 ± 0.03 and 0.15 ± 0.03 μmol/L, respectively.
Conclusions: Renal function and body surface area were identified as sources of troxacitabine pharmacokinetic variability. The population pharmacokinetic model model–derived dosage rates for continuous infusion administration successfully achieved predetermined target plasma concentrations. The present model may be used to optimize treatment with troxacitabine by developing a dosing strategy based on both renal function and body size.
Identification of Gains on 1q and Epidermal Growth Factor Receptor Overexpression as Independent Prognostic Markers in Intracranial Ependymoma
Authors: Mendrzyk Frank , Korshunov Andrey , Benner Axel , Toedt Grischa , Pfister Stefan , Radlwimmer Bernhard , Lichter Peter 
Published: April 2006

Abstract
Purpose: Pathogenesis of ependymomas is still poorly understood and molecular markers for risk-adapted patient stratification are not available. Our aim was to screen for novel genomic imbalances and prognostic markers in ependymal tumors.
Experimental Design: We analyzed 68 sporadic tumors by matrix-based comparative genomic hybridization using DNA microarrays containing &gt;6,400 genomic DNA fragments. Novel recurrent genomic gains were validated by fluorescence in situ hybridization using a tissue microarray consisting of 170 intracranial ependymomas. Candidate genes were also tested for mRNA expression by quantitative real-time PCR, and protein expression was determined by immunohistochemistry on the tissue microarray.
Results: Chromosomal gain of 1q correlated with pediatric patients (P = 0.004), intracranial ependymomas (P = 0.05), and tumors of grade III (P = 0.002). Gain of 1q21.1-32.1 was associated with tumor recurrence in intracranial ependymomas (P &lt; 0.001). Furthermore, gain of 1q25 as determined by fluorescence in situ hybridization represented an independent prognostic marker for either recurrence-free survival (P &lt; 0.001) or overall survival (P = 0.003). Recurrent gains at 5p15.33 covering hTERT were validated by immunohistochemistry, and elevated protein levels correlated with adverse prognosis (P = 0.01). In addition to frequent gains and high-level amplification of epidermal growth factor receptor (EGFR) at 7p11.2, immunohistochemistry revealed protein overexpression to be correlated with poor prognosis (P = 0.002). EGFR protein status subdivides intracranial grade II ependymomas into two different risk groups (P = 0.03) as shown by multivariate analysis.
Conclusions: Thus, the states of 1q25 and EGFR represent independent prognostic markers for intracranial ependymomas to identify patient subgroups with different risk profiles in further clinical investigations. Moreover, EGFR might serve as therapeutic target for more specific chemotherapy applications.
Targeting the Mitogen-Activated Protein Kinase Pathway in the Treatment of Malignant Melanoma
Authors: Panka David J. , Atkins Michael B. , Mier James W. 
Published: April 2006

Abstract
The mitogen-activated protein kinase (MAPK; i.e., Ras–Raf–Erk) pathway is an attractive target for therapeutic intervention in melanoma due to its integral role in the regulation of proliferation, invasiveness, and survival and the recent availability of pharmaceutical agents that inhibit the various kinases and GTPases that comprise the pathway. Genetic studies have identified activating mutations in either B-raf or N-ras in most cutaneous melanomas. Other studies have delineated the contribution of autocrine growth factors (e.g., hepatocyte growth factor and fibroblast growth factor) to MAPK activation in melanoma. Still, others have emphasized the consequences of the down-modulation of endogenous raf inhibitors, such as Sprouty family members (e.g., SPRY2) and raf-1 kinase inhibitory protein, in the regulation of the pathway. The diversity of molecular mechanisms used by melanoma cells to ensure the activity of the MAPK pathway attests to its importance in the evolution of the disease and the likelihood that inhibitors of the pathway may prove to be highly effective in melanoma treatment. MAPK inhibition has been shown to result in the dephosphorylation of the proapoptotic Bcl-2 family members Bad and Bim. This process in turn leads to caspase activation and, ultimately, the demise of melanoma cells through the induction of apoptosis. Several recent studies have identified non–mitogen-activated protein/extracellular signal-regulated kinase kinase–binding partners of raf and suggested that the prosurvival effects of raf and the lethality of raf inhibition are mediated through these alternative targets, independent of the MAPK pathway. Other studies have suggested that endothelial cells are the primary targets of raf inhibitors in vivo and that the antitumor effect of these agents are largely attributable to angiogenesis inhibition. This article reviews the genetic and biochemical factors contributing to MAPK activation in melanoma, the mechanisms by which inhibition of the pathway might prove deleterious to tumor cells, and the potential of MAPK inhibitors in the treatment of the disease.
Immune Monitoring of T-Cell Responses in Cancer Vaccine Development
Authors: Keilholz Ulrich , Martus Peter , Scheibenbogen Carmen 
Published: April 2006

AbstractMonitoring cellular immune responses is one prerequisite for rational development of cancer vaccines. The primary objective of immune monitoring is to determine the efficacy of a vaccine to induce or augment a specific T-cell response. Further questions relate to the prevalence and functional relevance of spontaneous tumor-directed immune responses, the functional characteristics of T-cell responses, and, finally and most importantly, the relationship between immune monitoring assay results and clinical end points. The issue of T-cell monitoring has become more complex as different types and generations of assays have been adopted during the past decade and both standardization and validation of assays have often been insufficient. Because the development of assays parallel the clinical development of cancer vaccines, technical advances have been achieved simultaneously with broadening understanding of cancer immunity. Suitable animal models for immune monitoring are, however, lacking, because preclinical vaccine development in rodents does not allow serial immune monitoring of the peripheral blood, as is commonly used in patients. The current situation is characterized by a lack of universal standards for T-cell assessment, uncertainty about the association between immune monitoring assay results and clinical antitumor end points, and lack of knowledge regarding the contribution of different aspects of T-cell function to clinical efficacy. It is acknowledged that T-cell monitoring will have to be validated in large trials with clinically effective vaccines, but this necessity should not discourage the current application of novel assays within clinical trials of all stages.
Peptide and Dendritic Cell Vaccines
Authors: Slingluff Craig L. , Engelhard Victor H. , Ferrone Soldano 
Published: April 2006

Abstract
There has been a rush to convert discovery of new melanoma antigens into cancer vaccines for the therapy of melanoma. The result has been disappointing from a clinical standpoint. The premise behind rapid pursuit of peptide vaccines for melanoma therapy was that the spontaneous tumor-associated immune response was too weak to be effective. However, it is increasingly clear that the host-tumor relationship is a complex interplay of immune response, immune escape, and immune adaptation, with multiple layers of regulatory control and modulation of responses over time. The lesion in the immune response to cancer is much more complex than simply a weak immune response to defined antigens. Current results should serve as a call to take a closer look at immune regulatory processes and principles and to develop more comprehensive and multiagent approaches to modulate the host-tumor relationship. Development of effective immune therapy for cancer will require (a) more comprehensive and real-time immune monitoring in various tissue compartments and (b) patient-specific modulation of immune responses, informed by the real-time monitoring. Peptide antigens associated with MHC class I or class II molecules are the molecular targets for T-cell recognition of cancer. To characterize the host-tumor relationship and to optimize cancer vaccines, clinical studies using defined peptide antigens offer special opportunities to advance the field and thus have an important place in the ongoing development of effective immune therapy of melanoma.
The Dated Coins of Herod the Great: Towards a New Chronology
Authors: Marshak Adam Kolman 
Published: April 2006

AbstractThis paper discusses and proposes a new chronology for a series of Herod the Great's coins, known as the dated series, which are largest and most artistic of his coin issues. While earlier scholarship dated these issues to the early Herodian period, this paper argues instead that the coins were struck in 27 B.C.E. to commemorate the rebuilding and renaming of Samaria/Sebaste in Augustus' honor. Herod minted these coins as a special series to celebrate this great achievement, an accomplishment that simultaneously advertised Herod's power and magnificence as well as his loyalty to the new Augustan regime.
Decadal Variability of the ENSO Teleconnection to the High-Latitude South Pacific Governed by Coupling with the Southern Annular Mode*
Authors: Fogt Ryan L. , Bromwich David H. 
Published: April 2006

Abstract
Decadal variability of the El Niño–Southern Oscillation (ENSO) teleconnection to the high-latitude South Pacific is examined by correlating the European Centre for Medium-Range Weather Forecasts (ECMWF) 40-yr Re-Analysis (ERA-40) and observations with the Southern Oscillation index (SOI) over the last two decades. There is a distinct annual contrast between the 1980s and the 1990s, with the strong teleconnection in the 1990s being explained by an enhanced response during austral spring. Geopotential height anomaly composites constructed during the peak ENSO seasons also demonstrate the decadal variability.
Empirical orthogonal function (EOF) analysis reveals that the 1980s September–November (SON) teleconnection is weak due to the interference between the Pacific–South American (PSA) pattern associated with ENSO and the Southern Annular Mode (SAM). An in-phase relationship between these two modes during SON in the 1990s amplifies the height and pressure anomalies in the South Pacific, producing the strong teleconnections seen in the correlation and composite analyses. The in-phase relationship between the tropical and high-latitude forcing also exists in December–February (DJF) during the 1980s and 1990s.
These results suggest that natural climate variability plays an important role in the variability of SAM, in agreement with a growing body of literature. Additionally, the significantly positive correlation between ENSO and SAM only during times of strong teleconnection suggests that both the Tropics and the high latitudes need to work together in order for ENSO to strongly influence Antarctic climate.
How Often Does It Rain?
Authors: Sun Ying , Solomon Susan , Dai Aiguo , Portmann Robert W. 
Published: April 2006

Abstract
Daily precipitation data from worldwide stations and gridded analyses and from 18 coupled global climate models are used to evaluate the models' performance in simulating the precipitation frequency, intensity, and the number of rainy days contributing to most (i.e., 67%) of the annual precipitation total. Although the models examined here are able to simulate the land precipitation amount well, most of them are unable to reproduce the spatial patterns of the precipitation frequency and intensity. For light precipitation (1–10 mm day−1), most models overestimate the frequency but produce patterns of the intensity that are in broad agreement with observations. In contrast, for heavy precipitation (&gt;10 mm day−1), most models considerably underestimate the intensity but simulate the frequency relatively well. The average number of rainy days contributing to most of the annual precipitation is a simple index that captures the combined effects of precipitation frequency and intensity on the water supply. The different measures of precipitation characteristics examined in this paper reveal region-to-region differences in the observations and models of relevance for climate variability, water resources, and climate change.
Observed Low-Frequency Covariabilities between the Tropical Oceans and the North Atlantic Oscillation in the Twentieth Century
Authors: King Martin P. , Kucharski Fred 
Published: April 2006

Abstract
The low-frequency covariabilities of tropical sea surface temperature (SST) and the North Atlantic Oscillation (NAO) during twentieth-century winters are investigated by maximum covariance analysis (MCA) using reanalysis data. It was found that the positive NAO phase is positively correlated to an increase in tropical SST, especially during the recent decades. The western tropical Pacific SST displays high correlation with the NAO throughout the whole of the twentieth century. For this ocean region, the MCA homogeneous map has a SST spatial pattern with meridional gradients. It was also found that a cooling of tropical Atlantic SST is correlated with positive NAO. The influence of the tropical Atlantic SST on the NAO is strongest during the pre-1960s period.
Natural history of cerebral vein thrombosis: a systematic review
Authors: Dentali Francesco , Gianni Monica , Crowther Mark A. , Ageno Walter 
Published: April 2006

Abstract
Cerebral vein thrombosis (CVT) has been considered, until a few years ago, an uncommon disease with significant long-term morbidity and high mortality rate. New noninvasive diagnostic techniques have increased the frequency with which this disease is diagnosed; despite this, there continues to be little data on its natural history. The objectives of this study were to evaluate the mortality rate, the rate of disability at long-term follow-up, and the incidence of recurrence after a first episode of CVT; to determine clinical and radiologic predictors of death and dependence; and to identify possible risk factors for recurrence. (Data source: MEDLINE and EMBASE databases, reference lists of selected articles and authors' libraries.) Nineteen studies were identified. Mortality rate during peri-hospitalization period is 5.6% (range, 0%-15.2%) and 9.4% (range, 0%-39%) at the end of follow-up period. Eighty-eight percent of surviving patients recover completely or have only a mild functional or cognitive deficit. Two thirds of patients with CVT recanalized within the first few months after presentation, and 2.8% (range, 0%-11.7%) had objectively confirmed recurrence. We conclude that patients with CVT have a low risk of death and that most patients have a good long-term prognosis.
Axillary Sentinel Lymph Nodes Can Be Falsely Positive Due to Iatrogenic Displacement and Transport of Benign Epithelial Cells in Patients With Breast Carcinoma
Authors: Bleiweiss Ira J. , Nagi Chandandeep S. , Jaffer Shabnam 
Published: April 2006

PurposeImmunohistochemical (IHC) staining for cytokeratins (CK) is common practice in evaluating sentinel lymph nodes (SLNs) in patients with breast carcinoma. IHC positivity typically indicates metastasis. SLN procedures are increasingly common in patients with pure intraductal carcinoma (DCIS). Iatrogenic epithelial cell displacement and benign transport of breast epithelial cells into axillary lymph nodes are recently described phenomena. We report 25 cases in which these factors probably resulted in benign epithelial cells in axillary SLNs (ie, false positivity).MethodsWe reviewed 25 cases of CK-positive SLNs in which the epithelial cells had histologic and IHC characteristics different from their respective patients’ underlying breast carcinomas.ResultsIn all cases, the cytologic features of the epithelial cells in the SLNs were benign, and 22 matched those of corresponding intraductal papillomas that were involved by or were separate from the DCIS in the original cores or surgical biopsies. Fifteen cases were pure DCIS; most invasive tumors were smaller than 1.0 cm. In six carcinomas (DCIS) showing strong Her-2/neu staining, the corresponding epithelial cells in the SLNs were negative. In 13 tumors that were strongly and uniformly positive for estrogen receptor (ER), the cytokeratin-positive cells in the SLNs were negative for ER. Nineteen cases showed benign epithelial cell displacement at the biopsy site.ConclusionEpithelial cells in SLNs may result from transport of displaced cells, usually originating in intraductal papillomas. Positive immunohistochemical results in SLNs should be interpreted with extreme caution to avoid automatically concluding that such cells represent metastasis. Sentinel lymph nodes in breast carcinoma can be falsely positive.
Does Helicobacter pylori cause gastric cancer via oxidative stress?
Authors: Correa Pelayo 
Published: April 2006

AbstractEpidemiologic evidence strongly supports a causal role forHelicobacter pyloriin gastric carcinogenesis. The infection was recognized as a Class I human carcinogen by the International Agency for Research on Cancer in 1994. The bacterium does not induce carcinogenesis by itself. The present scientific consensus is that the bacterial oncogenic role is mediated by the chronic active inflammation it elicits in the gastric mucosa. Although the ultimate basic mechanism of carcinogenesis is unknown, strongly suggestive evidence points to oxidative stress as having a pivotal role in the process. This review discusses some of the evidence accumulated so far to support such a role. Numerous avenues of research are open and represent an intriguing challenge to the scientific community.
Comparison of cell lines for stable production of fucose‐negative antibodies with enhanced ADCC
Authors: Kanda Yutaka , Yamane‐Ohnuki Naoko , Sakai Naoto , Yamano Kazuya , Nakano Ryosuke , Inoue Miho , Misaka Hirofumi , Iida Shigeru , Wakitani Masako , Konno Yoshinobu , Yano Keiichi , Shitara Kenya , Hosoi Shinji , Satoh Mitsuo 
Published: April 2006

AbstractSeveral methods have been described to enhance antibody‐dependent cellular cytotoxicity (ADCC) using different host cells that produce antibody with reduced levels of fucose on their carbohydrates. We compared the suitability of these methods for the serum‐free fed‐batch production of antibody for clinical trials and commercial uses. Recombinant anti‐human CD20 chimeric IgG1‐producing clones were established from host‐cells that have been shown to produce more than 90% fucose‐negative antibody. The cell lines were a FUT8 (α‐1,6‐fucosyltransferase) knockout Chinese hamster ovary (CHO) cell line, Ms704, and two Lens culinaris agglutinin (LCA)‐resistant cell lines, one derived from a variant CHO line, Lec13 and the other from a rat hybridoma cell line, YB2/0. The amount of fucose‐negative antibody produced by Lec13 and YB2/0 significantly decreased with the culture. The increase in fucosylation was due to remaining synthesis of GDP‐fucose via de novo pathway for the CHO line and the elevation of FUT8 expression by the YB2/0 cells. In contrast, Ms704 cells stably produced fucose‐negative antibody with a consistent carbohydrate structure until the end of the culture. The productivity of the Ms704 cells reached 1.76 g/L with a specific production rate (SPR) of 29 pg/cell/day for 17 days in serum‐free fed‐batch culture using a 1 L spinner bioreactor. Our results demonstrate that FUT8 knockout has the essential characteristics of host cells for robust manufacture of fucose‐negative therapeutic antibodies with enhanced ADCC. © 2006 Wiley Periodicals, Inc.